Pathophysiology and Therapeutics of Thoracic Aortic Aneurysm in Marfan Syndrome

About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic dissection often without associated syndromic features. One widely studied exception is Marfan syndrome (MFS) in which mutations in the extracellular protein fibrillin-1 cause additional abnormalities in the heart, eyes, and skeleton. Mouse models of MFS have been instrumental in delineating major cellular and molecular determinants of thoracic aortic disease. In spite of research efforts, translating experimental findings from MFS mice into effective drug therapies for MFS patients remains an unfulfilled promise. Here, we describe a series of studies that have implicated endothelial dysfunction and improper angiotensin II and TGFβ signaling in driving thoracic aortic disease in MFS mice. We also discuss how these investigations have influenced the way we conceptualized possible new therapies to slow down or even halt aneurysm progression in this relatively common connective tissue disorder.

Efficient non-contrast enhanced 3D Cartesian cardiovascular magnetic resonance angiography of the thoracic aorta in 3 min

Background The application of cardiovascular magnetic resonance angiography (CMRA) for the assessment of thoracic aortic disease is often associated with prolonged and unpredictable acquisition times and residual motion artefacts. To overcome these limitations, we have integrated undersampled acquisition with image-based navigators and inline non-rigid motion correction to enable a free-breathing, contrast-free Cartesian CMRA framework for the visualization of the thoracic aorta in a short and predictable scan of 3 min. Methods 35 patients with thoracic aortic disease (36 ± 13y, 14 female) were prospectively enrolled in this single-center study. The proposed 3D T2-prepared balanced steady state free precession (bSSFP) sequence with image-based navigator (iNAV) was compared to the clinical 3D T2-prepared bSSFP with diaphragmatic-navigator gating (dNAV), in terms of image acquisition time. Three cardiologists blinded to iNAV vs. dNAV acquisition, recorded image quality scores across four aortic segments and their overall diagnostic confidence. Contrast ratio (CR) and relative standard deviation (RSD) of signal intensity (SI) in the corresponding segments were estimated. Co-axial aortic dimensions in six landmarks were measured by two readers to evaluate the agreement between the two methods, along with inter-observer and intra-observer agreement. Kolmogorov–Smirnov test, Mann–Whitney U (MWU), Bland–Altman analysis (BAA), intraclass correlation coefficient (ICC) were used for statistical analysis. Results The scan time for the iNAV-based approach was significantly shorter (3.1 ± 0.5 min vs. 12.0 ± 3.0 min for dNAV, P = 0.005). Reconstruction was performed inline in 3.0 ± 0.3 min. Diagnostic confidence was similar for the proposed iNAV versus dNAV for all three reviewers (Reviewer 1: 3.9 ± 0.3 vs. 3.8 ± 0.4, P = 0.7; Reviewer 2: 4.0 ± 0.2 vs. 3.9 ± 0.3, P = 0.4; Reviewer 3: 3.8 ± 0.4 vs. 3.7 ± 0.6, P = 0.3). The proposed method yielded higher image quality scores in terms of artefacts from respiratory motion, and non-diagnostic images due to signal inhomogeneity were observed less frequently. While the dNAV approach outperformed the iNAV method in the CR assessment, the iNAV sequence showed improved signal homogeneity along the entire thoracic aorta [RSD SI 5.1 (4.4, 6.5) vs. 6.5 (4.6, 8.6), P = 0.002]. BAA showed a mean difference of < 0.05 cm across the 6 landmarks between the two datasets. ICC showed excellent inter- and intra-observer reproducibility. Conclusions Thoracic aortic iNAV-based CMRA with fast acquisition (~ 3 min) and inline reconstruction (3 min) is proposed, resulting in high diagnostic confidence and reproducible aortic measurements.

Multi-Omics Profiling in Marfan Syndrome: Further Insights into the Molecular Mechanisms Involved in Aortic Disease

Thoracic aortic aneurysm is a potentially life-threatening disease with a strong genetic contribution. Despite identification of multiple genes involved in aneurysm formation, little is known about the specific underlying mechanisms that drive the pathological changes in the aortic wall. The aim of our study was to unravel the molecular mechanisms underlying aneurysm formation in Marfan syndrome (MFS). We collected aortic wall samples from FBN1 variant-positive MFS patients (n = 6) and healthy donor hearts (n = 5). Messenger RNA (mRNA) expression levels were measured by RNA sequencing and compared between MFS patients and controls, and between haploinsufficient (HI) and dominant negative (DN) FBN1 variants. Immunohistochemical staining, proteomics and cellular respiration experiments were used to confirm our findings. FBN1 mRNA expression levels were highly variable in MFS patients and did not significantly differ from controls. Moreover, we did not identify a distinctive TGF-β gene expression signature in MFS patients. On the contrary, differential gene and protein expression analysis, as well as vascular smooth muscle cell respiration measurements, pointed toward inflammation and mitochondrial dysfunction. Our findings confirm that inflammatory and mitochondrial pathways play important roles in the pathophysiological processes underlying MFS-related aortic disease, providing new therapeutic options.

Hybrid Approach in Acute and Chronic Aortic Disease

The management of patients with aortic disease that involves the ascending aorta, the aortic arch, and the descending aorta represent a surgical challenge. Open surgical repair remains the gold standard for aortic arch pathologies. However, this operation requires a cardiopulmonary bypass and a period of profound hypothermia and circulatory arrest, which carries a substantial rate of mortality and morbidity. For these reasons, hybrid arch repair that involves a combination of open surgery with endovascular aortic stent graft placement has been introduced as a therapeutic alternative for those patients deemed unfit for open surgical procedures. Hybrid repair requires varying degrees of invasiveness and can be performed as a single-stage procedure or as a two-stage procedure. The choice of the technique is multifactorial, depending on the characteristics of the diseased arch with regard to position of the stent graft proximal landing zone, patient fitness and comorbid status, as well as surgical expertise and hospital facilities. Among the evolving hybrid procedures is the so-called “frozen” or stented elephant trunk technique. Adapted from the classical elephant trunk technique, this approach facilitates the repair of a concomitant aortic arch and proximal descending aortic aneurysms in a single stage under circulatory arrest. This technique is increasingly being used to treat extensive thoracic aortic disease and has shown promising results.

Frank's sign with acute aortic dissection

A 59-year-old man with a long smoking history presented with sudden back pain. Frank’s sign was noticed in his bilateral ears, and computed tomography revealed Stanford type A acute aortic dissection. If young patients have Frank’s sign, attention should be paid to atherosclerotic disease including aortic disease.