In this report we update and extend prior work describing lumen diameter changes in lower extremity vein grafts over time,8-10
and their relationship to patient factors and clinical outcomes. Lumen remodeling is largely complete by 3 months, with most of the caliber change observed within 30 days. Early venous remodeling is strongly associated with hemodynamic forces particularly shear stress, but also with patient-specific factors including race and systemic inflammation. This study, for the first time, demonstrates that early vein remodeling is associated with subsequent graft patency, suggesting that factors which globally influence vein adaptation may also modulate the incidence and/or progression of critical lesions. Stated another way, although the pathology of vein graft failure is almost always segmental, the systemic and regional milieu of the entire
conduit appears to be a critical element of the healing response and the clinical outcome.
The relationship between initial vein diameter and patency of lower extremity bypass grafts has been established in a number of studies.15-17
The fundamental differences between previous reports and this study must be highlighted for correct interpretation of our findings. In most of the prior studies, such as Schanzer et al,17
the reported conduit diameter was an estimate of the minimal lumen diameter of the entire vein at the time of surgery. In other reports, initial vein graft imaging was performed up to one week following bypass surgery.7
In our study, we deliberately identified an “ideal” index segment of the graft intraoperatively for serial imaging. To facilitate later imaging, the segment was selected because it was a uniform diameter, valveless, without major branches, and at some distance from either anastomosis, without regard for the absolute minimum or maximum graft diameter. Furthermore, the selected cohort reported here may not be representative of a broader surgical series, particularly in relation to the use of higher risk conduits. Thus our observations on the relative importance of initial versus subsequent vein diameter must be appreciated within this context, and do not represent a departure from the well-established criteria by which surgeons have judged vein quality intraoperatively. Instead, the results highlight that early postoperative remodeling is distinct from initial size, and appears to correlate with graft patency. For example, a small vein that undergoes robust remodeling would be predicted to have better patency than a larger vein that fails to remodel.
These results extend and validate our prior findings by focusing on a carefully characterized subset of patients with multiple ultrasound measurements and detailed clinical follow-up for a median of nearly 3 years. The factors associated with early graft remodeling have remained consistent: initial lumen diameter/shear stress, baseline hsCRP, race, and statin use. The mechanisms underlying these observations remain to be defined, however we conjecture that endothelial dysfunction and vascular inflammation are the underlying key modifiers that influence biomechanical adaptation of the grafted vein. Ongoing and future studies hope to directly address these questions.
Systemic inflammation, represented here by plasma hsCRP level, has been demonstrated as a risk factor for incident cardiovascular disease and related clinical events.18-21
The relationship between inflammatory biomarkers and remodeling following vascular interventions has been less well studied,22-24
but we previously described an association between elevated hsCRP and outcomes of lower extremity bypass surgery.11, 24
Multiple studies have also observed a negative association between non-white racial status and vein graft patency.25-27
This study suggests that a common link may be found in the early postoperative remodeling response of the venous conduit. Our statistical analysis suggests that these factors have independent significance, however it should be noted that African-Americans, for example, have higher hsCRP levels across a number of large cohort studies, even when controlling for demographic and comorbid factors.28-31
We hypothesize that endothelial (dys-)function may be the common mechanism behind these associations, but additional research is required in this area.
Collectively these data suggest a conceptual evolution regarding the pathophysiology of vein graft failure. The observation that early caliber changes in a non-diseased section of the conduit—i.e. an “imaging biopsy”—correlate with the incidence of critical lesions elsewhere in the graft, implies that purely local factors (e.g. technical issues, surgical injury, local geometry) are only part of the story. This is further accented by the importance of patient-level factors such as race and hsCRP level, which have persisted in this and other studies. Thus we conjecture that systemic factors (genetic, biochemical, immunologic) and regional factors (hemodynamics) influence healing of the entire venous conduit and act as an important overlay to local determinants in graft lesion development. At present, the clinical relevance of these findings is limited by the modest size and single-center nature of the cohort. One intriguing hypothesis is that therapeutic modulation of inflammation may improve early remodeling and clinical outcomes of vein grafts; this requires formal testing in a prospective trial design.
In addition to sample size, our study is limited by a relative lack of racial and ethnic diversity, a mixture of indications and bypass configurations, as well as incomplete compliance with the longitudinal imaging protocol. Due to a variety of factors including clinical events, missed visits, and inadequate quality of some individual scans many patients did not have measurements available at all of the predetermined time points. Limitations of ultrasound in resolving the outer border of the graft limit our ability to characterize the structural changes in the graft wall i.e. neointima formation, wall composition, and mechanical compliance. Other imaging modalities32-34
may be more useful in this regard.
In conclusion, early remodeling of lower extremity vein bypass grafts is associated with hemodynamics, systemic inflammation, and patient-level risk factors such as race. Vein grafts that remodel poorly within the first month appear to be at increased risk for failure. Further investigation is needed to understand the mechanisms, and define potential clinical relevance for these findings.