Valve-sparing aortic root replacement-for all patients?

BACKGROUND: Valve-sparing root replacement (VSRR) has been associated with good survival and low rates of valve-related complications (VRCs). Whether these advantages are present irrespective of patient comorbidity or age is unclear. The aim of this study was to analyze survival and frequency of VRCs in relation to patient comorbidity and age. METHODS: Between October 1995 and December 2021, 1156 patients with a bicuspid or tricuspid aortic valve were treated by root remodeling. The mean patient age was 53.3 ± 14 years, and 973 (84%) were male. The mean duration of follow-up was 6.7 ± 5.5 years (median, 5.9 years), and follow-up was 95% complete (7746 patient-years). We analyzed the population according to comorbidity and age at surgery. A discriminating cutoff for the effect of age was determined using receiver operating characteristic curve (ROC) analysis. RESULTS: Mean survival at 15 years was 74.7 ± 2.5%. Deceased patients were older (mean, 65.3 ± 12 years vs 51.6 ± 14.1 years; P < .001) at the time of surgery and had more comorbidities (coronary artery disease [CAD], 28.4% vs 9.8%; P < .001). The sole significant adjusted predictor was age (P < .001). By ROC analysis (area under the curve, 0.780), the optimal cutoff for age was 61 years. Survival was 87.1 ± 2.8% at 15 years in patients age <61 years, compared to 55.3 ± 4.3% in patients age >61 years (P < .0001). Using competing risk analysis, VRC-free survival at 15 years was 66.8% at 15 years, including 76.7% in patients age <61 years and 52.4% in those age >61 years (P < .0001). CONCLUSIONS: VSRR is associated with a low incidence of VRC and excellent durability. Survival is decreased in the presence of comorbidities, mainly CAD, and patient age >61 years. Despite lower survival, freedom from VRC is good.

Twenty-five years of root remodelling for root aneurysm and tricuspid aortic valve.

OBJECTIVES: The aim of this retrospective study was to assess the long-term results of root remodelling with tricuspid aortic valves and the effects of concomitant cusp repair and annuloplasty. METHODS: Between October 1995 and December 2021, 684 patients with root aneurysm and regurgitant tricuspid valves were treated by root remodelling. The mean age was 56.5 [standard deviation (SD): 14] years, and 538 (77.6%) were male. Relevant aortic regurgitation was present in 68.3%. Concomitant procedures were performed in 374 patients. The long-term results were analysed. The mean follow-up of 7.2 (SD: 5.3) years (median 6.6 years); it was 95% complete (4934.4 patient-years). RESULTS: Cusp prolapse was repaired in 83%, and an annuloplasty was added in 353 instances (51.6%). Hospital mortality was 2.3%, and survival was 81.7% (SD: 1.2) and 55.7% (SD: 5.8) at 10 and 20 years; age and measurement of effective height were independent predictors for death. Freedom from Aortic insufficiency (AI) II was 90.5 (SD: 1.9) at 10 years and 76.7 (SD: 4.5) at 20 years. Cusp repair of all cusps showed a lower freedom from recurrent AI ≥II at 10 years (P < 0.001). Suture annuloplasty showed a lower freedom from recurrent AI II at 10 years (P = 0.07). Freedom from reoperation was 95.5 (SD: 1.1) and 92.8 (SD: 2.8) at 10 and 20 years. The addition of an annuloplasty showed no difference (P = 0.236). Cusp repair had no effect on valve durability (P = 0.390). CONCLUSIONS: Root remodelling leads to good long-term stability. The addition of cusp repair improves the valve stability over time. The addition of suture annuloplasty improves early valve competency; it showed no effect on freedom from reoperation up to 10 years.

Synthetic biology approaches and combinatorial biosynthesis towards heterologous lipopeptide production.

Synthetic biology techniques coupled with heterologous secondary metabolite production offer opportunities for the discovery and optimisation of natural products. Here we developed a new assembly strategy based on type IIS endonucleases and elaborate synthetic DNA platforms, which could be used to seamlessly assemble and engineer biosynthetic gene clusters (BGCs). By applying this versatile tool, we designed and assembled more than thirty different artificial myxochromide BGCs, each around 30 kb in size, and established heterologous expression platforms using a derivative of Myxococcus xanthus DK1622 as a host. In addition to the five native types of myxochromides (A, B, C, D and S), novel lipopeptide structures were produced by combinatorial exchange of nonribosomal peptide synthetase (NRPS) encoding genes from different myxochromide BGCs. Inspired by the evolutionary diversification of the native myxochromide megasynthetases, the ancestral A-type NRPS was engineered by inactivation, deletion, or duplication of catalytic domains and successfully converted into functional B-, C- and D-type megasynthetases. The constructional design approach applied in this study enables combinatorial engineering of complex synthetic BGCs and has great potential for the exploitation of other natural product biosynthetic pathways.

Genomics-Guided Exploitation of Lipopeptide Diversity in Myxobacteria.

Analysis of 122 myxobacterial genome sequences suggested 16 strains as producers of the myxochromide lipopeptide family. Detailed sequence comparison of the respective mch biosynthetic gene clusters informed a genome-mining approach, ultimately leading to the discovery and chemical characterization of four novel myxochromide core types. The myxochromide megasynthetase is subject to evolutionary diversification, resulting in considerable structural diversity of biosynthesis products. The observed differences are due to the number, type, sequence, and configuration of the incorporated amino acids. The analysis revealed molecular details on how point mutations and recombination events led to structural diversity. It also gave insights into the evolutionary scenarios that have led to the emergence of mch clusters in different strains and genera of myxobacteria.

A highly unusual polyketide synthase directs dawenol polyene biosynthesis in Stigmatella aurantiaca.

Enormous progress in the field of polyketide biosynthesis has led to the establishment of rules for general text book biosynthetic logic and consequently to the assumption that biosynthetic genes can be easily correlated with the corresponding natural products. However, non-textbook examples of polyketide assembly continue to be discovered suggesting the gene to product and product to gene predictions need improvement, especially as they are increasingly used in the post-genomic era. Here, we analyzed the genomic blueprint of a myxobacterial multi-producer of secondary metabolites, Stigmatella aurantiaca DW4/3-1, for its biosynthetic potential by genome-mining. In addition to the five polyketide synthase and/or nonribosomal peptide synthetase gene clusters of known function we identified a further 13 genomic regions exemplifying the enormous genetic potential for the production of additional chemical diversity by this strain. We show by gene inactivation and heterologous expression of the newly identified biosynthetic pathway for dawenol that the biosynthesis of this known polyene does not follow text book biosynthetic logic. Intriguingly, a genomic locus encoding an unusual polyketide synthase exhibiting similarity to gene loci involved in the formation of polyunsaturated fatty acids and secondary lipids was identified.