Genetics of Myocardial Interstitial Fibrosis in the Human Heart and Association with Disease

Myocardial interstitial fibrosis is a common thread in multiple cardiovascular diseases including heart failure, atrial fibrillation, conduction disease and sudden cardiac death. To investigate the biologic pathways that underlie interstitial fibrosis in the human heart, we developed a machine learning model to measure myocardial T1 time, a marker of myocardial interstitial fibrosis, in 42,654 UK Biobank participants. Greater T1 time was associated with impaired glucose metabolism, systemic inflammation, renal disease, aortic stenosis, cardiomyopathy, heart failure, atrial fibrillation and conduction disease. In genome-wide association analysis, we identified 12 independent loci associated with native myocardial T1 time with evidence of high genetic correlation between the interventricular septum and left ventricle free wall (r2g = 0.82). The identified loci implicated genes involved in glucose homeostasis (SLC2A12), iron homeostasis (HFE, TMPRSS6), tissue repair (ADAMTSL1, VEGFC), oxidative stress (SOD2), cardiac hypertrophy (MYH7B) and calcium signaling (CAMK2D). Transcriptome-wide association studies highlighted the role of expression of ADAMTSL1 and SLC2A12 in human cardiac tissue in modulating myocardial tissue characteristics and interstitial fibrosis. Harnessing machine learning to perform large-scale phenotyping of interstitial fibrosis in the human heart, our results yield novel insights into biologically relevant pathways for myocardial fibrosis and prioritize investigation of pathways for the development of anti-fibrotic therapies.

Myocardial interstitial fibrosis assessed by extracellular volume quantification is a determinant of symptoms in aortic valve regurgitation with preserved ejection fraction

Funding Acknowledgements Type of funding sources: None. Introduction According to current guidelines indication for surgery is straightforward with a class I recommendation in case of severe symptomatic aortic regurgitation (AR) and/or left ventricular ejection fraction (LVEF) decrease ≤50%. However, the management of patients with asymptomatic severe AR with preserved LVEF remains debated, with a cruel lack of prognostic factors to identify patients who may benefit from early intervention. An explanation to the absence of such factors is that the determinants of symptoms, a strong prognostic parameter, have been poorly identified. Beyond LV dilation and systolic dysfunction, which are both recognized prognostic factors in chronic AR, we hypothesized that interstitial myocardial fibrosis, as an early indicator of LV remodeling, may also influence the occurrence of symptoms. Cardiovascular magnetic resonance (CMR)-based myocardial extracellular volume (ECV) quantification by T1 mapping has emerged as a valuable tool to quantify diffuse myocardial fibrosis. Objective To study the relationship between myocardial interstitial fibrosis quantified by T1 mapping and the symptomatic status of patients with chronic aortic valve regurgitation. Methods We retrospectively included 38 consecutive patients with chronic, isolated, mild to severe AR who underwent a CMR at our institution. Exclusion criteria were the presence of any other heart condition that may induce myocardial fibrosis, ≥ mild associated valve disease, AR secondary to endocarditis, genetic, inflammatory or congenital disease except bicuspid aortic valve. T1 mapping of the basal segments was performed before and after contrast administration measuring native and post-contrast T1 relaxation time and ECV. Results Mean age was 56 ± 20 years, 30 patients (79%) were males, and symptoms were reported in 11 patients (29%). Mean LVEF was 57 ± 9% and ≥50% in 30 patients (79%). Aortic valve regurgitation fraction (RF) was 25 ± 13%, ECV 0.27 ± 0.04%, indexed LV end-diastolic volume (LVEDVi) 98 ± 32 ml/m2, end-systolic volume (LVESVi) 46 ± 19 ml/m2, and LV mass 79 ± 21 g/m2. LVESVi (r = 0.41,p = 0.01), LVEF (r=-0.59,p = 0.0001), and ECV (r = 0.42,p = 0.008) were correlated with symptoms, whereas age (r = 0.16,p = 0.33), gender (r=-0.24,p = 0.15), LVEDVi (r = 0.28,p = 0.09), LV mass index (r = 0.08,p = 0.62), and RF (r = 0.31,p = 0.06) were not. In the subgroup of patients with preserved LVEF (≥50%), after adjustment for LVESVi and RF, only ECV remained independently associated with symptoms (p = 0.046). Interestingly, when including the patients with a reduced LVEF < 50% in the multivariable analysis only LVESVi was an independent determinant of symptoms (p = 0.04) and ECV was not (p = 0.07) Conclusion myocardial fibrosis quantified by ECV calculation is a determinant of symptoms in AR with preserved LVEF. Further studies are warranted to determine the prognostic value of ECV that may justify earlier intervention. Abstract Figure. ECV in AR with preserved LVEF

Heart failure in chronic kidney disease: the emerging role of myocardial fibrosis

Heart failure (HF) is one of the main causes of morbidity and mortality in patients with chronic kidney disease (CKD). Decreased glomerular filtration rate is associated with diffuse deposition of fibrotic tissue in the myocardial interstitium [i.e. myocardial interstitial fibrosis (MIF)] and loss of cardiac function. MIF results from cardiac fibroblast-mediated alterations in the turnover of fibrillary collagen that lead to the excessive synthesis and deposition of collagen fibres. The accumulation of stiff fibrotic tissue alters the mechanical properties of the myocardium, thus contributing to the development of HF. Accumulating evidence suggests that several mechanisms are operative along the different stages of CKD that may converge to alter fibroblasts and collagen turnover in the heart. Therefore, focusing on MIF might enable the identification of fibrosis-related biomarkers and targets that could potentially lead to a new strategy for the prevention and treatment of HF in patients with CKD. This article summarizes current knowledge on the mechanisms and detrimental consequences of MIF in CKD and discusses the validity and usefulness of available biomarkers to recognize the clinical–pathological variability of MIF and track its clinical evolution in CKD patients. Finally, the currently available and potential future therapeutic strategies aimed at personalizing prevention and reversal of MIF in CKD patients, especially those with HF, will be also discussed.

Histomolecular fibrotic profile and an extent of the atrial and ventricular electroanatomical substrate in patients with atrial fibrillation and heart failure

Background and purpose The aim of this pilot study was to investigate the association between an extent of the atrial and ventricular electroanatomical substrate, serum fibrotic biomarkers and histological and immune-histochemical myocardial characteristics in ipatients with atrial fibrillation and heart failure. Methods We prospectively analyzed electroanatomical ultra-high density bipolar maps (HDBM) in 72 patients with AF and CHF, who underwent circular pulmonary veins (PVs) isolation. LA areas outside PVs ostia with bipolar signals ≤0.75mV, associated with local conduction velocity delay were considered as EAS and measured. Relative area of low voltage zones in right (RV) and left ventricles (RV) with bipolar signals in range of 0,5–1,5 mV were also consistently measured. Endomyocardial biopsy samples were taken from low, mediate and high septal areas of RV; histological and immune-histochemical staining was performed and an extent of myocardial interstitial fibrosis (MIF) was calculated. Before the operation we measured plasma MMP2, MMP9, TIMP, MMPs/TIMPs, galectin 3 (Gal3), TGF, soluble ST2 and the cross-linked collagen I/III synthesis and degradation product levels. The patients were divided into groups according to their ejection fraction Simpson (EF) (groups 1: EF≥50%, groups 2: EF 40–49%, and groups 3: EF<40%). Results The data of electroanatomical mapping, serum biomarkers and myocardial expression are presented in the table. According to results of correlation analysis, an extent of LA EAS were correlated with Gal3 and PIIICP plasma level and Gal3 myocardial expression and MIF extent (Rs=0,40, 0,45 and 0,42 respectively). The relative extent of LV EAS was correlated with MMP9 serum level (Rs=0,38); LV volume (LVV) was correlated with sST2 serum level and RVV was correlated with CD 133 myocardial expression (Rs=0,42) (picture 1). The patients with lower EF had larger extent of the LA EAS, (group 3: 28±12.4% vs. 1: 17.7±11.6%, p=0.03), an extent of LV EAS and LVV (group 3: 8,4±4,5% vs. 1: 5,1±3,8% p=0.02; group 3 vs group 1 p=0,05 relatively),higher Gal3 plasma level (group 1: 7,1±2 vs. group 2: 8,9±1,5, p=0.05) and higher MIF extent (group 2: 134±56 vs. 3: 151±30 p=0.04) (picture 2). Conclusion Our data suggest that relative extent of LA EAS in patients with atrial fibrillation is associated with Gal3 plasma level and Gal3 myocardial expression; severity of myocardial remodeling is connected to CD 3/133 myocardial expression and myocardial interstitial fibrosis extent, especially in patients with HF with restricted LV ejection fraction. Funding Acknowledgement Type of funding source: None