BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension.

BACKGROUND: Deficiencies of iron-sulfur (Fe-S) clusters, metal complexes that control redox state and mitochondrial metabolism, have been linked to pulmonary hypertension (PH), a deadly vascular disease with poorly defined molecular origins. BOLA3 (BolA Family Member 3) regulates Fe-S biogenesis, and mutations in BOLA3 result in multiple mitochondrial dysfunction syndrome, a fatal disorder associated with PH. The mechanistic role of BOLA3 in PH remains undefined. METHODS: In vitro assessment of BOLA3 regulation and gain- and loss-of-function assays were performed in human pulmonary artery endothelial cells using siRNA and lentiviral vectors expressing the mitochondrial isoform of BOLA3. Polymeric nanoparticle 7C1 was used for lung endothelium-specific delivery of BOLA3 siRNA oligonucleotides in mice. Overexpression of pulmonary vascular BOLA3 was performed by orotracheal transgene delivery of adeno-associated virus in mouse models of PH. RESULTS: In cultured hypoxic pulmonary artery endothelial cells, lung from human patients with Group 1 and 3 PH, and multiple rodent models of PH, endothelial BOLA3 expression was downregulated, which involved hypoxia inducible factor-2α-dependent transcriptional repression via histone deacetylase 1-mediated histone deacetylation. In vitro gain- and loss-of-function studies demonstrated that BOLA3 regulated Fe-S integrity, thus modulating lipoate-containing 2-oxoacid dehydrogenases with consequent control over glycolysis and mitochondrial respiration. In contexts of siRNA knockdown and naturally occurring human genetic mutation, cellular BOLA3 deficiency downregulated the glycine cleavage system protein H, thus bolstering intracellular glycine content. In the setting of these alterations of oxidative metabolism and glycine levels, BOLA3 deficiency increased endothelial proliferation, survival, and vasoconstriction while decreasing angiogenic potential. In vivo, pharmacological knockdown of endothelial BOLA3 and targeted overexpression of BOLA3 in mice demonstrated that BOLA3 deficiency promotes histological and hemodynamic manifestations of PH. Notably, the therapeutic effects of BOLA3 expression were reversed by exogenous glycine supplementation. CONCLUSIONS: BOLA3 acts as a crucial lynchpin connecting Fe-S-dependent oxidative respiration and glycine homeostasis with endothelial metabolic reprogramming critical to PH pathogenesis. These results provide a molecular explanation for the clinical associations linking PH with hyperglycinemic syndromes and mitochondrial disorders. These findings also identify novel metabolic targets, including those involved in epigenetics, Fe-S biogenesis, and glycine biology, for diagnostic and therapeutic development.

Combined longitudinal and radial dyssynchrony predicts ventricular response after resynchronization therapy.

OBJECTIVES: The purpose of this study was to test the hypothesis that a combined echocardiographic assessment of longitudinal dyssynchrony by tissue Doppler imaging (TDI) and radial dyssynchrony by speckle-tracking strain may predict left ventricular (LV) functional response to cardiac resynchronization therapy (CRT). BACKGROUND: Mechanical LV dyssynchrony is associated with response to CRT; however, complex patterns may exist. METHODS: We studied 190 heart failure patients (ejection fraction [EF] 23 +/- 6%, QRS duration 168 +/- 27 ms) before and after CRT. Longitudinal dyssynchrony was assessed by color TDI for time to peak velocity (2 sites in all and 12 sites in a subgroup of 67). Radial dyssynchrony was assessed by speckle-tracking radial strain. The LV response was defined as > or =15% increase in EF. RESULTS: One hundred seventy-six patients (93%) had technically sufficient baseline and follow-up data available. Overall, 34% were EF nonresponders at 6 +/- 3 months after CRT. When both longitudinal dyssynchrony by 2-site TDI (> or =60 ms) and radial dyssynchrony (> or =130 ms) were positive, 95% of patients had an EF response; when both were negative, 21% had an EF response (p < 0.001 vs. both positive). The EF response rate was lowest (10%) when dyssynchrony was negative using 12-site TDI and radial strain (p < 0.001 vs. both positive). When either longitudinal or radial dyssynchrony was positive (but not both), 59% had an EF response. Combined longitudinal and radial dyssynchrony predicted EF response with 88% sensitivity and 80% specificity, which was significantly better than either technique alone (p < 0.0001). CONCLUSIONS: Combined patterns of longitudinal and radial dyssynchrony can be predictive of LV functional response after CRT.

Speckle-tracking radial strain reveals left ventricular dyssynchrony in patients with permanent right ventricular pacing.

OBJECTIVES: Speckle-tracking strain analysis was used to assess the effects of permanent right ventricular (RV) pacing on the heterogeneity in timing of regional wall strain and left ventricular (LV) dyssynchrony. BACKGROUND: Recent studies have shown detrimental effects of RV pacing, possibly related to the induction of LV dyssynchrony. METHODS: Fifty-eight patients treated with His bundle ablation and pacemaker implantation were studied. To assess the effect of RV pacing on time-to-peak radial strain of different LV segments, we applied speckle-tracking analysis to standard LV short-axis images. In addition, New York Heart Association (NYHA) functional class, LV volumes, and systolic function were assessed at baseline and after long-term RV pacing. RESULTS: At baseline, similar time-to-peak strain for the 6 segments was observed (mean 371 +/- 114 ms). In contrast, after a mean of 3.8 +/- 2.0 years of RV pacing, there was a marked heterogeneity in time-to-peak strain of the 6 segments. In 33 patients (57%), LV dyssynchrony, represented by a time difference > or =130 ms between the time-to-peak strain of the (antero)septal and the posterolateral segments, was present. In these patients, a deterioration of LV systolic function and NYHA functional class was observed. In 11 patients, an "upgrade" of the conventional pacemaker to a biventricular pacemaker resulted in partial reversal of the detrimental effects of RV pacing. CONCLUSIONS: Speckle-tracking analysis revealed that permanent RV pacing induced heterogeneity in time-to-peak strain, resulting in LV dyssynchrony in 57% of patients, associated with deterioration of LV systolic function and NYHA functional class. Biventricular pacing may reverse these adverse effects of RV pacing.