Excessive activation of the transforming growth factor beta signaling pathway and disorganized cellular skeleton caused by genetic mutations are known to be responsible for the inherited thoracic aortic aneurysms and dissections (TAAD), a life-threatening vascular disease. To investigate the genotype-phenotype correlation, we screened genetic mutations of fibrillin-1 (FBN1), transforming growth factor-β receptor-1 (TGFBR1) and transforming growth factor-β receptor-2 (TGFBR2) for TAAD in 7 affected families and 22 sporadic patients. Of 19 potential mutations identified in FBN1, 11 appeared novel while the others were recurrent. Two mutations were detected in TGFBR2. Eight patients carried no mutation in either of these genes. Characterization of FBN1 c.5917+6T>C in transfected HEK293 cells demonstrated that it caused skipping of exon 47, leading to the loss of the 33th calcium binding epidermal growth factor-like domain associated with Marfan syndrome. Compared with exon 46, skipping of 47 did not cause patients ectopia lentis in all carriers. To correlate genotypes with phenotypes in different human ancestries, we reviewed the published mutational studies on FBN1 and found that the probability of cardiovascular defects were significantly increased in Chinese patients with premature termination codon or splicing mutations than those with missense mutations (91.7 % vs 54.2 %, P = 0.0307) or with noncysteine-involved point mutations than those with cysteine-involved mutations (88.9 % vs 33.3 %, P = 0.0131). Thus, we conclude that exon 47 skipping of FBN1 leads preferentially to cardiovascular defects and human ancestries influence genotype-phenotype correlation in TAAD.

BACKGROUND: A novel intra-ventricular assist device (iVAD) was established as a new pulsatile assist device to address various disadvantages, such as bulky configuration and reduced arterial pulsatility, observed in conventional ventricular assist devices.OBJECTIVE: Analyzed the native left ventricular stroke volume (SV) after iVAD support in vitro.METHODS: The SV of iVAD was examined in a home-designed mock circulatory system (MCS) at different heart rates and drive pressures and the SV of a failure ventricle was examined with iVAD at 75, 90, 120 bpm and 120–180 mmHg drive pressure after iVAD support. Data pertaining to native left ventricular SV before and after iVAD support were compared.RESULTS: The native ventricular SV was improved by iVAD when its drive pressure (DP) was slightly greater than that of the mock system. Conversely, the native ventricular SV was decreased when DP was much greater than that (150 mmHg) of MCS. A high DP had a significant effect on SV.CONCLUSIONS: The proposed device improved the dysfunctional native left ventricular SV when DP of iVAD was slightly greater than that of MCS. However, iVAD reduced the SV when the drive pressure was greater than that of MCS.

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