Quantification of diffuse myocardial fibrosis using CMR extracellular volume fraction and serum biomarkers of collagen turnover with histologic quantification as standard of reference

Aim Collagens are major cardiac extracellular matrix components, known to be actively remodelled and accumulated during diffuse myocardial fibrosis. We evaluated whether accelerated collagen turnover described by neo-epitope biomarkers reflecting collagen formation and degradation separates patients with diffuse myocardial fibrosis from asymptomatic controls. Methods and results Seventy-one women with angina pectoris without significant coronary artery disease assessed by invasive coronary angiogram were included. Competitive enzyme-linked immunosorbent assays (ELISAs) measuring circulating protein fragments in serum assessed the formation and degradation of collagen type III (Pro-C3, C3M and C3C), IV (P4NP7S and C4M), V (Pro-C5 and C5M) and VI (Pro-C6 and C6M), and degradation of collagen type I (C1M). Serum samples from 32 age-matched asymptomatic women were included as controls. Symptomatic women presented significantly elevated levels of Pro-C6, C3C, C3M, C4M and C8-C ( p < 0.0001–0.0058) and significantly decreased levels of Pro-C3, C5M and C6M ( p < 0.0001–0.041), reflecting accelerated collagen turnover and an imbalanced collagen formation and degradation compared to controls. Cardiac magnetic resonance T1 mapping was performed to determine extracellular volume fraction and thus diffuse myocardial fibrosis. A significant association was identified between C5M and extracellular volume fraction by cardiac magnetic resonance ( p = 0.01). Conclusion Women with angina pectoris, but without significant obstructive coronary artery disease, showed an imbalanced collagen turnover compared to asymptomatic controls. The examined biomarkers are tools to monitor active collagen remodelling in patients with angina pectoris, in risk of developing myocardial fibrosis.

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The link between left ventricular extracellular volume determined by T1 myocardial mapping and gut microbiota composition in individuals with heart failure and preserved ejection fraction

European Heart Journal ◽

10.1093/ehjci/ehaa946.0864 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

A.N Kaburova ◽

O.M Drapkina ◽

S.M Uydin ◽

M.V Vishnyakova ◽

M.S Pokrovskaya ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Gut Microbiota ◽

Myocardial Fibrosis ◽

Volume Fraction ◽

Extracellular Volume ◽

Left Ventricular ◽

Diffuse Myocardial Fibrosis ◽

Rrna Gene ◽

Preserved Ejection Fraction

Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) represents a major challenge in modern cardiology. As described previously, in HFpEF comorbidities promote a systemic inflammatory state, leading to diffuse myocardial fibrosis resulting in myocardial stiffening. Gut dysbiosis which is considered as the novel source of chronic systemic inflammation has been actively investigated as the risk factor for the development and aggravation of cardiovascular diseases including heart failure. Cardiac magnetic resonance T1-mapping is a novel tool, which allows noninvasive quantification of the extracellular space and diffuse myocardial fibrosis. Moreover, the extracellular volume (ECV) fraction can be calculated, providing information on the relative expansion of the extracellular matrix, thus being a noninvasive alternative to myocardial biopsy studies. Purpose The research was aimed at investigating the correlation between the left ventricular ECV and gut microbial genera in patients with HFpEF. Methods 42 patients with confirmed HF-pEF (mediana and interquartile range of age 67 [64; 72] years, 47% men, body mass index <35 kg/m2 with no history of myocardial infarction or diabetes mellitus) were enrolled in the study. The patients underwent transthoracic echocardiography with Doppler study, HF-pEF was confirmed according to the recent ESC guidelines (based on E/e' ratio, N-terminal pro-B type natriuretic peptide >125 pg/ml and symptoms of heart failure). The intestinal microbiome was investigated using high-throughput sequencing of bacterial 16S rRNA gene. As the last step of research T1-myocardial mapping with the modified look-locker inversion-recovery protocol (MOLLI) sequence at 1.5 Tesla was performed to assess left ventricular extracellular volume fraction. Results The mean±std in ECV was 31.02±4.4%. The relative abundance (%) of the most prevalent phyla in gut microbiota was 48±22.5 for Firmicutes, 47.4±22.8 for Bacteroidetes and 1.5 [1.5; 2.5] for Proteobacteria. The analysis showed significant negative correlations between ECV and the following bacterial genera: Faecalibacterium (r=−0.35), Blautia (r=−0.43), Lachnoclostridium (r=−0.32). Moreover ECV positively correlated with Holdemania (r=0.4), Victivallis (r=0.38), Dehalobacterium (r=0.38), Enterococcus (r=0.33) and Catabacter (r=0.32). All correlation values with p<0.05. Conclusion We discovered both negative and positive significant correlations between ECV – the non-invasive marker of myocardial fibrosis and several bacterial genera, which may have negative impact on myocardial remodeling in HF-pEF. Funding Acknowledgement Type of funding source: None

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Electrocardiogram-less, free-breathing myocardial extracellular volume fraction mapping in small animals at high heart rates using motion-resolved cardiovascular magnetic resonance multitasking: a feasibility study in a heart failure with preserved ejection fraction rat model

Journal of Cardiovascular Magnetic Resonance ◽

10.1186/s12968-020-00699-9 ◽

2021 ◽

Vol 23 (1) ◽

Cited By ~ 1

Author(s):

Pei Han ◽

Rui Zhang ◽

Shawn Wagner ◽

Yibin Xie ◽

Eugenio Cingolani ◽

...

Keyword(s):

Heart Failure ◽

Volume Fraction ◽

Extracellular Volume ◽

Small Animal ◽

Free Breathing ◽

Extracellular Volume Fraction ◽

Diffuse Myocardial Fibrosis ◽

Small Animals ◽

Preserved Ejection Fraction ◽

Heart Rates

Abstract Background Extracellular volume fraction (ECV) quantification with cardiovascular magnetic resonance (CMR) T1 mapping is a powerful tool for the characterization of focal or diffuse myocardial fibrosis. However, it is technically challenging to acquire high-quality T1 and ECV maps in small animals for preclinical research because of high heart rates and high respiration rates. In this work, we developed an electrocardiogram (ECG)-less, free-breathing ECV mapping method using motion-resolved CMR Multitasking on a 9.4 T small animal CMR system. The feasibility of characterizing diffuse myocardial fibrosis was tested in a rat heart failure model with preserved ejection fraction (HFpEF). Methods High-salt fed rats diagnosed with HFpEF (n = 9) and control rats (n = 9) were imaged with the proposed ECV Multitasking technique. A 25-min exam, including two 4-min T1 Multitasking scans before and after gadolinium injection, were performed on each rat. It allows a cardiac temporal resolution of 20 ms for a heart rate of ~ 300 bpm. Myocardial ECV was calculated from the hematocrit (HCT) and fitted T1 values of the myocardium and the blood pool. Masson's trichrome stain was used to measure the extent of fibrosis. Welch’s t-test was performed between control and HFpEF groups. Results ECV was significantly higher in the HFpEF group (22.4% ± 2.5% vs. 18.0% ± 2.1%, P = 0.0010). A moderate correlation between the ECV and the extent of fibrosis was found (R = 0.59, P = 0.0098). Conclusions Motion-resolved ECV Multitasking CMR can quantify ECV in the rat myocardium at high heart rates without ECG triggering or respiratory gating. Elevated ECV found in the HFpEF group is consistent with previous human studies and well correlated with histological data. This technique has the potential to be a viable imaging tool for myocardial tissue characterization in small animal models.

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CMR–Derived Extracellular Volume Fraction as a Marker for Myocardial Fibrosis

JACC Cardiovascular Imaging ◽

10.1016/j.jcmg.2017.01.025 ◽

2018 ◽

Vol 11 (1) ◽

pp. 38-45 ◽

Cited By ~ 40

Author(s):

Julia Anna Lurz ◽

Christian Luecke ◽

David Lang ◽

Christian Besler ◽

Karl-Philipp Rommel ◽

...

Keyword(s):

Myocardial Fibrosis ◽

Volume Fraction ◽

Extracellular Volume ◽

Extracellular Volume Fraction

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Native T1 Relaxation Time and Extracellular Volume Fraction as Accurate Markers of Diffuse Myocardial Fibrosis in Heart Valve Disease　– Comparison With Targeted Left Ventricular Myocardial Biopsy –

Circulation Journal ◽

10.1253/circj.cj-15-1309 ◽

2016 ◽

Vol 80 (5) ◽

pp. 1202-1209 ◽

Cited By ~ 24

Author(s):

Radka Kockova ◽

Petr Kacer ◽

Jan Pirk ◽

Jiri Maly ◽

Lucie Sukupova ◽

...

Keyword(s):

Relaxation Time ◽

Volume Fraction ◽

Extracellular Volume ◽

Extracellular Volume Fraction ◽

Left Ventricular ◽

Diffuse Myocardial Fibrosis ◽

Heart Valve Disease ◽

Myocardial Biopsy ◽

T1 Relaxation Time ◽

T1 Relaxation

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Extracellular volume fraction by T1 mapping predicts omprovement of left ventricular ejection fraction after catheter ablation in patients with non-ischemic cardiomyopathy and atrial fibrillation

European Heart Journal ◽

10.1093/ehjci/ehaa946.0261 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M Azuma ◽

S Kato ◽

S Kodama ◽

K Hayakawa ◽

M Kagimoto ◽

...

Keyword(s):

Atrial Fibrillation ◽

Catheter Ablation ◽

Myocardial Fibrosis ◽

T1 Mapping ◽

Volume Fraction ◽

Extracellular Volume ◽

Extracellular Volume Fraction ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Risk Of Death

Abstract Background The Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) trial has shown that the catheter ablation (CA) for atrial fibrillation (AF) significantly reduced the risk of death and hospitalization for heart failure in patients with non-ischemic dilated cardiomyopathy (NIDCM) and AF (N Engl J Med 2018; 378:417–27). In addition, the Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction (CAMERA-MRI) study demonstrated that the absence of myocardial fibrosis on late gadolinium enhanced (LGE) magnetic resonance imaging (MRI) is associated with improvement of left ventricular systolic function after CA in NIDCM patients with AF (J Am Coll Cardiol 2017; 70:1949–61). Extracellular volume fraction (ECV) by T1 mapping has emerges as a non-invasive mean to quantify diffuse myocardial fibrosis. Purpose The aim of this study was to compare the predictive value of LGE-MRI and ECV by T1 mapping for the prediction of improvement of LVEF after CA in NIDCM patients. Methods A total of twenty-eight patients with NIDCM and AF (age: 67±10 years; 25 (89%) male; LVEF: 34.1±8.8%) were studied. Using a 1.5T MR scanner and 32 channel cardiac coils, cine MRI, LGE-MRI, pre- and post- T1 mapping images of LV wall at mid-ventricular level (modified Look-Locker inversion recovery sequence) were acquired. Myocardial fibrosis on LGE was defined as area with >5SD signal intensity of normal myocardium. ECV from six segments of mid ventricular level were averaged for each patient. All patients underwent CA for AF, and the improvement of LVEF before and after CA were evaluated by echocardiography. Results All patients restored sinus rhythm after CA at the time of echocardiography. The mean LVEF was 34.1±8.8% before CA and 49.1±12.0% after CA (p<0.001), resulting an improvement of 15.0±11.8%. Significant correlation was found between improvements in LVEF and amount of fibrosis on LGE-MRI (r=−0.40, p=0.034), improvement of LVEF and ECV (r=−0.55, p=0.008). In the ROC analysis, ECV had a higher discriminative ability for the improvement of LVEF after CA compared with amount of fibrosis on LGE-MRI (AUC 0.885 vs 0.650) (Figure). Conclusions In NIDCM patients with AF, ECV by T1 mapping had better predictive ability for improvement of LVEF after CA in comparison to LGE-MRI. ROC curves of ECV and LGE-MRI Funding Acknowledgement Type of funding source: None

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Effect of sarcomere and mitochondria-related mutations on myocardial fibrosis in patients with hypertrophic cardiomyopathy

Journal of Cardiovascular Magnetic Resonance ◽

10.1186/s12968-021-00718-3 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Hyemoon Chung ◽

Yoonjung Kim ◽

Chul-Hwan Park ◽

Jong-Youn Kim ◽

Pil-Ki Min ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Myocardial Fibrosis ◽

Nuclear Dna ◽

Volume Fraction ◽

Wide Spectrum ◽

Extracellular Volume ◽

Extracellular Volume Fraction ◽

Gadolinium Enhancement ◽

Uncertain Significance ◽

Mutation Group

Abstract Background Myocardial fibrosis is an important prognostic factor in hypertrophic cardiomyopathy (HCM). However, the contribution from a wide spectrum of genetic mutations has not been well defined. We sought to investigate effect of sarcomere and mitochondria-related mutations on myocardial fibrosis in HCM. Methods In 133 HCM patients, comprehensive genetic analysis was performed in 82 nuclear DNA (33 sarcomere-associated genes, 5 phenocopy genes, and 44 nuclear genes linked to mitochondrial cardiomyopathy) and 37 mitochondrial DNA. In all patients, cardiovascular magnetic resonance (CMR) was performed, including 16-segmental thickness, late gadolinium enhancement (LGE), native and post-T1, extracellular volume fraction (ECV), and T2, along with echo-Doppler evaluations. Results Patients with sarcomere mutation (SM, n = 41) had higher LGE involved segment, % LGE mass, ECV and lower post-T1 compared to patients without SM (n = 92, all p < 0.05). When classified into, non-mutation (n = 67), only mitochondria-related mutation (MM, n = 24), only-SM (n = 36) and both SM and MM (n = 5) groups, only-SM group had higher ECV and LGE than the non-mutation group (all p < 0.05). In non-LGE-involved segments, ECV was significantly higher in patients with SM. Within non-SM group, patients with any sarcomere variants of uncertain significance had higher echocardiographic Doppler E/e’ (p < 0.05) and tendency of higher LGE amount and ECV (p > 0.05). However, MM group did not have significantly higher ECV or LGE amount than non-mutation group. Conclusions SMs are significantly related to increase in myocardial fibrosis. Although, some HCM patients had pathogenic MMs, it was not associated with an increase in myocardial fibrosis.

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