F13A1 Gene Variant (V34L) and Residual Circulating FXIIIA Levels Predict Short- and Long-Term Mortality in Acute Myocardial Infarction after Coronary Angioplasty

Abstract

Factor XIIIA (FXIIIA) levels are independent predictors of early prognosis after acute myocardial infarction (AMI) and the Valine-to-Leucine (V34L) single nucleotide polymorphism (SNP) seems associated with lower AMI risk. Since the long-term AMI prognosis merits deeper investigation, we performed an observational study evaluating relationships between FXIIIA residual levels, cardiovascular risk-factors, and inherited genetic predispositions. FXIIIA V34L was genotyped in 333 AMI patients and a five-year follow-up was performed. FXIIIA levels assessed at day-zero (d0) and four days after AMI (d4), and conventional risk factors were analyzed, focusing on the development of major adverse cardiovascular events (MACE). FXIIIA assessed at d0 and d4 was also an independent MACE predictor in the long-term follow-up (FXIIIA_d0, Odds Ratio (OR) = 3.02, 1.79⁻5.1, p = 0.013; FXIIIA_d4, OR = 4.46, 2.33⁻8.55, p = 0.0001). FXIIIA_d4 showed the strongest MACE association, suggesting that the FXIIIA protective role is maximized when high levels are maintained for longer time. Conversely, FXIIIA levels stratified by V34L predicted MACE at a lesser extent among L34-carriers (Hazard Risk (HR)_VV34 = 3.89, 2.19⁻6.87, p = 0.000003; HR_L34-carriers = 2.78, 1.39⁻5.57, p = 0.0039), and V34L did not predict all MACE, only multiple-MACE occurrence (p = 0.0087). Finally, in survival analysis, heart failure and death differed significantly from stroke and recurrent ischemia (p = 0.0013), with FXIIIA levels appreciably lower in the former (p = 0.05). Overall, genetically-determined FXIIIA levels have a significant long-term prognostic role, suggesting that a pharmacogenetics approach might help to select those AMI patients at risk of poor prognosis in the need of dedicated treatments.

Keywords: coagulation factor XIII; left ventricular remodeling and heart failure; myocardial healing; myocardial infarction; pharmacogenetics; prognostic biomarkers; translation cardioprotective strategies.

Figure 1

(A) Distribution of patients carrying FXIIIA VV34 genotype or L34-allele stratified by FXIIIA quartiles (I-IV) assessed at baseline (d0; left panel) and four days (d4; right panel) after AMI. Patients having FXIIIA levels in the first quartile had a non-significant slight overrepresentation of L34-carriers both at d0 and at d4. Their frequency significantly decreased from the first to the fourth quartile, the opposite of the frequency for the VV34 genotype (p = 0.0014 and p = 0.023 at d0 and d4, respectively); (B) Distribution of patients with and without major adverse cardiovascular events (MACE+ and MACE−) stratified by FXIIIA quartiles (I-IV) assessed at baseline (d0; left panel) and four days (d4; right panel) after AMI. Patients having FXIIIA levels in the first quartile had a non-significant slight overrepresentation of MACE+ at d0, whilst at d4 they were significantly overrepresented (p = 0.0001). MACE+ frequency significantly decreased from the first to the fourth quartile, the opposite to that of MACE− (p = 0.00016 and p < 0.00001 at d0 and d4 respectively).

Figure 2

(A). Distribution of patients with and without major adverse cardiovascular events (MACE+ and MACE−) stratified by FXIIIA quartiles (I-IV) assessed at baseline (d0) among L34-carriers (left panel) and VV34-homozygotes (right panel). Patients having FXIIIA levels in the first quartile had a non-significant slight overrepresentation of MACE+ among L34-carriers or VV34-homozygotes. MACE+ frequency significantly decreased from the first to the fourth quartile, the opposite to that of MACE−, and this was more evident among VV34-homozygotes (p = 0.06 and p = 0.0064 among L34-carriers and VV34-homozygotes, respectively); (B) Distribution of patients with and without major adverse cardiovascular events (MACE+ and MACE−) stratified by FXIIIA quartiles (I-IV) assessed at day-four (d4) among L34-carriers (left panel) and VV34-homozygotes (right panel). Patients having FXIIIA levels in the first quartile had MACE+ overrepresented both among L34-carriers (p = 0.0036) and VV34-homozygotes (p = 0.0007). The fall in MACE+ occurrence was more evident among the VV34 genotype (p = 0.0105 and p = 0.00013 among L34-carriers and VV34-homozygotes, respectively).

Figure 3

Plots of Kaplan-Meier survival analysis estimated after AMI according to FXIIIA quartiles assessed at baseline (day-zero) and four days after AMI (day-four). (A) Survival curve comparison according to FXIIIA quartiles I-IV measured at day-zero. At five-year follow-up, survival rates among the different quartiles were significantly different (p = 0.000034); (B) Survival curve comparison according to FXIIIA quartiles I-IV measured at day-four. At five-year follow-up, survival rates among the different quartiles were significantly different (p = 0.000009); (C) Survival curve comparison according to FXIIIA quartile I versus quartiles II-IV computed together at day-zero. At five-year follow-up, survival in the I quartile significantly differed from that of the II-IV quartiles (p = 0.000012); (D) Survival curve comparison according to FXIIIA quartile I versus quartiles II-IV computed together at day-four. At five-year follow-up, survival in the I quartile significantly differed from that of the II-IV quartiles (p < 0.000001).

Figure 4

Plots of Kaplan-Meier survival analysis estimated after AMI according to FXIIIA V34L genotypes. (A) Survival curve comparison between LL34-homozygotes (LL34), VL34-heterozygotes (VL34), and VV34-homozygotes (VV34). Survival rate was not significantly different between the different genotypes; (B) Survival curve comparison between VL34-heterozygotes and LL34-homozygotes taken together (L34-carriers), and VV34-homozygotes (VV34). Survival rate was not significantly different between the two different groups of genotypes.

Figure 5

Plots of Kaplan-Meier survival analysis estimated after AMI according to different kinds of MACE at five-year follow-up. Cardiovascular (CV) death and heart failure (HF) combined together (red line), stroke and recurrent non-fatal ischemic events (RI) combined together (blue line). Survival significantly differed between subgroups (p = 0.0013).