Angiotensin receptor blockers and β blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials

Pitcher, Alex; Spata, Enti; Emberson, Jonathan; Davies, Kelly; Halls, Heather; Holland, Lisa; Wilson, Kate; Reith, Christina; Child, Anne H.; Clayton, Tim; Dodd, Matthew; Flather, Marcus; Jin, Xu Yu; Sandor, George G.S.; Groenink, Maarten; Mulder, Barbara J.M.; Backer, Julie De; Evangelista, Arturo; Forteza, Alberto; Teixidó-Turà, Gisela; Boileau, Cathérine; Jondeau, Guillaume; Lacro, Ronald V.; Sleeper, Lynn A.; Chiu, Hsin–Hui; Wu, Mei‐Hwan; Neubauer, Stefan; Watkins, Hugh; Dietz, Hal; Baigent, Colin

doi:10.1016/s0140-6736(22)01534-3

Cited by 54 publications

(33 citation statements)

References 38 publications

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“…We reviewed the seven latest meta-analyses, and five of them concluded that the combination of ARB and BB most effectively slowing the aortic root dilatation (Table S19). 17,[39][40][41][42] The inconsistency in the significance of the outcomes may be contributed to the patients included in the follow-up study was 37 years for men and 46 years for women. 43 Likewise, population in Denmark and France demonstrated similar statistics, the former comprised 412 patients, in whom fifty percent were event free at age 49.6, median age at prophylactic surgery was 33.3 years and 41.2 years at dissection; 44 after a mean follow-up period of 6.6 years, 732 patients from the latter studies bore an aortic risk of 0.10% per year when normalized aortic diameter < 20 mm/m2, 0.14% for 20 to 30 mm/m2, 0.43% for 30 to 42.5 mm/m2, and 5.07% for greater diameters.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Medication Strategies on Cardiovascular Outcomes in Patients with Marfan Syndrome: A Consistency Model Analysis

Huang

Lin

et al. 2023

Preprint

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BACKGROUND: Drug options for the treatment of Marfan syndrome (MFS) still warrant further investigation. Beta-blockers (BB) have long been considered the standard treatment, though several medications other than BB and angiotensin receptor blockers (ARB) have entered clinical practice and trials. However, no synthesis gathers evidence on medications other than BB or ARB. Therefore, this study aimed to investigate the effects and safety of medication strategies in managing MFS by synthesizing relevant randomized controlled trials (RCT). METHODS: Three databases were searched for potential evidence using relevant keywords in both free-text and medical subject headings. Outcomes of interests were aortic root growth, aortic root Z score, aortic surgery, moderate-to-severe adverse events, cardiovascular and all-cause mortality. Quantitative data were pooled using frequentist-approach network meta-analysis in random-effects model. RESULTS: Sixteen reports derived from 13 RCTs contributed to a seven-node consistency model including no treatment, BB, ARB, ARB+BB, calcium channel blockers (CCB), angiotensin converting enzyme inhibitor (ACEI), and combination of BB and renin inhibitor (RI). As compared with no treatment, RI+BB showed significant protection of aortic root growth (standardized mean difference [SMD]= -1.90, 95% confidence interval [CI]: -2.91, -0.89), followed by ARB+BB (SMD= -1.75, 95%CI: -2.40, -1.10). Nevertheless, no significant findings were seen in other clinical outcomes. CONCLUSION: RI or ARB added on BB appear to be the optimal medication strategies to slow the progression of aortic root growth in MFS patients. However, we found no statistically significant difference in the risk of aortic surgeries, adverse effects, cardiovascular and all-cause mortality among medications. More RCTs with longer follow-up periods or bigger populations are needed to draw stronger evidence for clinical practices.

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Section: Discussionmentioning

confidence: 99%

The Effects of Medication Strategies on Cardiovascular Outcomes in Patients with Marfan Syndrome: A Consistency Model Analysis

Huang

Lin

et al. 2023

Preprint

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“…Moreover, ARBs were effective in reducing aneurysm formation in angiotensin-II receptor deficient mice by targeting EC function 32 . Since ARBs have been shown protective in MFS patients in the meta-analysis of most ARB clinical trials, a potential contributing mechanism is through modulation of ECs 90 . These data show that ECs may be a suitable target cell type in MFS aortic disease, since ECs are more readily in contact with circulating compounds than vSMCs.…”

Section: Discussionmentioning

confidence: 99%

Endothelial dysfunction in Marfan syndrome mice is restored by resveratrol

Mieremet

Stoel

et al. 2022

Sci Rep

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Patients with Marfan syndrome (MFS) develop thoracic aortic aneurysms as the aorta presents excessive elastin breaks, fibrosis, and vascular smooth muscle cell (vSMC) death due to mutations in the FBN1 gene. Despite elaborate vSMC to aortic endothelial cell (EC) signaling, the contribution of ECs to the development of aortic pathology remains largely unresolved. The aim of this study is to investigate the EC properties in Fbn1C1041G/+ MFS mice. Using en face immunofluorescence confocal microscopy, we showed that EC alignment with blood flow was reduced, EC roundness was increased, individual EC surface area was larger, and EC junctional linearity was decreased in aortae of Fbn1C1041G/+ MFS mice. This modified EC phenotype was most prominent in the ascending aorta and occurred before aortic dilatation. To reverse EC morphology, we performed treatment with resveratrol. This restored EC blood flow alignment, junctional linearity, phospho-eNOS expression, and improved the structural integrity of the internal elastic lamina of Fbn1C1041G/+ mice. In conclusion, these experiments identify the involvement of ECs and underlying internal elastic lamina in MFS aortic pathology, which could act as potential target for future MFS pharmacotherapies.

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“…47 Yet, the clinical benefit of ARBs was found to be modest and failed to reach such impressive results in patients as observed in animal studies: A recent meta-analysis reported an annual change in aortic growth rate of 0.38 mm vs. 0.52 mm in patients randomized to ARBs vs. control treatment. 48 . Accumulating evidence suggests the involvement of an inflammatory response in the pathogenesis of MFS.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of myeloperoxidase attenuates thoracic aortic aneurysm formation in Marfan disease

Mehrkens

Nettersheim

Ballmann

et al. 2022

Preprint

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Marfan syndrome (MFS) is a prevalent inherited connective tissue disorder associated with premature mortality due to thoracic aortic aneurysms and subsequent fatal aortic events. Current treatment options improve outcomes only partially and better preventive pharmacotherapies are needed. By utilizing patient samples and animal disease models, we herein demonstrate that leukocyte-derived myeloperoxidase (MPO) critically contributes to disease progression. MFS patients and mice displayed increased circulating MPO levels as well as marked aortic MPO deposition compared to controls. Mechanistically, MPO induced inflammatory endothelial activation and endothelial-to-mesenchymal transition which triggered aortic leukocyte recruitment. Furthermore, MPO directly contributed to adverse extracellular matrix remodeling by promoting oxidative stress and nitrosylation of extracellular matrix proteins. Genetic MPO deficiency and pharmacological MPO inhibition attenuated MFS-related aneurysm formation. We herein identify MPO as a critical mediator of MFS-related thoracic aortic aneurysm formation and a promising target to influence disease progression.

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Angiotensin receptor blockers and β blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials

Cited by 54 publications

References 38 publications

The Effects of Medication Strategies on Cardiovascular Outcomes in Patients with Marfan Syndrome: A Consistency Model Analysis

The Effects of Medication Strategies on Cardiovascular Outcomes in Patients with Marfan Syndrome: A Consistency Model Analysis

Endothelial dysfunction in Marfan syndrome mice is restored by resveratrol

Inhibition of myeloperoxidase attenuates thoracic aortic aneurysm formation in Marfan disease

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