Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury.

Polymorphisms in VEGFA and KDR encoding proteins have been associated with anterior cruciate ligament (ACL) injury risk. We leveraged a collective sample from Sweden, Poland, and Australia to investigate the association of functional polymorphisms in VEGFA and KDR with susceptibility to ACL injury risk. Using a case-control genetic association approach, polymorphisms in VEGFA and KDR were genotyped and haplotypes inferred from 765 controls, and 912 cases clinically diagnosed with ACL rupture. For VEGFA, there was a significant overrepresentation of the rs2010963 CC genotype (p = 0.0001, false discovery rate [FDR]: p = 0.001, odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.47-3.19) in the combined ACL group (18%) compared to the combined control group (11%). The VEGFA (rs699947 C/A, rs1570360 G/A, rs2010963 G/C) A-A-G haplotype was significantly (p = 0.010, OR: 0.85, 95% CI: 0.69-1.05) underrepresented in the combined ACL group (23%) compared to the combined control group (28%). In addition, the A-G-G construct was significantly (p = 0.036, OR: 0.81, 95% CI: 0.64-1.02) underrepresented in the combined ACL group (12%) compared to the combined CON group (16%). Our findings support the association of the VEGFA rs2010963 CC genotype with increased risk and (ii) the VEGFA A-A-G haplotype with a reduced risk, and are in alignment with the a priori hypothesis. Collectively identifying a genetic interval within VEGFA to be implicated in ACL risk modulation and highlight further the importance of vascular regulation in ligament biology.

Predictive Factors for Hamstring Autograft Diameter in Anterior Cruciate Ligament Reconstruction.

Multiple studies found hamstring tendon (HT) autograft diameter to be a risk factor for anterior cruciate ligament (ACL) reconstruction failure. This study aimed to determine which preoperative measurements are associated with HT autograft diameter in ACL reconstruction by directly comparing patient characteristics and cross-sectional area (CSA) measurement of the semitendinosus and gracilis tendon on magnetic resonance imaging (MRI). Fifty-three patients with a primary ACL reconstruction with a four-stranded HT autograft were included in this study. Preoperatively we recorded length, weight, thigh circumference, gender, age, preinjury Tegner activity score, and CSA of the semitendinosus and gracilis tendon on MRI. Total CSA on MRI, weight, height, gender, and thigh circumference were all significantly correlated with HT autograft diameter (p < 0.05). A multiple linear regression model with CSA measurement of the HTs on MRI, weight, and height showed the most explained variance of HT autograft diameter (adjusted R 2 = 44%). A regression equation was derived for an estimation of the expected intraoperative HT autograft diameter: 1.2508 + 0.0400 × total CSA (mm2) + 0.0100 × weight (kg) + 0.0296 × length (cm). The Bland and Altman analysis indicated a 95% limit of agreement of ± 1.14 mm and an error correlation of r = 0.47. Smaller CSA of the semitendinosus and gracilis tendon on MRI, shorter stature, lower weight, smaller thigh circumference, and female gender are associated with a smaller four-stranded HT autograft diameter in ACL reconstruction. Multiple linear regression analysis indicated that the combination of MRI CSA measurement, weight, and height is the strongest predictor.

Functional polymorphisms within the inflammatory pathway regulate expression of extracellular matrix components in a genetic risk dependent model for anterior cruciate ligament injuries.

OBJECTIVES: To investigate the functional effect of genetic polymorphisms of the inflammatory pathway on structural extracellular matrix components (ECM) and the susceptibility to an anterior cruciate ligament (ACL) injury. DESIGN: Laboratory study, case-control study. METHODS: Eight healthy participants were genotyped for interleukin (IL)1B rs16944 C>T and IL6 rs1800795 G>C and classified into genetic risk profile groups. Differences in type I collagen (COL1A1), type V collagen (COL5A1), biglycan (BGN) and decorin (DCN) gene expression were measured in fibroblasts either unstimulated or following IL-1ß, IL-6 or tumor necrosis factor (TNF)-α treatment. Moreover, a genetic association study was conducted in: (i) a Swedish cohort comprised of 116 asymptomatic controls (CON) and 79 ACL ruptures and (ii) a South African cohort of 100 CONs and 98 ACLs. Participants were genotyped for COL5A1 rs12722 C>T, IL1B rs16944 C>T, IL6 rs1800795 G>C and IL6R rs2228145 G>C. RESULTS: IL1B high-risk fibroblasts had decreased BGN (p=0.020) and COL5A1 (p=0.012) levels after IL-1ß stimulation and expressed less COL5A1 (p=0.042) following TNF-α treatment. Similarly, unstimulated IL6 high-risk fibroblasts had lower COL5A1 (p=0.012) levels than IL6 low-risk fibroblasts. In the genetic association study, the COL5A1-IL1B-IL6 T-C-G (p=0.034, Haplo-score 2.1) and the COL5A1-IL1B-IL6R T-C-A (p=0.044, Haplo-score: 2.0) combinations were associated with an increased susceptibility to ACL injury in the Swedish cohort when only male participants were evaluated. CONCLUSIONS: This study shows that polymorphisms within genes of the inflammatory pathway modulate the expression of structural and fibril-associated ECM components in a genetic risk depended manner, contributing to an increased susceptibility to ACL injuries.

Predictive Factors of Hamstring Tendon Regeneration and Functional Recovery After Harvesting: A Prospective Follow-up Study.

BACKGROUND: Semitendinosus and gracilis tendons may regenerate after harvesting for ligament reconstruction procedures. However, predictive factors of tendon regeneration and the extent of functional recovery remain unclear. PURPOSE: To identify predictive factors for hamstring tendon regeneration and to examine the morbidity of nonregenerated hamstring tendons. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Of the 154 patients who were included in a prospective follow-up study, 79 underwent reconstruction of the anterior cruciate ligament entailing the hamstring tendons and met the following inclusion criteria: (1) anterior cruciate ligament rupture diagnosed by physical examination and magnetic resonance imaging (MRI), (2) MRI within 6 months after trauma, (3) age between 18 and 45 years, and (4) 2-year follow-up MRI data available. Hamstring tendon regeneration was assessed as complete if a tendon-like structure could be visualized at the level of the joint line or more cranially. Patient characteristics-such as age, sex, body mass index, alcohol/nicotine use, activity level (Tegner scores), and functional instability (1-legged hop test)-were evaluated preoperatively and at 2 years to determine predictive factors for tendon regeneration or examine functional recovery of hamstring tendon regeneration. RESULTS: At 2 years' follow-up, 67.1% of the patients showed regeneration of semitendinosus tendons, 81.0% of gracilis tendons, and 59.5% of both tendons. The likelihood of semitendinosus tendon regeneration significantly decreased with aging (odds ratio [OR], 0.92 change per year of age; 95% CI, 0.84-0.99; P = .03) and smoking (OR, 0.20; 95% CI, 0.05-0.77; P = .02). No predictive factor was found for gracilis tendon regeneration. Regeneration of the semitendinosus and gracilis tendons was negatively related with smoking (OR, 0.22; 95% CI, 0.06-0.79; P = .02). Patients without regeneration showed similar postoperative visual analog scale scores during physical activity, similar Tegner scores, and a significant decrease of the upper leg circumference, as compared with their preoperative results. Regardless of the regeneration status, 1-legged hop test results significantly increased at 2-year follow-up. CONCLUSION: Hamstring tendon regeneration occurs less frequently in older patients and in smokers. However, absence of regenerated tendons does not seem to cause a loss of function.

Hamstring Tendon Regeneration After Harvesting: A Systematic Review.

BACKGROUND: Hamstring tendons are often used as autografts for anterior cruciate ligament (ACL) reconstruction. However, no systematic review has been performed describing consequences such as hamstring tendon regeneration rate and determinants of hamstring tendon regeneration. PURPOSE: To summarize the current literature regarding hamstring tendon rate regeneration, the time course of regeneration, and determinants of hamstring regeneration. STUDY DESIGN: Systematic review. METHODS: A search was performed in the Embase, Medline (OvidSP), Web of Science, Cochrane, PubMed, and Google Scholar databases up to June 2014 to identify relevant articles. A study was eligible if it met the following inclusion criteria: tendons were harvested, regeneration at harvest site was assessed, population size was at least 10 human subjects, full-text article was available, and the study design was either a randomized controlled trial, prospective cohort study, retrospective cohort study, or case control study. A risk of bias assessment of the eligible articles was determined. Data describing hamstring tendon regeneration rates were pooled per time period. RESULTS: A total of 18 publications met the inclusion criteria. The mean regeneration rate for the semitendinosus and gracilis tendons was, in all cases, 70% or higher. More than 1 year after harvesting, 79% (median [IQR], 80 [75.5-90]) of the semitendinosus tendons and 72% (median [IQR], 80 [61-88.5]) of the gracilis tendons were regenerated. No significant differences in regeneration rate could be found considering patient sex, age, height, weight, or duration of immobilization. Results did not clearly show whether absence of regeneration disadvantages the subsequent hamstring function. Five studies measured the regeneration rate at different moments in time. CONCLUSION: Hamstring tendons regenerated in the majority of patients after ACL reconstruction. The majority of the hamstring tendon regeneration was found to occur between 1 month and 1 year after harvest. No significant determinants for hamstring tendon regeneration could be identified because of a lack of research. The function and strength of the regenerated hamstring remained unclear.