Fibrosis Burden Research Articles

Ultrasound shear wave elastography for detection of myocardial fibrosis

Abstract Background Myocardial fibrosis has important clinical and prognostic implications. Cost-effective imaging tools for fibrosis screening to enable personalized therapies are thus of major interest. Echocardiographic shear wave (SW) elastography is an emerging approach for measuring myocardial stiffness (MS). SWs occur after mechanical excitation of the myocardium, e.g. after mitral valve closure (MVC,i.e natural SW), and their propagation velocity is directly related to MS. Purpose To investigate if natural SW velocities can detect myocardial fibrosis. Methods We included 99 subjects (31 heart transplant patients[52±17years, 77% male], 23 patients with hypertrophic cardiomyopathy [55±16 years, 78% male] and 45 healthy volunteers [HV, 44±17 years, 71% male]). SW elastography was performed in parasternal long axis views of the left ventricle (LV) using an experimental scanner (HD-PULSE) at 1134±255 frames per second. Tissue acceleration maps were extracted from an anatomical M-mode line along the midline of the LV septum. SW propagation velocity at MVC was measured as slope in the M-mode image. Patients underwent besides conventional echocardiography also 1.5T cardiac magnetic resonance with T1 mapping as well as late gadolinium enhancement (LGE) to assess the presence of myocardial fibrosis (Fig 1). Subjects were divided into 4 groups: HV, patients with no fibrosis (NF), interstitial fibrosis (MIF) and replacement fibrosis (MRF). Results SW velocities differed significantly among groups (p<0.0001, Fig 2A). The NF group showed higher SW velocities than HV (4.3±1.3 vs. 3.4±0.9 m/s, p=0.02), while both MIF and MRF groups showed significantly higher values than NF subjects (6.5±1.1 and 8.7±1.2 m/s, respectively). SW velocity showed significant correlations with ECV values (r=0.70) and T1 values (r=0.47), and markers of LV diastolic function (E/e’: r=0.54; isovolumetric relaxation time: r=0.41; deceleration time: r=0.30 (all p<0.01)(Fig 2B-D). A cut-off SW velocity of 3.86m/s allowed to differentiate between HV and the NF group with a sensitivity of 65% and a specificity of 76% (area under the curve (AUC)= 0.73). A cut-off of 4.58 m/s distinguished between HV and all patient groups (sensitivity 95%, specificity 73%, AUC 0.88). SW velocities below 6.01 m/s showed highest accuracy to identify patients without any type of fibrosis (sensitivity 97%, specificity 90%, AUC=0.97). A cut-off of 8.11 m/s could distinguish MRF from MIF with a sensitivity and specificity of 100% and 69%, respectively (AUC=0.92). Conclusions SW velocity measurements can differentiate between fibrotic myocardium and healthy tissue with very good accuracy. Different types of fibrosis (interstitial vs. replacement) could also be distinguished. Nevertheless, we hypothesize that stiffness changes relate mainly to the fibrosis burden. Shear wave elastography appears as promising new tool for the non-invasive assessment of myocardial fibrosis.

P0079 Serum calprotectin [cpa9-hne], a biomarker of neutrophil activity, is associated with histological inflammation and fibrosis burden

Abstract Background Infiltration of neutrophils into the intestinal tissue is a crucial component of the inflammatory response in Crohn‘s disease (CD). CPa9-HNE, a calprotectin fragment released by human neutrophil elastase during NETosis, has been shown to strongly correlate with endoscopic disease activity in inflammatory bowel disease (IBD) and serves as an indicator for pharmacodynamic response. Furthermore, emerging data suggests that neutrophil extracellular traps (NETs) significantly contribute to the pathogenesis of fibrosis. For the first time, we investigated the association of CPa9-HNE with histological grading of both inflammation and fibrosis. Methods The cohort included 62 patients with stenotic Crohn‘s disease. Inclusion criterion was the presence of stenotic disease requiring bowel resection, as confirmed by radiographic assessment. Upon surgery, the resected specimens were collected and histologically graded according to transmural fibrosis burden, and inflammation (D'Haens score). Serum was drawn at baseline (before resection). CPa9-HNE was measured, reflecting a human neutrophil elastase-derived fragment of calprotectin. Spearman’s rank correlation was applied. Results CPa9-HNE showed an overall positive correlation to the D'Haens score (ρ=0.279, p<0.005). Significant positive correlation was observed between CPa9-HNE and the presence of neutrophils, both in the epithelium and the lamina propria (ρ=0.309, ρ=0.349, p<0.005 both), as well as with epithelial damage (ρ=0.262, p<0.005). We also observed a positive correlation between CPa9-HNE and transmural fibrosis burden, specifically fibrosis in the submucosa (ρ=0.294, p<0.005) Conclusion This study showed that CPa9-HNE, a biomarker of neutrophil activity, correlated with the presence of neutrophils in the intestinal tissue, as well as epithelial damage. Interestingly, CPa9-HNE also showed association to submucosal fibrosis, emphasizing the importance of considering neutrophil activity when targeting the fibro-inflammatory axis. These findings highlight the potential use of CPa9-HNE as a complementary tool for histological grading of inflammation and fibrosis burden, and could be used to further explore the role of neutrophil extracellular traps in intestinal fibrosis.

P0114 Tracking Crohn’s Disease Progression through Extracellular Matrix Remodeling: A Longitudinal Study of Pre- and Post-Resection Samples

Abstract Background Crohn's disease (CD) is a chronic inflammatory condition that can lead to irreversible intestinal damage. Fibrosis, caused by imbalanced extracellular matrix (ECM) remodeling, is difficult to manage, as current anti-inflammatory treatments do not prevent or reverse these processes. ECM fragments released during remodeling may serve as biomarkers for transmural disease activity and fibrosis burden. This study evaluated the correlation of serum C3M, PRO-C3, and PRO-C16 levels and their potential to differentiate between stenosing and luminal CD. Methods In this prospective cohort study 62 patients with stenosing CD requiring resection without residual disease and 49 with luminal CD managed medically were included. Phenotype was assessed by diagnostic imaging and/or endoscopy at inclusion. Serum levels of C3M, PRO-C3, and PRO-C16 were measured pre- and post-resection, Neo-epitope specific biomarkers of type III collagen degradation (C3M) and type III and XVI collagen formation (PRO-C3, PRO-C16) were measured in serum using a competitive ELISA. To compare the stenotic and luminal groups, the Wilcoxon signed-rank test was used, and for pre- and post-resection ECM marker values, one-way ANOVA with Tukey’s post hoc was applied. Results Baseline levels of PRO-C3 were significantly higher in patients with stenosing CD compared to those with luminal CD (57.3 (IQR: 47.7-75.7)) vs 43.4 (36.0-52.9) ng/ml, p<0.001). Conversely, PRO-C16 levels were higher in the luminal group compared to the stenotic group (2961.5 (2780.8-3264.3) vs 2677.0 (2407.5-2904.5), p<0.001). C3M levels showed no difference at baseline between stenotic and luminal patients (596.0 (546.0-677.5) vs 585.0 (538.5-643.3), p=0.394). Post-resection, C3M and PRO-C3 levels decreased initially (p=0.003 and <0.001), then showed an increase at one month, stabilizing from three to twelve months. The median PRO-C16 value decreased significantly the day after surgery and subsequently increased throughout the first year to levels exceeding pre-resection values (Figure 1). Conclusion Baseline biomarker differences between stenosing and luminal CD suggest their potential to distinguish disease phenotypes. However, a sustained post-operative change in ECM markers linked to fibrostenotic phenotype was not observed in patients, challenging this explanation. Day one post-resection ECM marker changes likely reflected wound healing, while subsequent dynamics may indicate collagen processes relevant to stenosis formation without being primary local drivers. These findings underscore the need for longitudinal and cross-sectional studies to clarify ECM biomarkers' role in tissue repair and fibrosis in CD.

Exploring the regulatory impact of insulin on type I collagen synthesis in hepatic stellate cells through α5β1 integrin

In the present study by Dodig and colleagues, published in Metabolism and Target Organ Damage , the authors investigate the role of insulin in promoting type I collagen synthesis in hepatic stellate cells (HSCs) through α5β1 integrin signaling. Using L-SACC1 transgenic mice, which exhibit hyperinsulinemia and insulin resistance without fasting hyperglycemia, the researchers demonstrate that elevated insulin levels significantly increase type I collagen production in HSCs. This effect is mediated by α5β1 integrin signaling rather than the PI3 kinase pathway. These findings suggest that chronic hyperinsulinemia may preprogram HSCs for enhanced fibrogenesis following liver injury, contributing to advanced fibrosis associated with metabolic disorders such as metabolic dysfunction-associated steatosis liver disease (MASLD) and type 2 diabetes. It further suggests that chronic hyperinsulinemia increases the risk of significant fibrosis burden in chronic liver disease. In this commentary, the strengths and limitations of this study are discussed, along with the potential impact of these findings on current treatment strategies for insulin resistance, endogenous hyperinsulinemia, and exogenous hyperinsulinemia in the development of MASLD and disease progression to fibrosis, cirrhosis, and hepatocellular carcinoma.

3D quantification of maximal left ventricular wall thickness: associations with global fibrosis burden and future adverse outcomes in hypertrophic cardiomyopathy

3D quantification of maximal left ventricular wall thickness: associations with global fibrosis burden and future adverse outcomes in hypertrophic cardiomyopathy

Current Burden of Steatotic Liver Disease and Fibrosis among Adults in the United States, 2017-2023.

Multi-society experts proposed the adoption of new terminology, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatotic liver disease (SLD). We studied the current prevalence of SLD and its subcategories in the US. Using the recent National Health and Nutrition Examination Survey from 2017 to 2023, we analyzed data from 12,199 participants (≥18 years) who completed transient elastography. SLD and its subcategories, including MASLD, metabolic and alcohol-related liver disease (MetALD), and alcohol-related liver disease (ALD), were categorized according to consensus nomenclature. The age-adjusted prevalence of SLD (cut-off: 285 dB/m) was 35.0% (95% confidence interval [CI]: 33.4-36.7). Within this category, the age-adjusted prevalence for MASLD was 31.9% (95% CI: 30.4-33.4), MetALD 2.2% (95% CI: 1.8-2.6), and ALD 0.8% (95% CI: 0.6-1.1). The prevalence of SLD and MASLD showed a statistically insignificant decrease during COVID-19, while ALD increased without significance. In contrast, the prevalence of advanced fibrosis in SLD was significantly higher during the COVID-19 era, at 9.8% for 285 dB/m and 7.8% for 263 dB/m, compared to 7.4% (P=0.039) and 6% (P=0.041) in the pre-COVID-19 era. The proportion of advanced fibrosis and cirrhosis in individuals with ALD was two-fold higher than MASLD and MetALD, largely due to increases during the COVID-19 era. While the prevalence of SLD and its subcategories remained stable, there was a significant increase in advanced fibrosis among SLD individuals during the COVID-19 era, with ALD having a proportion of advanced fibrosis and cirrhosis that was twice as high as MASLD and MetALD.

Insulin increases type I collagen synthesis in hepatic stellate cells via α5β1 integrin

Aim: A direct effect of insulin on the synthesis of extracellular matrix proteins has been described in extrahepatic organs. The current study investigates the role of insulin in type 1 collagen production in hepatic stellate cells (HSCs). Methods: Primary HSC cultures from wild-type mice and from L-SACC1 transgenic mice that exhibit hyperinsulinemia and resultant insulin resistance due to a defect in hepatic insulin clearance were used. Results: Insulin significantly increased type I collagen synthesis in HSC primary cultures in the presence of high but not low glucose concentrations. Although HSCs contain a functional, insulin-activated PI3 kinase signaling pathway, insulin increases type I collagen synthesis by mechanisms independent of PI3 kinase. Insulin stimulated α5β1 integrin levels and phosphorylation of focal adhesion kinase, a major signaling mediator in the integrin pathway. In addition, α5β1 integrin siRNA interference abolished insulin-mediated type I collagen synthesis by HSCs. L-SACC1 mice showed increased hepatic collagen deposition as compared to wild-type mice. HSCs isolated from L-SACC1 mice synthesize more type I collagen and α5β1 integrin than HSCs isolated from wild-type controls. Conclusion: Insulin exerts a direct profibrotic impact on HSCs by an α5β1 integrin-mediated mechanism, independently of the PI3 kinase signaling pathway. Thus, chronic hyperinsulinemia may potentiate liver collagen deposition in insulin resistance states. This likely increases the risk of significant fibrosis burden in chronic liver disease associated with insulin resistance.

Burden of liver steatosis and liver fibrosis in a large cohort of people living with HIV.

Liver steatosis (LS) and liver fibrosis (LF) can increase the risk of cardiovascular disease in people with HIV, but their prevalence and associated factors are poorly understood. This study aimed to assess the prevalence of and factors associated with LS and LF in a large cohort of people with HIV. We conducted a cross-sectional study of consecutive people with HIV attending the Clinic of Barcelona from September 2022 to September 2023, excluding those with chronic B or/and C hepatitis virus coinfection. LS was assessed using the Hepatic Steatosis Index (HSI) and Fatty Liver Index (FLI), and LF was assessed using the Non-Alcoholic Fatty Liver Disease Fibrosis Score (NFS), Fibrosis-4 score (FIB-4), and the European AIDS Clinical Society (EACS) algorithm in both the whole cohort (cohort 1) and in a specific cohort more susceptible to liver disease (cohort 2). We identified independent variables associated with LS and LF using logistic regression. Cohort 1 included 4664 people with HIV; 76% and 37% of them had available HSI and FLI data, LS was present in 28% and 19%, respectively. LF risk was present in 1%, 2%, and 1% of people with HIV according to NFS, FIB-4, and EACS algorithm scores, respectively. Cohort 2 included 1345 people with HIV; 60% and 30% of them had available HSI and FLI data, LS affected 55% and 43% and LF 2%, 5%, or 3%, respectively. Factors associated with LS included current CD4 cell count, diabetes, and hypertension, whereas LF was associated with previous exposure to dideoxynucleoside drugs and current CD4 to LF. Current integrase strand transfer inhibitor (INSTI) therapy appeared protective for LF in cohort 1. In this study, one in four people with HIV had LS, and the prevalence rose to one in two in those with cardiovascular risk factors. The prevalence of LF was low, but it should be considered in older people with HIV with low CD4 counts or high aspartate transaminase levels. A possible protective effect from INSTIs deserves further investigation.

Impaired myocardial energetics in both sarcomere positive and negative HCM are linked to arrhythmic risk

Abstract Background Impaired myocardial energetics play a pivotal role in the complex pathophysiology of hypertrophic cardiomyopathy (HCM), and are thought to be mediated by energy-costly sarcomeric mutations and mitochondrial dysfunction (1). Two thirds of HCM patients, however, do not possess pathogenic sarcomeric mutations (2) and instead develop the condition due to a combination of increased polygenic susceptibility and comorbidities. Whether energetic impairment, a target of novel HCM treatments (e.g., myosin modulators such as Mavacamten), similarly affects sarcomere mutation positive (Sarc+) and negative (Sarc-) HCM remains unclear, as does the association between impaired energetics and markers of arrhythmic risk such as hypertrophy severity, cardiac function and non-sustained ventricular tachycardia (NSVT). This study aimed to investigate differences in resting myocardial energetics between Sarc+ and Sarc- HCM by measuring the phosphocreatine-to-adenosine triphosphate (PCr/ATP) ratio using phosphorus magnetic resonance spectroscopy (31P-MRS) and explore the association between impaired energetics and markers of arrhythmic risk in HCM. Methods We recruited one hundred (100) participants (80 non-obstructive HCM patients and 20 age- and sex-matched controls). Myocardial energetics were assessed using 31P-MRS to measure the PCr/ATP ratio. Cardiac magnetic resonance (CMR) imaging including cine, T1 (ShMOLLI), quantitative pixel-wise perfusion mapping (3) and late gadolinium enhancement (LGE) imaging was also performed. In addition, HCM patients underwent 7-day ECG monitoring to document NSVT episodes (3 beats ≥120 bpm). Results HCM patients had impaired myocardial energetics (PCr/ATP ratio) relative to controls (HCM 1.64±0.36 vs controls 1.97±0.32 p<0.001). PCr/ATP ratios did not differ between Sarc+ and Sarc- HCM even after adjustment for confounders including age, hypertrophy and fibrosis burden (Sarc+ 1.64 [1.50-1.78] vs Sarc- 1.64 [1.52-1.77], p=0.993). PCr/ATP ratio showed no correlation with maximum wall thickness (p=0.257), left ventricular ejection fraction (p=0.727) or myocardial perfusion reserve (p=0.851), but did inversely correlate with global longitudinal strain (r=-0.3, p=0.025). Reduced PCr/ATP was associated with presence of fibrosis (LGE+ 1.58±0.35 vs LGE- 1.79±0.37 p=0.025) and with NSVT, independent of age or fibrosis burden (NSVT+ 1.54 [1.40-1.67] vs NSVT- 1.73 [1.62-1.86], p=0.046). Conclusion Myocardial energetics are similarly impaired in Sarc+ and Sarc- HCM, and are independently associated with impaired contractility, greater fibrosis severity and heightened arrhythmic risk. Our findings provide novel mechanistic insights into the potentially favourable response of HCM patients to energy-sparing myosin modulator therapies irrespective of genotype and highlight the potential for cardiac energetics to serve as a marker of arrhythmic risk.

Cardiovascular magnetic resonance to differentiate veteran athlete's heart with cavity dilatation and mild dilated cardiomyopathy

Abstract Introduction Endurance athletic training may lead to left ventricular (LV) dilatation and mildly reduced resting LV function which can be difficult to differentiate from dilated cardiomyopathy (DCM). Myocardial fibrosis is increasingly recognised in lifelong athletes and is also prevalent in DCM where it confers adverse prognosis.(1,2) However, it is unknown whether the pattern and prevalence of fibrosis in athletes with cavity dilatation differs from DCM. In this study, we compared the CMR fibrosis distribution and tissue characteristics between athletic LV dilatation and mild DCM patients. Methods We prospectively recruited 113 males; 64 endurance athletes and 49 mild DCM patients. Inclusion criteria Age 50-80 years, LVEF 45-54% and LV end-diastolic volume indexed to body surface area (LVEDVi)≥110ml/m2. Athletes trained≥10 weekly hrs for≥15 yrs. Exclusion criteria; Chest pain, prior coronary revascularisation, severe valvular disease, myocarditis, hypertrophic cardiomyopathy, inducible ischaemia or myocardial infarction on CMR. CMR protocol included volumetric assessment, T1 mapping, quantitative stress perfusion and quantitative late gadolinium enhancement. Statistical analysis between groups was performed using unpaired t-test and receiver-operator curve (ROC) analysis. Results LVEDVi was not significantly different between athletes and mild DCM patients (123.3±12.6 vs 129.8±23.1ml/m2, P=0.057). However, LVEF (52.0±6.1 vs 47.6±5.2%, P<0.001) and right ventricular (RV) EDVi (121.0±14.3 vs 97.6±25.2ml/m2, P<0.001) were both greater in athletes. There was no difference in non-ischaemic fibrosis prevalence between both groups (50.0 vs 49.0%, P=0.915) nor the burden of fibrosis (3.5±2.9 vs 7.4±12.0g, P=0.087). However, the distribution of fibrosis varied with a significantly greater prevalence of basal mid-myocardial inferolateral fibrosis amongst athletes (87.5 vs 50.0%, P=0.002) whereas basal mid-myocardial inferoseptal fibrosis was significantly more common in mild DCM (45.8 vs 9.4%, P=0.002). Native T1 (1249.0±38.1 vs 1308.3±47.1ms, P<0.001) and extracellular volume (ECV) (22.0±2.1 vs 25.9±3.5%, P<0.001) were both lower in athletes than mild DCM patients. Furthermore, athletes had higher myocardial perfusion reserve (MPR) (3.65±1.30 vs 2.76±0.92, P<0.001) and stress myocardial blood flow (MBF) (2.09±0.70 vs 1.62±0.66, P<0.001). On ROC analysis, native T1 (area under curve (AUC) 0.89, P<0.001), ECV (AUC 0.85, P<0.001) and stress MBF (AUC 0.68, P<0.001) were able to differentiate athletes and mild DCM. Native T1 and ECV were significantly better at discriminating than MPR (P<0.001). Conclusion Myocardial fibrosis was highly prevalent in both veteran endurance athlete's heart and mild DCM whilst its distribution was distinctive between the groups. Native T1 and ECV were the best discriminators. Recognition of fibrosis patterns and associated tissue characteristics may be clinically useful to differentiate these two overlapping phenotypes.Figure 1; LGE distribution in athletes cFigure 2; CMR tissue characteristics to

Left atrial morpho-functional parameters and their correlation with other phenotypic and functional characteristics of hypertrophic cardiomyopathy

Abstract Background Left atrial (LA) volume index (LAVI), LA reservoir strain (LARS) and total atrial conduction time (TACT) (estimated by tissue Doppler imaging) are morphological and functional parameters reflecting LA structural and electrical remodeling, connected to atrial fibrillation development and heart failure progression in various substrates. In hypertrophic cardiomyopathy (HCM), correlation of the above-mentioned parameters with other disease characteristics is not fully investigated. Purpose Aim of this study was to estimate the prevalence of atrial myopathy characteristics such as increased LAVI, impaired LARS and elongated TACT in a cohort of HCM patients without AF history and investigate their correlation with other phenotypic and functional characteristics of the disease such as left ventricular (LV) hypertrophy magnitude, fibrosis extent and diastolic dysfunction grade. Methods We included 100 HCM patients (54±21 years, 75% male, maximum wall thickness 19±3.4mm) without history of atrial fibrillation who have consecutively undergone 2D-speckle tracking echocardiography and cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE). TACT and LARS measurement is shown on left panel. Burden of fibrosis (percentage of LV mass) was defined by LGE extent (>5 standard deviations compared to nulled myocardium) in CMR slices. Results All HCM patients had preserved EF (60±7.5%), while 28 (28%) presented outflow tract obstruction and 10 (10%) diastolic dysfunction stage≥2. LGE was observed in 64 patients (64%) occupying 8±5% of left ventricular (LV) mass. Mean TACT was 140±22 msec, with LAVI being 32±16 mL/m2 and LARS 26±14%. Among HCM demographic, phenotypic and functional characteristics tested, age and LV mass index were found to be the only independent regressors of TACT (r=0.54, p<0.0005 and r=0.44, p=0.002 respectively, right upper panel), while E/E’ (r=-0.44, p=0.003) and fibrosis extent (r=0.36, p=0.02) were the strongest predictors of LARS and LAVI values respectively (right lower panel). Conclusions Atrial myopathy parameters seem to correlate with various morphological and functional characteristics of HCM. Atrial electro-mechanical delay assessed through TDI based TACT correlates significantly with LVMI, whereas LARS and LAVI are strong regressors of elasticity properties, partially expressed through diastolic function and underlying fibrosis.

CMR phenotypes and clinical outcomes in NYHA class I versus II-IV hypertrophic cardiomyopathy: identifying high-risk asymptomatic patients

Abstract Background Cardiac myosin inhibition therapy can deliver symptomatic benefit for NYHA class≥II patients with obstructive hypertrophic cardiomyopathy (HCM) and is being actively explored for non-obstructive phenotypes. However, expanding interest in clinical outcome reduction supports growing need to identify high risk cohorts across both symptomatic and asymptomatic cohorts. We aimed to examine phenotypic characteristics of NYHA-I versus NYHA≥II patients with HCM and their association with future outcomes. Methods 727 patients with HCM from the CIROC Registry who completed simultaneous CMR and patient health assessments, inclusive of NYHA evaluation and quality of life surveys, were studied. Baseline clinical and CMR characteristics were compared between NYHA-I and NYHA≥II cohorts, followed by risk modelling for the prediction of major adverse cardiovascular events (MACE), defined as: all-cause mortality, heart failure hospitalization, ventricular arrhythmia, new onset atrial fibrillation, or stroke. Cox models were constructed to identify independent predictors of MACE. Results Of the 727 patients, 546 (75%) reported NYHA-I and 181 (25%) NYHA≥II symptoms. Baseline characteristics are shown in Table 1. Compared to NYHA≥II, NYHA-I patients were younger, more likely male, and had a lower prevalence of diabetes and hypertension. No meaningful differences in CMR chamber volumes, function, left ventricular (LV) mass, or fibrosis burden were observed. Over a median follow up of 3.7 years, 109 patients (15%) experienced MACE: 12% in NYHA-I and 23% in NYHA≥II sub-groups (p<0.001). Baseline LV mass z-scores (determined from sex-matched, BSA-indexed SCMR healthy reference values) were independently associated with MACE by multivariable Cox modelling. An optimal LV mass z-score threshold of 3.9 for prediction of MACE was identified and combined with NYHA status to stratify patients into 4 categories. Kaplan-Meier curves showed patients with LV Mass z-scores >3.9 experienced worse event-free survival in both NYHA sub-groups (Figure 1a). Cox modelling in the overall cohort (Figure 1b) showed NYHA-I patients with LV Mass z-scores >3.9 experienced a 2.2-fold increased risk (p=0.007) of MACE, this exceeding the risk of NYHA ≥II patients below this threshold. Separate NYHA I and ≥II sub-group multivariable models showed LV Mass z-score >3.9 to remain a strong and independent predictor of MACE, providing respective hazards of 2.6 and 4.7 (p=0.001 and <0.001). Conclusions NYHA-I patients with HCM experience significantly lower rates of MACE versus NYHA≥II. However, LV mass z-scoring permits powerful sub-stratification of these sub-groups, identifying NYHA-I patients with higher LV mass who will experience worse outcomes versus NYHA≥II patients with lower LV mass. This simple yet powerful stratification offers unique potential to identify asymptomatic patients with HCM who may benefit from targeted therapeutics to reduce future MACE.

Subclinical myocardial fibrosis is almost ubiquitous in the hearts of older British persons: 'MyoFit46' cardiovascular sub-study of the NSHD

Abstract Background Unprecedented numbers are now surviving to older age, but little is known about the burden or pattern of myocardial fibrosis in the asymptomatic elderly population. Previous 1.5 Tesla (T) cardiovascular magnetic resonance (CMR) studies found a prevalence of unexpected infarct-pattern late gadolinium enhancement (LGE) of 17-20% above 75 years but less is known about non-infarct pattern scar in this group. We investigated the prevalence, patterns, and clinical predictors of left ventricular (LV) scar in a large asymptomatic older age cohort. Methods CMR with a single 3T magnet was performed on participants all born in the same week in March 1946, as part of the longest running continued surveillance birth cohort: the National Survey of Health and Development. LV short-axis stack LGE imaging was performed using a free-breathing motion-corrected balanced steady-state free precession sequence with phase-sensitive inversion-recovery. Two blinded observers independently recorded the prevalence, extent, and pattern of LGE per participant. Logistic regression was used to study the association between clinicodemographic parameters and LGE. Results 460 participants were prospectively recruited of which 406 completed CMR with LGE imaging (77.8 ± 0.1 years, 44% male). 341 (84%) demonstrated LGE affecting a mean of 2.1±1.2 myocardial segments per participant (Figure 1). The commonest pattern of LGE was inferior right ventricular insertion point (RVIP), observed in 66.9%. Other patterns included (Figure 2): Linear mid-wall (19.6%) of which 38% were located in the inferior/lateral walls; subepicardial (12.1%); subendocardial infarct-pattern (8.8%); patchy/diffuse (1.6%); embolic LGE (0.6%). Sub-analysis was performed comparing those without significant unexpected fibrosis (LGE–) vs those with focal fibrosis (LGE+, excluding RVIP and those participants with a known history of prior myocardial infarction). LGE+ participants were more likely to be female (71.7% vs 49.1%, p<0.001) or diabetic (11.3% vs 5.1%, p=0.05), had a higher body surface area (BSA, 1.9 vs 1.8 m2, p<0.001), weight (80.1 vs 72.8 kg, p<0.001), LV indexed end systolic volume (24.2 vs 20.4 ml/m2, p=0.001) and LV indexed mass (59.2 vs 55.4 g/m2, p<0.001), and a lower LV ejection fraction (67.9 vs 71.8%, p<0.001) In multivariable logistic regression: BSA, LV indexed mass, LV ejection fraction and diabetic status were independently associated with LGE+ status (odds ratios [95% confidence intervals]: 9.4 [0.7–3.8]; 1.0 [0.01–0.05]; 0.9 [-0.08--0.02]; and 2.5 [0.03–1.7] respectively, p<0.05). Conclusion Advanced PSIR MOCO LGE imaging at 3T reveals that the majority (84%) of asymptomatic British persons above the age of 75 harbour unexpected ‘subclinical’ focal fibrosis, with a substantial proportion of these scars consistent with probable historical myocarditis events. Further work will now explore the life-course determinants of this scar burden in the older age human heart.

Non-specific myocardial fibrosis in young competitive athletes: clinical significance and risk prediction by a powerful machine learning-based model.

Non-specific myocardial fibrosis (NSMF) is a heterogeneous entity. We aimed to evaluate young athletes with and without NSMF to establish potentially clinically significance. We analysed data from 328 young athletes. We identified 61 with NSMF and compared them with 75 matched controls. Athletes with NSMF were divided into Group 1 (n = 28) with 'minor' fibrosis and Group 2 (n = 33) with non-insertion point fibrosis, defined as 'major'. Athletes were followed-up for adverse events. Finally, we tested various machine learning (ML) algorithms to create a prediction model for 'major' fibrosis. We created 4 different classifiers. Athletes of black ethnicity were more likely to have a subepicardial pattern (OR: 5.0, p = 0.004). Athletes with 'major' fibrosis demonstrated a higher prevalence of lateral T-wave inversion (TWI) ( < 0.001) and ventricular arrhythmias (VEs > 500/24h, p = 0.046; non-sustained VT, p = 0.043). Athletes with 'minor' fibrosis demonstrated higher right ventricular volumes (p = 0.013), maximum Watts (p = 0.022) and maximum VO2 (p = 0.005). Lateral TWI (p = 0.026) and VO2 < 44mL/min/Kg (p = 0.040) remained the only significant predictors for 'major' fibrosis. During follow up, athletes with 'major' fibrosis were 9.1 times more likely to exhibit adverse events (OR 13.4, p = 0.041). All ML models outperformed the benchmark method in predicting significant MF, best accuracy achieved by the random forest classifier (90%). Lateral TWI and reduced exercise performance are associated with higher burden of fibrosis. Fibrosis was associated with increased ventricular arrhythmia and adverse events. A comprehensive assessment can help develop a ML-based model for significant fibrosis, which could also guide clinical practice and appropriate CMR referrals.

Autonomic modulation impacts conduction velocity dynamics and wavefront propagation in the left atrium.

Atrial fibrosis and autonomic remodelling are proposed pathophysiological mechanisms in atrial fibrillation (AF). Their impact on conduction velocity (CV) dynamics and wavefront propagation was evaluated. Local activation times (LATs), voltage, and geometry data were obtained from patients undergoing ablation for persistent AF. LATs were obtained at three pacing intervals (PIs) in sinus rhythm (SR). LATs were used to determine CV dynamics and their relationship to local voltage amplitude. The impact of autonomic modulation- pharmacologically and with ganglionated plexi (GP) stimulation, on CV dynamics, wavefront propagation, and pivot points (change in wavefront propagation of ≥90°) was determined in SR. Fifty-four patients were included. Voltage impacted CV dynamics whereby at non-low voltage zones (LVZs) (≥0.5 mV) the CV restitution curves are steeper [0.03 ± 0.03 m/s ΔCV PI 600-400 ms (PI1), 0.54 ± 0.09 m/s ΔCV PI 400-250 ms (PI2)], broader at LVZ (0.2-0.49 mV) (0.17 ± 0.09 m/s ΔCV PI1, 0.25 ± 0.11 m/s ΔCV PI2), and flat at very LVZ (<0.2 mV) (0.03 ± 0.01 m/s ΔCV PI1, 0.04 ± 0.02 m/s ΔCV PI2). Atropine did not change CV dynamics, while isoprenaline and GP stimulation resulted in greater CV slowing with rate. Isoprenaline (2.7 ± 1.1 increase/patient) and GP stimulation (2.8 ± 1.3 increase/patient) promoted CV heterogeneity, i.e. rate-dependent CV (RDCV) slowing sites. Most pivot points co-located to RDCV slowing sites (80.2%). Isoprenaline (1.3 ± 1.1 pivot increase/patient) and GP stimulation (1.5 ± 1.1 increase/patient) also enhanced the number of pivot points identified. Atrial CV dynamics is affected by fibrosis burden and influenced by autonomic modulation which enhances CV heterogeneity and distribution of pivot points. This study provides further insight into the impact of autonomic remodelling in AF.

Socioeconomic burden of cystic fibrosis in Canada

BackgroundCost of illness studies are important tools to summarise the burden of disease for individuals, the healthcare system and society. The lack of standardised methods for reporting costs for cystic...

Clonal haematopoiesis is associated with major adverse cardiovascular events in patients with hypertrophic cardiomyopathy.

The heterogeneous phenotype of hypertrophic cardiomyopathy (HCM) is still not fully understood. Clonal haematopoiesis (CH) is emerging as a cardiovascular risk factor potentially associated with adverse clinical events. The prevalence, phenotype and outcomes related to CH in HCM patients were evaluated. Patients with HCM and available biospecimens from the Peter Munk Cardiac Centre Cardiovascular Biobank were subjected to targeted sequencing for 35 myeloid genes associated with CH. CH prevalence, clinical characteristics, morphological phenotypes assessed by echocardiogram and cardiac magnetic resonance and outcomes were assessed. All patients were evaluated for a 71-plex cytokines/chemokines, troponin I and B-type natriuretic peptide analysis. Major adverse cardiovascular events (MACE) were defined as appropriate implantable cardioverter-defibrillator shock, stroke, cardiac arrest, orthotopic heart transplant and death. Among the 799 patients, CH was found in 183 (22.9%) HCM patients with sarcomeric germline mutations. HCM patients with CH were more symptomatic and with a higher burden of fibrosis than those without CH. CH was associated with MACE in those HCM patients with sarcomeric germline mutations (adjusted hazard ratio [HR] 6.89, 95% confidence interval [CI] 1.78-26.6; p = 0.005), with the highest risk among those that had DNMT3A, TET2 and ASXL1 mutations (adjusted HR 5.76, 95% CI 1.51-21.94; p = 0.010). Several cytokines (IL-1ra, IL-6, IL-17F, TGFα, CCL21, CCL1, CCL8, and CCL17), and troponin I were upregulated in gene-positive HCM patients with CH. These results indicate that CH in patients with HCM is associated with worse clinical outcomes. In the absence of CH, gene-positive patients with HCM have lower rates of MACE.

Structural phenotyping in atrial fibrillation with combined cardiac CT and atrial MRI: Identifying and differentiating individual structural remodelling types in AF.

Atrial remodelling (AR) is the persistent change in atrial structure and/or function and contributes to the initiation, maintenance and progression of atrial fibrillation (AF) in a reciprocal self-perpetuating relationship. Left atrial (LA) size, geometry, fibrosis, wall thickness (LAWT) and ejection fraction (LAEF) have all been shown to vary with pathological atrial remodelling. The association of these global remodelling markers with each other for differentiating structural phenotypes in AF is not well investigated. Patients referred for first-time AF ablation and controls without AF were prospectively recruited to undergo cardiac computed tomographic angiography (CCTA) and magnetic resonance imaging (MRI) with 3D atrial late-gadolinium enhanced (LGE) sequences. LAWT, atrial myocardial mass, LA volume and sphericity were calculated from CT. Biplane LA EF and LA fibrosis burden were derived from atrial MRI. Results were compared between patients with AF and controls. Forty two AF patients (64.3% male, age 64.6 ± 10.2 years, CHA2DS2-VASc 2.48 ± 1.5, 69.0% paroxysmal AF, 31% persistent AF, LVEF 57.9 ± 10.5%) and 37 controls (64.9% male, age 56.6 ± 7.2, CHA2DS2-VASc 1.54 ± 1.1, LVEF 60.4 ± 4.9%) were recruited. Patients with AF had a significantly higher LAWT (1.45 ± 0.52 mm vs 1.12 ± 0.42 mm, p = 0.003), tissue mass (15.81 ± 6.53 g vs. 12.18 ± 5.01 g, p = 0.011), fibrosis burden (9.33 ± 8.35% vs 2.41 ± 3.60%, p = 0.013), left atrial size/volume (95.68 ± 26.63 mL vs 81.22 ± 20.64 mL, p = 0.011) and lower LAEF (50.3 ± 15.3% vs 65.2 ± 8.6%, p < 0.001) compared to controls. There was no significant correlation between % fibrosis with LAWT (p = 0.29), mass (p = 0.89), volume (p = 0.49) or sphericity (p = 0.79). LAWT had a statistically significant weak positive correlation with LA volume (r = 0.25, p = .041), but not with sphericity (p = 0.86). LAEF had a statistically significant but weak negative correlation with fibrosis (r = -0.33, p = 0.008) and LAWT (r = -0.24, p = 0.07). AF is associated with significant quantifiable structural changes that are evident in LA size, tissue thickness, total LA tissue mass and fibrosis. These individual remodelling markers do not or only weakly correlate with each other suggesting different remodelling subtypes exist (e.g. fibrotic vs hypertrophic vs dilated). If confirmed, such a detailed understanding of the structural changes observed has the potential to inform clinical management strategies targeting individual mechanisms underlying the disease process.

Clinical, economic, and societal burden of cystic fibrosis and the impact of the CFTR modulator, lumacaftor/ivacaftor: an assessment using linked registry data in Sweden

Aims We aimed to describe the clinical, economic, and societal burdens of cystic fibrosis (CF) and impact of CF transmembrane conductance regulator modulator (CFTRm) treatment on people with CF, caregivers, and healthcare systems. Material and methods This retrospective study used linked real-world data from Swedish national population-based registries and the Swedish CF Quality Registry to assess clinical, economic, and societal burden and CFTR impact in CF. Records from people with CF and a ten-fold control population without CF matched by sex, birth year, and location were compared during 2019. Outcomes for a subset aged >6 years initiating lumacaftor/ivacaftor (LUM/IVA) in 2018 were compared 12 months pre- and post-treatment initiation. Results People with CF (n = 743) had >10 times more inpatient and outpatient specialist visits annually vs controls (n = 7406). Those aged >18 had an additional 77·7 (95% CI: 70·3, 85·1) days of work absence, at a societal cost of €11,563 (95% CI: 10,463, 12,662), while caregivers of those aged <18 missed an additional 6.1 (5.0, 7.2) workdays. With LUM/IVA treatment, people with CF (n = 100) had significantly increased lung function (mean change in ppFEV1 [3·8 points; 95% CI: 1·1, 6·6]), on average 0·5 (95% CI: −0·8, −0·2) fewer pulmonary exacerbations and 45·2 (95% CI: 13·3, 77·2) fewer days of antibiotics. Days of work lost by caregivers of people with CF aged <18 decreased by 5·4 days (95% CI: 2·9, 7·9). Conclusion CF is associated with a high clinical economic and societal burden in Sweden. Improvements in clinical status observed in people with CF treated with LUM/IVA were reflected in reduced caregiver and societal burden.

Cardiac fibrosis as a predictor for sudden cardiac death after transcatheter aortic valve implantation.

Cardiac fibrosis plays a major pathophysiological role in any form of chronic heart disease, and high levels are associated with poor outcome. Diffuse and focal cardiac fibrosis are different subtypes, which have different pathomechanisms and prognostic implications. The total fibrosis burden in endomyocardial biopsy tissue was recently proved to play an independent prognostic role in aortic stenosis patients after transcatheter aortic valve implantation (TAVI). Here, for the first time, we aim to assess the specific impact of different fibrosis subtypes on sudden cardiac death (SCD) as a primary reason for cardiovascular mortality after TAVI. The fibrosis pattern was assessed histologically in the left ventricular biopsies obtained during TAVI interventions in 161 patients, who received a structured follow-up thereafter. Receiver operating characteristic analyses, performed 6, 12, 24 and 48 months after TAVI, showed diffuse, but not focal, fibrosis as a significant predictor for SCD at all timepoints, with the highest area under the curve at the first time point and a decrease in its SCD predictivity over time. In both multivariate Cox proportional hazards and Fine-Gray competing risk models, including both fibrosis subtypes, as well as age, sex and ejection fraction, high diffuse fibrosis remained statistically significant. Accordingly, it represents an independent SCD predictor, most importantly for the occurrence of early events. The burden of diffuse cardiac fibrosis plays an important and independent prognostic role regarding SCD early after TAVI. Therefore, the histological evaluation of fibrosis topography has value as a prognostic tool for TAVI patients and may help to tailor individualised approaches to optimise their postinterventional management.