Long-term clinical outcomes of losartan in patients with Marfan syndrome: follow-up of the multicentre randomized controlled COMPARE trial

Andĕl, M; Indrakusuma, Reza; Jalalzadeh, Hamid; Balm, Ron; Timmermans, Janneke; Scholte, Arthur J.; Berg, Maarten P. van den; Zwinderman, Aeilko H.; Mulder, Barbara J.M.; Waard, Vivian de; Groenink, Maarten

doi:10.1093/eurheartj/ehaa377

Cited by 60 publications

(50 citation statements)

References 21 publications

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“…Accumulating evidence has demonstrated that losartan and metformin have the potential to delay expansion of the aortic root or abdominal aorta or even prevent this major life-threatening manifestation in patients with MFS or AAA ( 27 , 28 ). Thus, we wondered whether LOXs are involved in the effect of losartan and metformin on the aorta.…”

Section: Resultsmentioning

confidence: 99%

The Expression Patterns and Roles of Lysyl Oxidases in Aortic Dissection

Zhou

Chen

et al. 2021

Front. Cardiovasc. Med.

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Background: Lysyl oxidases (LOXs), including LOX, LOXL1, LOXL2, LOXL3, and LOXL4, catalyze the formation of a cross-link between elastin (ELN) and collagen. Multiple LOX mutations have been shown to be associated with the occurrence of aortic dissection (AD) in humans, and LOX-knockout mice died during the perinatal period due to aortic aneurysm and rupture. However, the expression levels and roles of other LOX members in AD remain unknown.Methods: A total of 33 aorta samples of AD and 15 normal aorta were collected for LOXs mRNA and protein levels detection. We also analyzed the datasets of AD in GEO database through bioinformatics methods. LOXL2 and LOXL3 were knocked down in primary cultured human aortic smooth muscle cells (HASMCs) via lentivirus.Results: Here, we show that the protein levels of LOXL2 and LOXL3 are upregulated, while LOXL4 is downregulated in AD subjects compared with non-AD subjects, but comparable protein levels of LOX and LOXL1 are detected. Knockdown of LOXL2 suppressed MMP2 expression, the phosphorylation of AKT (p-AKT) and S6 (p-S6), but increased the mono-, di-, tri-methylation of H3K4 (H3K4me1/2/3), H3K9me3, and p-P38 levels in HASMCs. These results indicate that LOXL2 is involved in regulation of the extracellular matrix (ECM) in HASMCs. In contrast, LOXL3 knockdown inhibited PCNA and cyclin D1, suppressing HASMC proliferation. Our results suggest that in addition to LOX, LOXL2 and LOXL3 are involved in the pathological process of AD by regulating ECM and the proliferation of HASMCs, respectively. Furthermore, we found that LOXL2 and LOXL4 was inhibited by metformin and losartan in HASMCs, which indicated that LOXL2 and LOXL4 are the potential targets that involved in the therapeutic effects of metformin and losartan on aortic or aneurysm expansion.Conclusions: Thus, differential regulation of LOXs might be a novel strategy to prevent or treat AD.

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Section: Resultsmentioning

confidence: 99%

The Expression Patterns and Roles of Lysyl Oxidases in Aortic Dissection

Zhou

Chen

et al. 2021

Front. Cardiovasc. Med.

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“…Despite the statistical limitations, the most recent metanalysis of available data showed that AT 1 R antagonism slows the progression of aortic root dilation and is not associated with a statistically significant difference in adverse aortic events [ 366 , 459 ]. Additionally, a recently published long-term follow-up of the multicenter COMPARE trial, which originally reported a small but significant reduction in aortic root dilatation [ 450 ], showed that losartan treatment in MFS patients was associated with a decreased number of adverse aortic events in the treatment group [ 460 ]. Although more studies with sufficient power to confirm this study are both needed and planned, losartan is currently considered an acceptable treatment in combination with β-adrenergic receptor blockers, or when the latter are not tolerated [ 117 , 455 ].…”

Section: Adaptive and Maladaptive Responses In Taa: Implications Fmentioning

confidence: 99%

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Creamer

Bramel

MacFarlane

2021

Genes

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Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.

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“…From a clinical perspective, the concept of effective ARB‐mediated attenuation of MFS aortic root growth in the absence of BP lowering may represent a novel but unexpected opportunity to improve patient management. Recent MFS management trials have helped cast doubts about the causal role of BP in aortic root widening, where studies have found no correlation between changes in BP‐lowering and changes in aortic root diameters in patients treated with losartan versus atenolol (Andel et al, 2020; Forteza et al, 2016; Groenink et al, 2013). These doubts have been further materialized in pre‐clinical settings using rodent models of MFS.…”

Section: Discussionmentioning

confidence: 99%