Angiotensin-Converting Enzyme Inhibitors for Cardiac Allograft Vasculopathy After Heart Transplantation∗

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 69, NO. 23, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jacc.2017.04.046

EDITORIAL COMMENT

Angiotensin-Converting Enzyme Inhibitors for Cardiac Allograft Vasculopathy After Heart Transplantation* Howard J. Eisen, MD, Shelley Hankins, MD, Denise Wang, BS

O

utcomes of cardiac transplantation have

also treat hypertension, proteinuria, and diabetic

been improved with immunosuppressive

nephropathy (5). These additional benefits are useful

therapies that effectively reduce the risk

given the comorbidities of patients with heart failure

of rejection and with prophylaxis against opportu-

and the ability of ACEIs to prevent unfavorable heart

nistic infections. With the current management lead-

remodeling. Thus, ACEIs can theoretically be benefi-

ing to decreased likelihood of hyperacute and acute

cial to post-transplant patients. An intravascular

rejections, efforts have been focused on improving

ultrasound (IVUS) study assigned 32 heart transplant

long-term survival by targeting post-transplant com-

recipients to ACEIs (n ¼ 9), calcium-channel blockers

plications associated with chronic rejection. Cardiac

(CCBs) (n ¼ 10), both CCBs and ACEIs (n ¼ 7), or

allograft vasculopathy (CAV) has been 1 of the main

control (n ¼ 6) within 1 month after heart trans-

causes of mortality for heart transplant recipients

plantation. At 1 year, participants receiving no treat-

(1). The CAV progression has been traditionally

ment demonstrated a greater degree of CAV than

managed with mechanistic target of rapamycin inhib-

those taking CCBs and/or ACEIs (4). A similar single-

itors, such as sirolimus and everolimus. Though

center IVUS study that was later conducted with

mechanistic target of rapamycin inhibitors have

82 heart transplant participants yielded CAV results

been successful in ameliorating or preventing CAV,

consistent with the prior study (6). ACEIs seemed

they frequently cause many significant side effects,

promising when a study also found plaque regression

like pancytopenia, wound healing issues, renal

and positive vascular remodeling to be associated

dysfunction and hyperlipidemia (2). This has limited

with their use in post-transplant patients (7). How-

their widespread use. Statins have been demon-

ever, the effect of ACEIs on CAV is difficult to deter-

strated to reduce the incidence of CAV (3). Today,

mine

post-transplant patients are commonly placed drugs

studies when longitudinal outcomes and survival of

such as statins for potential CAV improvement

patients has not been assessed. These previous

as well angiotensin-converting enzyme inhibitors

studies focused mainly on morphological changes as

(ACEIs) for their most common indications, like

reflected by IVUS and not coronary physiology.

hypertension (3,4). Patients with heart failure often take ACEIs prior to

from

these

single-center,

nonrandomized

SEE PAGE 2832

heart transplantation. Not only do ACEIs decrease

In this issue of the Journal, Fearon et al. (8) pro-

mortality in patients with heart failure, but they

spectively studied the effects of ACEIs, specifically ramipril, on early CAV development as well as endothelial function in 96 patients after heart transplantation using coronary angiography, endothelial

*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Division of Cardiology, Drexel University College of Medicine,

functional testing, measurement of fractional flow reserve, coronary flow reserve, index of microcirculatory resistance (IMR), and IVUS with volumetric

Philadelphia, Pennsylvania. The authors have reported that they have no

assessments. In this prospective trial, 39 patients on

relationships relevant to the contents of this paper to disclose.

ramipril and 38 patients on placebo reached the

Eisen et al.

JACC VOL. 69, NO. 23, 2017 JUNE 13, 2017:2842–4

ACEIs for Allograft Vasculopathy After Heart Transplants

1-year endpoint for evaluation of CAV. The assess-

significant effect on maximal intimal thickness in this

ment at 1 year was compared with the baseline pa-

prospective and randomized study, compared with

rameters that were obtained within 8 weeks of heart

the prior retrospective studies that suggested lesser

transplantation and after patients were placed on

degrees of CAV from ACEIs with or without CCB us-

standard post-transplant therapy, which included

age. This study design also eliminates subject bias

cyclosporine in children or tacrolimus in adults,

that may have characterized the prior retrospective

mycophenolate mofetil, prednisone, co-trimoxazole,

studies and calls into question the benefits in CAV

and pravastatin. Valganciclovir and CCBs were given

progression seen in prior studies. The lack of decrease

as needed for CMV prophylaxis and high blood pres-

in EPCs in the ramipril group compared with the

sure, respectively. Ramipril or placebo was given at

decrease in the placebo group illustrates that ramipril

2.5 mg/day a week after baseline was established. The

minimally at least stabilizes EPC quantity and func-

dosage was doubled every 2 weeks until a maximum

tion, which may benefit microvascular function,

of 20 mg/day was reached if no renal dysfunction was

although the exact significance of the EPC findings is

found, which was monitored through creatinine

not clear. The additional parameters included in the

levels. Ramipril was well-tolerated by patients,

trial compared with prior studies help to further un-

without severe adverse effects, and blood pressures

earth the effects of ACEIs on CAV in post-transplant

were maintained below 130/80 mm Hg when checked

patients.

every 4 months, similar to the results of the control

This study’s limitations mainly stem from the lack

group. The study defined coronary endothelial

of clarity of the role of ACEIs in CAV, which could be

dysfunction as a $20% decrease in LAD diameter

more apparent in a longitudinal study focused on

after acetylcholine infusion compared with baseline.

clinical outcomes. A longitudinal study can measure

The results at 1 year showed no significant dysfunc-

the effect of ACEIs on patient survival, CAV, long-

tion or difference between ramipril (9.4  25.6%;

term major adverse cardiac events, and allograft

p ¼ 0.63) and placebo (5.6  27.8%; p ¼ 0.39) groups.

function. These factors can influence the current

The coronary physiological assessments showed

standard therapy for post-heart transplantation and

improvement, with IMR (14.4  6.3; p ¼ 0.001)

determine if ACEIs produce beneficial long-term ef-

and fractional flow reserve (0.88  0.04; p ¼ 0.007)

fects beyond potential early endothelial function.

decreases and coronary flow reserve (4.8  1.5;

Such a study can also investigate if ACEIs have long-

p ¼ 0.017) increase after 1 year of ramipril. Ramipril

term effects that are time- or dosage-dependent on

displayed no significant change in the log10 quantity

CAV and whether they affect long-term clinical out-

of endothelial progenitor cells (EPCs) at 1 year

comes like major adverse cardiac events. Although

(1.12  0.32; p ¼ 0.66), whereas EPCs significantly

this study emphasizes the physiological effects from

decreased with placebo (1.19  0.41; p ¼ 0.035). Last,

the use of ACEIs, it lacks evidence of morphological

the maximal intimal thickness as measured by

benefits on CAV. Morphological changes in CAV as

2-dimensional IVUS showed no significant difference

assessed by IVUS have robust prognostic power. From

(p ¼ 0.90) at 1 year between ramipril (0.89 

the current randomized prospective study performed

0.49 mm) and placebo (0.91  0.52 mm), indicating

by 2 highly experienced transplant teams, it can be

that plaque progression and negative vessel remod-

concluded that ACEIs when used post-transplant

eling were no different in the treatment and control

are safe and effective in treating the hypertension

groups.

that is a consequence of immunosuppression in

This study demonstrates that the use of ramipril in

these patients, and that they have a salutary effect on

patients after heart transplantation produces physi-

coronary arterial physiology. However, these effects

ological changes in coronary artery flow that could be

do not translate into amelioration or prevention

beneficial, but that did not translate into morpho-

of CAV as defined by IVUS. This contrasts with the

logical improvements in CAV as defined by IVUS.

beneficial effects seen with statins, which may be due

Ramipril maintained lower systolic and diastolic

to their anti-inflammatory and immunomodulatory

blood pressures with a significantly lower rate and

effect.

dose of amlodipine. The coronary physiological

The authors have shown that ACEI therapy im-

assessment suggests better long-term outcomes for

proves IMR in heart transplant recipients. A previous

patients on ramipril with decreased IMR—a predictor

study by the Stanford group in 63 patients showed

of death or retransplantation, CAV development, and

that lower IMR not only correlated with improved

graft dysfunction (9). The 2-dimensional IVUS results

cardiac index and improved right and left ventricular

highlight the complexity and varying effects of ACEIs

myocardial performance indexes determined echo-

on CAV development. Ramipril did not have a

cardiographically within the first year post-transplant,

2843

2844

Eisen et al.

JACC VOL. 69, NO. 23, 2017 JUNE 13, 2017:2842–4

ACEIs for Allograft Vasculopathy After Heart Transplants

but also associated with a lesser likelihood of

Heart and Lung Transplantation Nomenclature (10).

death, allograft failure, retransplantation, or cardiac

Morphological improvement in CAV in ACEI-treated

allograft vasculopathy at 5 years after transplant (9).

patients would provide an additional compelling

The authors should continue to follow the patients in

reason for these drugs to be first-line therapy for hy-

the present study to 5 years post-transplant. If ACEI

pertension in heart transplant patients and, perhaps,

patients have better clinical outcomes because of

for ACEIs to be used judiciously in all heart transplant

improved IMR, this would be a convincing argument

recipients regardless of blood pressure, as statins are

for ACEIs to be first-line therapy for hypertension in

used now regardless of serum lipids.

heart transplant patients. Additional information could be obtained to assess allograft function, such as

ADDRESS FOR CORRESPONDENCE: Dr. Howard J.

echocardiographic assessments and cardiac index. The

Eisen, Division of Cardiology, Drexel University

authors should also assess the severity of CAV either

College of Medicine, 245 North 15th Street, Mailstop

with IVUS or by coronary angiography and grading of

#1012, Philadelphia, Pennsylvania 19102. E-mail:

severity of CAV using the International Society for

[email protected].

REFERENCES 1. Lund LH, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-second official adult lung and heart-lung transplantation report— 2015; focus theme: early graft failure. J Heart Lung Transplant 2015;34:1244–54. 2. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J of Med 2003;349:847–58. 3. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995; 333:621–7.

cardiac allograft vasculopathy. Am J Cardiol 1995; 75:853–4. 5. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/ AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic). J Am Coll Cardiol 2006;47:1239–312. 6. Erinc K, Yamani MH, Starling RC, et al. The effect of combined angiotensin-converting enzyme inhibition and calcium antagonism on allograft coronary vasculopathy validated by intravascular ultrasound. J Heart Lung Transplant 2005;24: 1033–8.

4. Mehra MR, Ventura HO, Smart FW, et al. An

7. Bae JH, Rihal CS, Edwards BS, et al. Association of angiotensin-converting enzyme inhibitors and

intravascular ultrasound study of the influence of angiotensin-converting enzyme inhibitors and calcium entry blockers on the development of

serum lipids with plaque regression in cardiac allograft vasculopathy. Transplantation 2006;82: 1108–11.

8. Fearon WF, Okada K, Kobashigawa JA, et al. Angiotensin-converting enzyme inhibition early after heart transplantation. J Am Coll Cardiol 2017;69:2832–41. 9. Haddad F, Khazanie P, Deuse T, et al. Clinical and functional correlates of early microvascular dysfunction following heart transplantation. Circ Heart Fail 2012;5:759–68. 10. Mehra MR, Crespo-Leiro MG, Dipchand A, et al. International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy—2010. J Heart Lung Transplant 2010;29:717–27.

KEY WORDS ACE inhibitors, cardiac allograft vasculopathy, heart transplantation