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Agdamag et al. Vessel Plus 2020;4:42 I http://dx.doi.org/10.20517/2574-1209.2020.60 Page 5 of 9

coronary intima affecting all large epicardial vessels, intramuscular arteries as well as the microvascular
bed [40,41] . The initial, immune-mediated arteritis is followed by the diffuse deposition of cholesterol particles
within the intima. Risk factors include the host-mediated immunological response towards the graft as
well as non-immune factors, such as dyslipidemia, hypertension, smoking, CMV infection and ischemia-
reperfusion injury [42,43] . Dyslipidemia is extremely common in heart transplant recipients. Many patients
have long-standing hyperlipidemia prior to transplantation, and it is also a well-established side effect
of immunosuppressive agents, including corticosteroids, rapamycin and calcineurin inhibitors (e.g.,
[44]
tacrolimus, cyclosporine) . As such, statin therapy is a Class I recommendation in current guidelines for
[38]
heart transplant recipients, irrespective of serum cholesterol levels . Despite being the standard of care,
many statins have significant interactions with immunosuppressants, may cause myositis, rhabdomyolysis
[45]
or myalgias, and may provide suboptimal lipid control .

Due to the above limitations and the unfavorable side effect profile of statin therapy in the post-transplant
population, there are ongoing investigations to test therapeutic alternatives for lipid management, such as
PCSK9 inhibitors. Agents in this class bind specifically to an extracellular target and do not interact with
the cytochrome P450 system. Therefore, they have low risk for significant drug-drug interactions, including
with immunosuppressants, and their properties render them well tolerated overall [46,47] . Interestingly, Simha
and colleagues reported that mammalian target of rapamycin (mTOR) inhibition with sirolimus increases
PCSK9 expression in both humans and in-vitro cell culture studies; however, the increased PCSK9 levels
did not correlate with sirolimus-induced hypercholesterolemia. It is postulated that sirolimus may cause
[48]
hyperlipidemia via multiple pathways and further studies are under-way . Although no large, randomized
clinical trials have yet been completed, several case series reported single center experiences on the use of
PCKS9 inhibitors in statin-intolerant heart transplant recipients [Table 1]. The reduction in serum LDL-C
in response to PCSK9 initiation averaged between 40% and 70% [44,49] . Both drugs in the class demonstrated
a favorable safety profile with adverse reactions limited to injection site erythema, rhinorrhea, nausea and
clinically insignificant transaminitis [49,50] . These case series reported no increase in the risk of graft rejection,
infections or fluctuation in serum immunosuppressant levels [44,49,51,52] . In addition to their direct benefit
on circulating LDL-C levels, the anti-inflammatory properties of PCSK9 inhibitors may also reduce the
activation of the innate immune system encountered after solid organ transplantation [33,53] . While the results
of current observational data on the use of PCSK9 inhibitors in heart transplant recipients are promising,
most reports are limited by the number of patients and short-term follow-up, highlighting the need for
additional studies in the field.

A recent paper by Bjerre and colleagues reported elevated levels of PCSK9 in patients with macrovascular
[54]
CAV, as detected by coronary angiography and optic coherence tomography . In addition, the authors
found a trend towards higher circulating PCSK9 levels in the subgroup taking mTOR inhibitors. Note,
however, that it is routine practice to initiate patients on an mTOR inhibitor once CAV is established, and
therefore this observation might be unrelated to the immunosuppressant used. Nevertheless, further larger
scale randomized studies are needed to establish the possible benefit of PCSK9 inhibition in de novo heart
transplant recipients to prevent CAV development and progression.

FUTURE DIRECTION
Given their clinical efficacy in reducing serum LDL-C, limited side effect profile, and the lack of
interactions with immunosuppressants, it is imperative to further explore the idea of PCSK9 inhibitor use
in heart transplant recipients for CAV prevention. Two clinical trials are currently open and are actively
enrolling patients. EVOLVD is a multicenter, randomized, controlled, double-blind study aiming to
determine whether the addition of evolocumab on top of background statin therapy, can ameliorate CAV
[55]
in de novo heart transplant patients at 12 months, as assessed by coronary intravascular ultrasound . First
results are expected to be published in 2022. The PCSK9 Inhibition After Heart Transplantation trial lead