Aspirin—At a Ripe Old Age: How to Prevent Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy (CAV) is increasing over time, leading to graft failure and death in the long term after heart transplantation. The actual number of CAV-related deaths is even higher as far as CAV is undiagnosed in many cases of sudden cardiac death. Additionally, once CAV is detected, it more than doubles the risk of death in the following years, accounting for 30% after 5 y.1 CAV is a multifactorial disease caused by donor- and recipient-related factors. However, to be honest, the whole picture of the pathogenesis of CAV is still not fully understood. Clinical symptoms in patients with CAV are often unspecific, rare, and mostly evident in the late phase of the disease for the first time. On top of this, diagnostic tools are missing, which are ideally precise, noninvasive, and inexpensive to detect CAV. Instead, coronary angiography has been the gold standard for decades. With this background, what is the best strategy? In general, prevention of a disease is better than treatment of a disease, but how can we prevent CAV? Definitely, only the optimal donor should be accepted for heart transplantation. In reality, however, donor selection is mainly influenced by organ shortage and recipient urgency, resulting in acceptance of donors with extended criteria, including risk factors for developing CAV, for example, older age, explosive brain death, and ischemia/reperfusion injury, vascular disease, hyperlipidemia, hyperglycemic, obesity, or viral infections. Thus, for donor selection, it is recommended to follow the guidelines of the International Society of Heart and Lung Transplantation to find the optimal donor-to-recipient match.2 The recipient characteristics have changed over the past decade. As a result, there are more recipients with older age and with more comorbidities, such as impaired renal function and cardiovascular risk factors (eg, obesity, diabetes mellitus, arterial hypertension, hyperlipidemia). In general, male recipients have more comorbidities than female ones and, therefore, have a higher risk of developing CAV. Aspirin is a drug celebrating its 125th anniversary this year, with many pharmacological properties leading to new clinical therapeutic indications. For example, aspirin blocks platelet activation in inflammation and immune response processes.3 Thus, aspirin has a grade I recommendation by the International Society of Heart and Lung Transplantation guidelines as a possible therapeutic option for CAV prophylaxis.4 Despite single-center studies with small patient numbers, the role of aspirin, however, has not been studied quite well after heart transplantation. Thus, we have to applaud Cassia Kessler Iglesias et al5 for their large 2-center retrospective study (372 recipients) about the early use of aspirin, published in this issue of Transplantation. Multivariable analyses found a significant reduction in mortality and a trend toward a lower incidence of moderate or severe CAV for the early use of aspirin after heart transplantation. Although these results must be confirmed in a larger prospective study, they are promising. Aspirin appears as a potential modifier of CAV, taking into account that it has antiviral effects, for example, against cytomegalovirus.3,6 Maybe this property of aspirin could also be studied in the future? Apart from this, prevention and treatment of cytomegalovirus infection do help to prevent CAV development, for example, prophylactic use of patients at high risk of infection or the early use of mammalian targets of rapamycin inhibitors.1 Additionally, the antiproliferative property of mammalian targets of rapamycin inhibitors makes this drug class favorable in CAV prevention, as study results have shown previously.7 Nevertheless, it is, of course, imperative to find the optimal immunosuppressive drug regimen with optimal exposure to be effective while reducing drug toxicities related to CAV development.7 Certainly, reducing the cardiovascular risk factors, preexisting or new onset, of the recipient is a necessity in prevention strategies for CAV, preferable by change of lifestyle to control arterial hypertension, diabetes mellitus, and hyperlipidemia in addition to specific drugs (eg, statins) if indicated.7 Immune-related risk factors are more prominent in the contribution of CAV development than nonimmune ones. Accordingly, every acute cellular rejection or antibody-mediated rejection (AMR) does bear the risk of triggering the immune system for the development of CAV in the long term. Especially, late onset of chronic AMR diagnosed in response to graft dysfunction, mainly resulting in CAV, is associated with 50%–60% mortality.8 Current knowledge is that circulating de novo donor-specific antibodies (DSAs) are associated with the development of AMR and CAV and, therefore, with worse outcomes. Thus, an interdisciplinary team approach is recommended to use precision diagnostic tools for early detection of acute rejection or de novo DSAs and to use novel therapeutic options for a consequent treatment to prevent CAV.8 Notably, prevention of CAV also means avoiding nonadherence to immunosuppressive drug treatment, resulting in acute cellular rejection, AMR, or DSA. Nonadherence is highest in the youngest recipients (18–29 y) compared with recipients at age between 50 and 59 y.1 As an alternative therapy in the prevention of CAV, extracorporeal photopheresis (ECP) could be useful as it has been shown to prevent rejection (T cell–dependent effect) despite the reduction of calcineurin inhibitor exposure. ECP could, therefore, be part of renal sparing regimens to allow recovery of renal function and maybe reduction of cardiovascular calcineurin inhibitor toxicities. In contrast, ECP also downregulates transforming growth factor-β–dependent fibrogenesis (T cell–independent effects) responsible for the pathogenesis of CAV.9 Finally, the prediction of CAV for a personalized prevention strategy might be possible by using artificial intelligence in the clinical routine, for example, machine learning in combination with diagnostic tools, in the near future.10 Encouragingly, the incidence of CAV may change in response to the implemention of both existing and new prevention strategies in the clinical routine with advanced multidisciplinary care. The task of this working group is characterized (1) to find the optimal donor-to-recipient match, (2) to apply precision diagnostic, (3) to prescribe personalized medical therapy, and (4) to educate and counsel the patients.1 Sometimes it is just smart to study what is already there: aspirin—at a ripe old age.