Systemic rapamycin to prevent in-stent stenosis in peripheral pulmonary arterial disease: early clinical experience

Hallbergson, Anna; Esch, Jesse J.; Tran, Trang X.; Lock, James E.; Marshall, Audrey C.

doi:10.1017/s1047951115002516

Cited by 12 publications

(8 citation statements)

References 19 publications

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“…Most patients had multi-vessel, bilateral PVS with recurrent restenosis requiring multiple interventions (surgical and transcatheter) prior to sirolimus initiation authenticating the aggressiveness of the disease in this cohort. Systemic sirolimus was administered based on the early clinical results for the treatment of ISS in pediatric patients with peripheral pulmonary artery disease as well as for its safety profile studied in larger cohorts [11,13,14]. Previous work in adult patients with coronary artery disease has also documented efficacy of systemic sirolimus in preventing stent restenosis [15][16][17].…”

Section: Discussionmentioning

confidence: 99%

“…The drug therapy protocol was adopted from the experience treating ISS in peripheral pulmonary artery disease [11]. Patients typically received 8 weeks of systemic sirolimus (off-label use) with target serum levels of 6-10 ng/ml (trough levels drawn prior to daily dose).…”

Section: Methodsmentioning

confidence: 99%

“…This treatment is burdened with the development of in-stent stenosis (ISS) with a reported freedom from at least moderate (> 50%) ISS at 12 months of 37 ± 10% [10]. Systemic sirolimus (rapamycin) has been used in the treatment of ISS in peripheral pulmonary artery disease [11]. Based on this clinical experience, sirolimus was administered to patients who underwent stent placement as treatment for intraluminal PVS, either as prophylactic therapy or after the occurrence of ISS.…”

Section: Introductionmentioning

confidence: 99%

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Systemic Sirolimus to Prevent In-Stent Stenosis in Pediatric Pulmonary Vein Stenosis

et al. 2019

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Evaluate the efficacy of systemic sirolimus (rapamycin) in preventing in-stent stenosis (ISS) in pediatric intraluminal pulmonary vein stenosis (PVS). Report the adverse events related to sirolimus therapy. There is a high incidence of ISS following stent implantation in PVS. The use of sirolimus in preventing ISS has not been reported. Retrospective review of all patients who received sirolimus (8 week course) for treatment of ISS for PVS between January 2013 and June 2018. Forty stents (37 bare metal, 3 drug-eluting) in 20 patients were treated with sirolimus; 20 at the time of implantation (primary prevention [1P]) and 20 following documented ISS requiring transcatheter reintervention (secondary prevention [2P]). Treated patients were young (median 2 y/o [0.7-5.7]) and most had PVS associated with congenital heart disease (75%, 15/20; 4/15 with TAPVC). In the 1P group, 85% (17/20) of stents were without significant (< 50%) ISS at median of 102 days (range 56-527); the growth rate of ISS in this group was 7.5 ± 7.1%/month. In the 2P group, most stents had a slower growth rate of ISS after sirolimus therapy compared to pre-treatment (median 3.7 [− 0.2 to 13.1] vs. 10.4 [1.3 to 19.5] %/month; p < 0.001). One patient developed pneumonia on drug while concurrently taking another immunosuppressive agent. No other serious adverse events were related to sirolimus therapy. Systemic sirolimus slows the growth rate of ISS following stent implantation in PVS compared to pre-treatment rates and was administered safely in a small number of pediatric patients with complex heart disease.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Systemic Sirolimus to Prevent In-Stent Stenosis in Pediatric Pulmonary Vein Stenosis

et al. 2019

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“…140 Importantly, based on clinical experience, rapamycin has been shown to be safe for the treatment of right ventricular hypertension caused by peripheral pulmonary artery stenosis. 141 The aforementioned studies suggest that rapamycin has a critical effect in regulating hypertension. Nevertheless, this relationship needs to be further investigated, especially to reduce the side effects of rapamycin-induced hypertension in clinical practice.…”

Section: Targeting Mtor Signaling: a Promising Therapeutic Strategy T...mentioning

confidence: 99%

Mammalian Target of Rapamycin as the Therapeutic Target of Vascular Proliferative Diseases: Past, Present, and Future

Huang

Zou

Tian

et al. 2022

Journal of Cardiovascular Pharmacology

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:The abnormal proliferation of vascular smooth muscle cells (VSMCs) is a key pathological characteristic of vascular proliferative diseases. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays an important role in regulating cell growth, motility, proliferation, and survival, as well as gene expression in response to hypoxia, growth factors, and nutrients. Increasing evidence shows that mTOR also regulates VSMC proliferation in vascular proliferative diseases and that mTOR inhibitors, such as rapamycin, effectively restrain VSMC proliferation. However, the molecular mechanisms linking mTOR to vascular proliferative diseases remain elusive. In our review, we summarize the key roles of the mTOR and the recent discoveries in vascular proliferative diseases, focusing on the therapeutic potential of mTOR inhibitors to target the mTOR signaling pathway for the treatment of vascular proliferative diseases. In this study, we discuss mTOR inhibitors as promising candidates to prevent VSMC-associated vascular proliferative diseases.

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“…28 Collagen gel-based scaffolds lined with vascular smooth muscle cells may improve vascular tissue assembly in vitro. 16 There is compelling evidence from clinical studies that target of rapamycin (TOR) inhibitors (sirolimus and everolimus), [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] cilostazol (a drug that elevates intracellular cyclic adenosine monophosphate (cAMP) concentration), and microtubule-destabilizing agents (colchicine) [72][73][74][75][76][77][78][79][80][81][82] improve vascular disease and confer cardiovascular protection, although their indications in the clinical field remain to be established. The mechanisms by which these agents improve vascular function are not fully understood, but they may converge with the actin cytoskeleton and its putative impact on ECM synthesis.…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular protection associated with cilostazol, colchicine and target of rapamycin inhibitors

Adeva‐Andany

Fernández‐Fernández

Carneiro-Freire

et al. 2022

Journal of Cardiovascular Pharmacology

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:An alteration in extracellular matrix (ECM) production by vascular smooth muscle cells is a crucial event in the pathogenesis of vascular diseases such as aging-related, atherosclerosis and allograft vasculopathy. The human target of rapamycin (TOR) is involved in the synthesis of ECM by vascular smooth muscle cells. TOR inhibitors reduce arterial stiffness, blood pressure, and left ventricle hypertrophy and decrease cardiovascular risk in kidney graft recipients and patients with coronary artery disease and heart allograft vasculopathy. Other drugs that modulate ECM production such as cilostazol and colchicine have also demonstrated a beneficial cardiovascular effect. Clinical studies have consistently shown that cilostazol confers cardiovascular protection in peripheral vascular disease, coronary artery disease, and cerebrovascular disease. In patients with type 2 diabetes, cilostazol prevents the progression of subclinical coronary atherosclerosis. Colchicine reduces arterial stiffness in patients with familial Mediterranean fever and patients with coronary artery disease. Pathophysiological mechanisms underlying the cardioprotective effect of these drugs may be related to interactions between the cytoskeleton, TOR signaling, and cyclic adenosine monophosphate (cAMP) synthesis that remain to be fully elucidated. Adult vascular smooth muscle cells exhibit a contractile phenotype and produce little ECM. Conditions that upregulate ECM synthesis induce a phenotypic switch toward a synthetic phenotype. TOR inhibition with rapamycin reduces ECM production by promoting the change to the contractile phenotype. Cilostazol increases the cytosolic level of cAMP, which in turn leads to a reduction in ECM synthesis. Colchicine is a microtubule-destabilizing agent that may enhance the synthesis of cAMP.

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Systemic rapamycin to prevent in-stent stenosis in peripheral pulmonary arterial disease: early clinical experience

Abstract: Our initial clinical experience supports that patients with peripheral pulmonary artery stenosis can be safely treated with rapamycin. Systemic rapamycin may provide a novel medical approach to reduce in-stent stenosis.

Cited by 12 publications

References 19 publications

Systemic Sirolimus to Prevent In-Stent Stenosis in Pediatric Pulmonary Vein Stenosis

Systemic Sirolimus to Prevent In-Stent Stenosis in Pediatric Pulmonary Vein Stenosis

Mammalian Target of Rapamycin as the Therapeutic Target of Vascular Proliferative Diseases: Past, Present, and Future

Cardiovascular protection associated with cilostazol, colchicine and target of rapamycin inhibitors

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