“Cardiac allograft vasculopathy: Pathogenesis, diagnosis and therapy”

doi:10.1016/j.trre.2020.100569

Transplantation Reviews

Volume 34, Issue 4, October 2020, 100569

https://doi.org/10.1016/j.trre.2020.100569 Get rights and content

Highlights

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CAV still represents one of the main cause of death in heart recipients.
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CAV is a fibroproliferative concentric circumferential intimal thickening of coronary tree.
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IVUS presents higher sensibility compared with coronary angiography in early detection of CAV.
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Plaque composition and vulnerability on VH/IVUS or OCT seem to relate to adverse clinical events.
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PCI seems to have only a palliative meaning and should be considered in focal CAV disease.

Abstract

Cardiac allograft vasculopathy (CAV) is a unique form of accelerated atherosclerosis that represents the main late cause of morbidity and mortality, affecting almost half patients at ten years after heart transplantation (HTx). Unless the pathogenesis of CAV is still not completely understood, it seems to be the result of a complex interplay between immunological and non-immunological factors that induce endothelial injury. Histologically epicardial and intramural vessels present a concentric circumferential intimal thickening caused by smooth muscle cell proliferation, inflammatory cells, and lipid deposition. Coronary angiography is still considered the gold-standard diagnostic tool for CAV detection but has reduced sensibility due to its inability to visualize beyond the arterial lumen. Intravascular ultrasound (IVUS) allows detecting early intimal thickening with high sensitivity. Plaque composition and vulnerability, detectable with virtual histology (VH/IVUS), and optical coherence tomography (OCT) seem to relate to adverse clinical events. Treatment approaches continue to evolve, but prevention and early detection remain the focus. Mammalian target of rapamycin inhibitors can significantly delay the development and the progression of CAV, but their optimal use remains to be established. New encouraging results come from monoclonal autoantibodies. At present percutaneous revascularization procedures seem to have only a palliative meaning, with no clear evidence of survival advantage over medical therapy and should be considered in case of a focal disease. Drug-eluting stents have proven to reduce in-stent restenosis, with a potential role of imaging-guided intervention in this setting. Heart re-transplantation is the only resolutive therapy and is considered in the case of CAV associated with graft dysfunction.

Introduction

Cardiac allograft vasculopathy (CAV) still represents a complex challenge after heart transplantation (HTx). Its prevalence at 1, 5, 10 years is estimated to be 8, 29, 47%, respectively, accounting for 10% of all cause-specific deaths in heart recipients, between the first and the fifteenth year after HTx [1].

Section snippets

Pathophysiology

CAV is a unique form of arteriosclerosis. This accelerated inflammatory fibroproliferative disease affects epicardial coronary arteries as well as the microcirculation of transplanted heart, determining diffuse stenosis due to concentric intimal expansion and inadequate compensatory (outward) remodeling, causing tissue altered perfusion, ischemic injury, and graft loss [2]. Diffuse intimal thickening is due to smooth muscle cells (SMc) proliferation, inflammatory cell infiltration, and in the

Diagnosis and suirveillance

Diagnosis of CAV can be difficult, as the disease is often clinically silent due to denervation of the transplanted heart. Indeed, patients are often asymptomatic for typical angina, and they may present with heart failure, arrhythmia, or sudden death when graft dysfunction has already occurred [16]. Thus routine surveillance is essential to achieve early diagnosis. A summary protocol for the diagnosis and surveillance of HTx patients is proposed in Fig. 1.

Statins

Evidence of benefits of early statins initiation on HTx outcomes and reduction of CAV are well known as confirmed by a recent metanalysis by Vallakati et al. [49] with a significant reduction of CAV among patients taking statins (OR: 0.33; 95% CI: 0.16–0.68; P = .003). Possible reasons for this effect were found in the NK-cells inhibition promoted by statins and the reduction of lipoprotein levels, which results in a higher concentration of unbound fraction of immunosuppressive drugs like

Revascularization

The ischemic status following the diffuse narrowing of coronary arteries represents a strong predictor of a negative outcome [61]. However, due to the lack of evidence-based data, the role of revascularization (both percutaneous and surgical) is not clearly established.

Redo heart transplantation

Despite the fact that CAV represents the main indication to redo-HTx in the United States, the significant perioperative mortality and the ethical issues related to the shortage of organs make this option controversial, preventing widespread adoption. In this context, a recent specific sub-analysis of the ISHLT registry on 4595 patients has found no benefits in terms of outcomes in patients who underwent redo-HTx versus those who were medically managed, with a more favourable advantage in those

Disclosures

The authors declare no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Early aspirin use and the development of cardiac allograft vasculopathy in pediatric heart transplant recipients: A pediatric heart transplant society analysis
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Cardiac allograft vasculopathy (CAV) remains a leading cause of graft loss in pediatric heart transplant (HTx) recipients. Adult literature suggests that aspirin (ASA) use in the early post-HTx period may reduce the risk of CAV. This study aimed to determine the impact of early ASA use on the development of CAV in pediatric HTx recipients.
All subjects <17 years of age at time of primary HTx who survived ≥3 years without evidence of CAV were identified for inclusion from the Pediatric Heart Transplant Society database (1996-2019). Early ASA use was defined as ASA started within the first 3 years post-HTx and was classified as continuous or intermittent. Frequency of ASA use was described across centers. Kaplan-Meier method assessed freedom from CAV and overall graft survival. Multiphase parametric hazard analyses and propensity score matched analysis were used to identify independent risk factors.
3,011 patients were included with 387 (13%) receiving continuous ASA, 676 (22%) receiving intermittent ASA, and 1,948 (65%) receiving no ASA. ASA use was highly variable across centers (0%-100%). At baseline patients receiving continuous ASA therapy demonstrated inferior graft survival (p < 0.001) and worse freedom from CAV (p = 0.002), but with lower CAV grades (p = 0.05). In multiphase parametric hazard modeling continuous ASA use was not independently associated with CAV, but remained associated with inferior graft survival. Propensity-matched sub-analysis between continuous and no ASA groups demonstrated no difference in freedom from CAV or overall graft loss.
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Citation Excerpt :
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Cardiac allograft vasculopathy (CAV) continues to be a significant risk factor for the recipient's long-term survival following heart transplantation. Our knowledge of its etiology is constantly changing as new imaging techniques provide direct insight into the disease's natural history. CAV identification continues to be difficult since symptoms may be varied or nonexistent. Due to the irreversible nature of the disease, early diagnosis is critical to halting development. Prognostic tools and biomarkers have proliferated as a result of advancements in diagnostic techniques. Simultaneously, pharmaceutical advancements have aided in the amelioration of the disease's progressive progression.
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Review article“Cardiac allograft vasculopathy: Pathogenesis, diagnosis and therapy”

Highlights

Abstract

Introduction

Section snippets

Pathophysiology

Diagnosis and suirveillance

Statins

Revascularization

Redo heart transplantation

Disclosures

Funding

J Heart Lung Transplant

J Am Coll Cardiol

Atherosclerosis.

Am J Transplant

Am J Transplant

J Heart Lung Transplant

J Am Soc Echocardiogr

Am J Transplant

J Nucl Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Am J Transplant

J Heart Lung Transplant

Transplant Proc

J Am Coll Cardiol

J Am Coll Cardiol

J Heart Lung Transplant

J Am Coll Cardiol

Int J Cardiol

J Heart Lung Transplant

JACC Cardiovasc Imaging

Systematic Findings and Risk Stratification by OCT JACC Cardiovasc Imaging

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

J Am Coll Cardiol

Lancet.

Am J Transplant

J Heart Lung Transplant

J Heart Lung Transplant

substudy from the Everolimus versus mycophenolate mofetil randomized, multicenter trial JACC Heart Fail

Can J Cardiol

Am J Cardiol

Am J Cardiol

Lancet.

JACC Cardiovasc Interv

Am J Med

Review article
“Cardiac allograft vasculopathy: Pathogenesis, diagnosis and therapy”