β-Blockers and Angiotensin Converting Enzyme Inhibitors: Comparison of Effects on Aortic Growth in Pediatric Patients with Marfan Syndrome

Phomakay, Venusa; Huett, Wilson G.; Gossett, Jeffrey M.; Tang, Xinyu; Bornemeier, Renee A.; Collins, R. Thomas

doi:10.1016/j.jpeds.2014.07.008

Cited by 19 publications

(9 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The antihypertensive medication losartan, an angiotensin II (AngII) receptor type 1 (ATR1) blocker, 9 is recommended by current treatment guidelines because of unique antiremodeling properties 7 that are not observed with either angiotensin-converting enzyme inhibitors or b blockers. 9,10 Losartan was shown to decrease the rate of aortic root dilation in rodent models of MFS and in pediatric patients refractory to b-blocker treatment. 7,11 Yet, a large multicenter trial failed to show the expected superiority of losartan treatment over atenolol, 12 which further stirred debate about optimal MFS patient management.…”

mentioning

confidence: 99%

Inhibition of Marfan Syndrome Aortic Root Dilation by Losartan

Sellers

Milad

Chan

et al. 2018

The American Journal of Pathology

View full text Add to dashboard Cite

Marfan syndrome (MFS) is a genetic disorder that frequently leads to aortic root dissection and aneurysm. Despite promising preclinical and pilot clinical data, a recent large-scale study using antihypertensive angiotensin II (AngII) receptor type 1 (ATR1) blocker losartan has failed to meet expectations at preventing MFS-associated aortic root dilation, casting doubts about optimal therapy. To study the deleterious role of normal ATR1 signaling in aortic root widening, we generated MFS mice lacking ATR1a expression in an attempt to preserve protective ATR2 signaling. Despite being hypotensive and resistant to AngII vasopressor effects, MFS/ATR1a-null mice showed unabated aortic root enlargement and remained fully responsive to losartan, confirming that blood pressure lowering is of minor therapeutic value in MFS and that losartan's antiremodeling properties may be ATR1 independent. Having shown that MFS causes endothelial dysfunction and that losartan can activate endothelial function in mice and patients, we found that nitric oxide synthase (NOS) inhibition renders losartan therapeutically inactive, whereas multiple transgenic and pharmacologic models of endothelial NOS activation block aortic root dilation by correcting extracellular signal-regulated kinase signaling. In vitro, losartan can increase endothelial NO release in the absence of AngII and correct MFS NO levels in vivo. Our data suggest that increased protective endothelial function, rather than ATR1 inhibition or blood pressure lowering, might be of therapeutic significance in preventing aortic root disease in MFS.

show abstract

mentioning

confidence: 99%

Inhibition of Marfan Syndrome Aortic Root Dilation by Losartan

Sellers

Milad

Chan

et al. 2018

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Currently, the only available and recommended therapeutic approach is treatment of MFS patients with blood pressure lowering medications such as beta blockers (atenolol) or angiotensin-II (ANG II) receptor blockers (ARBs) such as losartan, to reduce the hemodynamic overload in the aortic arch. However, such treatments can only delay the onset of the disease, without preventing the ultimate need for aortic replacement surgery (15,22). The therapeutic approach is more challenging in younger MFS patients (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) yr old), as there are no conclusive data on potential side effects of long-term use of such medications in children and young adults.…”

mentioning

confidence: 99%

Mild aerobic exercise blocks elastin fiber fragmentation and aortic dilatation in a mouse model of Marfan syndrome associated aortic aneurysm

Gibson¹,

Nielsen²,

R³

et al. 2017

Journal of Applied Physiology

View full text Add to dashboard Cite

Regular low-impact physical activity is generally allowed in patients with Marfan syndrome, a connective tissue disorder caused by heterozygous mutations in the fibrillin-1 gene. However, being above average in height encourages young adults with this syndrome to engage in high-intensity contact sports, which unfortunately increases the risk for aortic aneurysm and rupture, the leading cause of death in Marfan syndrome. In this study, we investigated the effects of voluntary (cage-wheel) or forced (treadmill) aerobic exercise at different intensities on aortic function and structure in a mouse model of Marfan syndrome. Four-week-old Marfan and wild-type mice were subjected to voluntary and forced exercise regimens or sedentary lifestyle for 5 mo. Thoracic aortic tissue was isolated and subjected to structural and functional studies. Our data showed that exercise improved aortic wall structure and function in Marfan mice and that the beneficial effect was biphasic, with an optimum at low intensity exercise (55-65% V̇o) and tapering off at a higher intensity of exercise (85% V̇o). The mechanism underlying the reduced elastin fragmentation in Marfan mice involved reduction of the expression of matrix metalloproteinases 2 and 9 within the aortic wall. These findings present the first evidence of potential beneficial effects of mild exercise on the structural integrity of the aortic wall in Marfan syndrome associated aneurysm. Our finding that moderate, but not strenuous, exercise protects aortic structure and function in a mouse model of Marfan syndrome could have important implications for the medical care of young Marfan patients. The present study provides conclusive scientific evidence that daily exercise can improve aortic health in a mouse model of Marfan syndrome associated aortic aneurysm, and it establishes the threshold for the exercise intensity beyond which exercise may not be as protective. These findings establish a platform for a new focus on promoting regular exercise in Marfan patients at an optimum intensity and create a paradigm shift in clinical care of Marfan patients suffering from aortic aneurysm complications.

show abstract

“… 171 Other clinical studies comparing the effect of ACEIs and β-blockers in MFS nevertheless concluded that ACEIs exert a beneficial effect on central aortic pressure, heart rate and aortic growth rate albeit to a lesser extent. 140 , 172 …”

Section: Current Medical Managementmentioning

confidence: 99%

An Overview of Investigational and Experimental Drug Treatment Strategies for Marfan Syndrome

Deleeuw¹,

Clercq²,

Backer³

et al. 2021

JEP

View full text Add to dashboard Cite

Marfan syndrome (MFS) is a heritable connective tissue disorder caused by pathogenic variants in the gene coding for the extracellular matrix protein fibrillin-1. While the disease affects multiple organ systems, the most life-threatening manifestations are aortic aneurysms leading to dissection and rupture. Other cardiovascular complications, including mitral valve prolapse, primary cardiomyopathy, and arrhythmia, also occur more frequently in patients with MFS. The standard medical care relies on cardiovascular imaging at regular intervals, along with pharmacological treatment with β-adrenergic receptor blockers aimed at reducing the aortic growth rate. When aortic dilatation reaches a threshold associated with increased risk of dissection, prophylactic surgical aortic replacement is performed. Although current clinical management has significantly improved the life expectancy of patients with MFS, no cure is available and fatal complications still occur, underscoring the need for new treatment options. In recent years, preclinical studies have identified a number of potentially promising therapeutic targets. Nevertheless, the translation of these results into clinical practice has remained challenging. In this review, we present an overview of the currently available knowledge regarding the underlying pathophysiological processes associated with MFS cardiovascular pathology. We then summarize the treatment options that have been developed based on this knowledge and are currently in different stages of preclinical or clinical development, provide a critical review of the limitations of current studies and highlight potential opportunities for future research.

show abstract

β-Blockers and Angiotensin Converting Enzyme Inhibitors: Comparison of Effects on Aortic Growth in Pediatric Patients with Marfan Syndrome

Cited by 19 publications

References 26 publications

Inhibition of Marfan Syndrome Aortic Root Dilation by Losartan

Inhibition of Marfan Syndrome Aortic Root Dilation by Losartan

Mild aerobic exercise blocks elastin fiber fragmentation and aortic dilatation in a mouse model of Marfan syndrome associated aortic aneurysm

An Overview of Investigational and Experimental Drug Treatment Strategies for Marfan Syndrome

Contact Info

Product

Resources

About