Effect of Everolimus on Left Ventricular Hypertrophy of De Novo Kidney Transplant Recipients

Paoletti, Ernesto; Marsano, Luigina; Bellino, Diego; Cassottana, Paolo; Cannella, Giuseppe

doi:10.1097/tp.0b013e318242be28

Cited by 45 publications

(27 citation statements)

References 27 publications

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“…32) Kushwaha, et al showed in HTx recipients that conversion from CNI to SRL decreased LVMI along with increased 14) Little has been reported about the anti-proliferative effect of EVL except for several studies in renal transplant recipients. Paoletti, et al showed in a randomized controlled study that EVL therapy along with reduced CyA was effective in the reduction of LVM among renal transplant recipients, mainly due to reduced LV wall thickness, 34) which was consistent with our results. In contrast, another randomized controlled trial by Murbraech, et al demonstrated that conversion from CyA to EVL had no relevant advantage on the reduction of LVM compared with the non-conversion group in renal transplant recipients.…”

Section: )supporting

confidence: 82%

Everolimus Attenuates Myocardial Hypertrophy and Improves Diastolic Function in Heart Transplant Recipients

et al. 2016

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SummaryEverolimus (EVL), one of the mammalian targets of rapamycin, is a next generation immunosuppressant that may have accessory anti-proliferative effects in heart transplant (HTx) recipients. However, little is known about the clinical relationship between EVL and regression of cardiac hypertrophy. A total of 42 HTx recipients received EVL therapy at post-HTx 150 days on median and had been followed at our institute for > 1 year between 2008 and 2014 [EVL (+) group]. We also observed 18 patients without EVL from post-HTx 150 days for 1 year [EVL (-) group]. There were no significant differences in baseline variables between the two groups. Left ventricular mass index (LVMI) and the ratio of early transmitral filling velocity to the peak early diastolic mitral annular motion velocity (E/e') decreased significantly during 1-year EVL treatment compared with the EVL (-) group. There were no differences in blood pressure and medications between the 2 groups. Improvement of LVMI and the E/e' ratio was not associated with trough levels of calcineurin inhibitors or EVL, but correlated with each baseline value. In conclusion, this EVL-incorporated immunosuppressant regimen attenuated cardiac hypertrophy as well as diastolic dysfunction in HTx recipients. (Int Heart J 2016; 57: 204-210)

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Section: )supporting

confidence: 82%

Everolimus Attenuates Myocardial Hypertrophy and Improves Diastolic Function in Heart Transplant Recipients

et al. 2016

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“…Administration of everolimus, a rapamycin analogue, decreases ventricle hypertrophy in kidney transplant patients. 39 The activation of Akt-mTOR signaling likely contributes to cardiac fibrosis and hypertrophy by enhancing protein synthesis. We provide in vivo evidence of Nox4-derived ROS generation in mTOR activation in the course of cardiac remodeling.…”

Section: Discussionmentioning

confidence: 99%

NADPH Oxidase 4 Induces Cardiac Fibrosis and Hypertrophy Through Activating Akt/mTOR and NFκB Signaling Pathways

et al. 2015

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Background NADPH oxidase 4 (Nox4) has been implicated in cardiac remodeling, but its precise role in cardiac injury remains controversial. Furthermore, little is known about the downstream effector signaling pathways activated by Nox4-derived ROS in the myocardium. We investigated the role of Nox4 and Nox4 associated signaling pathways in the development of cardiac remodeling. Methods and Results Cardiac-specific human Nox4 transgenic mice (c-hNox4Tg) were generated. Four groups of mice were studied: 1) control mice (CTL): littermates that are negative for hNox4 transgene but Cre positive; 2) c-hNox4 Tg mice; 3) angiotensin II (AngII)-infused CTL mice and 4) c-hNox4Tg mice infused with AngII. The c-hNox4Tg mice exhibited approximately 10-fold increase in Nox4 protein expression and 8-fold increase in the production of reactive oxygen species, and manifested cardiac interstitial fibrosis. AngII-infusion to CTL mice increased cardiac Nox4 expression and induced fibrosis and hypertrophy. The Tg mice receiving AngII exhibited more advanced cardiac remodeling and robust elevation in Nox4 expression, indicating that AngII worsens cardiac injury, at least partially by enhancing Nox4 expression. Moreover, hNox4 transgene and/or AngII-infusion induced the expression of cardiac fetal genes and activated the Akt-mTOR and NFκB signaling pathways. Treatment of AngII-infused c-hNox4Tg mice with GKT137831, a Nox4/Nox1 inhibitor, abolished the increase in oxidative stress, suppressed Akt-mTOR and NFκB signaling pathway and attenuated cardiac remodeling. Conclusion Upregulation of Nox4 in the myocardium causes cardiac remodeling through activating Akt-mTOR and NFκB signaling pathways. Inhibition of Nox4 has therapeutic potential to treat cardiac remodeling.

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“…In addition, Paoletti et al demonstrated in controlled studies that both SRL and EVL regress left ventricular mass in KT recipients [6-8]. However, no patient received combined treatment with m-TOR inhibitors and RAS blockers during the first 12 months post-conversion.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, nonrandomized controlled trials have shown that conversion from calcineurin inhibitors (CNI) to SRL may regress LVH in KT patients [6,7]. More recently, a randomized controlled study demonstrated that the use of everolimus (EVL) plus a reduced exposure of cyclosporine (CsA) proved effective in regressing LVH in KT recipients [8]. However, none of these studies included patients who had received renin-angiotensin system (RAS) blockers together with the m-TOR inhibitors during the first post-conversion year.…”

Section: Introductionmentioning

confidence: 99%

Regression of cardiac growth in kidney transplant recipients using anti-m-TOR drugs plus RAS blockers: a controlled longitudinal study

et al. 2014

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BackgroundLeft ventricular hypertrophy (LVH) is common in kidney transplant (KT) recipients. LVH is associated with a worse outcome, though m-TOR therapy may help to revert this complication. We therefore conducted a longitudinal study to assess morphological and functional echocardiographic changes after conversion from CNI to m-TOR inhibitor drugs in nondiabetic KT patients who had previously received RAS blockers during the follow-up.MethodsWe undertook a 1-year nonrandomized controlled study in 30 non-diabetic KT patients who were converted from calcineurin inhibitor (CNI) to m-TOR therapy. A control group received immunosuppressive therapy based on CNIs. Two echocardiograms were done during the follow-up.ResultsNineteen patients were switched to SRL and 11 to EVL. The m-TOR group showed a significant reduction in LVMi after 1 year (from 62 ± 22 to 55 ± 20 g/m2.7; P = 0.003, paired t-test). A higher proportion of patients showing LVMi reduction was observed in the m-TOR group (53.3 versus 29.3%, P = 0.048) at the study end. In addition, only 56% of the m-TOR patients had LVH at the study end compared to 77% of the control group (P = 0.047). A significant change from baseline in deceleration time in early diastole was observed in the m-TOR group compared with the control group (P = 0.019).ConclusionsSwitching from CNI to m-TOR therapy in non-diabetic KT patients may regress LVH, independently of blood pressure changes and follow-up time. This suggests a direct non-hemodynamic effect of m-TOR drugs on cardiac mass.

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Effect of Everolimus on Left Ventricular Hypertrophy of De Novo Kidney Transplant Recipients

Abstract: An immunosuppressive regimen consisting of EVL plus reduced exposure CsA proved to be effective in regressing LVH in RTRs regardless of BP, mainly by reducing left ventricular wall thickness.

Cited by 45 publications

References 27 publications

Everolimus Attenuates Myocardial Hypertrophy and Improves Diastolic Function in Heart Transplant Recipients

Everolimus Attenuates Myocardial Hypertrophy and Improves Diastolic Function in Heart Transplant Recipients

NADPH Oxidase 4 Induces Cardiac Fibrosis and Hypertrophy Through Activating Akt/mTOR and NFκB Signaling Pathways

Regression of cardiac growth in kidney transplant recipients using anti-m-TOR drugs plus RAS blockers: a controlled longitudinal study

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