A novel prognostic biomarker in acute myocardial infarction predicts the risk of heart failure or early Death: “Factor XIII-A dynamics in acute myocardial infarction: a novel prognostic biomarker?”

Ricercatori-973x615Autore del lavoro candidato: Donato Gemmati

SINTESI CONTENENTE UNA BREVE DESCRIZIONE DEL LAVORO SVOLTO E DEI RISULTATI OTTENUTI: After acute myocardial infarction (AMI) the damaged heart has to be repaired. Coagulation Factor XIII (FXIII) is considered a novel emerging key-molecule in promoting heart-healing (Gemmati et al; Curr Pharm Design; 2015). In a mice model, FXIII deficiency (Knock-out-FXIII-gene) was associated to severe heart failure (HF), anomalous left ventricular remodelling (LVR), and finally to death (due to cardiac rupture), in 100% of experimental induced AMI (Nahrendorf et al; Circulation, 2006). FXIII and Fibrinogen are molecules responsible for the formation of a fibrin-matrix at any injured tissue site, with the aim to counteract lesion expansion and to promote local angiogenesis and collagen deposition for the perfect wound healing (Zamboni & Gemmati; Thromb & Haemost 2007). During AMI, the injured heart could benefit of such a provisional fibrin-matrix and associated reparative processes. Collagenasis and other MMPs drastically increase during AMI and affect the provisional fibrin-matrix and tissues, impeding scar elasticity. An excessive fibrotic scar may lead to infarction extension into the remote region compromising the contractile heart function. Our group demonstrated that FXIII contrasts the detrimental effect of collagenasis preserving the provisional fibrin matrix and helping in turn in vitro cell viability (Zamboni et al; Vascular & Endovasc Surg 2004). Altogether these data ascribed to FXIII the role of “the cement of the heart after AMI” (Vanhoutte et al; Eur Heart J 2008). Therefore, higher FXIII activity/levels are crucial elements in heart repair and regenerati on, and may have positive effects on post-AMI patient survival (Gemma ti et al, Am J Hematol 2001; Gemmati et al; Molecular Medicine, 2007). FXIII is the unique and main director in regulating fibrin-matrix cross-linking/deposition and in the associated architecture. Accordingly, we recently hypothesized (Gemmati et al, Thromb & Haemost 2015) that during AMI, FXIII may have a dual and opposite role: ì. firstly, it contributes to the intracoronary thrombus formation, and shortly after, ìì. it contributes to heal the myocardial lesion by means the above mentioned statements. In our candidate work, we quantified the real contribution of FXIII in the heart healing process after infarction, and explored its possible prognostic role, by monitoring the FXIII A-subunit level in 350 AMI patients during the first six days of acute infarction (d0-d5) plus a control at 30–60 days (d30). One-year follow-up was performed for all the patients. At day5 after AMI, we found a significant transient drop in the FXIII A-subunit mean levels in the whole cohort of patients (FXIII d0: 99.48 ± 30.5 vs FXIII d5: 76.51 ± 27.02; p< 0.0001). Interestingly, patients who died showed drastic FXIII mean consumption at day5 (FXIII d5: 54.0 ± 22.5), and those who developed severe HF showed a similar fall (FXIII d5: 52.1 ± 25.2). On the contrary, patients with a good prognosis (free of major adverse cardiac events; MACEs) had a negligible FXIII consuming (FXIII d5: 84.4 ± 24.5). Interestingly, the FXIII drop was independent from the amount of injured heart assessed by Trop onin-T and CKMB levels. This ascribes to FXIII monitoring an independent prognostic role in AMI. Finally, the survival analysis ascribed an increased probability of early death or severe HF inversely related to FXIII quartiles (FXIII_25th< 59.5 %; Hazard Ratio 4.25; 2.2–5.1; p< 0.0001). In conclusion, different FXIII dynamics and levels could be utilised as a personalized early prognostic indicator during AMI, to reveal the individual potential to heal and suggest tailored treatments to avoid severe HF, its extreme consequence or death. We proposed to assess circulating FXIII levels in the earliest phases of AMI, independently or together with Troponin_T and CKMB, as novel prognostic biomarker useful to recognize in advance those AMI patients at high risk of non-optimal heart-healing causing in turn heart wall-rupture, severe HF or LVR. Accordingly, we recently patented this novel prognostic biomarker application: US2015004625_2015-01-01; “Novel Prognostic Biomarker in Acute Myocardial Infarction”. Applicability and spin-off of the presented research: In the recent past, experimental data suggested the possibility of stem cells (SCs) based-healing-approaches in post-AMI healing (Orlic et al, Nature 2001; Jackson et al, J Clin Invest 2001; Massa et al, Blood 2005; Massa et al, Exp Hematol 2009; Skorska et al, J Cell Mol Med 2015; Wu et al, Circ Res 2015; Freytes et al, Cells Tissues Organs 2012). However, SCs-based therapies are not so efficacious since the majority of transplanted cells do not survive or do not efficiently integrate within the cardiac tissue. Additionally innovative approaches, are the construction of bio-scaffolds (including SCs-seeding or not) aimed at sustaining myocardium healing (Mukherjee et al, Ann Thorac Surg 2008; Della Rocca, Med Hypotheses 2012). Even though this approach aroused great expectations, the practical approach is not easily realizable due to several issues such as low cell penetration, nutrient/oxygen availability and inflammation triggered during scaffold degradation. To overcome th is limitations, “intelligent” polymers have been developed, but it is anyway often required an intra-myocardial injection of the biomaterial (Rajabi-Zeleti et al, Biomaterials 2014; Pawani et al, Indian J Med Res 2013). Since, FXIII transforms fibrin biopolymers in a resistant and elastic-matrix useful for cell growth and tissue regeneration, in our opinion, Fibrin(ogen) is the ideal biomaterial for cardiac endogenous tissue self-engineering as it is an abundant and biodegradable polymer, it induces neovascularization, it promotes (stem)-cell attachment and recruitment, and its properties can be easily tuneable by FXIII. We believe, this can be considered the most “intelligent” polymer for promoting cardiomyocytes, endothelial cells, and circulating stem cells integration in the damaged cardiac tissue helping the self-healing processes the heart starts immediately after AMI. The novelty, applicability and great translationality of our application resides in the fact that by means of FXIII level measuring, we can recognize, within 72-96h from heart attack, those cases at risk of anomalous heart remodelling, HF, LVR, or wall rupture and start target adjuvant therapies. In addition, low FXIII levels can be replenished by several available products such as recombinant-FXIII TrettenÒ (Novo Nordisk), CorifactÒ (CSL Behring), Fibrogammin PÒ (CLS Behring), and Bio Products Laboratory. Though not yet prescriptible for healing purposes, the presence in the pharmaceutical industry of a molecule potentially candidate to help post-AMI healing, renders confident the applicability of our project. Worthy of note is the fact that by means of our method, we can avoid the potential high risk of an indiscriminate FXIII treatment in AMI by recognising those patients that really need FXIII infusion.