Quantification of myocardial interstitial fibrosis and extracellular volume for the detection of cardiac allograft vasculopathy

Heeswijk, Ruud B. van; Bastiaansen, Jessica; Iglesias, Juan F.; Degrauwe, Sophie; Rotman, Samuel; Barras, Jean‐Luc; Regamey, Julien; Lauriers, Nathalie; Tozzi, Piergiorgio; Yerly, Jérôme; Ginami, Giulia; Stuber, Matthias; Hullin, Roger

doi:10.1007/s10554-019-01733-3

Cited by 10 publications

(13 citation statements)

References 30 publications

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“…43 In a previous study with 27 heart transplantation patients, the early stage CAV measured by the coronary intima-media thickness ratio was correlated with the cardiac interstitial fibrosis quantified by the endomyocardial biopsy. 44 Along the same lines, our study found that CAV was associated with urinary peptides of collagen I and III, which are the major fibrotic components of ECM. Although future studies are required to verify this, the finding highlights the possibility of urinary collagen fragments being used as a surrogate for the fibrosis process of CAV.…”

Section: Pathway Enrichment Analysissupporting

confidence: 58%

The novel proteomic signature for cardiac allograft vasculopathy

Wei

Trenson

Keer³

et al. 2022

ESC Heart Failure

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Aims Cardiac allograft vasculopathy (CAV) is the major long-term complication after heart transplantation, leading to mortality and re-transplantation. As available non-invasive biomarkers are scarce for CAV screening, we aimed to identify a proteomic signature for CAV. Methods and resultsWe measured urinary proteome by capillary electrophoresis coupled with mass spectrometry in 217 heart transplantation recipients (mean age: 55.0 ± 14.4 years; women: 23.5%), including 76 (35.0%) patients with CAV diagnosed by coronary angiography. We randomly and evenly grouped participants into the derivation cohort (n = 108, mean age: 56.4 ± 13.8 years; women: 22.2%; CAV: n = 38) and the validation cohort (n = 109, mean age: 56.4 ± 13.8 years; women: 24.8%, CAV: n = 38), stratified by CAV. Using the decision tree-based machine learning methods (extreme gradient boost), we constructed a proteomic signature for CAV discrimination in the derivation cohort and verified its performance in the validation cohort. The proteomic signature that consisted of 27 peptides yielded areas under the curve of 0.83 [95% confidence interval (CI): 0.75-0.91, P < 0.001] and 0.71 (95% CI: 0.60-0.81, P = 0.001) for CAV discrimination in the derivation and validation cohort, respectively. With the optimized threshold of 0.484, the sensitivity, specificity, and accuracy for CAV differentiation in the validation cohort were 68.4%, 73.2%, and 71.6%, respectively. With adjustment of potential clinical confounders, the signature was significantly associated with CAV [adjusted odds ratio: 1.31 (95% CI: 1.07-1.64) for per 0.1% increment in the predicted probability, P = 0.012]. Diagnostic accuracy significantly improved by adding the signature to the logistic model that already included multiple clinical risk factors, suggested by the integrated discrimination improvement of 9.1% (95% CI: 2.5-15.3, P = 0.005) and net reclassification improvement of 83.3% (95% CI: 46.7-119.5, P < 0.001). Of the 27 peptides, the majority were the fragments of collagen I (44.4%), collagen III (18.5%), collagen II (3.7%), collagen XI (3.7%), mucin-1 (3.7%), xylosyltransferase 1 (3.7%), and protocadherin-12 (3.7%). Pathway analysis performed in Reactome Pathway Database revealed that the multiple pathways involved by the signature were related to the pathogenesis of CAV, such as collagen turnover, platelet aggregation and coagulation, cell adhesion, and motility. Conclusions This pilot study identified and validated a urinary proteomic signature that provided a potential approach for the surveillance of CAV. These proteins might provide insights into CAV pathological processes and call for further investigation into personalized treatment targets.

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Section: Pathway Enrichment Analysissupporting

confidence: 58%

The novel proteomic signature for cardiac allograft vasculopathy

Wei

Trenson

Keer³

et al. 2022

ESC Heart Failure

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“…Deposition in the Myocardium of WT Mice but Not SIRT3 KO Mice with TAC. Perivascular fibrosis and interstitial fibrosis are the main manifestations of myocardial fibrosis [32]. Collagen, shown in red by Sirius red staining, was significantly suppressed by NaHS in WT mice but not SIRT3 KO mice with TAC (Figure 6(a)).…”

Section: Nahs Ameliorates Perivascular and Interstitial Collagenmentioning

confidence: 99%

Hydrogen Sulfide Attenuates Angiotensin II‐Induced Cardiac Fibroblast Proliferation and Transverse Aortic Constriction‐Induced Myocardial Fibrosis through Oxidative Stress Inhibition via Sirtuin 3

Liu

Gong

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Sirtuin 3 (SIRT3) is critical in mitochondrial function and oxidative stress. Our present study investigates whether hydrogen sulfide (H2S) attenuated myocardial fibrosis and explores the possible role of SIRT3 on the protective effects. Neonatal rat cardiac fibroblasts were pretreated with NaHS followed by angiotensin II (Ang II) stimulation. SIRT3 was knocked down with siRNA technology. SIRT3 promoter activity and expression, as well as mitochondrial function, were measured. Male wild-type (WT) and SIRT3 knockout (KO) mice were intraperitoneally injected with NaHS followed by transverse aortic constriction (TAC). Myocardium sections were stained with Sirius red. Hydroxyproline content, collagen I and collagen III, α-smooth muscle actin (α-SMA), and dynamin-related protein 1 (DRP1) expression were measured both in vitro and in vivo. We found that NaHS enhanced SIRT3 promoter activity and increased SIRT3 mRNA expression. NaHS inhibited cell proliferation and hydroxyproline secretion, decreased collagen I, collagen III, α-SMA, and DRP1 expression, alleviated oxidative stress, and improved mitochondrial respiration function and membrane potential in Ang II-stimulated cardiac fibroblasts, which were unavailable after SIRT3 was silenced. In vivo, NaHS reduced hydroxyproline content, ameliorated perivascular and interstitial collagen deposition, and inhibited collagen I, collagen III, and DRP1 expression in the myocardium of WT mice but not SIRT3 KO mice with TAC. Altogether, NaHS attenuated myocardial fibrosis through oxidative stress inhibition via a SIRT3-dependent manner.

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“…Based on CMR, HCM cats in this study sample have increased interstitial fibrosis compared with normal cats. Native T1 and ECV are highly correlated with histological measures of collagen and fibrosis inhumans with a variety of cardiac diseases including HCM 17,[24][25][26]. Native T1 is a composite signal of both the cellular and extracellular components of the myocardium, whereas ECV is a more specific assessment of the extracellular matrix alone and therefore a measure of interstitial fibrosis.…”

mentioning

confidence: 99%

Cardiac extracellular volume fraction in cats with preclinical hypertrophic cardiomyopathy

Fries

Kadotani

Keating

et al. 2021

Veterinary Internal Medicne

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Background: Cardiac magnetic resonance imaging (CMR) allows for detection of fibrosis in hypertrophic cardiomyopathy (HCM) by quantification of the extracellular volume fraction (ECV). Hypothesis/Objectives: To quantify native T1 mapping and ECV in cats. We hypothesize that native T1 mapping and ECV will be significantly increased in HCM cats compared with healthy cats. Animals: Seventeen healthy and 12 preclinical HCM, age-matched, client-owned cats. Methods: Prospective observational study. Tests performed included indirect blood pressure, CBC, biochemical analysis including total thyroid, urinalysis, transthoracic echocardiogram, and CMR. Cats were considered healthy if all tests were within normal limits and a diagnosis of HCM was determined by the presence of left ventricular concentric hypertrophy ≥6 mm on echocardiography. Results: There were statistically significant differences in LV mass (healthy = 5.87 g, HCM = 10.3 g, P < .0001), native T1 mapping (healthy = 1122 ms, HCM = 1209 ms, P = .004), and ECV (healthy = 26.0%, HCM = 32.6%, P < .0001). Variables of diastolic function including deceleration time of early diastolic transmitral flow (DTE), ratio between peak velocity of early diastolic transmitral flow and peak velocity of late diastolic transmitral flow (E : A), and peak velocity of late diastolic transmitral flow

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Quantification of myocardial interstitial fibrosis and extracellular volume for the detection of cardiac allograft vasculopathy

Cited by 10 publications

References 30 publications

The novel proteomic signature for cardiac allograft vasculopathy

The novel proteomic signature for cardiac allograft vasculopathy

Hydrogen Sulfide Attenuates Angiotensin II‐Induced Cardiac Fibroblast Proliferation and Transverse Aortic Constriction‐Induced Myocardial Fibrosis through Oxidative Stress Inhibition via Sirtuin 3

Cardiac extracellular volume fraction in cats with preclinical hypertrophic cardiomyopathy

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