Cardiac sarcoidosis (CS) is a rare multisystem disorder characterized by granulomatous infiltration of the myocardium, which can lead to significant morbidity and mortality. Its clinical manifestations range from asymptomatic conduction abnormalities to severe heart failure (HF) and sudden cardiac death. This comprehensive review aims to provide an overview of the diagnosis, clinical features, and current medical management strategies for CS. Additionally, the role of implantable cardioverter-defibrillators (ICDs) and the potential use of positron emission tomography in guiding management decisions are explored. A comprehensive understanding of the medical management of CS is essential for improving patient outcomes and guiding future research endeavors. Cardiac sarcoidosis (CS) is a rare but potentially life-threatening condition characterized by the infiltration of noncaseating granulomas in the myocardium. The disease can lead to various clinical manifestations, including arrhythmias, heart failure (HF), and conduction abnormalities. Early and accurate diagnosis is crucial for appropriate management and improved outcomes. The diagnosis of CS can be challenging due to its heterogeneous presentation. Various diagnostic approaches, including imaging modalities such as cardiac magnetic resonance (CMR) imaging, PET, and gallium-67 scintigraphy, are utilized to identify cardiac involvement . CS may EpidemiologyThere are notable differences in the incidence and prevalence of sarcoidosis among different ethnicities. Based on comprehensive nationwide register data from Sweden, the incidence of sarcoidosis was found to be 11.5 per 100,000 individuals , slightlPathogenesisCS involves a complex interplay of factors contributing to its pathogenesis, including genetic susceptibility, immune dysregulation, possibly microbial agents, and environmental exposures. In sarcoidosis, the formation of granulomas is hypothesized to occur as a result of an exaggerated immune response to an unknown antigen in individuals with a genetic predisposition. Certain human leukocyte antigen (HLA) alleles, such as HLA-DR17, DRB1*03, HLA-DR15, and HLA-DR14, have been associated with distinct disease courses . The patThe hallmark histopathological finding of sarcoidosis is characterized by the presence of well-formed, discrete noncaseating granulomas. These granulomas consist of epithelioid histiocytes and multi-nucleated giant cells, surrounded by sparse lymphocytes, plasma cells, and fibroblasts at the periphery. The granuloma of sarcoidosis is sometimes also known as naked granuloma due to sparse lymphocytes. These extensive granulomas can lead to the destruction of normal tissue architecture. In CS, the granulomas most frequently involve the myocardium and are usually located in the basal inter-ventricular septum, left ventricular (LV) free wall, right ventricle, and atria . CS-relaClinical manifestationsClinical features of CS vary from palpitations, syncope, orthopnea, dyspnea, and peripheral edema to sudden cardiac death, depending upon the location of the granuloma. Involvement of the conduction pathways  can lead to heart block and arrhythmias. The most common clinical manifestation is an AV block, which can progress to a complete AV block and clinically present as syncope or sudden cardiac death . InflammHF is another frequent manifestation of CS. HF symptoms encompass fluid retention-related manifestations, including edema, cough, and dyspnea, arising from excessive fluid accumulation, as well as symptoms associated with reduced cardiac output, such as fatigue and exercise intolerance due to inadequate blood supply to meet the body's demands. Cardiomyopathy in CS can manifest as LV systolic dysfunction, HF with preserved biventricular systolic function, or predominant right ventricular (RV) systolic dysfunction . GranuloDiagnosis The diagnosis of CS remains a challenge due to the absence of standard diagnosis criteria and the fact that it relies on a high index of suspicion. The combination of clinical assessment, laboratory investigations, EKG, echocardiography, CMR imaging, radionuclide scanning, PET imaging, and endomyocardial biopsy (EMB) plays a crucial role in establishing a definitive diagnosis and guiding management decisions.Laboratory investigations serve as an initial step in the diagnostic workup. Although there are no specific biomarkers for CS, certain findings can raise suspicion. Elevations in angiotensin-converting enzyme, serum calcium, C-reactive protein, and erythrocyte sedimentation rate may be observed. Additionally, cardiac enzyme levels, including troponins and brain natriuretic peptide (BNP), may be increased, indicating myocardial injury and the presence of HF. EKG is a non-invasive and readily available tool for detecting cardiac abnormalities in CS. Common EKG findings include conduction disturbances, such as AV blocks, bundle branch blocks, and ventricular arrhythmias . These fEchocardiography provides valuable information regarding cardiac structure and function. In CS, it helps to identify ventricular wall motion abnormalities, regional wall thickening, and valvular dysfunction. Reduced LV ejection fraction (LVEF) and increased wall thickness may also be observed. CMR imaging has emerged as a powerful tool in the evaluation of CS. It allows for the visualization of myocardial inflammation, granulomas, fibrosis, and regional wall motion abnormalities in a patchy distribution. Delayed gadolinium enhancement/late gadolinium enhancement (LGE) reveals multifocal myocardial lesions usually in the basal inter-ventricular septum, which is suggestive of CS. CMR imaging has high sensitivity and specificity in detecting CS-related abnormalities .Radionuclide scanning using technetium-99m (Tc-99m) agents or gallium-67 (Ga-67) citrate can help to identify active inflammation in the myocardium. Increased radiotracer uptake within the heart on scintigraphy images indicates myocardial involvement. However, this method lacks specificity and cannot differentiate CS from other inflammatory or infectious processes. PET imaging with 18F-fluorodeoxyglucose (FDG) is an emerging modality for diagnosing CS. FDG-PET allows for the assessment of myocardial glucose metabolism. Increased FDG uptake in the myocardium indicates active inflammation. The combination of PET and CT imaging (PET/CT) improves accuracy by providing anatomical correlation. However, false-negative results may occur in patients with low-grade or fibrotic inflammation. The specificity of PET-CT for the diagnosis of CS is 78% with a sensitivity of 89% .Hybrid PET and CMR imaging, made possible by the development of new hybrid PET-CMR systems, allows for the integration of the strengths of PET and CMR in a single acquisition. Despite the higher costs associated with these scanners, the benefits are significant, including increased accuracy and reduced risk of complications. MRI demonstrates excellent sensitivity in detecting fibrosis, while PET enables visualization and quantification of inflammatory activity and extracardiac involvement. Limited studies indicate that combining both modalities leads to improved detection rates, enhanced accuracy, and potential impact on therapeutic decision-making, providing an additional evaluation of scar and inflammation findings for comprehensive disease management, staging, and prognosis .EMB involves obtaining myocardial tissue samples for histopathological analysis. The presence of noncaseating granulomas within the myocardium confirms the diagnosis of CS; thus, the test has high specificity. However, due to the patchy nature of granuloma distribution, EMB may yield false-negative results, leading to low sensitivity of 20-30% . AdditioThere are no established gold-standard criteria for the diagnosis of CS, but recommendations from the Heart Rhythm Society (HRS) Figure  and the Differential diagnosisDistinguishing CS from other conditions can be challenging due to overlapping clinical presentations. Myocarditis, characterized by ventricular arrhythmias, HF symptoms, LGE on CMR, and abnormal uptake on FDG-PET, shares similarities with CS . An EMB ManagementThe European Respiratory Society clinical practice guidelines on the treatment of sarcoidosis published in 2021 found the following features to be associated with increased risk for morbidity or mortality from CS : age >50The management of CS requires a comprehensive and multidisciplinary approach involving cardiologists, pulmonologists, electrophysiologists, and rheumatologists to optimize patient care. This multifaceted management strategy aims to control inflammation, prevent arrhythmias, preserve ventricular function, and improve overall outcomes. In this section, we will delve deeper into the specific aspects of CS management, including immunosuppressive therapy, ICDs, and HF management.Immunosuppressive therapy forms the cornerstone of CS management, aiming to suppress inflammation and halt disease progression. Glucocorticoids, particularly prednisone, play a central role in this treatment strategy. Steroids exert their action in the management of CS by suppressing granuloma formation. This is achieved through the inhibition of the production of interplaying cytokines and the restoration of functional CD4+ T cells while also balancing the subtypes of effector CD4+ T cells involved in the immune response . InitialIn cases where glucocorticoid monotherapy is inadequate, additional immunosuppressive agents are considered steroid-sparing agents. Methotrexate, an antimetabolite, is commonly used in combination with glucocorticoids. Administered orally at a starting dose of 5-10 mg once a week with gradual titration up to 20 mg once a week, methotrexate helps to reduce the dependence on glucocorticoids . MethotrPatients who do not respond to tiered therapy with corticosteroids and steroid-sparing agents, such as methotrexate, for the management of CS may require third-line treatment options. Biologic agents, specifically tumor necrosis factor-alpha (TNF-α) inhibitors, are considered in such cases. TNF-α is a pivotal cytokine involved in the formation and maintenance of granulomas, making TNF-α inhibitors, such as infliximab  and adalimumab , potential treatment options for CS . These bICDs play a crucial role in managing CS-related arrhythmias and preventing sudden cardiac death. The indications for ICD implantation in CS patients include sustained VT, hemodynamically unstable VT, or a history of cardiac arrest . ICDs arOptimal HF management is also crucial in CS, as cardiac involvement can lead to impaired ventricular function and HF symptoms. ACE inhibitors or ARBs are commonly prescribed to reduce afterload and improve ventricular function. Beta-blockers, such as carvedilol or metoprolol, are used to control heart rate, reduce myocardial oxygen demand, and improve ventricular remodeling. Diuretics are utilized to manage fluid retention and alleviate symptoms of congestion. In patients with reduced ejection fraction, guideline-directed medical therapy for HF, including the use of mineralocorticoid receptor antagonists and sacubitril/valsartan, may be considered . In advaRegular monitoring and follow-up are essential to assess treatment response, adjust therapeutic strategies, and detect potential complications. Imaging modalities such as CMR imaging and echocardiography can provide valuable information on disease activity, ventricular function, and response to therapy. Additionally, serial measurements of serum biomarkers, including BNP and troponin levels, can aid in monitoring disease progression and guiding treatment decisions.Ongoing research into the pathogenesis of CS and the development of targeted therapies offer promise for improved outcomes in the future. The collaborative efforts of a multidisciplinary team are paramount to providing optimal care for patients with CS, ensuring individualized treatment plans and comprehensive disease management. By combining immunosuppressive therapy, ICD implantation when indicated, and effective HF management, healthcare providers can strive to enhance the prognosis and quality of life for patients with CS.In conclusion, CS presents a complex clinical challenge, requiring a multidisciplinary approach for accurate diagnosis and optimal management. Diagnostic advancements, including CMR imaging, echocardiography, radionuclide scanning, and PET scanning, have improved disease detection and assessment. Corticosteroids remain the mainstay of treatment, targeting immune dysregulation and granuloma formation. For refractory cases, methotrexate or TNF-α inhibitors may be considered. Conduction abnormalities and arrhythmias necessitate careful monitoring and intervention, with ICD placement indicated in high-risk patients. Long-term follow-up and collaboration among healthcare professionals are crucial. Despite progress, unanswered questions and ongoing research efforts remain, offering hope for improved understanding and treatment. An individualized approach combining early diagnosis, appropriate therapy, and timely intervention is key to effectively managing CS and improving outcomes. Continued research and collaboration are essential for advancing care and addressing the complexities of CS.


Conclusion: Scar burden and MD assessed using cardiac scintigraphy are associated with response to CRT.Background: Cardiac resynchronization therapy (CRT) improves the outcome in patients with heart failure (HF). However, approximately 30% of patients are nonresponsive to CRT. The aim of this study was to determine the role of the left ventricular (LV) mechanical dyssynchrony (MD) and scar burden as predictors of CRT response. Methods: In this study, we included 56 patients with HF and the left bundle-branch block with QRS duration ≥ 150 ms who underwent CRT-D implantation. In addition to a full examination, myocardial perfusion imaging and gated blood-pool single-photon emission computed tomography were performed. Patients were grouped based on the response to CRT assessed via echocardiography (decrease in LV end-systolic volume ≥15% or/and improvement in the LV ejection fraction ≥5%). Results: In total, 45 patients (80.3%) were responders and 11 (19.7%) were nonresponders to CRT. In multivariate logistic regression, LV anterior-wall standard deviation (adjusted odds ratio (OR) 1.5275; 95% confidence interval (CI) 1.1472–2.0340;  Heart failure (HF) is a rapidly growing public health issue, with an estimated prevalence of more than 37.7 million individuals globally . In the Some studies have shown that the ventricular MD assessment using transthoracic echocardiography (TTE), magnetic resonance imaging (MRI), computed tomography (CT), and single-photon emission computed tomography (SPECT) can play a key role in the prediction of CRT response ,17,18,19The aim of this study was to identify the significance of MD and scar burden assessment using MPI and gBPS as a combined predictor of CRT response in patients with HF of ischemic and nonischemic etiologies. Patients with indications for CRT according to the ESC guidelines were included in this clinical, nonrandomized, open, prospective study . The incAll patients underwent full physical examination , electrocardiography (ECG), transthoracic echocardiography (TTE), Holter ECG monitoring, coronary angiography, and blood analyses), MPI with 99mTc–methoxy isobutyl isonitrile (99mTc–MIBI) and gBPS before device implantation. In all cases, CRT devices with the defibrillation function (CRT-D) were implanted, according to the ESC guidelines . All patThe study was carried out in accordance with the principles of the Helsinki Declaration and with the standards of good clinical practice. The study protocol was approved by the local ethics committee. All the participants received written informed consent prior to the study inclusion. Ethical approval by the hospital review committee and patient consent according to the institutional guidelines were obtained. -More than 551 m—the patient has no signs of HF;-A distance of 426–550 m—I FC of HF;-A distance of 301–425 m—II FC of HF;-A distance of 151–300 m—III FC of HF;-Less than 150 m—IV FC of HF.The assessment of HF FC was performed in accordance with the NYHA criteria, using 6MWDT before and 6 months after CRT-D implantation. For the analysis, the walking distance in meters and NYHA FC were used, and the following ranking was used:TTE with the intracardiac hemodynamic parameter assessment was performed using Philips HD15 PureWave (the Netherlands) ultrasound machine before and after 6 months of CRT-D implantation. The examination was carried out from standard positions with the determination of the left atrium (LA) and right ventricle (RV) sizes, interventricular septum (IVS) and LV posterior-wall (LVPW) thickness, LV end-systolic dimension (LVESD), LV end-diastolic dimension (LVEDD), LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV), the index of myocardial mass (IMM), LVEF, right ventricular systolic pressure (RVSP), stroke volume (SV), LV end-systolic index (LVESI), LV end-diastolic index (LVEDI), the left atrial index (LAI), and the right atrial index (RAI). The mitral, tricuspid, and aortic valve functions, as well as the right and left ventricular contractility, were assessed. The scintigraphy examination was performed using CZT SPECT/CT  with low-energy multi-pinhole collimators and 19 stationary detectors . Each deThe time interval between MPI and gBPS examinations ranged from 1 to 2 days. MPI was performed first in all patients. MPI was performed according to the standard ECG-gated (16 frames/cardiac cycle) rest protocol  approximgBPS was performed following in vivo labeling patient’s red blood cells with a 99mTc–pertechnetate dose of 555–720 MBq . The datThe severity of intra- and interventricular dyssynchrony was evaluated using the Fourier transform method. Global MD indices were evaluated for ventricles’ phase standard deviation (SD), histogram bandwidth (HBW), and phase entropy (PE). Interventricular dyssynchrony (IVD) was calculated according to the histogram peak of LV and RV. Moreover, the following regional MD indices were assessed: SD and E. The regional analysis of LV MD was based on the assessment of the free wall (FW), anterior wall (AW), lateral wall (LW), inferior wall (IW), and septal wall (SW) of LV. The mean effective radiation dose for the entire study protocol was 7.48 ±1 mSv (range 5.1–10.3 mSv) per patient.The active-fixation atrial (AL) and defibrillation leads (DLs), as well as the passive-fixation LV lead, were positioned under fluoroscopic guidance using a transvenous approach. DL was implanted into the right ventricular apex or interventricular septum. Lead positions were confirmed via fluoroscopy in the posteroanterior (PA) and left anterior oblique (LAO) view and the intraoperative threshold testing. The capture threshold, sensing amplitude, and impedance measurements of the leads were performed using the pacing system analyzer  with sterile crocodile clip cables. The implantation of the LV pacing lead was performed by cannulating one of the tributaries of the coronary sinus using the delivery system. The venogram was performed in AP and LAO projections. Access to the target branch within the coronary sinus and subsequent advancement of the LV lead was performed using an “over-the-wire” technique. In case of troubles with the target vein branch cannulation, we used the “interventional” technique with inner catheters (subselector). The intraoperative threshold testing was performed for checking the optimal pacing threshold and phrenic nerve stimulation after LV lead was positioned to the target vein.CRT-D programming was carried out in accordance with international standards . In everThe follow-up information was acquired for 56 of the 64 patients who were included in the prospective analysis. The information about arrhythmic events was determined from CRT-D interrogation reports. The arrhythmic events  and CRT-D lead system parameters were evaluated at follow-up. The flowchart of the study is shown in p values <0.05.Statistical analysis was performed using the software package Statistica 10.0, StatSoft (USA). The Shapiro–Wilk test was used to assess the normality of the distribution of the trait. For variables with the normal distribution, the mean value (M) and standard deviation (SD) were calculated, while for others, the median (Me) with an interquartile range  were calculated. The nonparametric Mann–Whitney test for independent samples and the Wilcoxon test for dependent samples were used. The nonparametric Spearman analysis was used to assess the correlations between the pairs of quantitative features. Efficacy analysis was performed using logistic regression analysis. The forward-stepwise logistic regression analysis was used to evaluate the independent predictors of CRT response. Receiver operating characteristic (ROC) analysis was used to determine the diagnostic efficiency of the method using MedCalc statistical software package. We considered significant A total of 56 (100.0%) patients who underwent MPI, gBPS, CRT-D implantation, and 6-month follow-up were included in this study. The first group consisted of 45 (80.3%) individuals with a response to CRT (RESP), and the second group comprised 11 (19.7%) patients without response (non-RESP). The baseline demographics and clinical characteristics of the included patients are shown in p = 0.005), the left ventricular anterior-wall entropy (LV AW_E) (p = 0.001), the left ventricular anterior-wall standard deviation (LV AW_SD) (p = 0.0001), the right ventricular free-wall standard deviation (RV FW_SD) (p = 0.011), the left ventricular entropy (LV_E) (p = 0.033), and IVD (p = 0.022) were significantly higher, and SRS (p = 0.018) and RV PFR2 (p = 0.028) were significantly lower than in non-RESP subjects. A detailed comparison of pre-CRT-D implantation scintigraphic parameters is presented in Both groups were comparable in terms of pre-CRT-D implantation scintigraphic parameters, except SRS, RV PFR, and MD indicators, assessed via MPI and gBPS. In RESP patients, the right ventricular peak filling rate (RV PFR) (p = 0.015), LVEDD (p = 0.04), LVESV (p = 0.005), LVESI (p = 0.019), and LVSI (p = 0.02) were significantly lower, and LVEF (p < 0.001) was significantly higher than in non-RESP patients. The QRS duration 6 months after CRT-D implantation did not differ significantly between the groups. In RESP patients, QRS duration was 140.0 ms , and non-RESP was 140.0 ms  (p = 0.243).Both groups were comparable in terms of TTE parameters before CRT-D implantation. In RESP patients 6 months after CRT-D implantation, LVESD (p = 0.215) and II (p = 0.332) HF class NYHA patients after 6 months of CRT-D implantation. The quantity of III HF class NYHA patients in the non-RESP (n = 7 (63.6%)) group was significantly higher than in the RESP (n = 9 (20.0%)) group (p = 0.026). Additionally, 6MWDT in the RESP (382.4 ± 88.1 m) group was significantly higher than in the non-RESP (288.1 ± 73.1 m) group (p = 0.003) after 6 months of CRT-D implantation. Both groups were comparable in terms of the number of I (p = 0.353). There were only three unsustained VT with spontaneous termination (p = 0.297). There were no lead dysfunction, dislocation, and inappropriate ICD therapy in either group. In RESP patients 6 months after device implantation, according to the CRT-D interrogation data, the paced atrioventricular delay was 148.7 ± 14.5 ms, the sensed atrioventricular delay was 110.0 ± 16.1 ms, the interventricular delay (first LV) was 25.0 ms , and the time of biventricular pacing was 98.1 ± 1.9%. In non-RESP individuals 6 months after CRT-D implantation, the paced atrioventricular delay was 153.6 ± 18.0 ms (p = 0.464), the sensed atrioventricular delay was 116.8 ± 18.2 ms (p = 0.215), the interventricular delay (first LV) was 20.0 ms  (p = 0.885), and the time of biventricular pacing was 98.7 ± 0.4% (p = 0.433).During 6 months of follow-up, VT events were registered in seven (12.5%) patients from both groups. In the first group (RESP patients), VT was registered in four (7.1%) patients: three unsustained VT with spontaneous termination and one sustained VT, terminated using ATP therapy. In the second group (non-RESP patients), VT was registered in three (5.4%) cases  were statistically significant predictors of CRT response . p = 0.0037) and SRS  and also HF with a nonischemic etiology  were the independent predictors of CRT response.The multivariate logistic regression analysis included the following indicators: QRS duration, gender, HF etiology, LV lead position, 6 min walk distance test, LVESV, LVEF, SRS, and MD. This analysis showed that only myocardial perfusion defects and MD indicators assessed via MPI and gBPS such as LV AW_SD , HF nonischemic etiology (p < 0.001), the mechanical dyssynchrony indicators assessed via MPS and gBPS (IVD (p = 0.01), LVE (p < 0.001), RV PFR 2 (p = 0.003), RV PFR (p = 0.005), LV AW_E (p = 0.037), and RV FW_SD (p = 0.014)) ROC curves showed significant differences, with the exception of LV AW_SD (p = 0.089)  . In the present study, it was shown that mechanical dyssynchrony  and the scar burden assessed via cardiac scintigraphy in patients with HF of different etiologies may have prognostic value. Thus, HF with a nonischemic etiology, a low value of SRS, and a high value of LV AW_SD are favorable predictive indicators of CRT response. This may be due to the smaller size of the scar and the involvement of the anterior LV wall in mechanical dyssynchrony.p = 0.124). However, multivariate logistic regression showed that the nonischemic etiology of HF is an independent predictor of CRT response . Furthermore, the subanalyses of multiple prospective randomized studies, including the Multicenter InSync Randomized Clinical Evaluation (MIRACLE), Cardiac Resynchronization—Heart Failure (CARE-HF), and Multicenter Automatic Defibrillator Implantation with Cardiac Resynchronization Therapy (MADIT-CRT), have confirmed the finding of greater reverse remodeling in HF with a nonischemic etiology [The nonischemic origin of HF was previously reported to predict reverse remodeling in patients with more advanced HF symptoms. According to Ypenburg et al., CRT responders and patients with super responses more frequently had a nonischemic etiology of HF . In a stetiology ,38.p = 0.0178).The clinical significance of the scar burden assessed with MPI was demonstrated in several studies. Thus, in a study by Adelstein E. et al., it was found that among ischemic cardiomyopathy patients, lesser scar burden evaluated via SPECT MPI SRS ˂ 27) was associated with more favorable survival and reverse remodeling following CRT, with outcomes similar to nonischemic cardiomyopathy patients  was asso. Recent p = 0.041), the diastolic-phase standard deviation , and the diastolic histogram bandwidth  were significant independent predictors of CRT response only for nonischemic HF patients [p = 0.033) [p = 0.0037) was the independent predictor of CRT response. This may indicate that the assessment of regional myocardial dyssynchrony may provide additional information for successful resynchronization therapy. However, disagreements with previous studies underline the importance of these findings and the need for future large-scale studies.The predictive value of LV mechanical dyssynchrony for CRT patient selection measured via MPI and gBPS was widely studied. In a study with 142 CRT patients, LV mechanical dyssynchrony parameters such as the systolic histogram bandwidth  [2 and left atrial volume ˂40 mL/m2). The multivariate analysis showed a 13% (p ˂ 0.001) increase in the clinical benefit of CRT-D per one-point increment in the response score  and a significant direct correlation between the risk reduction associated with CRT-D and the response score quartiles: Patients in the first quartile did not reveal a significant reduction in the risk of HF or death with CRT-D ; patients in the second and third quartiles had 33% (p = 0.04) and 36% (p = 0.03) risk reductions, respectively; and patients in the upper quartile experienced a 69% (p ˂ 0.001) risk reduction (p = 0.005). In our study, the multivariate logistic regression with inclusion factors such as QRS duration, gender, HF etiology, LV lead position, 6 min walk distance test, LVESV, LVEF, SRS, and mechanical dyssynchrony indicators assessed via gBPS showed that LV AW_SD, SRS, and HF with a nonischemic etiology were the independent predictors of CRT response .There are few publications about the combined assessment of the factors associated with reverse remodeling, which can be used for the improved selection of patients for CRT. The significance of the CRT response score was shown in a major randomized trial MADIT-CRT ( = 1761) . This scp = 0.392).According to a study by Forleo et al., quadripolar leads allowed for nonapical pacing with acceptable electrical parameters in the majority of CRT recipients, although differences were found among the currently available devices . In our Thus, the predictive model with the combination of LV AW_SD, SRS, and the presence of nonischemic HF etiology has a high prognostic value and can be used as an additional CRT response predictor in patients with HF of different etiologies.The limitations of this study included its relatively small sample size and short follow-up period; the left ventricular mechanical dyssynchrony indicators were not determined in terms of their dynamics, and this was a nonrandomized, single-center study. In patients with HF of ischemic and nonischemic etiologies, the left ventricular mechanical dyssynchrony assessed via gBPS may be useful in identifying responders to CRT. In these patients, a combined assessment of the factors associated with reverse remodeling  can be used for the improved selection of patients for CRT.


Mitral valve prolapse (MVP), characterized by a displacement > 2 mm above the mitral annulus of one or both bileaflets, with or without leaflet thickening, is a common valvular heart disease, with a prevalence of approximately 2% in western countries. Although this population has a generally good overall prognosis, MVP can be associated with mitral regurgitation (MR), left ventricular (LV) remodeling leading to heart failure, ventricular arrhythmia, and, the most devastating complication, sudden cardiac death, especially in myxomatous bileaflet prolapse (Barlow's disease). Among several prognostic factors reported in the literature, LV fibrosis and mitral annular disjunction may act as an arrhythmogenic substrate in this population. Cardiac magnetic resonance (CMR) has emerged as a reliable tool for assessing MVP, MR severity, LV remodeling, and fibrosis. Indeed, CMR is the gold standard imaging modality to assess ventricular volume, function, and wall motion abnormalities; it allows accurate calculation of the regurgitant volume and regurgitant fraction in MR using a combination of LV volumetric measurement and aortic flow quantification, independent of regurgitant jet morphology and valid in cases of multiple valvulopathies. Moreover, CMR is a unique imaging modality that can assess non-invasively focal and diffuse fibrosis using late gadolinium enhancement sequences and, more recently, T1 mapping. This review describes the use of CMR in patients with MVP and its role in identifying patients at high risk of ventricular arrhythmia. Mitral valve prolapse (MVP), the most common cause of chronic primary mitral regurgitation in developed countries , 2, is cDue to the excellent visualization of the mitral anatomy if affords, its high temporal resolution, and ease of use, two-dimensional echocardiography , is the first -line imaging modality for analyzing mitral leaflet motion and thickness and quantifying MR. However, the visualization and quantification of MR can be challenging in cases of poor image quality, especially in the parasternal window, or in the presence of eccentric jets (common in MVP). Moreover, recent studies have suggested a link between MVP, focal fibrosis , and sustained (or complex) ventricular arrhythmia  that echCardiac magnetic resonance (CMR), with its unique ability to characterize myocardial tissue using late gadolinium sequences, and more recently, T1 mapping, has emerged as a very useful non-invasive imaging modality to assess focal and diffuse myocardial fibrosis, in addition to its accuracy in evaluating ventricular volume and MR quantification .In this review, we will discuss the role of CMR in patients with MVP from diagnosis to LV fibrosis with risk stratification for malignant ventricular arrhythmia and SCD to MR quantification.Although the spatial resolution of CMR is lower than that of echocardiography, the mitral valve apparatus, including mitral valve leaflets, the mitral annulus, the chordae, and the papillary muscles, can be visualized using balanced steady-state free precession (b SSFP) imaging, ideal for assessing mitral leaflet motion. CMR techniques used to asses MVP are summarized in With the use of retrospective cardiac gating , MVP can be visualized in (1) standard long-axis views: 2-chamber, 3-chamber, and 4-chamber;  or (2) aMVP is diagnosed using the same criteria of the 2 mm single or bileaflet displacement beyond the long-axis annular plane in a 3-chamber view, equivalent to the trans-thoracic echocardiography parasternal long-axis view  Figure .As in echocardiography, the measurement of leaflet displacement should not be performed in the 2- or 4-chamber view due to the saddle-shaped mitral valve annulus, falsely creating the appearance of a prolapse.Leaflet thickness is defined as the maximal thickness measured during diastole in long axis views. A thickness ≥ 5 mm defines a classic MVP  vs. non-classic MVP, with a thickness <5 mm . HoweverThe mitral annular diameter, commonly greater in MVP , 18, is Due to its ability to measure ventricular volume and mass without the need for geometric assumptions, CMR is the imaging modality of choice for accurately assessing ventricular volumes in patients with MVP. Using b SSFP images acquired during a breath-hold on a stack of short-axis views covering both ventricles from the base through the apex, endocardial and epicardial contours are manually traced at end-diastole and end-systole, including papillary muscles as part of the ventricular volumes. The basal slice at end systole should be at the level of the mitral annulus and not at the mitral valve leaflets, especially for patients with bileaflet mitral valve prolapse  Figure .Left atrium contours are traced at end-systole using the biplane area-length method in the 2- and 4-chamber views . MVP, esLV basal inferolateral hypertrophy has been described and correlates with the degree of annular excursion by CMR . RegionaMAD, is characterized by a separation between the mitral valve annulus-left atrial wall junction and the basal segment of the left ventricular (LV) wall. Disjunction anywhere around the mural leaflet is common and found in 76% of a large cohort of patients without any known cardiovascular disease . HoweverIt can be visualized in end-systole from standard long-axis views as the absence of myocardium between the posterior mitral valve annulus and adjacent basal LV wall. On cine images, patients with MAD show a typical systolic curling motion of the basal LV wall, leading to annular hypermobility . MAD is A recent review that pooled 19 studies found a prevalence of MAD of 32.6% in patients with MVP, increasing to 50.8% for patients with myxomatous mitral valve disease . Using CInterestingly, MAD appears to be associated with fibrosis and ventricular arrhythmia , 27, 29,CMR, using late gadolinium enhancement (LGE) sequences acquired after contrast administration, allows the assessment of non-invasively regional myocardial replacement fibrosis, a risk marker of arrhythmic events for patients with MVP .Based on a comparison between healthy and fibrotic myocardium, pulse sequences (2D segmented inversion recovery GRE or PSIR or 3D sequences) are performed at least 10 min after gadolinium administration in mid-diastole during a breath hold using the standard long-axis view and a stack of short-axis views (used for LV volume and function) . In caseConventional bright-blood LGE imaging is preceded by a TI SCOUT, set to nullify the normal myocardium. Due to the poor scar-to-blood contrast of these conventional sequences, the detection of subtle papillary muscle fibrosis adjacent to the blood pool can be challenging. By suppressing the blood pool signal, dark-blood LGE imagining could improve the detection of LGE at the papillary muscle level . For DarThe most common LGE pattern for patients with MVP is a mid-wall or patchy, but non-coronary artery disease-related pattern, mostly visualized in the basal inferolateral or inferior wall and at the level of the papillary muscles , 31, 35 Excessive mobility of the mitral apparatus (including traction from the chordae tendinae) related to MVP and MAD can induce an abnormal mechanical stress/stretch, leading to the development of hypertrophy and fibrosis in these regions, well documented by histopathology or CMR , 41, 42.In addition to the detection of fibrotic myocardium, CMR by T1 mapping sequences allows quantification of the myocardial extracellular volume (ECV), a quantitative marker of diffuse myocardial fibrosis that correlates with the magnitude of histological fibrosis , 47.Modified look-locker inversion recovery (MOLLI), shortened MOLLI, or equivalent pulse sequences with motion correction are performed in a single breath hold at the level of the mid-basal and mid-LV short axis before and 15 to 20 min after contrast administration . CalculaThe ECV has an incremental diagnostic benefit in non-ischemic cardiomyopathy and correlates strongly with outcome, better than native T1 mapping .In MVP, a recent retrospective study by Pavon et al.  that useIn a large prospective study of 229 patients with MVP and 195 without, Kitkungvan et al.  showed tThere are three different CMR methods (two indirect and one direct) to quantify MR severity in MVP, all independent of geometric assumptions, unlike echocardiography.The most recommended method is indirect, requiring measurement of the left ventricular stoke volume (LVSV) and aortic forward flow (AFF) to calculate the MRvol and regurgitant fraction (RF) . The twoThe LVSV is expressed as the difference between the LV end diastolic volume (LVEDvol) and LV end systolic vol (LVESvol), calculated using manual contouring in end diastole and end systole, including that of trabeculae and papillary muscles on short-axis cine SSFP images covering the entire LV. The basal slice is defined as that in which the LV myocardium is detected at a minimum of 50% of its circumference, corresponding to the level of the mitral valve annulus. The AFF is obtained from phase-contrast velocity mapping performed in the proximal ascending aorta above the tip of the aortic valve and perpendicular to the vessel. A flow curve is generated allowing calculation of the area under the curve of the forward flow curve .The MRvol is defined as follows: LVSV-AFF and RF = MRvol/LVSV.This method, which is highly reproducible and valid in cases of multiple valvular regurgitation, is independent of the shape and morphology of the jets, which is particularly useful for patients with late systolic and eccentric regurgitant jets for which delimiting the radius of the converging hemisphere is difficult in echocardiography .p < 0.001)  and CMR in MR severity grading –56, espe< 0.001) . Applyin< 0.001) , 54.r = 0.79 and r = 0.67, respectively) and the LVEF and global myocardial strain  have been shown using the functional the anatomical method  unlike for the RF   means thl method . Howeverr the RF . As MRvor the RF , similarr the RF .Unlike 2D flow, 4D flow is possible in a single continuous free-breathing volume acquisition (7–10 min) covering the entire heart and allowing visualization of flow in multiple orientation with a possibility to retrospectively measure any flow in any direction.Regurgitant volume and fraction can be derived from direct measurement of regurgitant flow  or from indirect 4D flow quantification  (4F flow4D flow imaging has demonstrated promising results with good agreement in secondary MR  but low p < 0.001) with the best concordance between standard CMR and 4D indirect method  showed a good correlation between methods , a systematic CMR is recommended to identify specific arrhythmic risk factors such as focal or diffuse fibrosis.CMR has become an important component of MVP assessment due to its accuracy in assessing ventricular dimensions and function, mitral annulus motion, and mitral regurgitation severity, in addition to its unique ability to non-invasively assess focal and interstitial diffuse fibrosis.With use of cine images in standard long-axis views, MVP can be visualized and quantified, as well as mitral annular disjunction and prolapse volume. Using an indirect method that combines LV measurement and phase-contrast velocity mapping in the ascending aorta, MR can be quantified with a high level of accuracy using the regurgitant fraction and mitral regurgitant volume.With the use of late gadolinium enhancement sequences and T1 mapping, focal and diffuse fibrosis, with calculation of the extracellular volume, can be detected and quantified, providing useful information to identify MVP patients with a high risk of ventricular arrhythmias.As a complement to clinical and echocardiographic data, CMR, using a complete protocol as described above, should be integrated into the workup of patients with MVP.EV provided design of the research and wrote the manuscript. EV, LI, CR, and SM provided iconography. AA, LI, FL, YB, CR, FG, SM, and CT provided critical revision of the manuscript. All authors contributed to the article and approved the submitted version.


In this work, we performed a computational image-based study of blood dynamics in the whole left heart, both in a healthy subject and in a patient with mitral valve regurgitation. We elaborated multi-series cine-MRI with the aim of reconstructing the geometry and the corresponding motion of left ventricle, left atrium, mitral and aortic valves, and aortic root of the subjects. This allowed us to prescribe such motion to computational blood dynamics simulations where, for the first time, the whole left heart motion of the subject is considered, allowing us to obtain reliable subject-specific information. The final aim is to investigate and compare between the subjects the occurrence of turbulence and the risk of hemolysis and of thrombi formation. In particular, we modeled blood with the Navier–Stokes equations in the arbitrary Lagrangian–Eulerian framework, with a large eddy simulation model to describe the transition to turbulence and a resistive method to manage the valve dynamics, and we used a finite element discretization implemented in an in-house code for the numerical solution. The pathologies affecting the left heart (LH) are the most common cause of death in the world Tsao et al. . One of regurgitant volume and the regurgitant fraction may provide significant information about the global cardiac function; they are not able to capture local features such as 3D velocity distribution and wall shear stresses  models  with prescribed wall motion. For the latter, the prescribed motion could be obtained either from an electromechanical simulation . The latter approach has become, in the last decade, a valid alternative to FSI models when sufficiently detailed dynamic medical images are available to perform a DIB-CFD simulation of the whole heartbeat on a healthy subject and on a patient with MVR;(ii)to investigate the transition to turbulence, the risk of hemolysis formation and the prevention from thrombi formation with respect to the healthy subject.The main improvements and novelties of this work are: (i)a fully LH patient-specific DIB-CFD simulation with imposed motion of ventricle, atrium and aortic root together with the geometries of the mitral and aortic valve, all reconstructed from multi-series  cine-MRI during the whole heartbeat. In particular, unlike the works of Chnafa et al. , 2016, w(ii)the investigation of the transition to turbulence in the MVR case, so far investigated only in physiological cases the study of the risk of hemolysis in the atrium and the prevention from thrombi formation with respect to the healthy subject. These phenomena, so far, has not been investigated in the presence of native valve with MVR by means of a computational study.Moreover, the novelty with respect our previous work  measures in the healthy subject and by a qualitative comparison with a cine-MRI flow pattern in the MVR case.In this section, we first described the multi-series cine-MRI at disposal and the acquisitions of the ECD measurements; after that, we detailed the reconstruction techniques used to obtain the patient-specific geometries and displacements of the left ventricle (LV), left atrium (LA), aortic root (AR), mitral valve (MV) and aortic valve (AV); then, we briefly reported the mathematical and numerical methods used in this work; finally, we introduced the quantities of interest that has been analyzed in the Results section.Cardiac multi-series cine-MRI data of two subjects were provided by the Department of Radiology of Borgo Trento Hospital, Verona, Italy. Ethical review board approval and informed consent were obtained from all subjects. In particular, we acquired dynamic images, consisting of 30 acquisitions per heartbeat, of a healthy subject (H) and of a patient with a severe MVR due to a posterior leaflet prolapse (R). In Table Short Axis series of LV, the Long Axis series  and the Rotated series of MV. Moreover, for subject H we have at disposal also the Short Axis series of AR. Each series has a time resolution of 30 frames/cardiac cycle. Below we reported the other specific characteristics of each series , three-chamber (3CH) and four-chamber (4CH) planes; space resolution of 1 mm; slice thickness of 8 mm;Mitral valve: two-dimensional series of 18 evenly rotated (one every 10 degrees) planes around the axis passing through the annular center and aligned with the left ventricle apex; spatial resolution of 1.25 mm; slice thickness of 8 mm;AR Short Axis: volumetric series made of 4 slices; thickness and distancing of 8 mm along the aortic root main axis; spatial resolution of 1 mm.After the image acquisitions, patient R underwent to a surgical operation to restore a correct heart function.The acquisitions were performed with the Achieva 1.5T (TX) - DS  technology. Specifically, for each patient, we have at disposal different multi-series images: the standard cine-MRI data that are routinely acquired in the clinical procedure. Instead, the Short Axis series of AR and the Rotated series of MV represent ad hoc advanced cine-MRI acquisitions.We point out that the Long Axis series and the Short Axis series of LV are P1: P2: P3: After the cine-MRI acquisitions, ECD measurements with a EPIQ CVx ultrasounds scanner and linear 8MHz probe  were taken from subject H . The velocity measures were acquired at the peak instants at three different locations: entclass1pt{minimaIn this section, we describe a novel framework to reconstruct the LH geometry and displacement. This is based on combining two different reconstruction techniques proposed so far for LV and for LA/AR, respectively. The entire procedure is presented in Fig. Medical Image Toolkit (MITK) open-source software (www.mitk.org), see step A in Fig. Regarding the LV reconstruction, we adopted the strategy described in Fumagalli et al. . Startinr et al.  and implmentclass2pt{minimVascular Modeling Toolkit (VMTK) (www.vmtk.org) . Also notice that the 3D system of coordinates is absolute for all the series since the patients were kept supine throughout the examination. Furthermore, all the series have been acquired by the same machine within a few minutes of each other. Moreover, we assumed that no temporal mismatches were present between the series, since the maximum discrepancy of the frequency with respect to the short axis series of the left ventricle  Klein et al. , see  to our reconstructions. In particular, the FO configurations were geometrically deformed in order to match the annulus with that segmented from our cine-MRI (from the AR Short Axis series for subject H and from the Rotated series of MV for patient R), see step F in Fig. Concerning AV, the cine-MRI at disposal did not allow a complete reconstruction of the patient-specific leaflets. For such reason, what we have done is to reconstruct the patient-specific annulus of H and R in the open configuration and to adapt the aortic valve geometry taken from After, to guarantee a perfect adhesion between the valves and the reconstructed LH geometry at the end systolic instant , we used the Pope criterion Pope . In partved Pope , 2016. IWe simulated 13 heartbeats and we discarded the first one to remove the influence of the null initial condition.ensemble pressure and velocity numerical solutions of  is a function of space and time representing the viscous forces, per unit of area, exerted by the blood on the walls  is a function of space providing a surrogate information about the effective residence time spent by particles close to the myocardial wall. High values of this quantity may be a marker of stagnant flow  is the ratio between the space covered by the blood jet developing at the MV orifice during the E-wave and the length of the ventricle at the end diastolic configuration. Values of EPI < 1 could indicate an incomplete apical washout, leading to possible left ventricle thrombus formation  at each time and space of the blood velocity with respect to its ensemble value. This allowed us to quantify and localize the regions characterized by marked transition to turbulence  at each time, quantifying the velocity fluctuations by means of the fluid Reynolds stress tensor .In Fig. We observed that in R GTKE was much larger than in H in all the two chambers, with maximum values in LA at the end of systole due to the regurgitant jet and almost constant values in LV. With entclass1pt{minimaD of the cardiac cycle during which In Fig. entclass1pt{minimaTo assess the accuracy of the results obtained for subject H, we compared the values of the ensemble velocity computed by the numerical simulation with the available ECD measures in the locations P1, P2 and P3 reported in Fig. The maximum relative error In Fig. Notice the good qualitative agreement between computations and images, highlighting that the regurgitant jet firstly developed along the anterior leaflet (Frames 1 and 2) and then along the atrial walls assuming also a swirling structure (Frame 3).In this work, we performed an image-based computational fluid dynamic study in the left heart of a healthy subject and of a patient with a severe mitral regurgitation (MVR), with the aim of comparing the transition to turbulence, the risk of hemolysis and the risk of thrombi formation. The motion of the complete left heart (LH) , left atrium (LA) and aortic root (AR) internal wall surfaces, together with aortic valve (AV) and mitral valve (MV)) during the whole heartbeat was reconstructed and prescribed to DIB-CFD simulations from multi-series cine-MRI.At the best of our knowledge, this is the first work using the patient-specific geometry motion of LV, LA, AR in a mitral regurgitant DIB-CFD simulation. Moreover, ours is the first work which included also MV and AV geometries in a  DIB-CFD simulation. In particular, for the healthy case the majority of the previous DIB-CFD studies did not include LA or AR or employed template geometries  which consist in 2D Long Axis series of 18 evenly rotated planes (one every 10 degree) around the axis passing through the MV center and aligned with the LV apex, proposed for the first time in Stevanella et al.  cine-MRI at disposal: the LV Long Axis, the LV Short Axis, the AR Short Axis (when available) and the MV Rotated series. The latter stand out from the other series because they are based on a a et al.  for a puOwing to this specific and detailed imaging, we were able to quantitatively describe physiological and pathological/MVR mechanisms such as prevention from thrombi, transition to turbulence and hemolysis formation. In particular, for the first time at the best of our knowledge, we investigated by means of a computational study how the regurgitant jet could promote the washing out of regions with stagnant flow in LA, reducing the risk of thrombosis with respect to a healthy scenario. Our results highlighted that the regurgitant jet scratched against the atrial walls, see Fig. Notice, however, that RRT in the left atrial appendage was elevated in both the subjects, confirming that, even in the presence of MVR, LAA could be one of most common site for cardiac thrombus formation  images series elaborated in order to perform highly accurate DIB-CFD simulations. This allowed us to extract interesting general physiopathological findings of the healthy and regurgitant scenarios. As a consequence, our reconstruction technique is not suitable to study a wide range of specific subjects, for which standard images are enough;We did not model the valve dynamics; instead, we considered an instantaneous valve opening and closure. However, the opening and closing valve time duration is less than 5% of the heartbeat  in the LV geometry. This is a common choice, adopted also in Fumagalli et al. ; Su et aWe did not considered the MRI beat-to-beat variations in terms of acquired displacements and heart rate. Indeed, the average of MRI acquisitions along more heartbeats should provide more reliable input data for DIB-CFD. However, this may result in prolonged exposure time during the acquisitions of cine-MRI that is not advisable for patients with heart pathologies.Our meshes did not include any boundary layer to better capture the blood dynamic behavior close to the myocardial wall. This should be considered in future studies. However, we notice that our mesh resolution obtained after a refinement study was able to satisfy the Pope criterion.Some limitations characterized this work:


Aortopulmonary window is a rare congenital heart defect that results in severe pulmonary arterial hypertension (PAH), Eisenmenger syndrome, and congestive heart failure in the first months of life. Pregnancy is absolutely contraindicated in the patients with this condition.This paper describes two clinical cases of pregnancy in patients (28 and 20 years old) with aortopulmonary window defect, severe PAH, and Eisenmenger syndrome that ended in preterm delivery by caesarean section. One patient died in the postpartum period due to progression of right ventricular heart failure. The younger patient survived childbirth and the postpartum period; later, she continued therapy at the PAH centre.We describe unusual cases of clinical features in pregnant women with aortopulmonary window defect. Due to the rare occurrence and low survival rate of patients with uncorrected aortopulmonary window defect, descriptions of clinical cases of this defect in adults are very rare. It is very important to note the necessity of observation of these patients in specialized centres by a multidisciplinary team of healthcare professionals, due to the high risk of cardiovascular, obstetric complications, and death. The mortality rate of patients with aortopulmonary window defect in the structure of congenital heart defects without surgical repair in the first year of life reaches 40%.According to current clinical guidelines on the management of pregnant patients with cardiovascular diseases, the World Health Organization classifies pulmonary arterial hypertension as class IV risk and pregnancy is absolutely contraindicated.If the patients categorically refuse to terminate the pregnancy, they should be observed in specialized centres by a multidisciplinary team of healthcare professionals.2; the mortality rate of patients without surgical repair in the first year of life reaches 40%.4 According to current clinical guidelines on the management of pregnant patients with cardiovascular diseases, the World Health Organization classifies pulmonary arterial hypertension (PAH) as class IV risk (40–100% probability of cardiovascular events in the mother). Pregnancy is absolutely contraindicated in the patients with this condition.5The proportion of aortopulmonary window defect in the structure of congenital heart defects comprises 0.1–0.2%The paper reviews two clinical cases of pregnant patients (28 and 20 years old) with aortopulmonary window defect with Eisenmenger syndrome. Congenital heart disease (CHD) was verified by imaging techniques: transthoracic and transoesophageal echocardiography (EchoCG), non-contrast magnetic resonance imaging (MRI) of the heart and aorta and, after delivery, computed tomography (CT) of the aorta with contrast. The babies were delivered by caesarean section in the expert centre for pregnancy and cardiac disease. One of the patients underwent catheterization of the right heart chambers after delivery. The patients’ clinical and laboratory data were regularly monitored; electrocardiography (ECG), EchoCG, Dopplerometry, and fetometry were conducted.A 28-year-old primiparous female patient at 28–29 weeks gestation was hospitalized into the perinatal centre of V.A. Almazov National Medical Research Centre with clinical symptoms of heart failure [FC  III]. The symptoms had been observed since childhood. Congenital heart disease had not been verified by previous examinations.Present pregnancy is at the age of 27; EchoCG (24–25 weeks) showed stage III pulmonary insufficiency, dilated aorta in the ascending section (up to 50 mm), estimated pulmonary artery systolic pressure (ERASP) of 50–55 mm Hg, and left ventricular ejection fraction (LVEF) 62%. Due to the revealed changes, the patient was transferred to the expert centre for pregnancy and cardiac disease.2. Acrocyanosis at rest was found. Vesicular breathing was respiratory rate (RR) = 20/min and SpO2 at rest was 87%. Pulse was rhythmic with heart rate 82 b.p.m, and blood pressure (BP) was 100/60 mmHg. Auscultation showed a systolic murmur on the left sternal border. The abdomen was enlarged according to the gestational age. Foetal ultrasound and Dopplerometry (29 weeks) showed symmetrical foetal growth retardation. As the pregnancy progressed, there were signs of preeclampsia, reduced exercise tolerance, and desaturation to 85%. Pulmonary arterial hypertension–specific therapy with sildenafil was initiated. There was a progression of dyspnoea and desaturation to 78%. At 33 weeks of gestation, a caesarean section was performed. The patient’s intraoperative course was without complications.Examination showed satisfactory general state and body mass index of 19 kg/m2 = 40%, arterial hypertension, and tachycardia. The episode was treated as a paradoxical cerebral vascular embolism. The patient was intubated and transferred to mechanical lung ventilation (MLV). Sedative and anticoagulant therapy was administered, and PAH-specific therapy with inhaled iloprost was intensified. On the same day (the third postpartum day), the condition stabilized and the patient was extubated. On the fourth day, there was a recurrence of convulsive syndrome and a series of generalized clonic convulsions with loss of consciousness; there was desaturation to 60% on the sixth day. The patient was transferred to MLV with continuous infusion of barbiturates. In the course of ongoing MLV, the dynamics showed SpO2 decrease to 64%, increasing right ventricular heart failure; inotropic therapy with dobutamine was initiated. Subsequently, repeated episodes of increasing right ventricular heart failure at minimum exertion with desaturation to 45% were registered. FiO2 was increased to 100%, as well as the inotropic support.Activation of the patient on the third day of the postpartum period led to a generalized convulsive seizure accompanied by loss of consciousness, desaturation to SpOFigure 1B).On the 13th day of the postpartum period, a desaturation to 30% and cardiac arrest were registered. After prolonged unsuccessful resuscitation measures, biological death was registered. A complex congenital heart defect with a large defect of the aortopulmonary septum was identified as the main cause of death with cardiopulmonary failure, disseminated intravascular coagulation (DIC) syndrome being the immediate cause of death  with blood pressure difference of up to 10–15 mm Hg in the arms and legs. Membranous interventricular septal defect (5.8 mm) and open arterial duct were revealed at EchoCG in the first month of life.2. Left ventricle: interventricular septum, 8–15 mm; PW, 8 mm; EDD, 59 mm; ESD, 42 mm, EDV, 261 mL, and ESV, 105 mL. The right chambers were not enlarged. The right ventricle (RV) was 10 mm, and LVEF was 60%; tricuspid annular plane systolic excursion (TAPSE) was 2.6 cm. In the ascending section, the aorta formed a single vessel with the pulmonary artery; vessel diameter was up to 57 mm (aortopulmonary junction). There was grade 2 aortic insufficiency. Estimated pulmonary artery systolic pressure (EPASP) was 128 mm Hg.The patient categorically refused to terminate the pregnancy; she was referred to the expert centre for pregnancy and cardiac disease. Examination showed satisfactory general condition. Desaturation was not determined and foetal Dopplerometry was normal. Laboratory test results were normal, and NT-proBNP = 118.9 pg/mL. Echocardiography (26 weeks): significant left heart dilatation. Left atrium (LA), 49 mm; LA volume index, 56 mL/mFigure 2.Since no negative dynamics were registered by clinical, laboratory, or instrumental tests until 30 weeks of gestation, the pregnancy was prolonged up to 32 weeks. Data on EchoCG are shown at After 33 weeks of gestation, there were appeared episodes of shortness of breath in the supine position and the episodes of dizziness with minimal physical exertion. At 33 weeks of pregnancy, caesarean section was performed.Figure 2D–G. The patient categorically refused to have right heart catheterization (RHC). She was released in satisfactory condition on the 19th day of postpartum period without drug therapy and with the recommendation to have a planned RHC.Vasopressor and inotropic support was initiated on Day 1 of the postpartum period. On Days 4 and 7, there was an increase in estimated pulmonary artery systolic pressure , a decrease in Qp/Qs , and an increase in LV CER  and LV EDV . Bidirectional blood flow in the area of aortopulmonary window defect was registered. The patient’s condition was satisfactory. Data on CT angiography of the aorta are shown in Figure 2B and C. Thus, mixed pulmonary hypertension 3 FC associated with uncorrected congenital heart disease was verified. Pulmonary arterial hypertension–specific therapy was initiated of sildenafil 60 mg/day. Nine months after delivery, the patient complained of increasing dyspnoea and decreased exercise tolerance. Laboratory: NT-proBNP was 456 pg/mL. Echocardiography showed no dynamics. The results of subsequent RHC are shown in Table 1.Six months after delivery, the patient was re-hospitalized. NT-proBNP was 472.1 pg/mL. Data on EchoCG are shown in Nine months after delivery, the patient complained of increasing dyspnoea and decreased exercise tolerance. Laboratory: NT-proBNP was 456 pg/mL. Echocardiography showed no dynamics.Table 1.The results of subsequent RHC are shown in 7 Among the described cases, there are patients with and without Eisenmenger syndrome.9 The sources describe several clinical cases of patients with uncorrected aortopulmonary window defect, severe PAH, and completed pregnancy. Despite the fact that nowadays pregnancy in patients with PAH is considered safer, the mortality rate remains extremely high,11 reaching 12–20%. Labour and the early postpartum period should be attributed to the periods of greatest risk.13 Su-Mei et al.14 described a clinical case of low-symptomatic aortopulmonary window in a patient who successfully completed three pregnancies by vaginal delivery. There is no information on the course of previous pregnancies and deliveries in this clinical case. Thirunavukkarasu et al.15 described the cardiac autopsy findings of a woman with aortopulmonary window complicated by Eisenmenger syndrome. Death occurred at 21 weeks of gestation at the age of 20. Two clinical cases showing the development of Eisenmenger syndrome associated with aortopulmonary window defect with decompensation of heart failure (HF) in the postpartum period have also been described.17 However, the authors of these publications do not describe the course of pregnancy and delivery. In this paper, we present a novel detailed description of the course of pregnancy, delivery, and postpartum period in patients with aortopulmonary window defect, severe PAH, and Eisenmenger syndrome. Surgical repair at early age remains the main method of congenital heart disease treatment. Progression of the defect leads to irreversible changes that make surgical correction impossible.18Descriptions of clinical cases of this defect in adults are very rare.Early termination of pregnancy is the most preferable option for patients with aortopulmonary window defect complicated by PAH and Eisenmenger syndrome. If the decision is made to preserve the pregnancy, these patients should be observed in specialized centres by a multidisciplinary team of healthcare professionals, due to the high risk of cardiovascular, obstetric complications, and death. Earlier verification of the diagnosis, active monitoring of the pregnancy, a carefully elaborated plan of therapies, and the timing and mode of delivery are the key aspects in the successful management of pregnant patients in this risk group.16According to clinical guidelines, the examination as CT aorta or brain is contraindicated during pregnancy.Sefiyeva G.G. is a cardiologist in Almazov National Medical Research Centre. Her main areas of scientific activity are congenital and acquired valvular heart disease and clinical features of the pregnancy in patients with prosthetic heart valves.European Heart Journal – Case Reports online.ytad501_Supplementary_DataClick here for additional data file.


Decreased AVAD was independently associated with poorer survival, and demonstrated improved model discrimination after adjustment for diastolic function grading  and E/e’ , respectively. Therefore, decreased hydraulic forces, estimated by AVAD, are weakly associated with diastolic dysfunction and demonstrate an incremental prognostic association with survival beyond conventional measures used to grade diastolic dysfunction.Decreased hydraulic forces during diastole contribute to reduced left ventricular (LV) filling and heart failure with preserved ejection fraction. However, their association with diastolic function and patient outcomes are unknown. The aim of this retrospective, cross-sectional study was to determine the mechanistic association between diastolic hydraulic forces, estimated by echocardiography as the atrioventricular area difference (AVAD), and both diastolic function and survival. Patients  were selected from the National Echo Database Australia (NEDA) based on the presence of relevant transthoracic echocardiographic measures, LV ejection fraction (LVEF) ≥ 50%, heart rate 50–100 beats/minute, the absence of moderate or severe valvular disease, and no prior prosthetic valve surgery. NEDA contains echocardiographic and linked national death index mortality outcome data from 1985 to 2019. AVAD was calculated as the cross-sectional area difference between the LV and left atrium. LV diastolic dysfunction was graded according to 2016 guidelines. AVAD was weakly associated with E/e’, left atrial volume index, and LVEF (multivariable global R The term diastolic dysfunction can refer to mechanical abnormalities present during diastole which impair ventricular relaxation and filling3.Diastolic dysfunction contributes to the development of elevated left ventricular filling pressures and subsequent heart failure with preserved ejection fraction (HFpEF). Consequently, the physiological mechanisms underlying diastolic function remain an area of ongoing research in an attempt to develop effective therapeutic interventions for patients with HFpEF. Diastolic function is a composite description of the interaction between the mechanisms driving LV filling and the passive tension opposing LV filling which are responsible for lengthening the cardiomyocytes, increasing the volume of the LV, and generating the atrioventricular pressure gradient4. Hydraulic force is calculated as the product of the pressure in a liquid, and the surface area with which that liquid is in contact, in accordance with Pascal’s Law5. Since the blood pressure in both chambers of the left heart is nearly identical during diastole6, the difference in cross-sectional short-axis area between the LV and left atrium (LA) provides the geometric basis for a net hydraulic force exuded on the atrioventricular plane in the apex-to-base direction , as well as the human research ethics committees of each participating site across Australia, respectively. Echocardiographic measurements from studies performed in laboratories adhering to clinical calibration standards were transferred to a central database, with quality control measures implemented to remove duplicate, inconsistent and physiologically impossible measurements8. The inclusion criteria for the study cohort were the presence of relevant echocardiographic measures, a LV ejection fraction (LVEF) greater than or equal to 50%, sinus rhythm, and a heart rate between 50 and 100 beats per minute. Echocardiographic measures of interest included LV end-diastolic diameter, LA end-systolic diameter, and at least two measures of diastolic function . These measures were selected to identify diastolic dysfunction as they are the recommended variables in the 2016 American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) guidelines for evaluating LV diastolic function in patients with a LVEF greater than or equal to 50%9. Since average E/e’ was not consistently recorded in the database, E/septal e’ > 15 was used in the current study as per guideline recommendations. Exclusion criteria included moderate or severe valvular heart disease, and prosthetic valves. If multiple echocardiograms were available for a single patient, only the earliest recorded echocardiogram was included. The patient inclusion flowchart is described in Fig. The study population was derived using data from the National Echo Database Australia (NEDA). NEDA is an observational registry comprising of retrospectively and prospectively collected digital transthoracic echocardiographic measurements from patients referred to laboratories across Australia since 1985, and is linked to health outcome data, with patients followed up until the 2019 census or deathAVAD was calculated as the difference between LV and LA cross-sectional areas. LV and LA cross-sectional area were calculated by circular approximation using LV end-diastolic diameter and LA end-systolic diameter, respectively Fig. .Figure 39. Specifically, patients were graded as having normal diastolic function if less than half of the available parameters met cut off values, indeterminate diastolic function if exactly half met cut off values, and diastolic dysfunction if more than half met cut off values.For all measures, the designation of end diastole and end systole refers to LV systole and diastole. Using any available measures of diastolic function, patients were graded using the 2016 ASE/EACVI guidelines2 values were used to represent the proportion of the variation in AVAD explained by the variables, whilst standardised beta coefficients were used to compare the strength of association with AVAD between variables. Survival analysis was conducted to examine the association between selected variables and time to death using Kaplan–Meier curves and Cox proportional hazards models. The end-points used were 5-year all-cause mortality and 5-year cardiovascular mortality. Univariable Cox regression models were used to evaluate the association between survival and AVAD, E/e’, and diastolic function grading, in the overall population and both sexes. Multivariable Cox regression models were used to evaluate the association between AVAD and survival, adjusting for conventional parameters of diastolic function. Finally, multivariable analyses were repeated in patient subgroups stratified by clinically relevant LVEF ranges. The proportional hazards assumption was confirmed by visual inspection of the Schoenfeld residuals, and by demonstrating a non-significant relationship between the residuals and time. Wald’s chi-square values were reported to compare the strength of association of different variables within regression models. Hazard ratios for continuous variables were scaled by standard deviation to allow for comparison between models, whilst hazard ratios for diastolic function grading were reported using normal diastolic function as a reference level. The goodness of fit of univariable and multivariable models was compared using the concordance (C) statistic, and differences in C-statistics were evaluated using a one-shot nonparametric approach independent of any overlap between the 95% confidence intervals of the two C-statistics being compared10. A p-value less than 0.05 was considered statistically significant.All statistical analyses were conducted using programming language, R . The characteristics of the study cohort were calculated and reported as the median [interquartile range]. Differences in measured variables between patients were assessed using Wilcoxon rank-sum test. Univariable and multivariable linear regression were used to determine the relationship between AVAD and parameters of diastolic function in patient subgroups based on the availability of diastolic function measures. Rp < 0.001 for all).The population considered for this study consisted of 5176 patients, with cohort characteristics presented in Table 2 = 0.15, p < 0.001, Table AVAD was univariably associated with E/e’, e’ velocity, LAVI, peak tricuspid regurgitation velocity and LVEF. In multivariable linear regression, only E/e’, LAVI and LVEF remained associated with AVAD, with an overall weak association . These results were replicated in sex-disaggregated analysis (data not shown). The Kaplan–Meier survival curves for these univariable analyses are represented in Fig. p < 0.001, Table p < 0.001, Table The results of univariable and multivariable Cox regression analyses using 5-year all-cause mortality as the outcome measure are summarised in Tables The main finding of this study is that decreased diastolic hydraulic forces, estimated by AVAD, are associated with poor survival. This association between diastolic hydraulic forces and survival is independent of, and incremental to, current measures of diastolic function. Taken together, this suggests that further investigation evaluating increased LA size relative to LV size as a potential therapeutic target in HFpEF is justified.12, diastolic hydraulic forces provide a macroscopic explanation to a part of the physiology behind diastolic function, thus incorporating the effects of blood pressure and cardiac geometry into a unified theoretical framework. It is important to note that diastolic dysfunction refers to impaired myocardial relaxation and increased chamber stiffness contributing to raised LV filling pressures which is one of the mechanisms underlying the development of HFpEF. The contribution of diastolic hydraulic forces to LV filling in health has been found to be of comparable magnitude to other diastolic mechanisms such as active relaxation and restoring forces4. Meanwhile, conventional parameters recommended by the ASE/EACVI to grade diastolic function account for the contribution of LV early diastolic recoil, LV relaxation, LV filling pressure, and LA pressure13. The recommended algorithm from these guidelines has been previously associated with increased cardiovascular-related and all-cause mortality14. The current study shows that AVAD provides prognostic value beyond these measures to predict survival in a clinical population. When compared directly with E/e’, the echocardiographic parameter most closely related to LV filling pressure16, AVAD retained an independent association with survival, albeit with a somewhat weaker strength of association. These results, including the finding of merely a weak association between AVAD and conventional diastolic measures, indicate that AVAD provides novel information when assessing diastolic function and prognosis in patients.Expanding on previous attempts to find predictors of diastolic dysfunction4. Whilst there is no meaningful magnitude of change in LV cross-sectional area between mid-diastasis and end diastole, LA cross-sectional area is greater at end systole than at mid diastasis4. Specifically, in a study of healthy volunteers, LA short-axis area increased from 14 to 19 cm2 between mid-diastasis and end systole4. This change in area is related to the movement of the mitral annular plane, or mitral annular plane systolic excursion (MAPSE)18. Specifically, as the mitral annular plane is displaced towards the apex during systole, LA cross-sectional area increases. To account for the potential influence of MAPSE on our measurement of AVAD, we repeated our statistical analyses in patients stratified by subgroups of LVEF above 50%, and observed a similar trend in results. It is well established that MAPSE is positively associated with LVEF22. Therefore, it can be inferred that patients with a similar LVEF also have an adequately similar MAPSE and the movement of the mitral annular plane does not considerably affect the differences in AVAD between these patients. This is supported by the negligibly weak association found between AVAD and LVEF within each subgroup of LVEF above 50%  was a strong predictor of cardiovascular events and death, with improved discrimination and reclassification power when compared to individual LA and LV measures30. LACI was calculated by dividing LA end-diastolic volume by LV end-diastolic volume, with the authors acknowledging that LA and LV function and pressure are most closely related during diastole. Considering that cardiac chamber volume is dependent on mean cross-sectional area, the findings using LACI represent an approximate surrogate measure of diastolic hydraulic forces, albeit without specifically measuring the difference in LV and LA short-axis cross-sectional areas.Cardiac geometry is known to play an integral role in cardiovascular health. Changes to the structure of the LV and LA, either independently or simultaneously, have been demonstrated to impair function and contribute to cardiovascular disease and outcomes31. This may result in the LA cross-sectional area becoming equal to or larger than the LV cross-sectional area, orienting the net diastolic hydraulic force towards the apex of the heart and opposing LV filling7. Decreasing LA size in these patients may potentially restore the contribution of diastolic hydraulic forces to LV filling, possibly improving both diastolic function and survival. LA reduction surgery is already an established procedure36 primarily indicated alongside other surgical procedures to treat an enlarged LA or chronic atrial fibrillation in patients with mitral valve disease33. Several studies have highlighted the benefits of LA reduction surgery, most commonly resulting in increased restoration and maintenance of sinus rhythm, with no significant increases in mortality or post-operative complications43. The mechanism for these improvements is not clearly understood. However, it is thought to be related to electrophysiological remodelling and increased wall stress45. We hypothesise that these benefits may also be attributed to the subsequent improvement in net diastolic hydraulic force and diastolic function. Diastolic dysfunction is thought to contribute to increased atrial afterload, stretching and wall stress, ultimately increasing the risk of atrial fibrillation47. Considering the importance of cardiac geometry and diastolic function in HFpEF as well, the current results support the notion that LA reduction surgery concomitant with otherwise indicated open-heart surgery is a treatment option that merits prospective evaluation with regards to improving symptoms and outcomes in carefully selected patients with HFpEF.The independent prognostic value of AVAD indicates that increased LA size relative to LV size may be a new therapeutic target in patients with HFpEF. In HFpEF, elevated LV filling pressures are propagated to the LA, resulting in remodelling and dilatation51. Inspection of descriptive statistics of the included measures (data not shown) also did not indicate any reason for concern regarding systematic variations in the data. Additionally, our study may have been limited by the availability of data on the NEDA database. There was a limitation in the number of echocardiographic studies measuring both LA and LV diameter concurrently, thereby reducing the study population available for analysis. Measurement variability inherent to the assumption of circular cross-sectional areas and the variability in selecting the locations of measuring LV and LA diameters may have also limited our methodology. Alternative methods of measuring cardiac geometry, such as atrial and ventricular volumes using apical views to account for variations, were unavailable in the database. However, these alternatives were not needed for the mechanistic validation undertaken in the current study. In considering this mechanistic validation provided in the current study, it is important to consider the large proportion of the study graded as having indeterminate diastolic function. Ultimately, this represents the difficulty in stratifying the complex spectrum of diastolic function, acknowledged by the ASE/EACVI guidelines. Indeed, the guidelines encourage further testing with a wider variety of echocardiographic and haemodynamic measures in such instances. The fact that the current study consistently demonstrates a clear prognostic value using clinically acquired data despite these limitations indicates the robustness of these prognostic relationships. This also accounts for the magnitude of the predictive power of AVAD as well as the correlation with diastolic function markers, as the current study primarily aimed to demonstrate a potential mechanistic association between AVAD and both diastolic function and survival. Finally, our study did not perform a sample size calculation given that our study population was larger than any previously cited studies examining diastolic function and survival, and post-hoc power analyses are not appropriate for an already observed statistic and standard error. In light of the findings and limitations of the current study, future studies should look to further validate the prognostic value of AVAD, while overcoming the limitations of the current study by ideally measuring AVAD in mid diastole (diastasis), and including relevant clinical characteristics.As it currently stands, NEDA does not contain clinical data relating to patient comorbidities, cardiovascular disease risk factors, and pharmacotherapy. This information may impact results, as these clinical details affect both survival and diastolic function, especially since the NEDA population primarily consists of patients referred for echocardiography due to known or suspected cardiovascular disease. Additionally, the retrospective registry nature of the NEDA data used in the current study precludes analysis of individual laboratory reproducibility and assessment of inter- and intra-observer reliability of measurements. Nevertheless, echocardiographic data paired with survival from NEDA has previously been used to draw important prognostic information on pulmonary hypertension, aortic stenosis, and diastolic dysfunction, reflecting the validity and reliability of NEDA data, as well as the robustness of using mortality end-points despite a lack of clinical dataA decrease in diastolic hydraulic forces, estimated by AVAD, is weakly associated with diastolic dysfunction, and independently associated with poorer survival in a clinical population referred for echocardiography. Increased LA size relative to the LV may impair the longitudinal motion of the atrioventricular plane during diastole, impairing LV filling and contributing to a poorer prognosis for patients with cardiovascular disease.Supplementary Tables.