Cardiac Allograft Vasculopathy and Heart Transplant Failure
Cardiac Allograft Vasculopathy and Heart Transplant Failure
Early risk-prediction is essential to prevent cardiac allograft vasculopathy (CAV) and graft failure in heart transplant patients. We developed multivariate models to identify patients likely to experience CAV, severe CAV, and failure due to CAV, at 1, 5 and 10 years. A cohort of 172 patients was followed prospectively for 6.7 ± 3.9 years. Logistic regression models were developed and cross-validated using bootstrap resampling. Predictive markers of atherothrombosis (myocardial fibrin deposition, and loss of vascular antithrombin and tissue plasminogen activator) and arterial endothelial activation (intercellular adhesion molecule-1 expression) were measured in serial biopsies obtained within 3 months posttransplant. Most markers were univariately associated with outcome. Multivariate models showed that loss of tissue plasminogen activator was the dominant and, in most cases, only predictor of long-term CAV (p < 0.001), severe CAV (p < 0.001), and graft failure due to CAV (p < 0.001). The models discriminated patients having adverse outcomes, had particularly high negative predictive values (graft failure due to CAV: 99%, 99% and 95% at 1, 5 and 10 years) and predicted event incidence and time to event. Early absence of atherothrombotic risk identifies a patient subgroup that rarely develops CAV or graft failure, implying that this low-risk subgroup could possibly be followed with fewer invasive procedures.
Cardiac allograft vasculopathy (CAV), a particularly aggressive form of atherosclerosis, is a serious problem following heart transplantation. Unlike native atherosclerosis that develops over decades, CAV progresses quickly, within months or a few years. Its pathogenesis, although not fully understood, is characterized by a fibroproliferative process affecting all cardiac arteries and resulting in concentric narrowing, obliteration and, ultimately, allograft failure. Although immunosuppression has significantly reduced the incidence of acute rejection and prolonged early survival, it has done little to alter the incidence of CAV, the principal long-term cause of graft failure, accounting for 30% of all deaths.
Because the denervated heart exhibits no premonitory symptoms, CAV typically presents as a silent myocardial infarction, severe arrhythmia, or sudden death, making it mandatory to follow patients carefully for signs of developing CAV. Once it has fully developed, retransplantation is the only option. For this reason, attention has focused on preventing CAV or slowing its occurrence and the search for early biomarkers to identify patients at risk is a critical priority for transplantation research.
Herein we describe statistical risk-prediction models for grading heart transplant recipients' risk of CAV and graft failure using biopsy-derived immunohistochemical markers that summarize the degree of early coagulation and arterial endothelial activation in the allografts.
Abstract and Introduction
Abstract
Early risk-prediction is essential to prevent cardiac allograft vasculopathy (CAV) and graft failure in heart transplant patients. We developed multivariate models to identify patients likely to experience CAV, severe CAV, and failure due to CAV, at 1, 5 and 10 years. A cohort of 172 patients was followed prospectively for 6.7 ± 3.9 years. Logistic regression models were developed and cross-validated using bootstrap resampling. Predictive markers of atherothrombosis (myocardial fibrin deposition, and loss of vascular antithrombin and tissue plasminogen activator) and arterial endothelial activation (intercellular adhesion molecule-1 expression) were measured in serial biopsies obtained within 3 months posttransplant. Most markers were univariately associated with outcome. Multivariate models showed that loss of tissue plasminogen activator was the dominant and, in most cases, only predictor of long-term CAV (p < 0.001), severe CAV (p < 0.001), and graft failure due to CAV (p < 0.001). The models discriminated patients having adverse outcomes, had particularly high negative predictive values (graft failure due to CAV: 99%, 99% and 95% at 1, 5 and 10 years) and predicted event incidence and time to event. Early absence of atherothrombotic risk identifies a patient subgroup that rarely develops CAV or graft failure, implying that this low-risk subgroup could possibly be followed with fewer invasive procedures.
Introduction
Cardiac allograft vasculopathy (CAV), a particularly aggressive form of atherosclerosis, is a serious problem following heart transplantation. Unlike native atherosclerosis that develops over decades, CAV progresses quickly, within months or a few years. Its pathogenesis, although not fully understood, is characterized by a fibroproliferative process affecting all cardiac arteries and resulting in concentric narrowing, obliteration and, ultimately, allograft failure. Although immunosuppression has significantly reduced the incidence of acute rejection and prolonged early survival, it has done little to alter the incidence of CAV, the principal long-term cause of graft failure, accounting for 30% of all deaths.
Because the denervated heart exhibits no premonitory symptoms, CAV typically presents as a silent myocardial infarction, severe arrhythmia, or sudden death, making it mandatory to follow patients carefully for signs of developing CAV. Once it has fully developed, retransplantation is the only option. For this reason, attention has focused on preventing CAV or slowing its occurrence and the search for early biomarkers to identify patients at risk is a critical priority for transplantation research.
Herein we describe statistical risk-prediction models for grading heart transplant recipients' risk of CAV and graft failure using biopsy-derived immunohistochemical markers that summarize the degree of early coagulation and arterial endothelial activation in the allografts.
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