Author + information
- Howard J. Eisen, MD∗ (, )
- Shelley Hankins, MD and
- Denise Wang, BS
- ↵∗Address for correspondence:
Dr. Howard J. Eisen, Division of Cardiology, Drexel University College of Medicine, 245 North 15th Street, Mailstop #1012, Philadelphia, Pennsylvania 19102.
Outcomes of cardiac transplantation have been improved with immunosuppressive therapies that effectively reduce the risk of rejection and with prophylaxis against opportunistic infections. With the current management leading to decreased likelihood of hyperacute and acute rejections, efforts have been focused on improving long-term survival by targeting post-transplant complications associated with chronic rejection. Cardiac allograft vasculopathy (CAV) has been 1 of the main causes of mortality for heart transplant recipients (1). The CAV progression has been traditionally managed with mechanistic target of rapamycin inhibitors, such as sirolimus and everolimus. Though mechanistic target of rapamycin inhibitors have been successful in ameliorating or preventing CAV, they frequently cause many significant side effects, like pancytopenia, wound healing issues, renal dysfunction and hyperlipidemia (2). This has limited their widespread use. Statins have been demonstrated to reduce the incidence of CAV (3). Today, post-transplant patients are commonly placed drugs such as statins for potential CAV improvement as well angiotensin-converting enzyme inhibitors (ACEIs) for their most common indications, like hypertension (3,4).
Patients with heart failure often take ACEIs prior to heart transplantation. Not only do ACEIs decrease mortality in patients with heart failure, but they also treat hypertension, proteinuria, and diabetic nephropathy (5). These additional benefits are useful given the comorbidities of patients with heart failure and the ability of ACEIs to prevent unfavorable heart remodeling. Thus, ACEIs can theoretically be beneficial to post-transplant patients. An intravascular ultrasound (IVUS) study assigned 32 heart transplant recipients to ACEIs (n = 9), calcium-channel blockers (CCBs) (n = 10), both CCBs and ACEIs (n = 7), or control (n = 6) within 1 month after heart transplantation. At 1 year, participants receiving no treatment demonstrated a greater degree of CAV than those taking CCBs and/or ACEIs (4). A similar single-center IVUS study that was later conducted with 82 heart transplant participants yielded CAV results consistent with the prior study (6). ACEIs seemed promising when a study also found plaque regression and positive vascular remodeling to be associated with their use in post-transplant patients (7). However, the effect of ACEIs on CAV is difficult to determine from these single-center, nonrandomized studies when longitudinal outcomes and survival of patients has not been assessed. These previous studies focused mainly on morphological changes as reflected by IVUS and not coronary physiology.
In this issue of the Journal, Fearon et al. (8) prospectively 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 functional testing, measurement of fractional flow reserve, coronary flow reserve, index of microcirculatory resistance (IMR), and IVUS with volumetric assessments. In this prospective trial, 39 patients on ramipril and 38 patients on placebo reached the 1-year endpoint for evaluation of CAV. The assessment at 1 year was compared with the baseline parameters that were obtained within 8 weeks of heart transplantation and after patients were placed on standard post-transplant therapy, which included cyclosporine in children or tacrolimus in adults, mycophenolate mofetil, prednisone, co-trimoxazole, and pravastatin. Valganciclovir and CCBs were given as needed for CMV prophylaxis and high blood pressure, respectively. Ramipril or placebo was given at 2.5 mg/day a week after baseline was established. The dosage was doubled every 2 weeks until a maximum of 20 mg/day was reached if no renal dysfunction was found, which was monitored through creatinine levels. Ramipril was well-tolerated by patients, without severe adverse effects, and blood pressures were maintained below 130/80 mm Hg when checked every 4 months, similar to the results of the control group. The study defined coronary endothelial dysfunction as a ≥20% decrease in LAD diameter after acetylcholine infusion compared with baseline. The results at 1 year showed no significant dysfunction or difference between ramipril (9.4 ± 25.6%; p = 0.63) and placebo (5.6 ± 27.8%; p = 0.39) groups. The coronary physiological assessments showed improvement, with IMR (14.4 ± 6.3; p = 0.001) and fractional flow reserve (0.88 ± 0.04; p = 0.007) decreases and coronary flow reserve (4.8 ± 1.5; p = 0.017) increase after 1 year of ramipril. Ramipril displayed no significant change in the log10 quantity of endothelial progenitor cells (EPCs) at 1 year (−1.12 ± 0.32; p = 0.66), whereas EPCs significantly decreased with placebo (−1.19 ± 0.41; p = 0.035). Last, the maximal intimal thickness as measured by 2-dimensional IVUS showed no significant difference (p = 0.90) at 1 year between ramipril (0.89 ± 0.49 mm) and placebo (0.91 ± 0.52 mm), indicating that plaque progression and negative vessel remodeling were no different in the treatment and control groups.
This study demonstrates that the use of ramipril in patients after heart transplantation produces physiological changes in coronary artery flow that could be beneficial, but that did not translate into morphological improvements in CAV as defined by IVUS. Ramipril maintained lower systolic and diastolic blood pressures with a significantly lower rate and dose of amlodipine. The coronary physiological assessment suggests better long-term outcomes for patients on ramipril with decreased IMR—a predictor of death or retransplantation, CAV development, and graft dysfunction (9). The 2-dimensional IVUS results highlight the complexity and varying effects of ACEIs on CAV development. Ramipril did not have a significant effect on maximal intimal thickness in this prospective and randomized study, compared with the prior retrospective studies that suggested lesser degrees of CAV from ACEIs with or without CCB usage. This study design also eliminates subject bias that may have characterized the prior retrospective studies and calls into question the benefits in CAV progression seen in prior studies. The lack of decrease in EPCs in the ramipril group compared with the decrease in the placebo group illustrates that ramipril minimally at least stabilizes EPC quantity and function, which may benefit microvascular function, although the exact significance of the EPC findings is not clear. The additional parameters included in the trial compared with prior studies help to further unearth the effects of ACEIs on CAV in post-transplant patients.
This study’s limitations mainly stem from the lack of clarity of the role of ACEIs in CAV, which could be more apparent in a longitudinal study focused on clinical outcomes. A longitudinal study can measure the effect of ACEIs on patient survival, CAV, long-term major adverse cardiac events, and allograft function. These factors can influence the current standard therapy for post-heart transplantation and determine if ACEIs produce beneficial long-term effects beyond potential early endothelial function. Such a study can also investigate if ACEIs have long-term effects that are time- or dosage-dependent on CAV and whether they affect long-term clinical outcomes like major adverse cardiac events. Although this study emphasizes the physiological effects from the use of ACEIs, it lacks evidence of morphological benefits on CAV. Morphological changes in CAV as assessed by IVUS have robust prognostic power. From the current randomized prospective study performed by 2 highly experienced transplant teams, it can be concluded that ACEIs when used post-transplant are safe and effective in treating the hypertension that is a consequence of immunosuppression in these patients, and that they have a salutary effect on coronary arterial physiology. However, these effects do not translate into amelioration or prevention of CAV as defined by IVUS. This contrasts with the beneficial effects seen with statins, which may be due to their anti-inflammatory and immunomodulatory effect.
The authors have shown that ACEI therapy improves IMR in heart transplant recipients. A previous study by the Stanford group in 63 patients showed that lower IMR not only correlated with improved cardiac index and improved right and left ventricular myocardial performance indexes determined echocardiographically within the first year post-transplant, but also associated with a lesser likelihood of death, allograft failure, retransplantation, or cardiac allograft vasculopathy at 5 years after transplant (9). The authors should continue to follow the patients in the present study to 5 years post-transplant. If ACEI patients have better clinical outcomes because of improved IMR, this would be a convincing argument for ACEIs to be first-line therapy for hypertension in heart transplant patients. Additional information could be obtained to assess allograft function, such as echocardiographic assessments and cardiac index. The authors should also assess the severity of CAV either with IVUS or by coronary angiography and grading of severity of CAV using the International Society for Heart and Lung Transplantation Nomenclature (10). Morphological improvement in CAV in ACEI-treated patients would provide an additional compelling reason for these drugs to be first-line therapy for hypertension in heart transplant patients and, perhaps, for ACEIs to be used judiciously in all heart transplant recipients regardless of blood pressure, as statins are used now regardless of serum lipids.
↵∗ 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.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
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