Impairment of pulmonary vascular reserve and right ventricular systolic reserve in pulmonary arterial hypertension.

BACKGROUND: Exercise capacity is impaired in pulmonary arterial hypertension (PAH). We hypothesized that cardiovascular reserve abnormalities would be associated with impaired hemodynamic response to pharmacological stress and worse outcome in PAH. METHODS: Eighteen PAH patients (p) group 1 NYHA class II/III and ten controls underwent simultaneous right cardiac catheterization and intravascular ultrasound at rest and during low dose-dobutamine (10 mcg/kg/min) with trendelenburg (DST). We estimated cardiac output (CO), pulmonary vascular resistance (PVR) and capacitance (PC), and PA elastic modulus (EM). We concomitantly measured tricuspid annular plane systolic excursion (TAPSE), RV myocardial peak systolic velocity (Sm) and isovolumic myocardial acceleration (IVA) in PAH patients. Based on the rounded mean + 2 SD of the increase in mPAP in our healthy control group during DST (2.8 + 1.8 mm Hg), PAH p were divided into two groups according to mean PA pressure (mPAP) response during DST, 1: ΔmPAP > 5 mm Hg and 2: ΔmPAP ≤ 5 mm Hg. Cardiovascular reserve was estimated as the change (delta, Δ) during DST compared with rest, including ΔmPAP with respect to ΔCO (ΔmPAP/ΔCO). All patients were prospectively followed up for 2 years. RESULTS: PAH p showed significant lower heart rate and CO increase than controls during DST, with a significant mPAP and pulse PAP increase and higher ΔmPAP/ΔCO (p < 0.05). Neither hemodynamic, IVUS and echocardiographic data were different between both PAH groups at rest. In group 1, DST caused a higher ΔEM, ΔmPAP/ΔCO, ΔPVR, and ΔTAPSE than group 2, with a lower IVA increase and a negative ΔSV (p < 0.05). TAPSE correlated with mPAP and RVP (p < 0.05) and, IVA and Sm correlated with CO (p < 0.05). ΔEM correlated with ΔmPAP and ΔIVA with ΔCO (p < 0.05). There were two deaths/pulmonary transplantations in group 1 and one death in group 2 during the follow-up (p > 0.05). CONCLUSIONS: Pulmonary vascular reserve and RV systolic reserve are significantly impaired in patients with PAH. The lower recruitable cardiovascular reserve is significantly related to a worse hemodynamic response to DST and it could be associated with a poor clinical outcome.

Methylated arginines and nitric oxide in end-stage renal disease: impact of inflammation, oxidative stress and haemodialysis.

OBJECTIVES: To determine whether inflammation (C-reactive protein, CRP), oxidative stress (malondialdehyde, MDA) or haemodialysis (HD) affect associations between asymmetric (ADMA), symmetric (SDMA) dimethylarginine, NG-monomethyl-L-arginine (L-NMMA) and nitrite/nitrate (NOx) in end-stage renal disease (ESRD). METHOD: Metabolites were measured pre-HD, after 1 hour and end-HD in 40 ESRD patients (age 63 ± 14 years). RESULTS: Positive associations between NOx and ADMA (p = 0.04), SDMA (p < 0.001) and L-NMMA (p = 0.04) were observed pre-HD. Associations weakened during HD but were not significantly influenced by CRP or MDA. CONCLUSIONS: HD, oxidative stress or inflammation did not significantly affect the positive associations between methylated arginines and NOx in ESRD.

The biochemical basis of hereditary fructose intolerance.

Hereditary fructose intolerance is a rare, but potentially lethal, inherited disorder of fructose metabolism, caused by mutation of the aldolase B gene. Treatment currently relies solely on dietary restriction of problematic sugars. Biochemical study of defective aldolase B enzymes is key to revealing the molecular basis of the disease and providing a stronger basis for improved treatment and diagnosis. Such studies have revealed changes in enzyme activity, stability and oligomerisation. However, linking these changes to disease phenotypes has not always been straightforward. This review gives a general overview of the features of hereditary fructose intolerance, then concentrates on the biochemistry of the AP variant (Ala149Pro variant of aldolase B) and molecular pathological consequences of mutation of the aldolase B gene.

Pre-test probability prediction in patients with a low to intermediate probability of coronary artery disease: a prospective study with a fractional flow reserve endpoint.

AIMS: European and North American guidelines currently recommend pre-test probability (PTP) stratification based on simple probability models in patients with suspected coronary artery disease (CAD). However, no unequivocal recommendation has yet been established. We aimed to compare the ability of risk factors and different PTP stratification models to predict haemodynamically obstructive CAD with fractional flow reserve (FFR) as reference in low to intermediate probability patients. METHODS AND RESULTS: We prospectively included 1675 patients with low to intermediate risk who had been referred to coronary computed tomography angiography (CTA). Patients with coronary stenosis were subsequently investigated by invasive coronary angiography (ICA) with FFR measurement if indicated. Discrimination and calibration were assessed for four models: the updated Diamond-Forrester (UDF), the CAD Consortium Basic, the Clinical, and the Clinical + Coronary artery calcium score (CACS). At coronary CTA, 24% of patients were diagnosed with a suspected stenosis and 10% had haemodynamically obstructive CAD at the ICA. Calibration for all CAD Consortium models increased compared with the UDF score. However, all models overestimated the probability of haemodynamically obstructive CAD. Discrimination increased by area under the receiver operating curve from 67% to 86% for UDF vs. CAD Consortium Clinical + CACS. The proportion of low-probability patients (pre-test score < 15%) was for the UDF, CAD Consortium Basic, Clinical, and Clinical + CACS: 14%, 58%, 51%, and 66%, respectively. The corresponding negative predictive values were 97%, 94%, 95%, and 98%, respectively. CONCLUSION: CAD Consortium models improve PTP stratification compared with the UDF score, mainly due to superior calibration in low to intermediate probability patients. Adding the coronary calcium score to the models substantially increases discrimination. CLINICAL TRIALS. GOV IDENTIFIER: NCT02264717.

Trapezium Bone Density-A Comparison of Measurements by DXA and CT.

Bone density may influence the primary fixation of cementless implants, and poor bone density may increase the risk of implant failure. Before deciding on using total joint replacement as treatment in osteoarthritis of the trapeziometacarpal joint, it is valuable to determine the trapezium bone density. The aim of this study was to: (1) determine the correlation between measurements of bone mineral density of the trapezium obtained by dual-energy X-ray absorptiometry (DXA) scans by a circumference method and a new inner-ellipse method; and (2) to compare those to measurements of bone density obtained by computerized tomography (CT)-scans in Hounsfield units (HU). We included 71 hands from 59 patients with a mean age of 59 years (43-77). All patients had Eaton-Glickel stage II-IV trapeziometacarpal (TM) joint osteoarthritis, were under evaluation for trapeziometacarpal total joint replacement, and underwent DXA and CT wrist scans. There was an excellent correlation (r = 0.94) between DXA bone mineral density measures using the circumference and the inner-ellipse method. There was a moderate correlation between bone density measures obtained by DXA- and CT-scans with (r = 0.49) for the circumference method, and (r = 0.55) for the inner-ellipse method. DXA may be used in pre-operative evaluation of the trapezium bone quality, and the simpler DXA inner-ellipse measurement method can replace the DXA circumference method in estimation of bone density of the trapezium.

Using positron emission tomography to study human ketone body metabolism: a review.

Ketone bodies - 3-hydroxybutyrate and acetoacetate - are important fuel substrates, which can be oxidized by most tissues in the body. They are synthesized in the liver and are derived from fatty acids released from adipose tissue. Intriguingly, under conditions of stress such as fasting, arterio-venous catheterization studies have shown that the brain switches from the use of almost 100% glucose to the use of >50-60% ketone bodies. A similar adaptive mechanism is observed in the heart, where fasting induces a shift toward ketone body uptake that provides the myocardium with an alternate fuel source and also favorably affects myocardial contractility. Within the past years there has been a renewed interest in ketone bodies and the possible beneficial effects of fasting/semi-fasting/exercising and other "ketogenic" regimens have received much attention. In this perspective, it is promising that positron emission tomography (PET) techniques with isotopically labeled ketone bodies, fatty acids and glucose offer an opportunity to study interactions between ketone body, fatty acid and glucose metabolism in tissues such as the brain and heart. PET scans are non-invasive and thus eliminates the need to place catheters in vascular territories not easily accessible. The short half-life of e.g. 11C-labeled PET tracers even allows multiple scans on the same study day and reduces the total radiation burden associated with the procedure. This short review aims to give an overview of current knowledge on ketone body metabolism obtained by PET studies and discusses the methodological challenges and perspectives involved in PET ketone body research.

In vivo assessment of pulmonary arterial wall fibrosis by intravascular optical coherence tomography in pulmonary arterial hypertension: a new prognostic marker of adverse clinical follow-up.

BACKGROUND: The aim is to correlate pulmonary arterial (PA) remodeling estimated by PA fibrosis in PA hypertension (PAH) with clinical follow-up. Histology of PA specimens is also performed. METHODS: 19 patients, aged 54±16 (4 men), functional class II-III were studied with right heart catheterization, PA Intravascular Ultrasound and optical coherence tomography (OCT) in inferior lobe segment. PA wall fibrosis was obtained by OCT ( area of fibrosis/PA cross sectional area × 100). Patients follow-up was blind to OCT. Events were defined as mortality, lung transplantation, need of intravenous prostaglandins or onset of right ventricular failure. RESULTS: OCT measurements showed high intra- and interobserver agreement. There was a good correlation between OCT and histology in PA fibrosis from explanted lungs. Area of fibrosis was 1.4±0.8 mm(2), % fibrosis was 22.3±8. Follow-up was 3.5 years (2.5-4.5). OCT %Fib was significantly correlated with PA capacitance (r=-0.536) and with pulmonary vascular rsistance (r=0.55). Patients were divided according to the median value of PA fibrosis. There were 10 patients with a high (≥ 22%) and 9 with a low fibrosis (<22%). Events occurred in 6 (1 death, 1 lung transplantation, 2 intravenous prostaglandins, 2 right heart failure) out of 10 patients with high and in 0 out of 9 patients with low fibrosis (p<0.01). CONCLUSIONS: In PAH, the severity of PA remodeling assessed by OCT wall fibrosis was significantly predictive of severely unfavorable clinical outcome. In vivo assessment of pulmonary arterial wall fibrosis by intravascular OCT in PAH is a promising new prognostic marker of adverse clinical outcome.