Differential Effect of Everolimus on Progression of Early and Late Cardiac Allograft Vasculopathy in Current Clinical Practice

Masetti, M.; Potena, Luciano; Nardozza, Marianna; Prestinenzi, P.; Taglieri, Nevio; Saia, Francesco; Pece, V.; Magnani, Gaia; Fallani, Francesco; Coccolo, Fabio; Russo, Antonio; Rapezzi, Claudio; Grigioni, Francesco; Branzi, Angelo

doi:10.1111/ajt.12208

Cited by 55 publications

(24 citation statements)

References 34 publications

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“…[28][29][30] Therefore, a noninvasive means of early diagnosis of incipient CAV is highly desirable. Although the results of this study are preliminary in nature, they demonstrate a potential role for PET with absolute flow quantification as a marker of CAV, with prediction of subsequent adverse outcome and detection of more diffuse CAV involving both the epicardial vessels and the microvasculature at an earlier stage compared with other noninvasive imaging modalities.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of Rubidium-82 Positron Emission Tomography in Patients After Heart Transplant

Ardle

Davies

Chen

et al. 2014

Circ: Cardiovascular Imaging

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CAV results in diffuse concentric intimal thickening of the epicardial vessels affecting both the proximal and distal vessels as well as the microcirculation.3 This progressive luminal narrowing and loss of vasodilatory capacity culminates in myocardial ischemia and contractile dysfunction. Immunemediated injury plays a significant role in the development of epicardial vessel stenosis in addition to traditional risk factors. 4 Clinical symptoms such as angina are typically absent in cases of CAV because of allograft denervation, and therefore annual screening is used in most centers.Recent guidelines recommend periodic invasive coronary angiography for at least the first 3 to 5 years after transplantation. 5 However, this is inconvenient and adds risk. Hence, many centers have elected to monitor patients with noninvasive testing, but this strategy may be suboptimal because of the lower sensitivity for the detection of early CAV. 6,7 Rubidium-82 (Rb-82) positron emission tomography (PET) myocardial perfusion imaging is a noninvasive imaging modality that has the ability to quantify myocardial blood flow (MBF) 8 and has been shown to have prognostic value in patients being assessed for ischemia.9-11 This technique may facilitate earlier detection of CAV and thus may have prognostic value in HT patients. The objective of this study was to evaluate the prognostic value of Rb-82 PET in patients with a history of HT.Background-Cardiac allograft vasculopathy is a key prognostic determinant after heart transplant. Detection and risk stratification of patients with cardiac allograft vasculopathy are problematic. Positron emission tomography using rubidium-82 allows quantification of absolute myocardial blood flow and may have utility for risk stratification in this population. Methods and Results-Patients with a history of heart transplant undergoing dipyridamole rubidium-82 positron emission tomography were prospectively enrolled. Myocardial perfusion and left ventricular ejection fraction were recorded. Absolute flow quantification at rest and after dipyridamole stress as well as the ratio of mean global flow at stress and at rest, termed myocardial flow reserve, were calculated. Patients were followed for all-cause death, acute coronary syndrome, and heart failure hospitalization. A total of 140 patients (81% men; median age, 62 years; median follow-up, 18.2 months) were included. There were 14 events during follow-up (9 deaths, 1 acute coronary syndrome, and 4 heart failure admissions). In addition to baseline clinical variables (estimated glomerular filtration rate, previously documented cardiac allograft vasculopathy), relative perfusion defects, mean myocardial flow reserve, and mean stress myocardial blood flow were significant predictors of adverse outcome. Conclusions-Abnormalities on rubidium-82 positron emission tomography were predictors of adverse events in heart transplant patients. Larger prospective studies are required to confirm these findings. (Circ Cardiovasc Imaging. 2014;7:930-937.)

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Section: Discussionmentioning

confidence: 99%

Prognostic Value of Rubidium-82 Positron Emission Tomography in Patients After Heart Transplant

Ardle

Davies

Chen

et al. 2014

Circ: Cardiovascular Imaging

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“…While statins were protective against late CAV development, everolimus lost its protective effect on CAV 1 to 5 years after transplant, suggesting that immune-mediated injury plays a greater role in development of CAV early after transplant, while metabolic factors predominate later [56]. This was further explored in other studies.…”

Section: Proliferation Signal Inhibitors (Psi)mentioning

confidence: 91%

Drugs for the Prevention and Treatment of Cardiac Allograft Vasculopathy

Gupta¹

2014

Cardiol Pharmacol

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Cardiac allograft vasculopathy (CAV) of heart transplants is responsible for up to one-third of deaths at 5 years following cardiac transplantation. Risk factors for CAV include both traditional risk factors and immune factors. Drugs used for prevention and treatment of CAV include statins, calcium channel blockers and immunosuppressive agents. This review discusses the currently available drugs for CAV, the evidence behind their use, and future targets of therapy.

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“…These findings contrast the results of the NOCTET study (8) where everolimus failed to attenuate CAV progression in maintenance HTx recipients. It is possible that the discordant effect of everolimus therapy in de novo (with or without established intimal disease) versus maintenance HTx recipients could reflect that distinct pathophysiological processes are involved in early versus late CAV progression (20). This also highlights the need to consider the potential early window of opportunity that may exist to achieve the maximum beneficial effect of mTOR inhibition therapy.…”

mentioning

confidence: 99%

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial

Arora

Andreassen

Andersson

et al. 2015

American Journal of Transplantation

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Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12‐month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7–11 weeks after HTx or standard cyclosporine immunosuppression. Ninety‐five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm3 and 13.8 ± 28.0 mm3 [all p‐values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor‐1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus‐based CNI‐free can potentially be considered in suitable de novo HTx recipients.

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Differential Effect of Everolimus on Progression of Early and Late Cardiac Allograft Vasculopathy in Current Clinical Practice

Cited by 55 publications

References 34 publications

Prognostic Value of Rubidium-82 Positron Emission Tomography in Patients After Heart Transplant

Prognostic Value of Rubidium-82 Positron Emission Tomography in Patients After Heart Transplant

Drugs for the Prevention and Treatment of Cardiac Allograft Vasculopathy

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial

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