Myocardial Collagen Cross-Linking Is Associated With Heart Failure Hospitalization in Patients With Hypertensive Heart Failure

López, Begoña; Ravassa, Susana; González, Arantxa; Zubillaga, Elena; Bonavila, Claudia; Bergés, Magda; Echegaray, Kattalin; Beaumont, Javier; Moreno, María U.; José, Gorka San; Larman, Mariano; Querejeta, Ramón; Dı́ez, Javier

doi:10.1016/j.jacc.2015.10.063

Cited by 132 publications

(113 citation statements)

References 30 publications

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“…C-terminal telopeptide of collagen type I:MMP-1 ratio has been identified as a possible new biomarker of adverse collagen processing in patients with chronic hypertensive heart failure and is associated with hospitalization for heart failure. 153 Emerging novel markers of risk in patients with heart failure relating to cardiac injury and stress also include levels of soluble neprilysin, 154 soluble FLT-1 (Fms-related tyrosine kinase 1) 150,155,156 and secretoneurin.…”

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confidence: 99%

Novel Risk Markers and Risk Assessments for Cardiovascular Disease

Thomas

Lip

2017

Circulation Research

111

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Abstract:The use of risk markers has transformed cardiovascular medicine, exemplified by the routine assessment of troponin, for both diagnosis and assessment of prognosis in patients with chest pain. Clinical risk factors form the basis for risk assessment of cardiovascular disease and the addition of biochemical, cellular, and imaging parameters offers further refinement. Identifying novel risk factors may allow greater risk stratification and a steady, but gradual progression toward precision medicine. Indeed, the generation of data in this area of research is explosive and when combined with new technologies and techniques provides the potential for more refined, targeted approaches to cardiovascular medicine. Although discussing the most recent developments in this field, this review article aims to strike a balance between novelty and validity by focusing on recent large samplesize studies that have been validated in a separate cohort in most cases. Risk markers related to atherosclerosis, thrombosis, inflammation, cardiac injury, and fibrosis are introduced in the context of their pathophysiology. Rapidly developing new areas, such as assessment of micro-RNA, are also explored. Subsequently the prognostic ability of these risk markers in coronary artery disease, heart failure, and atrial fibrillation is discussed in detail. ( addition to these roles in the pathogenesis of coronary artery disease, lipid-related molecules have been identified to be markers of inflammation and oxidative stress (Table 1). Thrombosis-Related Risk MarkersAfter atherosclerotic plaque rupture, platelets adhere to exposed subendothelial components, such as collagen and von Willebrand factor, which promotes platelet activation and aggregation. 10 In addition, platelet activation is potentiated by exposure to released soluble agonists, such as thrombin and ADP.10 Activated platelets then further release ADP, which acts on platelet P2Y 12 ADP receptors and has a central role in amplifying the response of platelets to the initial stimulus. 10 Platelet reactivity to various agonists, including ADP, has been studied extensively in the context of acute coronary syndrome (ACS; Table 2). 11 The VerifyNow and Multiplate pointof-care tests allow for the measurement of platelet aggregation in response to stimulation, and it has been shown that high platelet reactivity is associated with adverse cardiovascular events. 26 Platelet microparticles are released on platelet activation, and their role in cardiovascular disease is an area of active investigation (Table 2). 15 Circulating microparticles are released from cells undergoing activation or apoptosis and are a type of small plasma membrane vesicle that retain defined properties from their original cell lineage. 15 Platelet activation and aggregation lead to the activation of the coagulation cascade and the formation of a stable crosslinked fibrin clot. The balance between prothrombotic factors and endogenous fibrinolysis determines whether the thrombus propagates or instead proceeds to dis...

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confidence: 99%

Novel Risk Markers and Risk Assessments for Cardiovascular Disease

Thomas

Lip

2017

Circulation Research

111

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“…The molecular basis of this biomarker is that the cleavage of PICP from the procollagen type I precursor will determine the ability of the resulting collagen type I molecule to form fibrils 18. Excessive myocardial collagen cross‐linking is associated with HF hospitalization in hypertensive patients with HF, and the serum C‐terminal telopeptide of collagen type I (CITP) : matrix metalloproteinase 1 (MMP‐1) ratio allows identification of patients with increased collagen cross‐linking and high risk for HF hospitalization 19. The molecular basis of this biomarker relies on the consideration that a diminished circulating level of CITP (corrected by circulating MMP‐1) reflects reduced collagen type I fibre degradation by MMP‐1 given that high lysyl‐oxidase‐mediated cross‐linking increases the resistance of the fibre to MMP‐1 proteolysis 20.…”

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confidence: 99%

Rationale of the FIBROTARGETS study designed to identify novel biomarkers of myocardial fibrosis

et al. 2017

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AimsMyocardial fibrosis alters the cardiac architecture favouring the development of cardiac dysfunction, including arrhythmias and heart failure. Reducing myocardial fibrosis may improve outcomes through the targeted diagnosis and treatment of emerging fibrotic pathways. The European‐Commission‐funded ‘FIBROTARGETS’ is a multinational academic and industrial consortium with the main aims of (i) characterizing novel key mechanistic pathways involved in the metabolism of fibrillary collagen that may serve as biotargets, (ii) evaluating the potential anti‐fibrotic properties of novel or repurposed molecules interfering with the newly identified biotargets, and (iii) characterizing bioprofiles based on distinct mechanistic phenotypes involving the aforementioned biotargets. These pathways will be explored by performing a systematic and collaborative search for mechanisms and targets of myocardial fibrosis. These mechanisms will then be translated into individualized diagnostic tools and specific therapeutic pharmacological options for heart failure.Methods and resultsThe FIBROTARGETS consortium has merged data from 12 patient cohorts in a common database available to individual consortium partners. The database consists of >12 000 patients with a large spectrum of cardiovascular clinical phenotypes. It integrates community‐based population cohorts, cardiovascular risk cohorts, and heart failure cohorts.ConclusionsThe FIBROTARGETS biomarker programme is aimed at exploring fibrotic pathways allowing the bioprofiling of patients into specific ‘fibrotic’ phenotypes and identifying new therapeutic targets that will potentially enable the development of novel and tailored anti‐fibrotic therapies for heart failure.

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“…Recently, we have demonstrated that a low serum CITP:MMP-1 ratio identifies with good sensitivity and specificity HF patients with histologically proven excessive myocardial collagen type I cross-linking, which account for approximately half of all HF patients. 17 Furthermore, the serum CITP:MMP-1 ratio is associated with the risk of presenting with hospitalization for HF. 17 The pathophysiological basis of this biomarker relies on the consideration that a diminished circulating level of CITP (corrected by circulating MMP-1) reflects reduced collagen type I fiber degradation by MMP-1 because a high LOX-mediated cross-linking augments the resistance of the fiber to proteolysis by MMP-1.…”

Section: Identifying Hf Patients To Be Treated With Torasemide To Redmentioning

confidence: 99%

“…17 Furthermore, the serum CITP:MMP-1 ratio is associated with the risk of presenting with hospitalization for HF. 17 The pathophysiological basis of this biomarker relies on the consideration that a diminished circulating level of CITP (corrected by circulating MMP-1) reflects reduced collagen type I fiber degradation by MMP-1 because a high LOX-mediated cross-linking augments the resistance of the fiber to proteolysis by MMP-1.…”

Section: Identifying Hf Patients To Be Treated With Torasemide To Redmentioning

confidence: 99%

Targeting the Cardiac Myofibroblast Secretome to Treat Myocardial Fibrosis in Heart Failure

Weber

Dı́ez

2016

Circ: Heart Failure

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Myocardial Collagen Cross-Linking Is Associated With Heart Failure Hospitalization in Patients With Hypertensive Heart Failure

Abstract: Excessive myocardial CCL is associated with HHF in hypertensive patients with HF. In this population, the serum CITP:MMP-1 ratio identifies patients with increased CCL and high risk of HHF.

Cited by 132 publications

References 30 publications

Novel Risk Markers and Risk Assessments for Cardiovascular Disease

Novel Risk Markers and Risk Assessments for Cardiovascular Disease

Rationale of the FIBROTARGETS study designed to identify novel biomarkers of myocardial fibrosis

Targeting the Cardiac Myofibroblast Secretome to Treat Myocardial Fibrosis in Heart Failure

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