Hypoxia Inducible Factors Modulate Mitochondrial Oxygen Consumption and Transcriptional Regulation of Nuclear-Encoded Electron Transport Chain Genes.

Hypoxia inducible factor-1 (HIF1) is a stress-responsive nuclear transcription factor that is activated with a decrease in oxygen availability. HIF1 regulates the expression of genes involved in a cell's adaptation to hypoxic stress, including those with mitochondrial specific function. To gain a more comprehensive understanding of the role of HIF1 in mitochondrial homeostasis, we studied the link between hypoxia, HIF1 transactivation, and electron transport chain (ETC) function. We established immortalized mouse embryonic fibroblasts (MEFs) for HIF1α wild-type (WT) and null cells and tested whether HIF1α regulates mitochondrial respiration by modulating gene expressions of nuclear-encoded ETC components. High-throughput quantitative real-time polymerase chain reaction was performed to screen nuclear-encoded mitochondrial genes related to the ETC to identify those whose regulation was HIF1α-dependent. Our data suggest that HIF1α regulates transcription of cytochrome c oxidase (CcO) heart/muscle isoform 7a1 (Cox7a1) under hypoxia, where it is induced 1.5-2.5-fold, whereas Cox4i2 hypoxic induction was HIF1α-independent. We propose that adaptation to hypoxic stress of CcO as the main cellular oxygen consumer is mediated by induction of hypoxia-sensitive tissue-specific isoforms. We suggest that HIF1 plays a central role in maintaining homeostasis in cellular respiration during hypoxic stress via regulation of CcO activity.

Transcatheter Myotomy to Reduce Left Ventricular Outflow Obstruction.

BACKGROUND: Left ventricular outflow tract (LVOT) obstruction is a source of morbidity in hypertrophic cardiomyopathy (HCM) and a life-threatening complication of transcatheter mitral valve replacement (TMVR) and transcatheter aortic valve replacement (TAVR). Available surgical and transcatheter approaches are limited by high surgical risk, unsuitable septal perforators, and heart block requiring permanent pacemakers. OBJECTIVES: The authors report the initial experience of a novel transcatheter electrosurgical procedure developed to mimic surgical myotomy. METHODS: We used septal scoring along midline endocardium (SESAME) to treat patients, on a compassionate basis, with symptomatic LVOT obstruction or to create space to facilitate TMVR or TAVR. RESULTS: In this single-center retrospective study between 2021 and 2023, 76 patients underwent SESAME. In total, 11 (14%) had classic HCM, and the remainder underwent SESAME to facilitate TMVR or TAVR. All had technically successful SESAME myocardial laceration. Measures to predict post-TMVR LVOT significantly improved (neo-LVOT 42 mm2 [Q1-Q3: 7-117 mm2] to 170 mm2 [Q1-Q3: 95-265 mm2]; P < 0.001; skirt-neo-LVOT 169 mm2 [Q1-Q3: 153-193 mm2] to 214 mm2 [Q1-Q3: 180-262 mm2]; P < 0.001). Among patients with HCM, SESAME significantly decreased invasive LVOT gradients (resting: 54 mm Hg [Q1-Q3: 40-70 mm Hg] to 29 mm Hg [Q1-Q3: 12-36 mm Hg]; P = 0.023; provoked 146 mm Hg [Q1-Q3: 100-180 mm Hg] to 85 mm Hg [Q1-Q3: 40-120 mm Hg]; P = 0.076). A total of 74 (97.4%) survived the procedure. Five experienced 3 of 76 (3.9%) iatrogenic ventricular septal defects that did not require repair and 3 of 76 (3.9%) ventricular free wall perforations. Neither occurred in patients treated for HCM. Permanent pacemakers were required in 4 of 76 (5.3%), including 2 after concomitant TAVR. Lacerations were stable and did not propagate after SESAME (remaining septum: 5.9 ± 3.3 mm to 6.1 ± 3.2 mm; P = 0.8). CONCLUSIONS: With further experience, SESAME may benefit patients requiring septal reduction therapy for obstructive hypertrophic cardiomyopathy as well as those with LVOT obstruction after heart valve replacement, and/or can help facilitate transcatheter valve implantation.