Rethinking the Paradigm: Modern Approach to Proximal Aortic Reconstruction Demonstrates Excellent Outcomes.

BACKGROUND: Techniques for aortic surgery continue to evolve. A real-world snapshot of patients undergoing elective surgery for aneurysm in the modern era is helpful to assist in deciding the appropriate timing for intervention. We herein describe our experience with 100 consecutive patients who underwent primary elective surgery for aneurysm of the proximal thoracic aorta over a two-year period at a single institution. METHODS: The majority of our patients were male, mean age 61.19 ± 13.33 years. Two patients had Marfan syndrome. Twenty-eight patients had bicuspid aortic valve. Thirty-four patients underwent aortic root replacement utilizing a composite valve/graft conduit; 23 had valve-sparing root replacements. The ascending aorta was replaced in 89 patients; 80 (89.9%) of these included a period of circulatory arrest at moderate hypothermia utilizing unilateral selective antegrade cerebral perfusion. RESULTS: Thirty-day mortality was zero. Perioperative stroke occurred in 2 patients, both of whom completely recovered prior to discharge. No patients required re-exploration for bleeding. One patient developed a sternal wound infection. Fifteen patients required readmission to hospital within thirty days of discharge. CONCLUSION: Elective surgery for aneurysm of the proximal aorta is safe, reproducible, and is associated with outcomes that are superior to those seen in an acute aortic syndrome. It may be appropriate to offer surgery to younger patients with proximal aortic aneurysms at smaller diameters, even if their aortic dimensions do not yet meet traditional guidelines for surgical intervention.

Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function.

Deficiency of iron­sulfur (FeS) clusters promotes metabolic rewiring of the endothelium and the development of pulmonary hypertension (PH) in vivo. Joining a growing number of FeS biogenesis proteins critical to pulmonary endothelial function, recent data highlighted that frataxin (FXN) reduction drives Fe-S-dependent genotoxic stress and senescence across multiple types of pulmonary vascular disease. Trinucleotide repeat mutations in the FXN gene cause Friedreich's ataxia, a disease characterized by cardiomyopathy and neurodegeneration. These tissue-specific phenotypes have historically been attributed to mitochondrial reprogramming and oxidative stress. Whether FXN coordinates both nuclear and mitochondrial processes in the endothelium is unknown. Here, we aim to identify the mitochondria-specific effects of FXN deficiency in the endothelium that predispose to pulmonary hypertension. Our data highlight an Fe-S-driven metabolic shift separate from previously described replication stress whereby FXN knockdown diminished mitochondrial respiration and increased glycolysis and oxidative species production. In turn, FXN-deficient endothelial cells had increased vasoconstrictor production (EDN1) and decreased nitric oxide synthase expression (NOS3). These data were observed in primary pulmonary endothelial cells after pharmacologic inhibition of FXN, mice carrying a genetic endothelial deletion of FXN, and inducible pluripotent stem cell-derived endothelial cells from patients with FXN mutations. Altogether, this study indicates FXN is an upstream driver of pathologic aberrations in metabolism and genomic stability. Moreover, our study highlights FXN-specific vasoconstriction in vivo, prompting future studies to investigate available and novel PH therapies in contexts of FXN deficiency.

Frataxin deficiency promotes endothelial senescence in pulmonary hypertension.

The dynamic regulation of endothelial pathophenotypes in pulmonary hypertension (PH) remains undefined. Cellular senescence is linked to PH with intracardiac shunts; however, its regulation across PH subtypes is unknown. Since endothelial deficiency of iron-sulfur (Fe-S) clusters is pathogenic in PH, we hypothesized that a Fe-S biogenesis protein, frataxin (FXN), controls endothelial senescence. An endothelial subpopulation in rodent and patient lungs across PH subtypes exhibited reduced FXN and elevated senescence. In vitro, hypoxic and inflammatory FXN deficiency abrogated activity of endothelial Fe-S-containing polymerases, promoting replication stress, DNA damage response, and senescence. This was also observed in stem cell-derived endothelial cells from Friedreich's ataxia (FRDA), a genetic disease of FXN deficiency, ataxia, and cardiomyopathy, often with PH. In vivo, FXN deficiency-dependent senescence drove vessel inflammation, remodeling, and PH, whereas pharmacologic removal of senescent cells in Fxn-deficient rodents ameliorated PH. These data offer a model of endothelial biology in PH, where FXN deficiency generates a senescent endothelial subpopulation, promoting vascular inflammatory and proliferative signals in other cells to drive disease. These findings also establish an endothelial etiology for PH in FRDA and left heart disease and support therapeutic development of senolytic drugs, reversing effects of Fe-S deficiency across PH subtypes.

The molecular rationale for therapeutic targeting of glutamine metabolism in pulmonary hypertension.

INTRODUCTION: Pulmonary hypertension (PH) is a deadly enigmatic disease with increasing prevalence. Cellular pathologic hallmarks of PH are driven at least partly by metabolic rewiring, but details are just emerging. The discovery that vascular matrix stiffening can mechanically activate the glutaminase (GLS) enzyme and serve as a pathogenic mechanism of PH has advanced our understanding of the complex role of glutamine in PH. It has also offered a novel therapeutic target for development as a next-generation drug for this disease. Area covered: This review discusses the cellular contribution of glutamine metabolism to PH together with the possible therapeutic application of pharmacologic GLS inhibitors in this disease. Expert opinion: Despite advances in our understanding of glutamine metabolism in PH, questions remain unanswered regarding the development of therapies targeting glutamine in PH. The comprehensive mechanisms by which glutamine metabolism rewiring influences pulmonary vascular cell behavior to drive PH are incompletely understood. Because glutamine metabolism exhibits a variety of functions in organ repair and homeostasis, a better understanding of the overall risk-benefit ratio of these strategies with long-term follow-up is needed. This knowledge should pave the way for the design of new strategies to prevent and hopefully even regress PH.