Meta-analysis Examining the Usefulness of Angiotensin Receptor blockers for the Prevention of Aortic Root Dilation in Patients With the Marfan Syndrome

Al-abcha, Abdullah; Saleh, Yehia; Mujer, Mark; Boumegouas, Manel; Herzallah, Khader; Charles, Lawrenshey; El-khatib, Layan; Abdelkarim, Ola; Kehdi, Michael; Abela, George S.

doi:10.1016/j.amjcard.2020.04.034

Cited by 34 publications

(20 citation statements)

References 24 publications

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“…Current therapeutic strategies focus on decreasing the rate of dilation, and the associated risk for acute aortic events, by reducing hemodynamic stress on the vessel wall with anti-hypertensive drugs, such as inhibitors of the β-adrenergic receptor [366]. A better understanding of adverse and beneficial signaling pathways activated in response to the primary genetic insult might allow the development of therapies that attempt to disentangle homeostatic and adaptive processes from maladaptive responses [367].…”

Section: Proposed Model Of Taa Pathogenesis Based On the Function Of Known Causal Variantsmentioning

confidence: 99%

“…The relative low frequency of adverse aortic events (dissection, rupture, death) makes it difficult to perform clinical trials with sufficient power to assess the effect of treatment on these clinically relevant outcomes, and most trials rely on the measurement of aortic size or growth to assess efficacy. 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].…”

Section: Adaptive and Maladaptive Roles Of Angiotensin II Signalingmentioning

confidence: 99%

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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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Section: Proposed Model Of Taa Pathogenesis Based On the Function Of Known Causal Variantsmentioning

confidence: 99%

Section: Adaptive and Maladaptive Roles Of Angiotensin II Signalingmentioning

confidence: 99%

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

Creamer

Bramel

MacFarlane

2021

Genes

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“…A long‐term follow‐up of the COMPARE trial documents a significant and sustained decrease in clinical endpoints such as aortic surgery, dissection, and death in MFS patients receiving losartan (van Andel et al, 2020). Finally, a recent meta‐analysis of seven prospective trials and >1500 patients showed that ARB therapy is associated with slower progression of aortic root or ascending aortic dilation when compared to placebo or when added to beta‐blocker therapy (Al‐Abcha et al, 2020). Many experts in the field agree that both beta‐blockers and ARBs are safe and generally well tolerated in MFS, and that the earlier intervention is initiated, the better the outcome—even in very young children.…”

Section: Looking Back: Marfan Syndromementioning

confidence: 99%

Toward precision medicine in vascular connective tissue disorders

Ziegler

MacCarrick

Dietz

2021

American J of Med Genetics Pt A

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Tremendous progress has been made in understanding the etiology, pathogenesis, and treatment of inherited vascular connective tissue disorders. While new insights regarding disease etiology and pathogenesis have informed patient counseling and care, there are numerous obstacles that need to be overcome in order to achieve the full promise of precision medicine. In this review, these issues will be discussed in the context of Marfan syndrome and Loeys‐Dietz syndrome, with additional emphasis on the pioneering contributions made by Victor McKusick.

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“…Interestingly, 81% of these patients used concomitant β-blockade therapy. In addition, a recent meta-analysis demonstrated that the addition of an ARB to β-blocker therapy reduced the rate of aortic root dilatation, but did not significantly reduce the number of aortic complications [ 180 ]. This latter result could be a consequence of low statistical power to demonstrate differences in these complications due to low event rates.…”

Section: Clinical Trials In Syndromic Taa Patientsmentioning

confidence: 99%

Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment

Dorst

Wagenaar

Pluijm

et al. 2020

Cardiovasc Drugs Ther

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Thoracic aortic aneurysms (TAAs) are permanent pathological dilatations of the thoracic aorta, which can lead to life-threatening complications, such as aortic dissection and rupture. TAAs frequently occur in a syndromic form in individuals with an underlying genetic predisposition, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Increasing evidence supports an important role for transforming growth factor-β (TGF-β) and the renin-angiotensin system (RAS) in TAA pathology. Eventually, most patients with syndromic TAAs require surgical intervention, as the ability of present medical treatment to attenuate aneurysm growth is limited. Therefore, more effective medical treatment options are urgently needed. Numerous clinical trials investigated the therapeutic potential of angiotensin receptor blockers (ARBs) and β-blockers in patients suffering from syndromic TAAs. This review highlights the contribution of TGF-β signaling, RAS, and impaired mechanosensing abilities of aortic VSMCs in TAA formation. Furthermore, it critically discusses the most recent clinical evidence regarding the possible therapeutic benefit of ARBs and β-blockers in syndromic TAA patients and provides future research perspectives and therapeutic implications.

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Meta-analysis Examining the Usefulness of Angiotensin Receptor blockers for the Prevention of Aortic Root Dilation in Patients With the Marfan Syndrome

Cited by 34 publications

References 24 publications

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

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

Toward precision medicine in vascular connective tissue disorders

Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment

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