Fibrosis Burden Research Articles

Diffuse myocardial fibrosis by T1 mapping is associated with heart failure in pediatric primary dilated cardiomyopathy

BackgroundIn adult cardiomyopathy (CM), diffuse myocardial fibrosis is associated with adverse clinical outcome. However, its relevance in pediatric patients remains relatively unknown. The study aimed to evaluate myocardial extracellular volume (ECV) reflecting diffuse myocardial fibrosis with cardiovascular magnetic resonance (CMR) T1 mapping, and to analyze correlations with clinical and functional data in children and adolescents with different CM phenotypes. MethodsPatients with primary dilated (DCM), hypertrophic (HCM) or left ventricular non-compaction CM (LVNC) were prospectively enrolled and compared with healthy controls. Study participants underwent standardized CMR with modified Look-Locker Inversion recovery (MOLLI) T1 mapping. ResultsIn total, 33 patients (median age 12.0 years; DCM: n = 10, HCM: n = 13; LVNC: n = 10) and 7 controls (14.5 years) were included.DCM: ECV was higher than in controls (38.1 ± 7.5% vs. 27.2 ± 3.6%; p = 0.014). Patients with elevated ECV were younger than those with normal values (p = 0.044). ECV correlated with N-terminal pro brain natriuretic peptide (r = 0.66, p = 0.038), left ventricular ejection fraction (r = −0.63, p = 0.053), and stroke volume of left (r = −0.75, p = 0.013) and right ventricle (r = −0.67, p = 0.033). During a median follow-up of 25.3 months, 3 patients underwent heart transplantation (HTx), and 2 were listed for HTx. All 5 patients had elevated ECV.HCM/LVNC: ECV was within normal range in HCM (25.5 ± 4.5%) and LVNC (29.6 ± 4.2), and was not related with clinical and/or functional parameters. ConclusionsOur results indicate an increased burden of diffuse myocardial fibrosis in relation with younger age in pediatric DCM. ECV was associated with clinical and biventricular functional markers of heart failure in DCM.

Myocardial extracellular space expansion is related to burden of premature ventricular contractions in patients with hypertrophic cardiomyopathy without non-sustained ventricular tachycardia

Abstract Funding Acknowledgements Type of funding sources: None. Background Current guidelines suggest the presence of non-sustained ventricular tachycardia (NSVT) as a risk factor of sudden cardiac death in patients with hypertrophic cardiomyopathy (HCM). However, high burden of premature ventricular contraction (PVC) may reflect myocardial fibrosis although the absence of NSVT. Purpose We investigated the association between PVC burden and myocardial extracellular space expansion in HCM patients without NSVT. Methods Of the 212 patients prospectively enrolled to the HCM registry of genetics, 84 patients were evaluated with both cardiac magnetic resonance and 24hr holter. Among them, 71 patients (58 males, mean age: 71 ± 13 years) have not been diagnosed with NSVT. Results Patients with NSVT (n = 13) showed more impaired LA functional indices and higher myocardial fibrosis burden compared with patients without NSVT (n = 71). Among patients who have not been diagnosed with NSVT, patients with late gadolinium enhancement (LGE, n = 46) had a higher total beats (109 ± 332 vs. 7 ± 13 beats per a day, p = 0.003) and burden (0.114 ± 0.225 vs. 0.008 ± 0.014 %, p = 0.003) of PVC during 24-hour compared with patients without LGE (n = 25). %LGE was correlated with total beats of PVC (r = 0.358, p = 0.002) and PVC burden (r = 0.377, p = 0.001). ECV also correlated with total beats of PVC (r = 0.387, p = 0.001) and PVC burden (r = 0.401, p = 0.001). The optimal cutoff value for PVC number was 45 (37.0% of sensitivity and 100% of specificity) with 0.733 of the area under the ROC curve (p < 0.001). Pathogenic or likely pathogenic sarcomere mutation was higher in NSVT group than no NSVT group (p < 0.05), and had a higher tendency in higher PVC burden group (0.05 < p < 0.1) than lower PVC burden group. Conclusions Total beats and burden of PVC are significantly related to increase in myocardial fibrosis in HCM patients without NSVT. Abstract Figure. Mechanism of ventricular arrhythmia

Local electromechanical alterations determine the left ventricle rotational dynamics in CRT-eligible heart failure patients

Left ventricle, LV wringing wall motion relies on physiological muscle fiber orientation, fibrotic status, and electromechanics (EM). The loss of proper EM activation can lead to rigid-body-type (RBT) LV rotation, which is associated with advanced heart failure (HF) and challenges in resynchronization. To describe the EM coupling and scar tissue burden with respect to rotational patterns observed on the LV in patients with ischemic heart failure with reduced ejection fraction (HFrEF) left bundle branch block (LBBB). Thirty patients with HFrEF/LBBB underwent EM analysis of the left ventricle using an invasive electro-mechanical catheter mapping system (NOGA XP, Biosense Webster). The following parameters were evaluated: rotation angle; rotation velocity; unipolar/bipolar voltage; local activation time, LAT; local electro-mechanical delay, LEMD; total electro-mechanical delay, TEMD. Patients underwent late-gadolinium enhancement cMRI when possible. The different LV rotation pattern served as sole parameter for patients’ grouping into two categories: wringing rotation (Group A, n = 6) and RBT rotation (Group B, n = 24). All parameters were aggregated into a nine segment, three sector and whole LV models, and compared at multiple scales. Segmental statistical analysis in Group B revealed significant inhomogeneities, across the LV, regarding voltage level, scar burdening, and LEMD changes: correlation analysis showed correspondently a loss of synchronization between electrical (LAT) and mechanical activation (TEMD). On contrary, Group A (relatively low number of patients) did not present significant differences in LEMD across LV segments, therefore electrical (LAT) and mechanical (TEMD) activation were well synchronized. Fibrosis burden was in general associated with areas of low voltage. The rotational behavior of LV in HF/LBBB patients is determined by the local alteration of EM coupling. These findings serve as a strong basic groundwork for a hypothesis that EM analysis may predict CRT response.Clinical trial registration: SUM No. KNW/0022/KB1/17/15.

Impaired Left Atrial Performance Resulting From Age-Related Arial Fibrillation Is Associated With Increased Fibrosis Burden: Insights From a Clinical Study Combining With an in vivo Experiment.

Background: Atrial fibrillation (AF) is increasingly considered an age-related degenerative disease, whose process is associated with the development of impaired left atrial (LA) performance. However, the subtle dynamic changes of LA performance in AF during aging have yet to be fully elucidated. Atrial fibrosis is a key substrate for the development of AF, but the progression of fibrosis during aging and its relationship with LA dysfunction need to be further explored.Methods: A total of 132 control individuals and 117 persistent AF patients were prospectively studied. Subjects were further stratified into three age groups (age group 1: younger than 65 years, age group 2: between 65 and 79 years old, and age group 3: older than 80 years). The two-dimensional speckle tracking imaging was carried out for analyzing the alterations in LA function underlying LA remodeling, whereas electroanatomic mapping was performed to investigate LA fibrosis burden. In animal study, aged mice and young mice served as research subjects. Echocardiography and histological staining were used to assess LA performance and fibrosis burden, respectively.Results: Echocardiography showed progressive increases in LA dimension and LA stiffness index, and progressive decreases in LA global longitudinal strain and LA strain rates with advancing age in both AF and control cohorts, which was more prominent in AF cohort. Electroanatomic mapping showed progressive decrease in mean LA voltage and progressive increases in LA surface area, low-voltage area %, and LA volume with advancing age, whereas more significant alterations were observed in AF patients. Moreover, left atrial global longitudinal strain was positively correlated with mean LA voltage, whereas LA stiffness index was negatively related to mean LA voltage. In animal experiment, increased LA size and pulmonary artery dimension as well as longer P-wave duration and more prominent LA fibrosis were found in aged mice.Conclusions: This study provides new evidence of subtle changes in structure and performance of left atrium and their association with atrial fibrosis in both AF and non-AF subjects during physiological aging. In addition, our study also provides normal values for LA structure and performance in both AF and non-AF conditions during aging. These measurements may provide an early marker for onset of AF and LA adverse remodeling.

Immune Dysregulation in Myocardial Fibrosis, Steatosis, and Heart Failure: Current Insights from HIV and the General Population.

HIV is an independent risk factor for heart failure (HF). Cardiac imaging studies in people with HIV (PWH) have identified myocardial pathologies, namely fibrosis and steatosis, that likely contribute to the higher risk of HF. In this review, we survey existing epidemiological, clinical, and mechanistic literature to identify potential pathways that may contribute to the burden of myocardial fibrosis and steatosis among PWH. Multiple cohort studies over the past 20years have demonstrated a roughly 2-fold higher risk of incident HF in PWH, as well as a disproportionate burden of myocardial fibrosis and steatosis in PWH without HF. Both myocardial fibrosis and steatosis are known contributors to HF in adults without HIV. Pathways involving the NLRP3 inflammasome, TGF-β1, and adipocyte dysfunction are known to play a crucial role in the development of myocardial fibrosis and steatosis. Upregulation of these pathways in HIV due to direct effects of viral proteins, persistent immune dysregulation, gut epithelial breakdown and dysbiosis, and toxicities from antiretroviral therapy may contribute to myocardial dysfunction in HIV. Understanding these pathways may lead to more precise diagnostic and therapeutic targets to curb HF in PWH. During the past three decades, observational and mechanistic studies have provided important insights into risk factors and pathways that may contribute to the increased HF risk in PWH. Future work is needed to characterize these pathways more precisely in mechanistic studies of PWH, with the goal of ultimately deriving valuable targets for prevention, early diagnosis, and treatment of HF in PWH.

Fibroscan and Doppler Ultrasonography in the Assessment of Hepatocellular Carcinoma Interventional Therapy

Background: studying hepatocellular carcinoma (HCC) interventional therapy by a simple, noninvasive techniquesthat doesn’t require contrast material is valuable. Doppler ultrasound and fibroscanimaging gives anon-invasive demonstration of blood flow by real time observation and the fibrosis burden which can be related to HCC recurrence. Objectives: The aim of this study was to evaluate the role of fibroscan and Doppler ultrasonography in the assessment of efficacy and safety of hepatocellular carcinoma interventional therapy. Methods: this prospective study was conducted on HCC patients undergoing interventional therapy. The vasculature of both the liver and the focal lesion were assessed using Doppler ultrasonography and liver fibrosis burden was assessed usingfibroscan and compared to CT results. These tests were done one month before and 6 months after intervention. A cut off point of liver stiffness measurement (LSM) at which well ablation can be predicted was evaluated by receiver operating characteristic (ROC) curve. Results: Enrollment of 56 Egyptian patients was done. Portal hypertension (PHT) indices increased significantly after transarterial chemoembolization (TACE) and while did not after microwave ablation (MWA) indicating the safety of MWA. The vascularity of hepatocellular carcinoma point out areas of residual tumor. The TACE group showed high statistically significant increase in LSM after intervention (P<0.001). ROC curve analysis showed that LSM at cut off value ≤ 35.2 KPa can predict good ablation of HCC with a sensitivity 78.38% and specificity 70.83%. Conclusion: TACE is associated with increased portal hypertension indices than MWA and Doppler parameters is a non-invasive simple technique that can be used for follow up of HCC patients after interventional therapy. Also liver stiffness measurement can be used as a good predictor of good ablation of HCC.

P078 The burden of cystic fibrosis beyond medical costs in Switzerland

P078 The burden of cystic fibrosis beyond medical costs in Switzerland

Asymmetric Regional Work Contributes to Right Ventricular Fibrosis, Inefficiency, and Dysfunction in Pulmonary Hypertension versus Regurgitation

Right ventricular (RV) pressure loading from pulmonary hypertension (PH) and volume loading from pulmonary regurgitation (PR) lead to RV dysfunction, a critical determinant of clinical outcomes, but their impact on regional RV mechanics and fibrosis is poorly characterized. The aim of this study was to test the hypothesis that regional myocardial mechanics and efficiency in RV pressure and volume loading are associated with RV fibrosis and dysfunction. Eight PH, six PR, and five sham-control rats were studied. The PH rat model was induced using Sugen5416, a vascular endothelial growth factor receptor 2 inhibitor, combined with chronic hypoxia. PR rats were established by surgical laceration of the pulmonary valve leaflets. Six (n=4) or 9 (n=4) weeks after Sugen5416 and hypoxia and 12weeks after PR surgery, myocardial strain and RV pressure were measured and RV pressure-strain loops generated. We further studied RV regional mechanics in 11 patients with PH. Regional myocardial work was calculated as the pressure-strain loop area (mm Hg ∙ %). Regional myocardial work efficiency was quantified through wasted work (ratio of systolic lengthening to shortening work). The relation of regional myocardial work to RV fibrosis and dysfunction was analyzed. In rats, PH and PR induced similar RV dilatation, but fractional area change (%) was lower in PH than in PR. RV lateral wall work was asymmetrically higher in PH compared with sham, while septal work was similar to sham. In PR, lateral and septal work were symmetrically higher versus sham. Myocardial wasted work ratio was asymmetrically increased in the PH septum versus sham. Fibrosis in the RV lateral wall, but not septum, was higher in PH than PR. RV fibrosis burden was linearly related to regional work and to measures of RV systolic and diastolic function but not to wasted myocardial work ratio. Patients with PH demonstrated similar asymmetric and inefficient regional myocardial mechanics. Asymmetric RV work and increased wasted septal work in experimental PH are associated with RV fibrosis and dysfunction. Future investigation should examine whether assessment of asymmetric regional RV work and efficiency can predict clinical RV failure and influence patient management.

Exploring the potential effect of paricalcitol on markers of inflammation in de novo renal transplant recipients.

Following a successful renal transplantation circulating markers of inflammation may remain elevated, and systemic inflammation is associated with worse clinical outcome in renal transplant recipients (RTRs). Vitamin D-receptor (VDR) activation is postulated to modulate inflammation and endothelial function. We aimed to explore if a synthetic vitamin D, paricalcitol, could influence systemic inflammation and immune activation in RTRs. Newly transplanted RTRs were included in an open-label randomized controlled trial on the effect of paricalcitol on top of standard care over the first post-transplant year. Fourteen pre-defined circulating biomarkers reflecting leukocyte activation, endothelial activation, fibrosis and general inflammatory burden were analyzed in 74 RTRs at 8 weeks (baseline) and 1 year post-engraftment. Mean changes in plasma biomarker concentrations were compared by t-test. The expression of genes coding for the same biomarkers were investigated in 1-year surveillance graft biopsies (n = 60). In patients treated with paricalcitol circulating osteoprotegerin levels increased by 0.19 ng/ml, compared with a 0.05 ng/ml increase in controls (p = 0.030). In graft tissue, a 21% higher median gene expression level of TNFRSF11B coding for osteoprotegerin was found in paricalcitol-treated patients compared with controls (p = 0.026). Paricalcitol treatment did not significantly affect the blood- or tissue levels of any other investigated inflammatory marker. In RTRs, paricalcitol treatment might increase both circulating and tissue levels of osteoprotegerin, a modulator of calcification, but potential anti-inflammatory treatment effects in RTRs are likely very modest. [NCT01694160 (2012/107D)]; [www.clinicaltrials.gov].

Atrial fibrillation\u2014a complex polygenetic disease

Atrial fibrillation (AF) is the most common type of arrhythmia. Epidemiological studies have documented a substantial genetic component. More than 160 genes have been associated with AF during the last decades. Some of these were discovered by classical linkage studies while the majority relies on functional studies or genome-wide association studies. In this review, we will evaluate the genetic basis of AF and the role of both common and rare genetic variants in AF. Rare variants in multiple ion-channel genes as well as gap junction and transcription factor genes have been associated with AF. More recently, a growing body of evidence has implicated structural genes with AF. An increased burden of atrial fibrosis in AF patients compared with non-AF patients has also been reported. These findings challenge our traditional understanding of AF being an electrical disease. We will focus on several quantitative landmark papers, which are transforming our understanding of AF by implicating atrial cardiomyopathies in the pathogenesis. This new AF research field may enable better diagnostics and treatment in the future.

T1 mapping and feature tracking imaging of left ventricular extracellular remodeling in severe aortic stenosis.

Left ventricular (LV) extracellular remodeling is a critical process in aortic stenosis (AS), which is related to functional abnormalities. Data regarding the use of combined T1 mapping and feature tracking (FT) to assess LV extracellular remodeling in severe AS are scarce. This study aimed to investigate the ability of T1-derived and FT-derived parameters to identify and assess the changes in process of LV extracellular remodeling in patients with severe AS. A total of 49 patients with severe AS and 20 healthy volunteers were prospectively recruited. Modified look-locker inversion-recovery T1 mapping and FT imaging were performed in all participants using 3.0-T cardiac magnetic resonance imaging. The degree of myocardial fibrosis was quantified using Masson trichrome stain in biopsy specimens obtained intraoperatively from 13 patients and expressed as collagen volume fraction (CVF). Patients were divided into subgroups according to preserved LV ejection fraction (LVEF) (LVEF ≥50%) or reduced LVEF (LVEF <50%). Regarding the diffuse fibrosis burden, extracellular volume (ECV) was statistically insignificant between patients with preserved LVEF) and controls (28.0%±3.3% vs. 26.5%±2.3%, P>0.05). ECV in the reduced LVEF group (n=20) was significantly higher than that in the preserved LVEF group (n=29) (30.4%±3.9% vs. 28.0%±3.3%, P<0.05). Regarding the myocardial strain, global longitudinal strain (GLS) showed increasing impairment from the control group to the preserved LVEF AS group to the reduced LVEF AS group (-23.4%±3.3% vs. -18.6%±3.8% vs. -11.2%±4.8%, P<0.05). A significant correlation was found between ECV and CVF (r=0.64, P=0.020), whereas the correlation between GLS and CVF was insignificant. Significant correlations were observed between GLS and LV mass index (r=0.72, P=0.006) and LVEF (r=0.82, P<0.001). However, no correlations were found between ECV and LV mass index (P=0.172) and between ECV and LVEF (P=0.339). Discrimination of patients with preserved LVEF from controls, GLS yielded the best diagnostic performance as defined by the area of under the curve (-0.83), and GLS, ECV, and post-T1 were significant discriminators after regression analysis. In the process of LV extracellular remodeling in severe AS, ECV is the structural marker of extracellular fibrosis burden, and GLS is the functional marker before the fibrosis burden intensifies.

Fully Automatic Atrial Fibrosis Assessment Using a Multilabel Convolutional Neural Network.

Pathological atrial fibrosis is a major contributor to sustained atrial fibrillation. Currently, late gadolinium enhancement (LGE) scans provide the only noninvasive estimate of atrial fibrosis. However, widespread adoption of atrial LGE has been hindered partly by nonstandardized image processing techniques, which can be operator and algorithm dependent. Minimal validation and limited access to transparent software platforms have also exacerbated the problem. This study aims to estimate atrial fibrosis from cardiac magnetic resonance scans using a reproducible operator-independent fully automatic open-source end-to-end pipeline. A multilabel convolutional neural network was designed to accurately delineate atrial structures including the blood pool, pulmonary veins, and mitral valve. The output from the network removed the operator dependent steps in a reproducible pipeline and allowed for automated estimation of atrial fibrosis from LGE-cardiac magnetic resonance scans. The pipeline results were compared against manual fibrosis burdens, calculated using published thresholds: image intensity ratio 0.97, image intensity ratio 1.61, and mean blood pool signal +3.3 SD. We validated our methods on a large 3-dimensional LGE-cardiac magnetic resonance data set from 207 labeled scans. Automatic atrial segmentation achieved a 91% Dice score, compared with the mutual agreement of 85% in Dice seen in the interobserver analysis of operators. Intraclass correlation coefficients of the automatic pipeline with manually generated results were excellent and better than or equal to interobserver correlations for all 3 thresholds: 0.94 versus 0.88, 0.99 versus 0.99, 0.99 versus 0.96 for image intensity ratio 0.97, image intensity ratio 1.61, and +3.3 SD thresholds, respectively. Automatic analysis required 3 minutes per case on a standard workstation. The network and the analysis software are publicly available. Our pipeline provides a fully automatic estimation of fibrosis burden from LGE-cardiac magnetic resonance scans that is comparable to manual analysis. This removes one key source of variability in the measurement of atrial fibrosis.

PRS78 Burden of Idiopathic Pulmonary Fibrosis (IPF) on Quality of Life (QOL), Work Productivity and Healthcare Use

Despite recent advances, current IPF therapies fail to halt progression and have limited impact on QoL. Hospitalization due to IPF is common. We studied real-world burden of IPF on QoL (EQ-5D), hospitalization, work impairment and healthcare visits. A large cross-sectional survey was conducted in France, Germany, Japan and the USA; 244 physicians reported data on 1,249 patients with IPF, 739 of whom provided self-reported data. EQ-5D health utility values in IPF were worse than moderate-to-severe chronic obstructive pulmonary disease and similar to non-small cell lung cancer, based on comparative real-world data. Those on treatment (84.7%) consulted a healthcare professional more than those untreated (8.5 vs 5.2 visits/year); 33% and 10% made ≥10 visits/year, respectively, largely for routine check-ups and repeat prescriptions. Hospitalization was more common when disease was perceived as severe by physicians, but 5–17% of patients with mild functional impairment were still hospitalized in the last year. Work productivity was impaired by 28%, 45%, 40% and 34% in France, Germany, Japan and USA, respectively. Data show the marked burden of IPF on QoL, work productivity and healthcare resource use, highlighting the need for optimization of current management. ACKNOWLEDGMENTS : This study was funded by Galapagos NV (Mechelen, Belgium). Writing support from Hannah Mace MPharmacol, CMPP (Aspire Scientific Ltd, Bollington, UK) was funded by Galapagos NV.

Abstract 14899: Personalized Computational Modeling Identifies Embolic Stroke of Undetermined Source Patients With Potential Arrhythmic Substrate

Introduction: Late-gadolinium enhanced (LGE)-MRI has revealed atrial fibrotic remodeling in embolic stroke of undetermined source (ESUS) patients. Curiously, fibrosis levels in ESUS patients are the same as those observed in AF. A potential explanation is that ESUS patients have pre-clinical arrhythmic substrate, but lack the triggers needed to initiate AF. Hypothesis: Simulations in computational models reconstructed from LGE-MRI scans can determine if the fibrotic substrate of a particular ESUS patient has the capacity to sustain reentry. Methods: ESUS (per standard criteria) was verified by a neurologist. 45 ablation-naïve AF patients and 45 ESUS patients within three months of stroke underwent LGE-MRI for fibrosis assessment. Left atrial (LA) models were built from LGE-MRI scans. Fiber orientations were mapped into each LA model using universal atrial coordinates. Burst pacing from 15 sites was used to test inducibility of arrhythmia sustained by reentry (Fig A). Results: In 23/45 (51%) ESUS and 29/45 (64%) AF models, we observed sustained reentry. Fibrosis burden was significantly higher for patients in whom simulations suggested the existence of pre-clinical arrhythmic substrate; however, within the inducible and non-inducible sub-groups, there was no significant difference in fibrosis burden for ESUS vs. AF patients (Fig B). This suggests that the presence of pre-clinical substrate in ESUS is correlated with fibrosis burden, although exceptions to this supposition were not uncommon (i.e., inducible low-fibrosis and non-inducible high-fibrosis models; Fig C). Conclusions: In this modeling study, pro-arrhythmic properties of fibrosis in ESUS and AF are indistinguishable. This suggests that some ESUS patients have pre-clinical fibrotic substrate, but do not have AF due to a lack of suitable triggers. Ongoing clinical follow-up will test whether abundance of pre-clinical substrate is predictive of incident AF.

Abstract 16758: Presence of Left Atrial Fibrosis Contributes to Aberrant Hemodynamics and Increased Risk of Stroke in Atrial Fibrillation Patients

Introduction: Atrial fibrillation (AF) patients are at high risk of stroke, with the left atrial appendage (LAA) found to be the most common site of clot formation. Left atrial (LA) fibrosis is also associated with higher stroke risk. However, the mechanisms for increased stroke risk in patients with atrial fibrotic remodeling are poorly understood. We sought to explore these specific mechanisms using fluid dynamics analysis. Hypothesis: The presence of LA fibrosis leads to aberrant hemodynamics in the atria, contributing to increased stroke risk in AF patients. Methods: We retrospectively collected LGE-MRI images of 3 AF patients and reconstructed their 3D LA endocardial surfaces. Fibrotic regions were identified as those with intensity 3 standard deviations greater than the mean LA blood-pool intensity. Personalized computational fluid dynamic simulations were performed, and hemodynamics at the LA wall were quantified by wall shear stress (WSS, friction of blood) and oscillatory shear index (OSI, temporal directional change of WSS). For each case, WSS and OSI were compared between fibrotic and normal regions. Results: WSS was significantly lower in the fibrotic region as compared to normal region for all 3 cases. Additionally, OSI was higher in the fibrotic region as compared to normal region for all 3 cases. However, this different was statistically significant for cases 1 and 3; case 2 was not statistically significantly different. Low WSS and high OSI in the vicinity of the fibrotic wall suggest that local blood-flow was slow and oscillating, enabling pro-thrombotic conditions for circulating blood. Conclusion: LA fibrosis correlates with regions of aberrant hemodynamics, which renders it susceptible to blood thrombosis. AF patients with high LA fibrosis burden will have more pro-thrombotic regions, in addition to low flow in the LAA, providing more sites for a potential clot formation. These conditions might get exacerbated during an AF event and cause stroke.

Haploidentical Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide in Patients with Myelofibrosis: A Multi-Institutional Experience

Haploidentical Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide in Patients with Myelofibrosis: A Multi-Institutional Experience

Precision medicine: myocardial fibrosis burden and genotype predict outcome in non-ischemic dilated cardiomyopathy (DCM)

Abstract Introduction Myocardial fibrosis occurs during pathological remodeling of the heart and can be associated with worse outcome in affected patients. Genetic background is also known to affect patients' survival. In this study we sought to estimate patients' overall fibrosis burden by combining independent modalities including left ventricular endomyocardial biopsy (LV-EMB), circulating biomarkers, and cMRI. We also aimed to use patients' genetics information to predict outcome. Furthermore, we investigated the correlation between cardiac fibrosis and genetic variations to detect novel susceptibility loci for fibrosis in DCM. Methods A total number of 542 DCM patients were included. Collagen volume fraction (CVF) was automatically estimated from biopsies. 13 circulating fibrosis biomarkers were measured using Human Magnetic Luminex Screening Assays, and the cMRIs were screened for presence of LGE. Whole exome sequencing (WES) was performed in 410 patients of the cohort using illumina HiSeq 2000. Common (MAF ≥0.05 in the study population OR gnomAD NFE AF ≥0.01) and non-common missense variants (MAF &amp;lt;0.05 in the study population AND gnomAD NFE AF &amp;lt;0.01) in 42 DCM genes were tested for associations with end points using single variants and burden analyses respectively. Analyses were adjusted for age and sex and performed using R and SKAT. End points were all-cause mortality and a composite of heart failure (HF) associated events. Results The median follow-up time was 43.2 months (2084 patient-years). Sixty-two patients reached the composite end point and 55 died. LV-EMB proved to be a safe procedure with a total complication rate of 2.3%. Machine learning based characterization of biopsies was highly accurate. Although the 3 different modalities did not significantly correlate with one another, the extent of CVF, levels of MMP-2, TIMP-1, OPN, and GDF-15, and presence of LGE were each significantly associated with worse outcome. Four possible susceptibility loci for cardiac fibrosis in DCM were introduced and underwent eQTL analyses. Rare missense variants in a list of 11 DCM-related genes showed to be associated with the 2 outcome measures or fibrosis burden. Conclusions LV-EMB, fibrosis biomarkers, and cMRI likely capture different aspects of a detrimental fibrosis process and may be combined to estimate patients' prognosis and monitor therapeutic success. Phenotype-genotype association studies help elucidate novel disease pathomechanisms and individualize patients' treatment. Funding Acknowledgement Type of funding source: Other. Main funding source(s): German Centre for Cardiovascular Research: DZHK

Three-dimensional volume-strain loops may reflect fibrosis in hypertrophic cardiomyopathy

Abstract Background Combined plotting of deformation parameters against other indices [e.g. arterial pressure, left ventricular (LV) volume] might offer additional information about different diseases. Especially in hypertrophic cardiomyopathy (HCM) this approach might offer new insights into the various phenotypic and pathophysiologic features of this entity. Purpose Aim of this study was i) to apply strain-volume loops in HCM based on simultaneous frame-by-frame strain and volume changes' recordings acquired by means of three-dimensional (3D) speckle tracking imaging and ii) to investigate potential correlations between these loops and phenotypic features of HCM (including thickness, obstruction and fibrosis). Methods We included 40 HCM patients (54.1±14.3 years, 82.5% male, maximum wall thickness 19.3±4.8mm) who have consecutively undergone 3D-speckle tracking echocardiography and cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE). Values of 3D strain were plotted vs. volume for each frame to build a strain–volume loop. Peak of radial, longitudinal, and circumferential systolic strain (Rsp, Lsp, and Csp, respectively), systolic slopes of the loops (RsSl, LsSl, CsSl), and strain to end-diastolic volume (EDV) ratio (Rs/V, Ls/V, Cs/V) were computed for the analysis (panel A). Additionally, burden of fibrosis (percentage of LV mass) was defined by LGE extent (&amp;gt;5 standard deviations compared to nulled myocardium) in CMR slices. Results All HCM patients had preserved EF (60.5±5,7%), while 16 (40%) had LV outflow tract obstruction (LVOTO&amp;gt;30 mm Hg at rest). Mean LV mass index was 78.9±14.5 g (evaluated by 3D echocardiography). LGE was observed in 23 patients (57.5%) occupying 5.2±4.5% of LV mass. Concerning strain-volume loops the following values were recorded for radial (Rsp 30.8±9.8%, RsSl 0.4±0.13 and Rs/V 0.25±0.09), longitudinal (Lsp −9.4±3.7%, LsSl 0.12±0.06 and Ls/V 0.08±0.04) and circumferential deformation (Csp −14.2±3.5%, CsSl 0.18±0.05 and Cs/V 0.11±0.03). Among typical HCM characteristics tested (LV mass, LVOTO and LGE), only LV mass presented significant correlations with LsSl (r=−0.41, p&amp;lt;0.01). Interestingly, HCM patients with smaller LVMI and without LGE presented steeper and narrower (difference between systolic and diastolic strain for the same volume) longitudinal strain-volume loops compared to patients with larger LVMIs and fibrosis (panel B). Conclusions Strain-volume loop is an innovative application of 3D deformation imaging in HCM. According to this new non-invasive method, increase of LVMI in HCM is accompanied by less longitudinal contribution to stroke volume, whereas better systolic-diastolic coupling may exclude the presence of underlying fibrosis. Funding Acknowledgement Type of funding source: None

Novel Concepts of Treatment for Patients with Myelofibrosis and Related Neoplasms.

Simple SummaryMyelofibrosis (MF) is an advanced form of a group of rare, related bone marrow cancers termed myeloproliferative neoplasms (MPNs). Some patients develop myelofibrosis from the outset, while in others, it occurs as a complication of the more indolent MPNs, polycythemia vera (PV) or essential thrombocythemia (ET). Patients with PV or ET who require drug treatment are typically treated with the chemotherapy drug hydroxyurea, while in MF, the targeted therapies termed Janus kinase (JAK) inhibitors form the mainstay of treatment. However, these and other drugs (e.g., interferons) have important limitations. No drug has been shown to reliably prevent the progression of PV or ET to MF or transformation of MPNs to acute myeloid leukemia. In PV, it is not conclusively known if JAK inhibitors reduce the risk of blood clots, and in MF, these drugs do not improve low blood counts. New approaches to treating MF and related MPNs are, therefore, necessary.Janus kinase (JAK) inhibition forms the cornerstone of the treatment of myelofibrosis (MF), and the JAK inhibitor ruxolitinib is often used as a second-line agent in patients with polycythemia vera (PV) who fail hydroxyurea (HU). In addition, ruxolitinib continues to be studied in patients with essential thrombocythemia (ET). The benefits of JAK inhibition in terms of splenomegaly and symptoms in patients with MF are undeniable, and ruxolitinib prolongs the survival of persons with higher risk MF. Despite this, however, “disease-modifying” effects of JAK inhibitors in MF, i.e., bone marrow fibrosis and mutant allele burden reduction, are limited. Similarly, in HU-resistant/intolerant PV, while ruxolitinib provides excellent control of the hematocrit, symptoms and splenomegaly, reduction in the rate of thromboembolic events has not been convincingly demonstrated. Furthermore, JAK inhibitors do not prevent disease evolution to MF or acute myeloid leukemia (AML). Frontline cytoreductive therapy for PV generally comprises HU and interferons, which have their own limitations. Numerous novel agents, representing diverse mechanisms of action, are in development for the treatment of these three classic myeloproliferative neoplasms (MPNs). JAK inhibitor-based combinations, all of which are currently under study for MF, have been covered elsewhere in this issue. In this article, we focus on agents that have been studied as monotherapy in patients with MF, generally after JAK inhibitor resistance/intolerance, as well as several novel compounds in development for PV/ET.

Magnetic Resonance Imaging-Guided Fibrosis Ablation for the Treatment of Atrial Fibrillation: The ALICIA Trial.

Myocardial fibrosis is key for atrial fibrillation maintenance. We aimed to test the efficacy of ablating cardiac magnetic resonance (CMR)-detected atrial fibrosis plus pulmonary vein isolation (PVI). This was an open-label, parallel-group, randomized, controlled trial. Patients with symptomatic drug-refractory atrial fibrillation (paroxysmal and persistent) undergoing first or repeat ablation were randomized in a 1:1 basis to receive PVI plus CMR-guided fibrosis ablation (CMR group) or PVI alone (PVI-alone group). The primary end point was the rate of recurrence (>30 seconds) at 12 months of follow-up using a 12-lead ECG and Holter monitoring at 3, 6, and 12 months. The analysis was conducted by intention-to-treat. In total, 155 patients (71% male, age 59±10, CHA2DS2-VASc 1.3±1.1, 54% paroxysmal atrial fibrillation) were allocated to the PVI-alone group (N=76) or CMR group (N=79). First ablation was performed in 80% and 71% of patients in the PVI-alone and CMR groups, respectively. The mean atrial fibrosis burden was 12% (only ≈50% of patients had fibrosis outside the pulmonary vein area). One hundred percent and 99% of patients received the assigned intervention in the PVI-alone and CMR group, respectively. The primary outcome was achieved in 21 patients (27.6%) in the PVI-alone group and 22 patients (27.8%) in the CMR group (odds ratio: 1.01 [95% CI, 0.50-2.04]; P=0.976). There were no differences in the rate of adverse events (3 in the CMR group and 2 in the PVI-alone group; P=0.68). A pragmatic ablation approach targeting CMR-detected atrial fibrosis plus PVI was not more effective than PVI alone in an unselected population undergoing atrial fibrillation ablation with low fibrosis burden. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02698631.