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1.  Coenzyme Q supplementation in pulmonary arterial hypertension 
Redox Biology  2014;2:884-891.
Mitochondrial dysfunction is a fundamental abnormality in the vascular endothelium and smooth muscle of patients with pulmonary arterial hypertension (PAH). Because coenzyme Q (CoQ) is essential for mitochondrial function and efficient oxygen utilization as the electron carrier in the inner mitochondrial membrane, we hypothesized that CoQ would improve mitochondrial function and benefit PAH patients. To test this, oxidized and reduced levels of CoQ, cardiac function by echocardiogram, mitochondrial functions of heme synthesis and cellular metabolism were evaluated in PAH patients (N=8) in comparison to healthy controls (N=7), at baseline and after 12 weeks oral CoQ supplementation. CoQ levels were similar among PAH and control individuals, and increased in all subjects with CoQ supplementation. PAH patients had higher CoQ levels than controls with supplementation, and a tendency to a higher reduced-to-oxidized CoQ ratio. Cardiac parameters improved with CoQ supplementation, although 6-minute walk distances and BNP levels did not significantly change. Consistent with improved mitochondrial synthetic function, hemoglobin increased and red cell distribution width (RDW) decreased in PAH patients with CoQ, while hemoglobin declined slightly and RDW did not change in healthy controls. In contrast, metabolic and redox parameters, including lactate, pyruvate and reduced or oxidized gluthathione, did not change in PAH patients with CoQ. In summary, CoQ improved hemoglobin and red cell maturation in PAH, but longer studies and/or higher doses with a randomized placebo-controlled controlled design are necessary to evaluate the clinical benefit of this simple nutritional supplement.
Graphical abstract
•Pulmonary arterial hypertension (PAH) is characterized by mitochondrial dysfunction.•Co-enzymeQ (CoQ) is important for mitochondria function.•CoQ supplementation improved heart function and red cell production in PAH.•The findings support the concept of mitochondrial-targeted therapies for PAH.
PMCID: PMC4143816  PMID: 25180165
Pulmonary hypertension; Mitochondria; Coenzyme Q; Hemoglobin; Heart failure; Metabolism
2.  Fasting 2-Deoxy-2-[18F]fluoro-d-glucose Positron Emission Tomography to Detect Metabolic Changes in Pulmonary Arterial Hypertension Hearts over 1 Year 
Background: The development of tools to monitor the right ventricle in pulmonary arterial hypertension (PAH) is of clinical importance. PAH is associated with pathologic expression of the transcription factor hypoxia-inducible factor (HIF)-1α, which induces glycolytic metabolism and mobilization of proangiogenic progenitor (CD34+CD133+) cells. We hypothesized that PAH cardiac myocytes have a HIF-related switch to glycolytic metabolism that can be detected with fasting 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) and that glucose uptake is informative for cardiac function.
Methods: Six healthy control subjects and 14 patients with PAH underwent fasting FDG-PET and echocardiogram. Blood CD34+CD133+ cells and erythropoietin were measured as indicators of HIF activation. Twelve subjects in the PAH cohort underwent repeat studies 1 year later to determine if changes in FDG uptake were related to changes in echocardiographic parameters or to measures of HIF activation.
Measurements and Results: FDG uptake in the right ventricle was higher in patients with PAH than in healthy control subjects and correlated with echocardiographic measures of cardiac dysfunction and circulating CD34+CD133+ cells but not erythropoietin. Among patients with PAH, FDG uptake was lower in those receiving β-adrenergic receptor blockers. Changes in FDG uptake over time were related to changes in echocardiographic parameters and CD34+CD133+ cell numbers. Immunohistochemistry of explanted PAH hearts of patients undergoing transplantation revealed that HIF-1α was present in myocyte nuclei but was weakly detectable in control hearts.
Conclusions: PAH hearts have pathologic glycolytic metabolism that is quantitatively related to cardiac dysfunction over time, suggesting that metabolic imaging may be useful in therapeutic monitoring of patients.
PMCID: PMC3960991  PMID: 23509326
hypoxia-inducible factor 1; alpha subunit; positron emission tomography; fluorodeoxyglucose F18; right ventricle; heart failure
3.  Ventricular Geometry, Strain, and Rotational Mechanics in Pulmonary Hypertension 
Circulation  2010;121(2):259-266.
We tested the hypothesis that right ventricular (RV) pressure overload affects RV function, and further influences left ventricular (LV) geometry that adversely affects LV twist mechanics and segmental function.
Methods and Results
Echocardiographic images were prospectively acquired in 44 (46±12 years; 82%F) patients with evidence of pulmonary hypertension (PH) (estimated pulmonary systolic pressure [PASP] =71±23 mmHg) and in 44 age and gender-matched healthy subjects. Patients with intrinsic LV diseases were excluded. RV lateral wall (RVLAT) longitudinal strain (LS) and interventricular septal (IVS) LS were reduced in PH group compared with controls (-15.9±7.6% vs.-25.5±6.1%, p<0.001 and -17.3±4.4% vs.-20.2±3.9%, p=0.002, respectively), while LV lateral wall (LVLAT) LS was preserved. RVLAT and IVS LS, but not LVLAT LS, correlated with PASP(r=0.56, p<0.01; r=0.32, p<0.01) and LV eccentricity index (LVEI) (r=0.57, p<0.01; r=0.57, p<0.01). IVS and LVLAT circumferential strains (CS) were both reduced in the PH group. Although IVS CS and LVLAT CS correlated with PASP and LVEI, after adjusting CS for LVEI, differences between groups persisted for IVS CS (p<0.01) but not LVLAT CS (p=0.09). LV torsion was decreased in patients with PH compared with controls (9.6±4.9° vs. 14.7±4.9°, p<0.001). LV torsion inversely correlated with PASP (r=-0.39, p<0.01) and LVEI (r=-0.3, p<0.01). LV untwisting rates were similar in both groups (p=0.7).
Chronic RV pressure overload directly affects RV longitudinal systolic deformation. RV pressure overload further influences IVS and LV geometry, which impairs LV torsion and segmental LS and CS, more for the IVS than the free wall of the LV.
PMCID: PMC2846516  PMID: 20048214
Torsion; pulmonary hypertension; strain; echocardiography

Results 1-3 (3)