Association of myocardial fibrosis and cardiovascular events: the multi-ethnic study of atherosclerosis

Ambale-Venkatesh, Bharath; Liu, Chia Ying; Liu, Yuan Chang; Donekal, Sirisha; Ohyama, Yoshiaki; Sharma, Ravi; Wu, Colin O.; Post, Wendy S.; Hundley, Gregory; Bluemke, David A.; Lima, João A.C.

doi:10.1093/ehjci/jey140

Cited by 44 publications

(36 citation statements)

References 47 publications

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“…Integrating previously published data, we propose that ECV represents the most robust T1 mapping metric to quantify MF. Specifically, we note: a) the inherent specificity of ECV for the interstitial space (exploiting the extracellular nature of gadolinium contrast agents), b) the outcomes data presented herein which agrees with population studies, (33) Several limitations affect native T1 . Native T1 measures disease processes from whole myocardium without specificity for MF or the interstitial space.…”

Section: Association With Outcomes Represents An Integral Component Osupporting

confidence: 77%

Extracellular Volume Associates With Outcomes More Strongly Than Native or Post-Contrast Myocardial T1

Treibel¹,

Fridman²,

Bering³

et al. 2020

JACC: Cardiovascular Imaging

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Since risk stratification data represents a key domain of biomarker validation, we compared associations between outcomes and various cardiovascular magnetic resonance (CMR) metrics quantifying myocardial fibrosis (MF) in noninfarcted myocardium: extracellular volume fraction (ECV), native T1, post contrast T1, and partition coefficient. Background: MF associates with vulnerability to adverse events e.g., mortality and hospitalization for heart failure (HHF), but investigators still debate its optimal measurements; most histologic validation data show strongest ECV correlations with MF. Methods: We enrolled 1714 consecutive patients without amyloidosis or hypertrophic cardiomyopathy from a single CMR referral center serving an integrated healthcare network. We measured T1 (MOLLI) in noninfarcted myocardium, averaged from 2 short axis slices (basal and mid) before and 15-20 minutes after a gadolinium contrast bolus. We compared chi square (χ 2) values from CMR MF measures in univariable and multivariable Cox regression models. We assessed "dose-response" relationships in Kaplan Meier curves using log-rank statistics for quartile strata. We also computed net reclassification improvement (NRI) and integrated discrimination improvement (IDI for Cox models with ECV vs. native T1. Results: Over a median of 5.6 years, 374 events occurred after CMR (162 HHF events and 279 deaths, 67 with both). ECV yielded best separation of Kaplan-Meier curves and highest log-ranks statistics. In univariable and multivariable models, ECV associated most strongly with outcomes, demonstrating the highest χ 2 values. Native T1 or post contrast T1 did not associate with outcomes in the multivariable model. ECV provided added prognostic value to models with native T1, e.g., in multivariable models IDI=0.

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Section: Association With Outcomes Represents An Integral Component Osupporting

confidence: 77%

Extracellular Volume Associates With Outcomes More Strongly Than Native or Post-Contrast Myocardial T1

Treibel¹,

Fridman²,

Bering³

et al. 2020

JACC: Cardiovascular Imaging

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“…Recent studies identified that contrast-enhanced cardiac magnetic resonance imaging of patients with aS indicated that individuals who had a history of cardiovascular events were more likely to present with myocardial fibrosis than those who did not (29,30). in the present study, disordered collagen metabolism was significantly improved in rats with AS following treatment.…”

Section: Discussionmentioning

confidence: 99%

The peptide compound urantide regulates collagen metabolism in atherosclerotic rat hearts and inhibits the JAK2/STAT3 pathway

et al. 2020

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The aim of the present study was to investigate the effect of urantide on collagen metabolism in the hearts of rats with atherosclerosis (aS) by evaluating the expression of Janus kinase 2 (JaK2)/signal transducer and activator of transcription 3 (STaT3) pathway constituents. urantide was delivered to rats with aS via tail vein injection for 3, 7 and 14 days. Serological indicators were identified by an automated biochemical analyzer. Histomorphological changes in the cardiac tissue of rats were observed by pathological staining techniques. The expression of genes and proteins was assessed using reverse transcription-quantitative Pcr and western blot analysis, respectively. localization of proteins was detected by immunofluorescence. overexpression of urotensin ii (uii) and its receptor, G protein-coupled receptor 14 (GPr14), was observed in the hearts of rats with AS and the expression of both proteins significantly declined after urantide administration. Triglyceride, total cholesterol, low-density lipoprotein, high-density lipoprotein and calcium levels were improved in rats with aS following treatment with urantide. notably, urantide was able to antagonize the uii/GPr14 system. urantide treatment resulted in markedly decreased expression levels of matrix metalloproteinase 2 (MMP-2), collagen type i/iii, and genes and proteins in the JaK2/STaT3 pathway. By contrast, TiMP metallopeptidase inhibitor 2 (TiMP-2) levels were increased. in addition, the MMP-2/TIMP-2 protein ratio was significantly decreased in rats treated with urantide compared with aS rats with no urantide treatment. constituents of the JaK2/STaT3 pathway and collagen type i/iii were found to be localized in the diseased tissue and blood vessels of the hearts of rats with aS. in conclusion, urantide was able to effectively block the uii/GPr14 system by regulating the JaK2/STaT3 pathway and collagen metabolism. inhibition of the uii/GPr14 system may prevent and potentially treat atherosclerotic myocardial fibrosis. Based on the current results, it was hypothesized that collagen metabolism may be associated with the JaK2/STaT3 pathway.

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“…The advent of cardiac magnetic resonance (CMR) has been shown to provide an accurate, non-invasive means of detecting myocardial fibrosis, due to various forms of cardiomyopathies [ 21 , 22 , 223 , 224 ]. Indeed, in patients with various degrees of cardiac impairment, the extent of cardiac fibrosis reliably predicts the degree of diastolic dysfunction, and of adverse outcome [ 225 ].…”

Section: Clinical Perspectives and Future Directionsmentioning

confidence: 99%

Innate Immunity Effector Cells as Inflammatory Drivers of Cardiac Fibrosis

Baci

Bosi

Parisi

et al. 2020

IJMS

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Despite relevant advances made in therapies for cardiovascular diseases (CVDs), they still represent the first cause of death worldwide. Cardiac fibrosis and excessive extracellular matrix (ECM) remodeling are common end-organ features in diseased hearts, leading to tissue stiffness, impaired myocardial functional, and progression to heart failure. Although fibrosis has been largely recognized to accompany and complicate various CVDs, events and mechanisms driving and governing fibrosis are still not entirely elucidated, and clinical interventions targeting cardiac fibrosis are not yet available. Immune cell types, both from innate and adaptive immunity, are involved not just in the classical response to pathogens, but they take an active part in “sterile” inflammation, in response to ischemia and other forms of injury. In this context, different cell types infiltrate the injured heart and release distinct pro-inflammatory cytokines that initiate the fibrotic response by triggering myofibroblast activation. The complex interplay between immune cells, fibroblasts, and other non-immune/host-derived cells is now considered as the major driving force of cardiac fibrosis. Here, we review and discuss the contribution of inflammatory cells of innate immunity, including neutrophils, macrophages, natural killer cells, eosinophils and mast cells, in modulating the myocardial microenvironment, by orchestrating the fibrogenic process in response to tissue injury. A better understanding of the time frame, sequences of events during immune cells infiltration, and their action in the injured inflammatory heart environment, may provide a rationale to design new and more efficacious therapeutic interventions to reduce cardiac fibrosis.

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Association of myocardial fibrosis and cardiovascular events: the multi-ethnic study of atherosclerosis

Cited by 44 publications

References 47 publications

Extracellular Volume Associates With Outcomes More Strongly Than Native or Post-Contrast Myocardial T1

Extracellular Volume Associates With Outcomes More Strongly Than Native or Post-Contrast Myocardial T1

The peptide compound urantide regulates collagen metabolism in atherosclerotic rat hearts and inhibits the JAK2/STAT3 pathway

Innate Immunity Effector Cells as Inflammatory Drivers of Cardiac Fibrosis

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