Yeun Ying Wong

Right Ventricular Failure in Idiopathic Pulmonary Arterial Hypertension Is Associated with Inefficient Myocardial Oxygen Utilization

Background— In idiopathic pulmonary arterial hypertension (IPAH), increased right ventricular (RV) power is required to maintain cardiac output. For this, RV O2 consumption (MVO2) must increase by augmentation of O2 supply and/or improvement of mechanical efficiency–ratio of power output to MVO2. In IPAH with overt RV failure, however, there is evidence that O2 supply (perfusion) reserve is reduced, leaving only increase in either O2 extraction or mechanical efficiency as compensatory mechanisms. We related RV mechanical efficiency to clinical and hemodynamic parameters of RV function in patients with IPAH and associated it with glucose metabolism. Methods and Results— The patients included were in New York Heart Association (NYHA) class II (n=8) and class III (n=8). They underwent right heart catheterization, MRI, and H2 15O-, 15O2-, C15O-, and 18FDG-PET. RV power and O2 supply were similar in both groups (NYHA class II versus class III: 0.54±0.14 versus 0.47±0.12 J/s and 0.109±0.022 versus 0.128±0.026 mL O2/min per gram, respectively). RV O2 extraction was near-significantly lower in NYHA class II compared with NYHA class III (63±17% versus 75±16%, respectively, P=0.10). As a result, MVO2 was significantly lower (0.066±0.012 versus 0.092±0.010 mL O2/min per gram, respectively, P=0.006). RV efficiency was reduced in NYHA class III (13.9±3.8%) compared with NYHA class II (27.8±7.6%, P=0.001). Septal bowing, measured by MRI, correlated with RV efficiency (r=−0.59, P=0.020). No relation was found between RV efficiency and glucose uptake rate. RV mechanical efficiency and ejection fraction were closely related (r=0.81, P<0.001). Conclusions— RV failure in IPAH was associated with reduced mechanical efficiency that was partially explained by RV mechanical dysfunction but not by a metabolic shift.

Right ventricular oxygen supply parameters are decreased in human and experimental pulmonary hypertension

BACKGROUND In pulmonary arterial hypertension (PAH), high right ventricular (RV) power output requires increased myocardial oxygen consumption. Oxygen supply, however, does not increase in proportion. It is unknown what cellular mechanisms underlie this lack of adaptation. We therefore determined oxygen supply parameters in RV tissue slices of deceased PAH patients and compared them with RV tissue of patients who died from left ventricular myocardial infarction (MI). Because autopsy tissue only reflects end-stage disease, rat models with stable and progressive pulmonary hypertension (PH) were studied as well. METHODS Myocardial tissue of 10 PAH and 10 MI patients was collected at autopsy. In rats, stable PH (n = 6) and progressive PH (n = 6) was induced by 40 or 60 mg/kg monocrotaline, respectively. Six rats were used as controls. RESULTS RV cardiomyocyte cross-sectional area was strongly increased in PAH compared with MI patients (p < 0.001), whereas capillary density decreased (p < 0.01). Rat data showed similar RV hypertrophy in stable and progressive PH, and RV capillary density was decreased in both (p < 0.01 and p < 0.0001 vs control rats, respectively). RV myoglobin protein content and functional concentration were reduced in both human and rat PH RVs. In rats, this results from a lack of increase in myoglobin mRNA transcription per cardiomyocyte nucleus. CONCLUSIONS All measured cellular oxygen supply parameters are decreased in the failing human and rat pulmonary hypertensive RV. In contrast to stable PH rats, compensatory adaptations do not occur in end-stage PAH, despite higher myocardial oxygen consumption.

Systolic pulmonary artery pressure and heart rate are main determinants of oxygen consumption in the right ventricular myocardium of patients with idiopathic pulmonary arterial hypertension.

Increased afterload in idiopathic pulmonary arterial hypertension (IPAH) causes right ventricular (RV) hypertrophy and failure. Since RV remodelling occurs with alterations in RV oxygen metabolism, increasing our understanding in the factors determining RV O2 consumption in IPAH is necessary. In the left ventricle, it is known that heart rate and systolic blood pressure are the main determinants of myocardial O2 consumption (MVO2). However, the normal right heart has lower oxygen extraction and perfusion than the left myocardium, and RV energy metabolism is changed in hypertrophy. Therefore, it is not obvious that the relationsships of pressure and heart rate to MVO2 hold for the overloaded human right heart. We hypothesize that systolic pulmonary artery pressure (PAP) and heart rate (HR) are the major determinants of RV MVO2 in IPAH.

11C-Acetate Clearance as an Index of Oxygen Consumption of the Right Myocardium in Idiopathic Pulmonary Arterial Hypertension: A Validation Study Using 15O-Labeled Tracers and PET

Idiopathic pulmonary arterial hypertension (IPAH) results in increased right ventricular (RV) workload and oxygen demand. It has been shown that myocardial oxygen consumption (MVO2) of the hypertrophied right ventricle of IPAH patients can be measured using PET and 15O-labeled tracers. This method is, however, not very suitable for routine clinical practice. The purpose of the present study was to assess whether MVO2 can also be determined in the right ventricle of IPAH patients from the clearance of 11C-acetate, a simple method that is in use for MVO2 measurements of the left myocardium. Methods: Seventeen of 26 IPAH patients performed the total PET study. Nine other patients were scanned only for 11C-acetate. 15O-H2O, 15O-O2, and 15O-CO scans were used to derive RV flow, oxygen extraction fraction, and blood volume, respectively, from which RV MVO2 was calculated. The rate of clearance determined by monoexponential curve fitting (Kmono) and the efflux rate constant k2 were derived from the 11C-acetate scan. The RV rate–pressure product was also determined by means of right heart catheterization, as an index of the RV MVO2, and was calculated as the product of systolic pulmonary artery pressure and heart rate. Results: Both 11C-acetate clearance rates, Kmono (R2 = 0.41, P = 0.006) and k2 (R2 = 0.45, P = 0.003), correlated with RV MVO2. They also correlated with RV rate–pressure product (Kmono, R2 = 0.41, P = 0.0005; k2, R2 = 0.48, P < 0.0001). Conclusion: 11C-acetate clearance rates correlated moderately with quantitative RV MVO2 measurements in IPAH. Therefore, 11C-acetate PET can be used only as an index of RV oxidative metabolism in IPAH patients.

Myocardial Oxygen Extraction Fraction Measured Using Bolus Inhalation of 15O-Oxygen Gas and Dynamic PET

The aim of this study was to determine the accuracy of oxygen extraction fraction (OEF) measurements using a dynamic scan protocol after bolus inhalation of 15O2. The method of analysis was optimized by investigating potential reuse of myocardial blood flow (MBF), perfusable tissue fraction, and blood and lung spillover factors derived from separate 15O-water and C15O scans. Methods: Simulations were performed to assess the accuracy and precision of OEF for a variety of models in which different parameters from 15O-water and C15O scans were reused. Reproducibility was assessed in 8 patients who underwent one 10-min dynamic scan after bolus injection of 1.1 GBq of 15O-water, two 10-min dynamic scans after bolus inhalation of 1.4 GBq of 15O2, and a 6-min static scan after bolus inhalation of 0.8 GBq of C15O for region-of-interest definition. Results: Simulations showed that accuracy and precision were lowest when all parameters were determined from the 15O2 scan. The optimal accuracy and precision of OEF were obtained when fixing MBF, perfusable tissue fraction, and blood spillover to values derived from a 15O-water scan and estimating spillover from the pulmonary gas volume using an attenuation map. Optimal accuracy and precision were confirmed in the patient study, showing an OEF test–retest variability of 13% for the whole myocardium. Correction of spillover from pulmonary gas volume requires correction of the lung time–activity curve for pulmonary blood volume, which could equally well be obtained from a 15O-water rather than C15O scan. Conclusion: Measurement of OEF is possible using bolus inhalation of 15O2 and a dynamic scan protocol, with optimal accuracy and precision when other relevant parameters, such as MBF, are derived from an additional 15O-water scan.

Supine-exercise-induced oxygen supply to the right myocardium is attenuated in patients with severe idiopathic pulmonary arterial hypertension

Background Impaired right ventricular (RV) myocardial blood flow (MBF) has been associated with RV dysfunction and fatal RV failure in idiopathic pulmonary hypertension during stress. MBF and O2 extraction from myocardial capillaries (O2 extraction fraction (OEF)) influence myocardial O2 supply. Objective To determine how the baseline RV OEF affects the amount of MBF increase induced by supine exercise, the authors hypothesise that higher baseline OEF (H-OEF) results in limited O2 extraction during exercise and that MBF must therefore be increased to obtain sufficient O2. Methods In 18 patients with idiopathic pulmonary hypertension, baseline OEF, resting MBF and exercise-induced MBF at 40% of maximal cardiopulmonary exercise testing load were measured using positron emission tomography and [15O]O2, [15O]H2O and [15O]CO. Results For the whole population, exercise increased RV MBF from 0.68±0.16 to 1.13±0.38 ml/min/g (p<0.0001). The MBF exercise-to-rest ratio (reserve) was 1.7±0.7. The median baseline OEF was 0.73 at which the patient population was split into H-OEF and lower baseline OEF (L-OEF). Baseline MBF values (0.61±0.11 and 0.74±0.17 ml/min/g, respectively) were similar, and exercise induced a significant MBF increase in both groups (p=0.0001). However, exercise-induced increase in MBF was significantly less in the H-OEF group than in the L-OEF group (0.97±0.30 and 1.30±0.39 ml/min/g, respectively, p<0.05). Moreover, H-OEF patients had lower baseline stroke volume and cardiac output than the L-OEF group (52±19 ml and 4.0±1.1 l/min vs 78±18 ml and 5.5±0.9 l/min, respectively, both p<0.05). Conclusions H-OEF patients were hemodynamically poorer and showed a lower exercise-induced MBF increase compared to L-OEF patients, suggesting exercise-induced O2 supply limitation.

Pulmonary 2-deoxy-2-[18F]-fluoro-d-glucose uptake is low in treated patients with idiopathic pulmonary arterial hypertension

Glucose metabolism measurement using 2-deoxy-2-[18F]-fluoro-D-glucose (18FDG) positron emission tomography (PET) could provide in vivo information about pulmonary vascular remodeling. The purpose of this study was to assess whether pulmonary 18FDG uptake in idiopathic pulmonary arterial hypertension (IPAH) patients changes and, if so, to determine whether the change is related to disease severity and survival. Sixteen IPAH patients who were treated with IPAH-specific therapy and 7 patients who had a myocardial infarction (MI) without pulmonary hypertension were included. IPAH disease severity was determined using the 6-minute walk test and right heart catheterization 2 days before 18FDG PET. Regions of interest were defined for left and right lungs, and standardized uptake values (SUVs), normalized to body weight, injected dose, and plasma glucose level, were derived. Mean SUVs for IPAH left and right lungs were 0.40 ± 0.26 and 0.44 ± 0.18 (P = 0.32), respectively. In MI patients, SUVs were 0.38 ± 0.13 and 0.35 ± 0.10 (P = 0.24) in left and right lungs, respectively. Total lung SUVs were similar in IPAH and MI patients (0.41 ± 0.19 vs. 0.37 ± 0.11; P = 0.56). There was no correlation between SUV and IPAH disease severity parameters. In addition, lung SUV did not predict survival in IPAH patients (hazard ratio, 1.155; 95% confidence interval, 0.16–8.26; P = 0.88). In conclusion, pulmonary 18FDG uptake in treated IPAH patients is low and is not associated with disease severity and survival, thereby limiting its clinical use in patient care.

COX-2 Inhibition by Use of Rofecoxib or High Dose Aspirin Enhances ADP-Induced Platelet Aggregation in Fresh Blood

Aim: Increased cardiovascular risk after use of selective or nonselective cyclooxygenase-2 (COX-2)-inhibitors might partly be caused by enhanced platelet aggregability. However, an effect of COX-2 inhibition on platelets has so far not been observed in humans. Methods: We tested in healthy volunteers the effect of COX-2-inhibition nearly in-vivo, i.e. immediately after and even during blood sampling. Results: Measurement within 2 minutes after venipuncture, but not 60 minutes later, showed that 50 mg of rofecoxib (n=12) or 500 (n=8) or 1000 (n=8) mg of aspirin increased ADP-induced platelet aggregation in a whole-blood aggregometer to, respectively, 152, 176 and 204 % of basal level (p<0.01). No significant differences in aggregability were observed after ingestion of 80 mg of aspirin (n=16), or placebo (n=8). Plasma 6-keto-PGF1α was decreased to 74 % after rofecoxib and to 76 and 70 % after 500 and 1000 mg of aspirin but did not change after low dose aspirin. Continuous photometrical measurement of aggregation in blood flowing from a cannulated vein revealed that high dose aspirin did not elicit aggregation by itself, but increased ADP-induced aggregation in proportion to the decrease in prostacyclin formation (r=0.68, p = 0.004). Since in these experiments thromboxane production was virtually absent, the enhanced aggregation after partial COX-2 inhibition was not caused by unopposed thromboxane formation. Conclusions: We conclude that both selective and nonselective COX-2 inhibition enhances ADP-induced platelet aggregation in humans. This effect can only be detected during or immediately after venipuncture, possibly because of the short half-life of prostacyclin.