A doença está associada ao acúmulo anormal de glicogênio nos cardiomiócitos, predispondo à hipertrofia ventricular, arritmias e morte súbita.2 A mutação foi primeiramente descrita por Gollob et al. em 2001, despertando, na comunidade médica, a importância do diagnóstico diferencial com miocardiopatia hipertrófica.4 Embora a prevalência da síndrome do PRKAG2 não esteja estabelecida, o número de casos pode estar aumentando devido à maior disponibilidade de genotipagem. No entanto, ainda não foram descritos possíveis fatores prognósticos na literatura. Considerando a possível gravidade do quadro clínico e a escassez de dados a respeito da história natural, o objetivo deste estudo foi avaliar a evolução clínica de pacientes portadores da síndrome do PRKAG2, analisando a incidência de complicações cardíacas em longo prazo.A síndrome do PRKAG2 é uma doença genética rara, de herança autossômica dominante, causada por mutações no gene que codifica a subunidade γPRKAG2.5 Foram coletados dados clínicos, e realizados eletrocardiograma (ECG), ecocardiograma, e estudo eletrofisiológico. Hipertrofia ventricular esquerda foi definida como espessura de septo interventricular ou de parede posterior ≥ 13 mm no ecocardiograma, sem causa aparente. O teste exato de Fisher foi utilizado para comparações entre variáveis categóricas, e o teste t de Student para amostras independentes foi usado para comparações entre médias das variáveis contínuas. Foram calculadas as razões de prevalência entre as variáveis de interesse e os desfechos clínicos. O desfecho primário foi implante de marcapasso (MP); o desfecho combinado foi definido pela ocorrência de implante de marca-passo (MP) ou morte súbita. O método de Kaplan-Meier foi utilizado para estimar a incidência cumulativa do desfecho combinado. Um valor de p < 0,05 foi considerado estatisticamente significativo.Trata-se de estudo observacional, ambispectivo, envolvendo membros de uma única família portadora de mutação Arg302Gln do gene flutter ou fibrilação atrial, e 7 (54%) apresentaram hipertrofia ventricular esquerda ao ecocardiograma. Todos os pacientes apresentaram fração de ejeção preservada. Seis pacientes foram submetidos ao estudo eletrofisiológico, o qual foi consistente com a via fascículo-ventricular  idade média de 40±11 anos . As caratricular . A medidFlutter atrial foi significativamente mais prevalente nos pacientes que necessitaram de MP , estando associada a probabilidade 6,4 vezes maior de evolução para esse desfecho.A incidência cumulativa do desfecho combinado (implante de MP e morte súbita) está apresentada na PRKAG2 em uma família. Foi observado o caráter precoce de acometimento cardiovascular nesses pacientes, com eventos significativos, como implante de MP ou morte súbita, ocorrendo antes dos 50 anos. Em relação ao eletrocardiograma, todos os pacientes apresentaram pré-excitação ventricular, frequentemente associado a bloqueio de ramo direito e bradicardia sinusal. De acordo com estudos prévios, a prevalência dessas anormalidades é variável e pode aumentar com a idade.6 Em nosso estudo, a maioria dos pacientes desenvolveram hipertrofia ventricular ao longo do tempo, porém não encontramos associação desse achado com a indicação de MP. Gollob et al. descreveram complicações cardiovasculares importantes na síndrome do PRKAG2 na ausência de hipertrofia ventricular, sugerindo que essa variável não seja um fator preditor preciso.7Analisamos a evolução clínica em longo prazo de portadores de mutação Arg302Gln do gene 6 Em nossa coorte, o implante de MP foi frequente, acometendo 38,5% dos pacientes. Um achado interessante foi a prevalência de flutter atrial significativamente maior nesses casos, atingindo 100% dos maiores de 50 anos. Embora essa associação possa ser explicada meramente por coincidência de eventos, parece plausível que o flutter atrial desempenhe papel preditor de complicações cardiovasculares.Outra característica marcante da síndrome do PRKAG2 é o comprometimento progressivo do sistema de condução cardíaco, com disfunção do nó sinusal e bloqueio atrioventricular.8 A possibilidade de arritmia ventricular parece ser baixa, sem relatos de terapias apropriadas com cardioversor desfibrilador implantável (CDI) na literatura. Em nosso estudo identificamos via acessória fascículo-ventricular, cujo envolvimento em arritmias malignas não foi comprovado.9 Além disto, não foi registrado arritmia ventricular durante estudo eletrofisiológico ou monitorização por MP/CDI. Portanto, é provável que o bloqueio atrioventricular total tenha sido a causa de morte nesta família, potencialmente evitável com implante de MP. O desafio que persiste é identificar os pacientes com maior risco de evolução desfavorável e instituir terapia adequada preventiva.O mecanismo de morte súbita na doença é controverso; o bloqueio atrioventricular e a fibrilação ventricular são possíveis causas, sendo essa última provocada por fibrilação atrial com condução rápida por via acessória.flutter atrial e evolução para implante de marca-passo pode ter um papel no manejo dos portadores da síndrome. Futuros estudos devem esclarecer a importância clínica dessa observação.Em conclusão, deve-se suspeitar de síndrome do PRKAG2 em pacientes jovens com pré-excitação ventricular, taquiarritmias atriais e hipertrofia ventricular familiar. A associação significativa entre aparecimento de  2 regulatory subunit of AMP-activated protein kinase.2 It has been associated with abnormal glycogen accumulation in cardiomyocytes, predisposing to ventricular hypertrophy, arrhythmias, and sudden death. Gollob et al. were the first to describe the mutation in 2001, calling attention to the need for differential diagnosis with hypertrophic cardiomyopathy.4 Although the prevalence of PRKAG2 syndrome is not established, the number of reported cases may be increasing due to wider availability of genotyping. Despite that, possible prognostic factors have not yet been described in the literature. Given the possible severity of clinical presentations and the scarcity of data regarding the natural history, our objectives were to evaluate the clinical course of patients with PRKAG2 syndrome over time and analyze the incidence of long-term cardiac complications.The PRKAG2 syndrome is a rare autosomal dominant inherited disease caused by mutations in the gene encoding the γPRKAG2 gene.5 Collection of clinical data, electrocardiography (ECG), echocardiography, and electrophysiological studies were performed. Left ventricular hypertrophy was defined by an interventricular septum or left ventricular posterior wall thickness ≥ 13 mm on echocardiography without any other apparent cause. Differences between means of continuous variables were assessed using the Student's t-test for independent samples, and the Fisher's exact test was used for comparison between categorical variables. Prevalence ratios between the variables of interest and clinical outcomes were calculated. The primary outcome was pacemaker implantation; the composite endpoint was either PM implantation or sudden death. The Kaplan-Meier method was used to estimate the cumulative incidence of the composite outcome. A p-value < 0.05 was considered statistically significant.This observational, ambispective study was conducted with members of a single family with an Arg302Gln mutation in From March 1996 to January 2020, 16 individuals were assessed. Mean age was 40±11 years, and 63% (n=10) were male . BaselinThe cumulative incidence of the composite outcome is shown in PRKAG2 mutation in a family. Importantly, we observed early cardiovascular involvement in these patients, with significant events, such as PM implantation or sudden death, occurring before the age of 50 years. Regarding electrocardiographic findings, all patients had a pattern of ventricular pre-excitation, often associated with right bundle branch block and sinus bradycardia. According to previous reports, the prevalence of these abnormalities is variable and may increase with age.6 In our study, most patients developed ventricular hypertrophy over time. However, we found no significant association between ventricular hypertrophy and indication of PM. Gollob et al. described significant cardiovascular complications in PRKAG2 syndrome without ventricular hypertrophy, which suggests that this criterion is not an accurate predictor.7We analyzed the long-term clinical course of carriers of the Arg302Gln 6 In our cohort, 38.5% of patients ultimately required a PM. Interestingly, the prevalence of atrial flutter was significantly higher in these cases, reaching 100% in those over age 50. Although this association can be explained merely by coincidence of events, it seems plausible to suppose that atrial flutter plays a role in predicting cardiovascular complications.One of the hallmarks of PRKAG2 syndrome is the progressive impairment of the electrical conduction system of the heart, with sinus node dysfunction and atrioventricular block.8 The possibility of ventricular arrhythmia seems to be low, with no reports of appropriate implantable cardioverter defibrillator therapies in the literature. In our study, we identified a fasciculoventricular pathway, whose involvement in malignant arrhythmias has not been proven.9 In addition, no ventricular arrhythmias were recorded during electrophysiological study or monitoring through PM/ICD. Therefore, atrioventricular block was the possible cause of death in this family, potentially preventable with pacemaker implantation. The challenge that remains is to identify patients at greater risk of unfavorable outcomes and institute therapy before an event occurs.The mechanism of sudden death in the disease is controversial, with atrioventricular block and ventricular fibrillation being possible causes, the latter caused by atrial fibrillation with rapid conduction down an accessory pathway.In conclusion, PRKAG2 syndrome should be suspected in young patients with ventricular pre-excitation, atrial tachyarrhythmias, and family ventricular hypertrophy. The significant association between atrial flutter and progression to pacemaker implantation may play a role in the management of patients with the syndrome. Future studies should clarify the clinical relevance of this observation.


Atrial fibrosis can present as an arrhythmogenic substrate that is correlated with higher recurrence after catheter ablation for atrial fibrillation. Galectin-3, a beta-galactoside-binding lectin, is highly expressed and secreted from macrophages and is important in inflammation and fibrosis. We assessed the clinical implications of serum galectin-3 in patients with atrial fibrillation. This was a prospective cohort study of consecutive patients who underwent radiofrequency catheter ablation in a tertiary referral center from February 2017 to September 2017. Intracardiac blood sampling, echocardiographic measurements, magnetic resonance imaging with late gadolinium enhancement, electrophysiologic testing, and endocardial voltage mapping were consistently implemented in 75 patients before the ablation. Serum galectin-3 level was higher in patients with diabetes mellitus and was correlated with values that indicated the left atrial size. During a median 14 months of follow-up, atrial tachyarrhythmia recurred in 27% of patients. In multivariable Cox regression analysis, non-paroxysmal atrial fibrillation  and higher galectin-3 levels  were associated with increased risk of recurrence. Serum galectin-3 may be a prognostic biomarker for risk stratification in patients with atrial fibrillation planned catheter ablation. Atrial fibrillation not only increases the risk of morbidity and mortality, but also decrease the quality of life2. Since the recognition of triggers that initiate atrial fibrillation from the pulmonary veins, electrical isolation of the pulmonary veins using radiofrequency catheter ablation has become an important therapeutic option in patients with recurrent, drug-refractory symptoms3.Atrial fibrillation is the most common type of sustained cardiac arrhythmia, and the prevalence increases with corresponding increases in age4. Serologic and imaging tests that are able to detect atrial fibrosis have been found to be correlated with recurrence of atrial fibrillation6. Recently, serum galectin-3 has been refocused to reveal cardiac fibrosis and predict rhythm outcomes after ablation7. We assessed the clinical implications of serum galectin-3 in patients who underwent catheter ablation for atrial fibrillation.However, the efficacy of catheter ablation is difficult to predict in individual patients. Atrial structural remodeling with fibrosis contributes to the pathophysiologic mechanism that maintains atrial fibrillation by local conduction disturbanceThis was a prospective non-randomized study. Consecutive patients who were planning to undergo a catheter ablation for atrial fibrillation were enrolled from February 2017 to September 2017 in a tertiary referral center. The Ethics Committee of the Korea University Anam Hospital Institutional Review Board approved this study. The protocol was consistent with the ethical guidelines of the 2008 Declaration of Helsinki. Written informed consent was obtained from all participants before enrollment. Because galectin-3 secretion in fibroblasts and macrophages was increased in diseases associated with fibrosis other than cardiac diseases, patients who were more than 80 years of age or had a history of liver cirrhosis, renal impairment , lung disease, or cancer were excluded to reduce confounding factors. Patients who had a history of prior catheter ablation for atrial fibrillation were also excluded to evaluate the relationship between spontaneous cardiac fibrosis and serum galectin-3 level. The study was registered in CRIS (KCT0005496).8. The volume of late gadolinium enhancement in the left atrium was defined as the summation of enhanced pixels over all slices.Patients were examined on a 3-T magnetic resonance scanner  using a 32-element phased-array coil. Late gadolinium enhancement imaging was acquired using a 3-D inversion recovery-prepared, respiration-navigated, electrocardiography-gated, gradient-echo pulse sequence after the Look-Locker sequence to identify the optimal nulling time for the normal left ventricular myocardium. Pixels that showed increased enhancement in the left atrial wall were identified using the full width at half of the maximum technique and at 6-, 5-, 4-, 3-, and 2-standard deviations above the mean signal value of the unenhanced LV wall10. Serum levels of galectin-3 were measured using enzyme-linked immunosorbent assay kits . The mean minimum detectable dose was 0.016 ng/mL, which was determined by the intensity of color.Although there is no consensus on the preferred site for obtaining blood for measuring the level of serum galectin-3, we collected blood samples from the left atrium pertaining to the study protocol14. The mean atrial cycle length during atrial fibrillation was calculated using intervals of consecutive 20 signals acquired from each pulmonary vein.An internal cardioversion was performed when the initial rhythm was atrial fibrillation to obtain information about the endocardial voltage during sinus rhythm. Using intracardiac multielectrode catheters positioned in the right atrium and the distal coronary sinus, 3–10 Jules of energy was delivered from an external defibrillator via junction box that allowed multielectrode catheter to be switched between routine diagnostic electrophysiology study and cardioversion. The 3-D mapping system  was used with a circular multielectrode catheter  which generated an electroanatomical geometry with endocardial voltage information. The voltage ranged from 0.5 to 3.0 mV and was color-coded from grey to purple. The low voltage area was defined to be areas less than 0.5 mV in accordance with previous studiesRadiofrequency catheter ablation was performed using an open irrigated tip catheter . In patients with paroxysmal atrial fibrillation, the presence of a reproducible trigger that initiated atrial fibrillation was identified using high-frequency burst pacing and high-dose isoproterenol infusion before ablation. All patients had electrical isolation of the pulmonary veins and elimination of non-pulmonary vein triggers. Patients with non-paroxysmal atrial fibrillation had substrate modification focused on the automated complex fractionated atrial electrogram, or linear lesion, after pulmonary vein isolation, until atrial tachyarrhythmia could not be induced by burst pacing.Ambulatory monitoring and 12-lead electrocardiography were performed for 1–2 days after procedure during the patient’s hospital stay. An electrocardiography was routinely performed at each visit in the outpatient clinic, and 24-/48-Holter was performed at 1, 3, 6, 9, and 12 months, and then every 6 months thereafter. The physician determined whether antiarrhythmic drugs should be discontinued after 90 days (blanking period). Recurrence was defined as the occurrence of any sustained atrial tachyarrhythmia after a blanking period.2 test or Fisher’s exact test. Pearson’s correlation coefficients demonstrated the strength of the relationship between variables. Multivariable Cox regression analysis was used to establish the predictive factors for recurrence. The adjusted factors were age, sex, body mass index, comorbidities , clinical patterns of atrial fibrillation, hematocrit, renal function, left atrial diameter, late gadolinium enhancement in cardiac magnetic resonance imaging, and serum galectin-3 levels. The proportional hazard assumption was evaluated using log minus log survival curves, which were approximately parallel during the follow-up period. Statistical analyses were performed using SPSS . All tests of significance were two-tailed. A p value of < 0.05 indicated statistical significance.Continuous variables are presented as the mean and standard deviation and were analyzed using the Student’s t-test or the non-parametric Wilcoxon rank sum test. Categorical variables are presented as the number and percentage and were analyzed using a χ2DS2-VASc score was 1.8, and the mean left atrial diameter was 41 mm on transthoracic echocardiography , and total low voltage area in a 3-D mapping system . Serum galectin-3 was positively correlated with left ventricular thickness on echocardiography , the proportion of area with late gadolinium enhancement to total left atrial area  and hematocrit  did not demonstrate significant relationships with galectin-3. There was no significant relationship between galectin-3 and the atrial cycle length during atrial fibrillation (p = 0.360). Among paired groups of patients who were sorted according to the type of atrial fibrillation or comorbidities, serum galectin-3 was higher in the diabetic group than in the non-diabetic group  but was not different in other paired groups.Serum galectin-3 obtained from the left atrium was positively correlated with left atrial size measured by anteroposterior diameter in the long-axis parasternal view on echocardiography  and serum galectin-3 level  were found to be associated with an increased risk of recurrence  of atrial tachyarrhythmias  were identified. After adjusting for multiple clinical factors, non-paroxysmal atrial fibrillation  was a statistically significant predictor for recurrence in univariate analysis. However, additional analysis with the stepwise variable selection of the multivariable Cox proportional hazards model did not confirm this finding. However, serum galectin-3 and non-paroxysmal atrial fibrillation were predictors in the final model. Because serum galectin-3 levels were positively correlated with left atrial size, more powerful predictors between galectin-3 and left atrial size might be included in the final model.Left atrial enlargement has been reported to be a powerful predictor for recurrence after catheter ablation19. Expanding this approach to the atrium, Marrouche et al.6 reported the value of atrial late gadolinium enhancement for predicting recurrence after ablation. However, compared to ventricular imaging, atrial imaging has limited to assess myocardial fibrosis because the spatial resolution of the left atrial wall is insufficient, and is 2–3 times thinner than the left ventricular wall. Low voltage area (< 0.5 mV) that reflects conduction abnormalities caused by fibrosis has also been considered as a therapeutic approach20. However, the bipolar electrogram amplitude can be influenced by multiple factors that include the activation vector, angle of incidence, recording electrode size, interelectrode spacing, tissue contact, signal filtering, mapping density, and mapping resolution21.Fibrotic transformation of cardiomyocytes and interstitial accumulation of fibrotic tissue contribute to the development of arrhythmogenic substrates by slowing electrical conduction and enhancing anisotropy. Therefore, quantitative evaluation of the extent of atrial fibrosis may be helpful for predict rhythm outcomes after ablation. Instead of an endomyocardial biopsy which can have procedure-related complications and a low diagnostic yield, alternatives for assessing the extent of atrial fibrosis have been investigated in patients with atrial fibrillation. Early studies using magnetic resonance imaging reported that the late gadolinium enhanced area was positively correlated with myocardial collagen in the infarcted ventricle22. Because galectin-3 is implicated in inflammation and fibrosis in multiple organs, including the heart, liver, kidneys, lungs, spleen, ovary, and vessels10, we excluded patients with extracardiac dysfunction to reduce confounding bias. Interestingly, higher level of serum galectin-3 was seen in patients with thicker interventricular septum. This is not far from the result of previous studies which showed positive correlation between serum galectin-3 and diastolic dysfunction or ventricular mass index23. We presume that diastolic dysfunction may affect the serum galectin-3 level more than the degree of cardiac galectin-3 deposits does in patients with atrial fibrillation. Also, serum galectin-3 level had a weak correlation with either left atrial diameter or interventricular septal thickness in our study. Therefore, we could not discern the origin of serum galectin-3 between the atrium and ventricle. However, because atrial fibrillation is a progressive disease with structural remodeling of both the atrium and the ventricle, this would not change the clinical implication of serum galectin-3. Furthermore, serum galectin-3 has been associated with myocardial fibrosis and increased mortality in patients with heart failure24. Recently, inhibition of galectin-3 reduced atrial fibrosis and the total burden of atrial fibrillation7.Galecin-3 is a member of the animal lectins family, which is secreted by macrophages25. Galectin-3 from peripheral blood could be affected by other pathologies, such as cancer or non-cardiac fibrotic diseases25. Therefore, a further study to evaluate the clinical value of galecin-3 from peripheral blood is needed.Compared with peripheral blood sampling, the invasive intracardiac sampling required by our model limits its utility for pre-procedural assessment. However, galectin-3 levels in peripheral blood were higher and less predictive of recurrence after ablation compared with those in intracardiac bloodThere were several limitations to this study. First, this was a single center study with a small number of patients and a short duration of follow-up. However, all study patients were consecutively enrolled during the study period. Second, histopathological data for cardiac tissue was not available and could not be evaluated.In summary, elevated serum galectin-3 was related to the left atrial enlargement and increased risk of recurrence after radiofrequency catheter ablation in patients with atrial fibrillation. Therefore, serum galectin-3 could be used as a biomarker for evaluation of the atrial remodeling severity and post-ablative prediction of recurrence in patients with atrial fibrillation.


Background: Prior to any revascularization procedure for coronary artery disease, it is essential to identify viable myocardium which will likely benefit from it. In such a situation, delayed enhanced cardiac MRI is beneficial.Methods: Our study consisted of 50 patients with at least a one-month prior history of myocardial infarction (MI), abnormal findings on electrocardiography (ECG), and 2D-echocardiography (2D-ECHO), who were subjected to cardiac MRI performed on a 3T MRI machine. The MRI scans were evaluated for anatomical and especially functional characteristics of the heart, such as wall motion. On late gadolinium enhancement (LGE), the diseased segments were classified into two categories: < 50% LGE (viable) and > 50% LGE (non-viable).Results: Of the 378 diseased segments detected on LGE, 137 (36.2%) segments showed < 50% LGE and 241 (63.8%) segments showed > 50% LGE. The segments showing < 50% LGE showed normokinesia or hypokinesia, with none of the segments showing akinesia or dyskinesia, whereas the segments showing > 50% LGE showed akinesia or dyskinesia predominantly. This was found to be statistically highly significant . Conclusion: Delayed enhanced-cardiac magnetic resonance (DE-CMR) imaging in patients with ischemic heart disease (IHD) helps evaluate the severity of the infarcted myocardium by classifying the diseased myocardium into viable and non-viable, as viable myocardium is more likely to regain functional recovery than non-viable myocardium. It also predicts the functional recovery of the myocardium after revascularization therapy. Cardiovascular disease (CVD) remains the primary cause of mortality worldwide . IndiansHowever, revascularization will not be helpful for all patients. Echocardiography establishes the hypokinetic or akinetic myocardium as diseased. This diseased myocardium may be stunned and hibernating or fibrosed. The viable myocardium is described as hibernating or stunned. Due to decreased perfusion, it is hypokinetic or akinetic .After adequate revascularization, this hibernating and stunned myocardium is likely to regain normal myocardial activity, whereas the infarcted myocardium is less likely to recover -7. In adVarious techniques are used to assess myocardial viability in patients with ischemic heart disease (IHD). These techniques include echocardiography, 201Tl single-photon emission computed tomography (SPECT), fluoro-2-deoxyglucose (FDG) positron emission tomography (PET), and cardiac MRI.Cardiac MRI is a non-invasive, non-ionizing technique that is used for the evaluation of progression of infarcted segments, thinning of LV wall, LV volume, LV shape distortion, and compensatory hypertrophy of healthy myocardium . CardiacInfarct evaluation using contrast-enhanced CMR is a relatively novel approach. Extracellular contrast material reveals substantial signal strength in the infarcted areas on T1 weighted images. It is most likely that the extracellular contrast agent disperses into the intracellular space due to the breakdown of the myocyte membrane. Chronic infarcts have collagenous scars with increased interstitium between collagen fibers, leading to a higher contrast concentration and hence contrast enhancement . Due to In this study, we have highlighted the importance of LGE in delineating viable from non-viable myocardium, which will affect the selection of patients for revascularization procedures and predict the recovery of LV function. Patient selectionThis was an observational study comprising 50 patients conducted in the radiology department. Before starting the study, an Institutional Ethical Committee (IEC) clearance was obtained at Dr. DY Patil Medical College, Hospital and Research Center, Pune, with approval number IESC/PGS/2019/168.Patients ranging in age from 20 to 80 years were referred from the department of cardiology with at least a one-month prior history of myocardial infarction (MI), ECG findings of either ST-segment elevation myocardial infarction (STEMI) or non-ST segment elevation myocardial infarction (NSTEMI), abnormal 2D-echocardiography (2D-ECHO) findings, and were medically treated with thrombolysis. Patients who had undergone revascularization therapies like CABG surgery were excluded from the study. A thorough medical history was collected to rule out any potential contraindications to MRI, like metallic objects, pacemakers, and cochlear implants. Written informed consent was obtained from the patients before the MRI. Before the commencement of the MRI scan, each patient was given a brief explanation of the procedure. Imaging techniqueA Magnetom Vida 3T MRI  was used for the MRI evaluation. MRI was performed on patients supine (head first) with optimal placement and body stabilization. A standard Body Array 18 channel coil was used to acquire images. The participants were given light music to reduce the amount of noise in the MRI room. In addition, patients were trained for breath-holding . First, localizer sequences are done in various planes to localize the heart for anatomy and position. Pre-contrast scanning is done for morphology and function. The sequences used for morphology are T2 TRUFI, T2 HASTE Dark Blood, T2 TSE Dark Blood, T1 TSE Dark Blood, T2 STIR Dark Blood while 2 Chamber CINE TRUFI in Long Axis, 4 Chamber CINE TRUFI in Long Axis, CINE TRUFI Retro in Short Axis, CINE LVOT, and CINE RVOT are used to assess cardiac function. Contrast studies are done for perfusion and viability studies with dimeglumine gadopentetate (0.1 mmol/kg body weight). For perfusion, we used the DYNAMIC TRUFI SR EPAT sequence in 50 phases in 2-chamber, 4-chamber, and short-axis for the left side and a 2-chamber view for the right side of the heart. Following viability imaging, TI SCOUT is taken in the short axis after approximately 10 min of contrast injection to assess TI value. This TI value is further used for the delayed TRUFI high-resolution PSIR sequence. Except for CINE imaging, all image acquisitions were electrocardiogram (ECG)-gated (retrospective gating). The MRI images were analyzed for the structural anatomy of the heart as well as its functional aspect. Imaging evaluationThe American Heart Association's 17-segment LV model  was utilBased on the extent of LGE, we divided the diseased myocardium into segments showing <50% LGE Figure  and >50% Statistical analysisData were entered into Microsoft Excel, and statistical analysis was carried out in SPSS software version 17.0 . Qualitative variables like gender, LV clot, and microvascular obstruction (MVO) were presented as frequency and percentages. In addition, age and ejection fraction were categorized and represented as percentages. Bar diagrams and pie charts were used for the graphical representation of data. The Mann-Whitney U test and Kruskal-Wallis test were used to compare the number of segments diseased between gender and age categories. A Chi-square test was used to compare wall motion abnormality and the degree of LGE.A p-value of <0.05 was considered statistically significant. Some 50 patients with 850 myocardial segments and 150 coronary territories were evaluated. Thirty-four (68%) were males; the mean age of the cases was 54.04 years which ranged from 30 to 77 years. The mean ejection fraction was 30.11% (14.7), with a lowest of 12% and a highest of 67%.On DE-CMR, out of the total 850 segments, 378 segments showed DE-CMR , while the remaining 472 segments did not show any enhancement .The number of diseased segments was found to be higher in males than females, which was found to be statistically significant . A comparison of the number of diseased segments in different age groups was statistically not significant .The diseased segments were divided into those that showed <50% LGE and those that showed >50% LGE Table . Among tBased on visual eyeballing, out of the 137 segments showing <50% LGE, 121 (88.3%) segments showed hypokinesia, 16 (11.7%) segments showed normal wall motion, and none of the segments showed akinesia or dyskinesia. Out of the 241 segments showing >50% LGE, 14 (5.8%) segments showed hypokinesia, 162 (67.2%) segments showed akinesia, and 65 segments (27%) showed dyskinesia. None of the segments showed normal wall motion. Thus, the segments showing <50% LGE showed normokinesia or hypokinesia, with none showing akinesia or dyskinesia, whereas the segments showing >50% LGE showed akinesia or dyskinesia predominantly. This was found to be statistically highly significant . Hence, as the degree of LGE increases, the severity of wall motion abnormality also increases. A segment with <50% LGE is considered a viable segment, whereas a segment with >50% LGE is considered non-viable (Table Some 10 (20%) cases showed the presence of MVO in the LV wall Figure . Some 18Myocardial viability before any revascularization technique is an essential clinical issue in individuals with IHD. Among the different modalities used in assessing myocardial viability, delayed enhanced-cardiac magnetic resonance imaging (DE-MRI) is a well-known MRI method for assessing viability . The purIn our study, which involved 50 patients, 36.2% of the diseased segments showed <50% LGE and 63.8% showed >50% LGE, whereas in a similar study by Aggarwal et al. , consistThe two most important indicators of ventricular function recovery following revascularization operations are the degree of infarct as estimated by LGE and the end-diastolic wall thickness (EDWT) Figure  21]. Ac. Ac21]. Additionally, some investigations have hypothesized that delayed enhancement can effectively illustrate the amount of infarct, outcome, and occurrence of potential complications following revascularization. In 2016, Lee et al. assessed the effect of delayed gadolinium enhancement on long-term outcomes in patients undergoing CABG and found that the amount of LGE is a significant predictor of unfavorable cardiovascular events, regardless of LV function . Lim et There were 10 20%) study subjects in which microvascular obstruction (MVO) was detected in our study. In addition, these patients had severe LV systolic dysfunction. In the setting of acute MI, MVO may occur, which is a "no-reflow" process, indicating an inability to reperfuse a section of myocardium despite re-establishment of patency of epicardial coronary arteries. MVO is seen on MRI as a dark, non-enhancing region of the myocardium in both early and delayed enhancement % study s.Cardiac MRI is one of the most accurate tools in a radiologist's arsenal for assessing ventricular mass and volumes, aberrations of the wall motion, and ventricular function, both systolic and diastolic. With the use of DE-CMR in patients with IHD, it is possible to know the severity and extent of the infarcted myocardium, classifying the diseased myocardium into viable and non-viable, which helps with patient selection for revascularization therapy as viable myocardium is more likely to regain functional recovery after revascularization than non-viable myocardium.


Trypanosoma cruzi (Chagas) and 20 with saline (Control). Echocardiography was performed before the infection (baseline), at 1 month (acute phase), 4, 6, and 8 months (chronic phase) using Vevo 2100 (Fujifilm Inc.) ultrasound system. Left ventricular end-diastolic diameter, Left ventricular end-systolic diameter (LVESD), Left ventricular ejection fraction (LVEF), Global longitudinal (GLS), circumferential (GCS) and radial (GRS) strain were evaluated. Tricuspid annular plane systolic excursion (TAPSE) was used to assess right ventricular function. At 8 months, animals were euthanized and LV myocardial samples were analyzed for quantitation of inflammation and fibrosis. LVEF decreased over time in Chagas group and a difference from Control was detected at 6 months . There was a pronounced decrease in GLS, GCS and TAPSE in Chagas group  since the first month. LVESD, LVEF and GLS were significantly correlated to the number of inflammatory cells  but not to fibrosis. In the Syrian hamster model of CD STE parameters (GLS and GCS) showed an early decrease. Changes in LVEF, LVESD, and GLS were correlated to myocardial inflammation but not to fibrosis.Speckle tracking echocardiography (STE) enables early diagnosis of myocardial damage by evaluating myocardial strain. We aimed to study sequential changes in structural and ventricular functional parameters during Chagas disease (CD) natural history in an animal model. 37 Syrian hamsters were inoculated intraperitoneally with  Trypanosoma cruzi  if not normally distributed. Categorical data are presented as absolute values and percentages. Wilcoxon–Mann–Whitney tests were used to evaluate the differences between the two groups at baseline examination. Correlation of fibrosis and inflammation with echocardiographic parameters of LV and RV structural and functional assessment was verified by Pearson’s correlation coefficient.The analysis of variance for mixed models of repeated measures (mixed-ANOVA) was used to evaluate interaction (main effect) between the experimental groups (between-subject effect) and time (within-subject effect). Statistical analyses were performed using Stata 14.0  and P < 0.05 was considered statistically significant.A total of 62 female Syrian hamsters was selected. Three animals were excluded from the basal evaluation, one of them because of thoracic deformity and two because of significant arrhythmias right after anesthesia. Two animals died during the first anesthesia. At baseline, 57 animals were subjected to echocardiography and there were no significant differences in characteristics between both groups, except for a higher weight of the Chagas group compared to controls , Table During the follow-up time, the sequential analysis showed that Chagas group had a significant increase in the LVESD and a decrease in LVEF_2D in comparison with Control group  Fig. Additionally, GLS and GCS of Chagas group showed a significant reduction over time in Chagas group compared to the Control group  - Fig. The evolution of both ventricles’ structure and functional parameters is presented in Table The TAPSE index of the Chagas group also presented a significant reduction over time compared to the Control group  - Fig. Histological analysis demonstrated diffuse myocarditis characterized by lymphomononuclear interstitial infiltrate in the Chagas group. There was an increase of 50% in the amount of mononuclear rounded interstitial cells  . The increase in the volume fraction of fibrosis was around 30%  , as also to LVEF_Teichholz  and LVESD , Table All echocardiographic parameters for LV functional assessment revealed good interobserver reproducibility, with the intraclass correlation coefficient ranging from 0.52 (for LVEF_2D) to 0.91 (for GLS). LVEF by Teichholz’s method showed the lowest interobserver coefficient of variation (5.66%), while GRS exhibited the highest (13.63%).Intraobserver reproducibility showed an intraclass correlation coefficient ranging from 0.49 (for LVEF_2D) to 0.92 (for GLS) and a coefficient of variation from 4.25% (for LVEF by Teichholz’s method) to 10.85% (for GRS) Table .Table 6RThe present study evaluated biventricular geometrical and functional ventricular changes in an experimental model of Chagas disease in Syrian hamsters over time in comparison with a Control group.T. cruzi. In contrast, LVESD and LVEF showed changes at an advanced time point of CD, when mortality is high. Besides, the present investigation indicates an early involvement of the right ventricle in animals infected with T. cruzi, before the overt dysfunction of LV.The findings revealed that parameters of longitudinal and circumferential myocardial deformation obtained by STE are significantly depressed early after the infection with T. cruzi infection, in Syrian hamsters CD can be replicated through all clinical stages including the acute phase, the latent period (indeterminate), the chronic cardiomyopathy, with myocardial dysfunction caused by multifocal and diffuse myocarditis and interstitial fibrosis. The first month after infection in hamsters presents the acute phase of the disease, with a high mortality rate. In our study, we observed 27% of mortality at this point and this finding is similar to that reported in a previous study, which showed a mortality rate of 33% in the first month [Although the phases and forms of CD are difficult to be reproduced in rodent models of st month . After tst month  of chronst month , 16, 34.st month , which, T. cruzi [T. cruzi infected Syrian hamsters. Previous studies had already shown the feasibility of two-dimensional LVEF in mice and rat models of surgical myocardial overload, infarction, and LV dysfunction [Other studies reported on late LV dilatation in hamsters infected with T. cruzi . In our T. cruzi . Our stufunction . Howeverfunction , M-mode This was also the first study to prospectively evaluate RV function through the evolution of CD in Syrian hamsters. Our data showed RV is early compromised. These findings corroborate the results from studies in humans that have shown early changes of RV geometry and function even in the indeterminate form of CD –39. The T. cruzi. Our results demonstrated that GLS and GCS were able to detect early myocardial damage in animals infected with the protozoan when compared with control animals at the same age. It is noteworthy that the change in these parameters occurred despite normal values of LVEF, as early as one month after infection, a moment recognized in this model as the acute phase of the CD when mortality rates are high.This was the first study to use STE in Syrian hamsters infected with There have been some studies with STE in patients with Chagas disease. However, the behavior of myocardial deformation through all stages of the disease in a sequential analysis had not been previously demonstrated. Although in CCC global LV deformation parameters and LVEF are reduced , 42, resIn contrast to the reduction of LV GLS and GCS observed in infected animals since the very early phase of the disease, GRS was not different between Chagas and control groups in our study. Radial strain interpretation has been challenging in several aspects. The wide variability of GRS indexes and also low reproducibility are recognized even in normal human hearts . Also, wMeasurements of myocardial deformation in this study strictly followed the latest published guidelines . EKG sigT. cruzi infected animals compared to controls. The low extent of myocardial fibrosis (4%) corroborates this model as a representative of initial myocardial damage when studied until 8 months. Previous studies show fibrosis of 10% of the whole LV myocardial area when animals reach 10 months of infection [Corroborating previous findings from our laboratory , 51 histnfection . Despitenfection , 53 wereOur findings should be interpreted in the context of the various limitations. First, the fact that only animals who had all echocardiographic analyses in pre-specified time points were included, according to the inherent characteristic of mixed-ANOVA analysis . AlthougT. cruzi infection suggest STE as a potentially useful tool to study early sequential myocardial damage through CD evolution in humans. GRS and GLS can show myocardial impairment before the overt LV dysfunction shown by a reduction in LVEF. There is no robust evidence about how frequently echocardiographic examinations should be done in serological-positive patients without clinical signs of disease [Results of this investigation in the animal model of  disease . HoweverT. cruzi infection before LVEF reductions and testing reversibility of deformation parameters and myocardial function improvement.Future studies delineated to investigate the prognostic value of STE in CD are warranted. Syrian hamster experimental animal model could provide insights to therapeutic effects of drugs in In the Syrian hamster experimental model of CD, the left ventricular STE parameters (GLS and GCS) showed an early decrease, and RV dysfunction was also detected even before overt LV dysfunction. Changes in LVEF, LVESD, and GLS were correlated to myocardial inflammation but not to fibrosis.


Anthracyclines are widely employed in lymphoma’s chemotherapy and has been shown to induce heart failure. Echocardiographic parameters of left ventricular (LV) systolic function are usually used to monitor the cardiac side effects during and after anthracyclines treatment. The measurement of theTei index could anticipate the onset of LV dysfunction. The aim of this study was to evaluate the performance of the delta Tei index for the early detection of cardiac toxicity in a prospective population of anthracycline-treated lymphoma patients. Our preliminary data suggest that the Tei index may predict the risk for cardiotoxicity in this subset of patients earlier than LV ejection fraction alteration. Anthracycline therapy continues to be the cornerstone in the treatment of Hodgkin (HL) and non-Hodgkin’s lymphoma (NHL), with the best known limitation being the potential dose-dependent early and late cardiotoxicity ,2. Diffe2 for doxorubicin, 300 mg/m2 for epirubicine), patient’s age, family history of CHF and the clinical risk factors  seem to be related to the higher risk of developing signs and symptoms of heart failure. Currently, there is no score available to predict the individual risk of anthracycline-related toxicity, but a scheduled follow-up according to multiple risk factors has been recently proposed ), left ventricular end-diastolic diameter (LVEDD) (mm), left ventricular end-systolic diameter (LVESD) (mm). In the apical four chamber view, we calculated the LV end-diastolic volume (EDV), end-systolic volume (ESV) and stroke volume (SV) by the conventional method. LVEF (left ventricular ejection fraction): ejection fraction is the volume ejected from the left ventricle as a percentage of end-diastolic volume. LVEF is calculated from EDV and ESV estimates, using the following formula: (EDV-ESV)/EDV, with the biplane Simpson method. The biplane method of disks (a modified derivative of Simpson’s rule) is the currently-recommended 2D method to assess LVEF by consensus of the American Society of Echocardiography and the European Association of Cardiovascular Imaging . Pulsed-The Tei index was calculated for both ventricles by the formula (IVRT+IVCT)/ET . All diap-value < 0.05. All the analyses were performed using the Statistical Analysis System .The comparisons of the patients’ baseline characteristics between Tei+ and Tei- group were calculated with the Mann–Whitney U test for continuous variables and the Pearson χ2 test for categorical variables. The variation of other cardiac parameters with time was assessed with the Wilcoxon signed-rank test, separately for the two groups. The correlation between some measurements of interest was calculated with the Pearson’s correlation coefficient (r). The statistical significance was achieved at a A total of 41 patients were enrolled in the study. Two patients died before the completion of chemotherapy. Two patients were lost at follow-up. Baseline clinical characteristics are shown in Doxorubicin was the most commonly used molecule (93% of patients). There were no significant associations between baseline clinical characteristics and the Tei index value .All studied patients had no significant drop of LVEF in either arm (Tei+ and Tei-), during chemotherapy administration and follow-up. No correlation was demonstrated between the Tei index basal value and LVEF values measured during chemotherapy and follow-up . The strp = 0.04 and p = 0.02, respectively) between the first and the fourth cycles  and the end systolic volume (ESV) did not change either during the administration of therapy or during the follow-up On the other hand, in the Tei- patients, we observed a significant increase of EDV and ESV (h cycles .p = 0.04) and the SV value occur, both measured at 12 months of follow-up   for HL and NHL. None of the patients enrolled in the study showed signs or symptoms of heart failure or a significant reduction of LVEF. This data suggest that the studied population had no clinical or echocardiographic signs of established anthracycline-related cardiotoxicity.No statistically significant correlation was found between Tei index value and LVEF in either of the two groups of patients with low (Tei-) and with high (Tei+) index. This data can be easily explained because the Tei index represents an early marker of ventricular dysfunction, so its increase does not significantly impair the LVEF. This result is in accordance with the study conducted by Senju et al. that found an increase of the Δ-Tei index in 23 doxorubicin-treated patients affected by hematologic neoplasms, irrespective of the LVEF value. The study confirmed the greater sensitivity of the Tei index than the LVEF in identifying early anthracycline-related cardiotoxicity .In the Tei- group, a significant increase of the LV EDV and LV ESV, as well as a consequent increase of stroke volume (SV), were observed. This result may reflect an effective compensatory mechanism to a “cardiac insult” represented by anthracyclines with a dilatation of ventricular chambers and consequent increase of SV in patients without alterations of the LV systolic and diastolic function (Tei-). In such patients, in fact, the administration of anthracycline may represent the trigger for the establishment of compensatory mechanisms with the aim of maintaining unchanged SV, even in the presence of a cardiotoxic drug. This compensation mechanism is in agreement with the results reported by Lipshultzet al., which revealed an increase of ventricular afterload in children affected by ALL subjected to doxorubicin therapy .The increase in EDV and ESV values was not recognized in the group of Tei+ patients. Probably, the latter proved incapable of compensatory mechanisms producing an increase of ventricular volumes. For this incompetence of the compensatory mechanism, we think that the Tei+ patients presented a greater risk of anthracyclines-related cardiotoxicity.In our study, an inverse correlation between the Tei index and EDV at 12 months and between the Tei index and SV was observed. This inverse correlation suggests that increases of ventricular volumes, in order to maintain an appropriate SV, are a prerogative of patients with a good systolic and diastolic function (Tei-). This significant correlation is already evident just after the first cycle of chemotherapy, though with a lower statistical significance, highlighting that a functional heart (Tei-) is already able to modify its geometry even after the first chemotherapeutic “cardiac damage”.Based on these findings, the Tei index could represent an effective and valid echocardiographic marker able to identify asymptomatic patients at increased risk of developing anthracyclines-related cardiotoxicity, more sensitively than LVEF.2), enabling us to identify those patients who are at higher risk of developing cardiotoxicity [2), underlining the presence of a “continuum”of anthracycline cardiac damage [No statistically significant correlation was found between the value of Tei and the increase of anthracyclin doses. Ishii et al. evaluated the validity of the Tei index in identifying the presence of subclinical cardiotoxicity in a population of 65 anthracycline-treated children. The study showed that the Tei index value tends to increase even for moderate doses of anthracycline  should be prescribed to prevent a clinical heart failure. It might be interesting to evaluate the possible use of this measure as an alternative or complementary to LVEF or strain parameters such as global longitudinal LV systolic strain. However, even if in a small but strictly selected population, our study confirms the recognized role of the Tei index forearly identification of asymptomatic patients without significant reduction of LVEF at high risk of developing anthracycline-related cardiotoxicity.An individual stratification of the risk of cardiotoxicity that includes the Teiindex could help to personalize the therapies and guide the follow-up of patients.In conclusion, the Tei index could be a simple, easy to obtain and reliable measurement to monitor cardiac toxicity due to chemotherapy. Owing to its characteristics of easy-acquisition and low-level technical requirement, it may gain popularity amonghigh-volume hospitals.The Tei index evaluation during a standard 2D-echocardiogram can be used to identify a patient’s group at high risk for cardiotoxicity because it reveals the correlation between the systolic anddiastolic function measured with the Tei index and EDV during anthracycline therapy, as well as the correlation between the Tei index and SV at follow-up. Furthermore, this correlation between the Tei index and SV showed even after the first cycle of therapy, like an early marker of cardiac damage.


Self-healing subjects were defined on the basis of an absence of residual shunts at colorDoppler across the previous defect. (3) Results: no statistically significant differences were reported in the size of perimembranous ventricular septal defects between the two groups (p = ns). Conversely, prevalence of anaemia was significantly higher in those requiring intervention than in the self-healing group (p < 0.03), while haemoglobin, iron, ferritin, and albumin levels were lower . In multivariable linear regression analysis, only haemoglobin and albumin were found to be associated with spontaneous closure . In multiple logistic regression analysis, haemoglobin independently increased the probability of self-healing of perimembranous ventricular septal defects (p = 0.03). All patients needing an interventional closure of perimembranous ventricular septal defects presented with haemoglobin <12.7 g/dL. (4) Conclusion: the self-resolution of perimembranous ventricular septal defects seems to rely on numerous factors, including oxygen content, which is likely to promote cell proliferation as well as tissue regeneration. Haemoglobin blood concentration seems to influence the natural history of perimembranous ventricular septal defects and improvement of anaemia by supplementation of iron intake might represent a simple and reliable method to promote self-healing.(1) Background: the impact of a series of laboratory parameters  on perimembranous ventricular septal defects spontaneous healing was tested. (2) Methods: one hundred and seven patients were enrolled in the study  and were subsequently subdivided into two groups: self-healing ( Ventricular septal defect, manifested either as an isolated event or in conjunction with other cardiac abnormalities in syndromic and non-syndromic patients, is by far the most frequently encountered congenital heart defect (CHD) after bicuspid aortic valve in clinical practice, accounting for approximately 20% of all diagnoses when isolated ,2. NumerAt birth, approx. 8% of detected ventricular septal defects are perimembranous, i.e., involving both the membranous septum and the adjacent muscular area . DiagnosNumerous studies have demonstrated self-healing of perimembranous ventricular septal defects in 10–30% of cases, thus avoiding the potential peri-procedural complications associated with repairs performed by means of conventional surgery or transcatheter-occluding devices ,6.Anaemia is frequently observed in both children and adults affected by all types of CHD, including ventriular septal defects at all ages ,8. RenalThis study aimed to assess the impact of a series of laboratory parameters on spontaneous full healing of perimembranous ventricular septal defect: haemoglobin, haematocrit, foetal haemoglobin, peripheral oxygen saturation, iron, transferrin, ferritin, and albumin blood levels.In this retrospective study, medical records of patients affected by perimembranous ventricular septal defect attending the Paediatric Cardiology Unit of the University of Cagliari  from January 1986 to February 2006 were examined. No additional subjects could be evaluated due to closure of the above-cited unit. Following a review of hardcopy medical records and electronic health records, one hundred and seven patients were included in the study , ranging from 1 day of life to 6 years (mean age 2.1 ± 0.4 years). Clinical and echocardiographic characteristics of study participants are listed in n = 36) and those in need of intervention (n = 71).Inclusion criteria were: presence of a perimembranous ventricular septal defect without other CHD, with the exception of transient patent ductus arteriosus, small atrial septal defect and/or one or more minor muscular ventricular septal defects; when surgical closure was indicated due to a large volume left-to-right shunt (Qp/Qs > 2:1), in the presence of significant pulmonary arterial hypertension , clinical signs of congestive heart failure, banding of the pulmonary artery, or when closure of the perimembranous ventricular septal defect was deemed clinically necessary by the treating physician. Exclusion criteria comprised: ventricular septal defect exceeding 10 mm and/or a ventricular septal defect size/aortic diameter ratio higher than 2/3 (in which case spontaneous closure is improbable); patients presenting with multiple severe muscular ventricular septal defects and/or complex CHD; presence of ongoing bacterial infections/sepsis; haematological disorders (mainly haemolytic disease of the newborn); insufficient laboratory findings. Patients were subdivided into two groups: self-healing  echo machine coupled with two probes (3–5 Mhz and 8–10 Mhz) was used. Patients diagnosed with perimembranous ventricular septal defect were followed-up until either the hole in the interventricular septum closed spontaneously or surgical closure was performed. The net defect was measured, which may be smaller than the true due to tricuspid pouch formation. The self-healing group was defined on the basis of an absence of residual shunts at colorDoppler across the former perimembranous ventricular septal defect.Written informed consent was waived owing to the retrospective nature of the research, as per Italian Law. The research was formally approved by the internal Ethics Committee of the University of Cagliari (PG/2015/1859) and conducted in accordance with the Helsinki declaration.The following blood parameters capable of affecting tissue oxygenation were evaluated on a blood sample taken from an antecubital vein-haemoglobin: normal haemoglobin values for children vary according to the child’s age, sex, and race. Anaemia is defined in the presence of a haemoglobin value at or below the 2.5th percentile for age, race, and sex ,10. -haematocrit ,12-foetal haemoglobin: the most important oxygen-transport protein in the human foetus -oxygen saturation -serum iron levels . -transferrin -ferritin -albumin ,18 See .n = 107) were analysed and the findings obtained in the self-healing group subsequently compared with those from the group requiring intervention using the parametric Student’s t-test, as the sample was normally distributed. Normality was assessed by means of the Kolmogorov–Smirnov test. Multivariate analysis was also performed to analyse more than one outcome variable. The model included the hematic variables which tested statistically significantly different between the two subgroups  along with age and gender. For the purpose of this paper, statistical significance was set at <0.05. Commercially available computer software  was used for all analyses.The results obtained in the study population , while haemoglobin, iron, ferritin, and albumin levels were lower .Regarding the time required by the two groups to reach their outcome, it was statistically significant. Since no statistically significant differences were detected in the dimensions of ventricular septal defect between the two groups, the need for an early intervention was likely due to a drop in pulmonary vascular resistances, which led to a significant left-to-right shunt and in turn to pulmonary overflow and heart failure. Furthermore, anaemia was significantly more prevalent amongst subjects requiring intervention than in the self-healing group . Multiple logistic regression analysis revealed that haemoglobin independently raised the probability that self-resolution of ventricular septal defect would be achieved (p = 0.03).At multivariable linear regression analysis only haemoglobin and albumin featuring an association with spontaneous closure of perimembranous ventricular septal defect  the study was of a single centre retrospective design and therefore contingent on the inherent bias associated with this type of study ; (2) over the period examined (1986–2006), the majority of surgical procedures were delayed compared with current standard decision making and a smaller number of interventional perimembranous ventricular septal defect closures were performed . This maOverall, the self-resolution of perimembranous ventricular septal defect seems to rely on numerous different factors, including oxygen content, which likely promotes cell proliferation as well as tissue regeneration. Accordingly, in the presence of low oxygen saturation at a high altitude, ventricular septal defects are more likely to remain open . Further


JACC: Basic to Translational Science raise provocative questions about the state of our knowledge about heart failure, as well as where and how the field should advance.The recent clinical success with sodium-glucose cotransporter 2 (SGLT2) inhibitors and angiotensin receptor–neprilysin inhibitors (ARNIs) in treating heart failure patients with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF]: ≤40%) and preserved ejection fraction (HFpEF) (LVEF: ≥50%) has given rise to the proposition that LVEF cutoffs should no longer be used as the basis for subclassifying heart failure patients into different pathophysiologic phenotypes and that, going forward, for classification systems to have clinical importance, they should be “more representative of the state of our knowledge about heart failure, and should reflect contemporary approaches to how patients with heart failure are evaluated and treated.”Kaye et al1-adrenergic receptor blockade in heart failure patients with LVEFs of >50%The paper by Kaye et alBased on elevated transcardiac levels, Kaye et alA second interesting aspect of the paper by Kaye et alJACC: Basic to Translational Science raise the intriguing possibility that it may be possible to identify such hyperadrenergic subphenotypes of HFpEF patients in whom β blockers may prove to be effective in reducing heart failure events and suggest that this is an area that needs further investigation. However, at the time of this writing, the currently available limited clinical trial data for β-blockade in HFpEF, defined as heart failure with an LVEF of >50%, do not currently support the general application of β blockers in this setting.Do the findings by Kaye et alDr Bristow is an officer and director of ARCA Biopharma, which is developing a pharmacogenetically targeted β-blocker for treatment of atrial fibrillation in heart failure patients. Dr Mann has reported that he has no relationships relevant to the contents of this paper to disclose.


The objective of this review article is to provide the clinician with an overview and a practical clinical approach to MVP for risk stratification and treatment guidance.Mitral valve prolapse (MVP) is the most common valvular disease with a prevalence of 2%. It has generally a benign course; however, recent findings suggested an association between MVP and complex arrhythmias and eventually cardiac arrest and for this reason, it is also called arrhythmogenic MVP. Subjects who experience this complication are in general young women, with thickened mitral leaflets or bileaflet prolapse not necessarily associated with severe mitral regurgitation (MR). The nature of the relation between MVP and cardiac arrest is not clearly understood. Actually, the challenging task is to find the cluster of prognostic factors including T-wave inversion, polymorphic premature ventricular contractions, bileaflet prolapse, MR severity, but most importantly, those parameters of hypercontractility, mitral annulus disjunction (MAD), and myocardial fibrosis using a multimodality approach. Transthoracic echocardiography is the first-line imaging modality for the diagnosis of MVP, but also for detecting MAD and hypercontractility, followed by cardiac magnetic resonance for tissue characterization and detection of myocardial and papillary muscle fibrosis, using either late gadolinium enhancement  (macro-fibrosis), or diffuse fibrosis by T1 mapping (native and post contrast T1). Moreover, there are also preliminary data on positron emission tomography utilizing  Mitral valve prolapse (MVP) is the displacement of one or both mitral leaflets into the left atrium in systole, described for the first time by Barlow in 1963 ,3,4,5. IThe renewed interest in MVP derives from anatomo-pathological findings ,12,13,14MVP is defined as the displacement of one or both mitral valve leaflets or part of a leaflet  of more than 2 mm beyond the mitral annulus into the left atrium in the parasternal long-axis view with or without MR. Classic prolapse is defined as a mitral leaflet thickness of at least 5 mm and non-classic prolapse as a mitral leaflet thickness of less than 5 mm . MVP canMAD is an anatomical entity that has been associated with MVP; it is an abnormal insertion of the hinge line of the posterior mitral leaflet (PML) on the atrial wall, characterized by distinct separation of the mitral valve annulus-left atrial wall and the basal region of the posterolateral LV myocardium, also defined as atrialization of the posterior leaflet base. MAD can involve either a large or small portion of the mitral annulus, usually the mid and central portion. In early reports, this entity was also described in normal hearts, though as a rare finding  or as a Basso et al.  reportedOn the basis of the aforementioned data, the features of the AMVP phenotype at risk for SCD that need extensive investigation are: (i) young female; (ii) symptoms such as shortness of breath, chest pain, fatigue, anxiety. Particular attention should be paid to lightheaded/dizziness, palpitations, syncope that may be the epiphenomenon of premature ventricular contractions (PVCs), VA, sustained and non-sustained VT; (iii) on auscultation, a mid-systolic click is heard, which represents the abrupt fall and traction from the subvalvular apparatus of the mitral leaflets into the left atrium, with or without late systolic murmur that corresponds to MR; (iv) ECG abnormalities with inverted/biphasic T waves in the inferior leads, Holter ECG findings such as ventricular ectopy with RBBB morphology and c-VA; (v) thickened mitral leaflets and bileaflet prolapse, MAD and curling. In two-thirds of cases, MVP is not associated with significant MR; and (vi) presence of myocardial fibrosis on CMR .A multimodality approach is of paramount importance for the risk stratification of MVP patients .The first-line imaging modality for the diagnosis of MVP is transthoracic echocardiography (TTE), which allows assessment of the structural characteristics of the valve, i.e., leaflet thickness, uni- or bileaflet prolapse, prolapse size, presence and severity of MR, left atrial and LV dimension and function . AdditioMoreover, curling is suggested to be related to progressive myxomatous degeneration of the mitral leaflets . ProlapsFurthermore, Ermakov and colleagues  showed tTransesophageal echocardiography (TEE) provides the most accurate localization of the pathology, for example, showing which scallop is more involved, chordae rupture, MR severity, MAD length, and 3D TEE is more accurate than 2D TEE for this purpose ,40,41. TCine magnetic resonance imaging is an adequate tool to study the mitral valvular apparatus as well as thickness and severity of leaflet prolapse and presence of MAD. LGE images, which are usually obtained after 10 min of gadolinium contrast injection, are excellent for the detection of areas of papillary muscle and LV fibrosis. CMR is the gold standard for LV and right ventricular volumetric assessment. CMR can also provide additional and more precise information on mitral valve characteristics, is more sensitive in MAD and curling identification , localizTissue characterization and diffuse fibrosis can be performed using T1 mapping, a technique used in various cardiomyopathies with prognostic significance. Bui at al  showed tCMR can help in stratifying MVP patients at risk for malignant arrhythmias as it allows the detection of either focal or diffuse fibrosis that may be responsible for reentry circuits, providing also evidence of early structural and functional remodeling that may evolve to fibrosis, although these findings need wider clinical investigation.18F-fluorodeoxyglucose [FDG])/magnetic resonance imaging (LGE), focal 18F-FDG (PET positive) uptake was detected in 17 of 20 MVP patients and LGE was present in 14 of them. Patients with c-VA showed a higher LGE burden (50% with severe MR), whereas those with minor VA had higher 18F-FDG uptake (37.5% severe MR) [It seems recognized that repetitive traction by the prolapsing leaflets and mitral annular hypermobility are responsible for local fibrosis. The hypothesis is that repetitive stretch activates fibroblasts that induce local inflammation and then fibrosis. In a pilot study using hybrid positron emission tomography (Cardiac computed tomography (CCT) is another useful modality for the evaluation of mitral valve anatomy and MAD; however, it provides details on mitral valve anatomy, but does not allow tissue characterization or grading of MR severity and therefore it is underused. Very recently, Tho et al. , by evalMultimodality imaging is useful in identifying different MVP phenotypes and can help in therapeutic decision making. TTE and TEE are the preferred imaging techniques for assessing mitral valve morphology and grade of MR severity. For FED patients with severe MR, LV, and left atrial remodeling, eventually LV dysfunction, surgery is the only option. The same approach applies to MVP patients with BD and severe MR ,49.The rationale for surgical intervention in MVP is to relieve papillary muscle stretching and facilitate ventricular remodeling, leading to a reduction in VA burden. There are conflicting data on the role of mitral valve repair or replacement in VA control as only case reports or small single center studies are available. Eriksson et al.  hypothesManagement of AMVP with no severe MR is more challenging and multimodality imaging could also guide AMVP intervention: hypercontractility and fibrosis could be considered as “red flags” that may provide an indication for surgery, but no data are available except for sparse case reports. Implantable cardioverter-defibrillator (ICD) therapy or electrophysiologic (EP) ablation could represent further treatment options. Risk stratification for arrhythmic events is an important component of the assessment of MVP patients and multimodality imaging plus ECG/Holter ECG and stress test are essential in this context. Patients with VA, hypercontractility on TTE , fibrosis on CMR should undergo additional investigation with an implantable loop recorder or electrophysiologic study. As for ICD implantation, no data exist in primary prevention. Catheter ablation can be considered when the trigger of the arrhythmia has been documented or in VT due to scar-related reentry . It has 18F-FDG PET, are merging into the evaluation and risk stratification in this disease. MVP can present with or without MAD, and abnormal myocardial changes can be seen in both cases although MVP-MAD is more frequently associated with c-VA. Finally, multimodality imaging can guide treatment allowing the identification of different MVP phenotypes.MVP is the most common mitral valve disease. Serious complications such as VA and cardiac arrest are reported. In order to understand this pathology and identify those patients at risk for serious complications, an advanced multimodality approach is required. Advanced TTE and TEE play a key role in establishing the diagnosis of MVP and assessing as well as quantifying the severity of MVP and associated regurgitation. Tissue characterization and presence of myocardial inflammation and fibrosis can help in identifying at-risk patients. CMR with and without LGE (native and post contrast T1 mapping), and maybe in the near future,


The EF improvements from the seven patients varied from 2.87 to 6.01%. Surgical procedures using active contraction bands have great potential to improve RV function measured by ejection fraction for patients with repaired ToF. It is possible to have higher right ventricle ejection fraction improvement with more bands and higher band active contraction ratio. Our findings with computational models need to be further validated by animal experiments before clinical trial could become possible.Patients with repaired Tetralogy of Fallot (ToF), a congenital heart defect which includes a ventricular septal defect and severe right ventricular outflow obstruction, account for the majority of cases with late-onset right ventricle (RV) failure. Current surgery procedures, including pulmonary valve replacement (PVR) with right ventricle remodeling, yield mixed results. PVR with active band insertion was hypothesized to be of clinical usage on improving RV function measured by ejection fraction (EF). In lieu of risky open-heart surgeries and experiments on animal and human, computational biomechanical models were adapted to study the impact of PVR with five band insertion options. Cardiac magnetic resonance (CMR) images were acquired from seven TOF patients before PVR surgery for model construction. For each patient, five different surgery plans combined with passive and active contraction band with contraction ratio of 20, 15, and 10% were studied. Those five plans include three single-band plans with different band locations; one plan with two bands, and one plan with three bands. Including the seven no-band models, 147 computational bi-ventricle models were constructed to simulate RV cardiac functions and identify optimal band plans. Patient variations with different band plans were investigated. Surgery plan with three active contraction bands and band active contraction ratio of 20% had the best performance on improving RV function. The mean ± SD RV ejection fraction value from the seven patients was 42.90 ± 5.68%, presenting a 4.19% absolute improvement or a 10.82% relative improvement, when compared with the baseline models (38.71 ± 5.73%,  The symptoms include ventricular septal defect, pulmonary valve stenosis, aorta overriding, and right ventricular hypertrophy. Corrective surgery allows TOF patients to extend their life expectancy, and some patients manage to survive into adulthood . Many re = 0.38) . In sear = 0.38) . The ini = 0.38) .Recent development in computational modeling made it possible for patient-specific ventricle models to be used for heart disease study and surgical optimizations. Efforts were also made in moving ventricular computational models closer to clinical and surgical applications , 2020. UWe hypothesized that PVR with active contracting bands would improve RV cardiac function measured by ejection fraction (EF). RV EF was selected since it is easy to calculate and it is the single most commonly used measure for RV cardiac function in clinical practice. It is sufficient for the RV function assessment of our preliminary study. The normal RV EF range is 47–68% for a healthy male and 50–72% for a healthy female, respectively . In lieuvia cardiac catheterization procedures.Boston Children’s Hospital Committee on Clinical Investigation approved this study. The approval number is IRB-CRM09-04-0237. Written informed consent was obtained from participants. CMR data was acquired from seven TOF patients 6 months before and after PVR . Demographic and ejection fraction (EF) data of the seven TOF patients are given in Five band insertion plans with band location and number variations are proposed to find optimal surgical plan using active contracting bands. An illustration of the five band plans is given by The innovative PVR surgical plan using active contracting band was motivated by the fact that poor RV cardiac function indicated by low EF values were caused partially by RV’s weak contraction ability due to RV dilation. The contracting bands were used with the expectation that they would help RV to contract and improve its cardiac function. Passive elastic bands would not help since while they seem to be able to help RV to contract, they would hold the ventricle during its expansion (diastole) and defeat the purpose. Active contracting bands could help the ventricle to contract through active contraction and also allow the ventricle to re-expand through active relaxation. It is commonly known that myocardium active contraction is achieved by sarcomere shortening. However, active relaxation is equally important for the band models to work. The RV/LV/patch/band model includes governing equations, boundary conditions, and material models for ventricle tissue, scar tissue, patch, and bands. The governing equations are the same for all structure components :RV/LV combined geometry for each patient was obtained from CMR data and reconstructed following established procedures . Patch apRV and pLV were blood pressure conditions specified on RV and LV inner surfaces. Pressure on the RV/LV out-surface was set to be zero. Patch, scar, and band materials were assumed to be hyper-elastic, isotropic, nearly incompressible, and homogeneous. The isotropic Mooney–Rivlin strain energy function is given by  (where  Eq. (4) :I4 = Cij(nf)i(nf)j, nf is the fiber direction, and K1 and K2 are material constants. With parameters chosen properly, the modified Mooney–Rivlin model described in Eq. (6) could fit the directly measured myocardium stress-strain data from our biaxial test experiment  with a short-axis shrinking rate and reducing distance between each slice (long-axis direction) with a long-axis shrinking rate (3%). The shrink ratio for inner contours was 2–3% based on the RV end-systole volume (minimum volume in a cardiac cycle) and the corresponding RV pressure. The outer contours shrink ratio was determined to meet the conservation of mass of the total ventricular wall. c1, d1, and K1 in Eqs. (4)–(7) were adjusted iteratively until the relative error between the pressurized computational RV volume and CMR-measured in vivo volume data was less than 0.2%. This process was done semiautomatically using a secant method for fast convergence to in vivo RV volume. p = 0.313) and 359.53 ± 158.61 ml at begin ejection (p = 0.438). Details were described in Patient ventricle CMR images were obtained under L2 norm were less than 0.1%. The L2 norm of a given function F was computed with:The 147 models were constructed and solved with ADINA using unstructured finite elements and the Newton–Raphson iteration method . SimulatT is the period (one cardiac cycle), F will be | S(t)−S(t+T)| as the function difference over one period where S(t) stands for either stress-P1  or strain-P1 , the integration is taken over the entire RV domain and one cardiac cycle with discretization performed utilizing all available nodes and time steps. The results from the last period were recorded for analysis. For all 147 simulations, only three cycles were needed to obtain the solution. For each model, stress and strain data from 100 evenly spaced points for each slice of RV inner surface were extracted. Maximum principal stress and strain values were chosen to represent the stress and strain state of these points, and their mean values at begin filling (BF) and begin ejection (BE) were recorded as the stress and strain value of this model. RV Ejection fraction was used as the index (marker) for evaluating ventricle cardiac function. RV ejection fraction (EF) is defined as:where where RV EDV is right ventricle end-diastole volume and RV ESV is right ventricle end-systole volume. Higher EF value indicates that the ventricle is more efficient in pumping blood. Difference between pre- and post-PVR EF denoted by △EF was used to measure PVR (with and without active contracting bands) improvement:p = signrank from MATLAB statistical tool box.Preoperation (no-band) RV/LV models were regarded as the baseline model. The paired test Wilcoxon signed rank test was used to compare the differences of EF, stress, and strain values between band and baseline models and the differences between different surgery plans. The test was performed using the function: p = 0.016). Absolute EF improvements for each patient varied from 2.87 to 6%. Mean ± SD ΔEF values of the seven patients for band options A–D were 2.51 ± 0.80%, 2.13 ± 0.53%, 3.36 ± 1.07%, 1.90 ± 0.40%, respectively. The two-band plan (option C) had the second best performance. Similar results were also found when the band active contraction ratio was 15 or 10%, respectively.Simulation results from the seven patients using five band options with band contraction ratio of 20% are given in Intuitively, it might be reasonable to expect that a passive elastic band may be able to improve ejection fraction since elastic bands would help the ventricle to contract. Our simulations indicated that that was not the case. Mean ΔEF of models with surgery option E and passive bands was −3.27%, and ΔEF values ranged from −5.67 to −1.93%. For surgery option A–D, mean ± SD ΔEF were −1.37 ± 0.50, −1.04 ± 0.44, −2.32 ± 0.85, and −1.23 ± 0.79%, respectively. RV EF decreased after passive bands were inserted. The reason is actually simple: passive elastic bands would not “relax” by themselves after they contracted. The bands would actually hold the ventricle and became resistance for ventricle expansion. Mean ± SD volume values of surgery options A–D with passive bands at begin ejection were 349.76 ± 158.75, 352.08 ± 157.36, 344.56 ± 157.62, 350.83 ± 157.53, and 339.24 ± 157.82 ml, respectively, whereas the baseline model was 359.19 ± 158.41 ml. On the other hand, active bands help ventricle to contract by active contraction and would not resist ventricle expansion since active bands would “relax” through active relaxation .It should be noted that mean stress/strain values (average of seven patients) had very small variations for all five band options. At begin ejection, stress and strain values from models with active band were close to the baseline. RV mean ± SD stress values of the five plans with 20% band contraction ratio were 63.19 ± 14.85, 63.70 ± 14.23, 64.32 ± 14.64, 63.53 ± 14.08, and 66.31 ± 13.48 kPa, respectively. Meanwhile, baseline stress value was 62.89 ± 14.81 kPa. RV mean ± SD strain values of options A–E with 20% band contraction ratio were 0.297 ± 0.067, 0.296 ± 0.067, 0.298 ± 0.066, 0.298 ± 0.066, and 0.304 ± 0.067, which were also close to mean ± SD stress value of baseline models: 0.292 ± 0.062.How to manage the residual symptoms for repaired ToF cases such as pulmonary regurgitation has gradually become a great challenge for clinicians. Even though PVR could be an effective treatment for pulmonary regurgitation, other symptoms such as RV dysfunction may sometimes be irreversible after the PVR surgery . del Nidp = 0.016). At end filling/begin ejection, no significant difference was found between E020 and baseline RV volume values  since the active bands were able to relax and did not resist the ventricle to expand in diastole phase (filling phase). Compared with our previous work on band insert surgery simulation, 147 models were constructed for seven patients with repaired TOF in this paper, vs. only one patient was used in previous paper  using stem cells to cultivate muscle or (b) artificial mechanical muscle . Baar etRV EF was used as the measure of RV function in this paper because it is commonly used in practice and by many investigators, and it serves our demonstration purpose well. The concept is simple and calculation is easy. Outcome comparisons of different band options using a single indicator (EF) are straightforward and easy to understand. However, since it is only one number, it is lacking detailed local information for more careful evaluation of RV functions. 3D stress/strain distributions could compensate RV EV when detailed analysis is desired. RV kinetic energy due to its deformation in systole can be calculated as needed for a more detailed analysis. Since we currently have structure-only models, we would not be able to calculate the energy from the flow side and perform the analysis for that part. We are currently working on the corresponding fluid-structure interaction models. Full analysis from both structure and flow side will be reported when results become available. Those details will be helpful in band design and development of related tissue regeneration techniques .It is true that EF is a crude measure of ventricular function (LV and RV), does not reliably reflect the functional status of the myocardium, and is sensitive to preload and afterload . Despite these well-known limitations, EF has remained n inexplicably strong predictor of clinical outcomes in numerous diseases that affect the RV  and the LV . These observation have been confirmed by numerous large studies. However, why EF is such a strong predictor of clinical outcomes is not fully understood. So, if the goal is to detect subtle abnormalities of heart muscle function, there are more sensitive tools. If the goal is to use it as a predictor of clinical outcomes (which is what ultimately matters), EF is an excellent marker.Validation is always ideal for computational modeling effort. It should be noted that the parameter determination process is a self-validation process in some sense. Our pre-PVR models were self-validated since patient-specific tissue material parameter values were carefully adjusted to match MRI-measured ventricle volume data. Since the ventricles remained to be the same post-PVR, using the same parameter values was natural for our post-PVR band models. Without actual clinical post-PVR data, using pre-PVR material properties gave us the best-effort approximations for our band models. Accuracies of simulation results including calculation of ventricle volumes and ejection fractions should be interpreted with that understanding.Since materials with active-contraction properties are not currently available, direct validations using either patients or animal models are not possible at present time. Researchers have been working on myocardium regeneration for many years and encouraging progresses have been made. Clinical application of the active contraction band is what we would like to achieve in the future.Possible potential clinical implementation of PVR with active contracting bands primarily depends on the availability of the availability of the active contracting bands. This modeling study is the proof of the concept that PVR with active contraction band insertion may improve post-PVR RV cardiac function measured by ejection fraction for repaired ToF patients. The mean ± SD RV △EF value from the seven patients with plan E was 4.19 ± 1.11% , which is a significant improvement over the actual PVR surgery data ΔEF = −4.97 ± 7.44%. Meanwhile, among all seven studied TOF patients, only two of them had improved EF values after PVR (P1 and P6). A 9.16% average increase in RVEF compares favorably with published drug trials to treat heart failure where an improvement in LVEF of 3–4% resulted in a significant improvement in functional capacity .This paper used structure-only models to save model construction manpower and computing time (147 3D models). Fluid-structure interaction did not include algorithm that allows a more realistic simulation. Clearly, FSI models will provide a more complete structural and flow information. However, for our purpose, EF was used to measure surgical outcome for the surgical strategies under investigation. The model parameters in both structure-only and FSI will be adjusted to match MRI-measured ventricle volume data. Therefore, structure-only or FSI models will give the same EF. Another reason that structure-only model could be used as a good approximation to calculate EF is that ventricle volume is mainly determined by the flow pressure acting on the ventricle inner surface. The flow stress activating on ventricle inner surface could be decomposed into pressure  and flow shear stress (shear component). The magnitude of flow shear stress is nearly negligible compared with pressure. That was the reason we used structure-only models to save time. FSI models will take far more time to construct and will be needed when we investigate flow behaviors, valve functions, ventricle remodeling, etc.Lack of validation is definitely a limitation. This was discussed in section “Use of Ejection Fraction as a Measure of Surgical Outcome.”Several other limitations exist in our modeling study: (a) patient-specific TOF RV/LV myofibril orientations should be included if available in the future; (b) localized tissue material properties were not available; and (c) flow behaviors and valve dynamics were not included in this study. We are working hard to obtain better ventricle data and improve our models.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Boston Children’s Hospital Committee on Clinical Investigation. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.TG, RR, and PN collected the CMR and blood pressure data. KB did the biaxial test. HY, CY, XH, ZW, and DT did model construction. HY did statistical analysis. HY and DT wrote and revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AR-A declared a past collaboration with the authors TG and RR to the handling editor.