No abstract

Objectives. To investigate if the pulmonary arterial hypertension (PAH) risk assessment tool presented in the 2015 ESC/ERS guidelines is valid for patients with chronic thromboembolic pulmonary hypertension (CTEPH) when taking pulmonary endarterectomy (PEA) into account. Design. Incident CTEPH patients registered in the Swedish PAH Registry (SPAHR) between 2008 and 2016 were included. Risk stratification performed at baseline and follow-up classified the patients as low-, intermediate-, or high-risk using the proposed ESC/ERS risk algorithm. Results. There were 250 CTEPH patients with median age (interquartile range) 70 (14) years, and 53% were male. Thirty-two percent underwent PEA within 5 (6) months. In a multivariable model adjusting for age, sex, and pharmacological treatment, patients with intermediate-risk or high-risk profiles at baseline displayed an increased mortality risk (Hazard Ratio [95% confidence interval]: 1.64 [0.69-3.90] and 5.39 [2.13-13.59], respectively) compared to those with a low-risk profile, whereas PEA was associated with better survival (0.38 [0.18-0.82]). Similar impact of risk profile and PEA was seen at follow-up. Conclusion. The ESC/ERS risk assessment tool identifies CTEPH patients with reduced survival. Furthermore, PEA improves survival markedly independently of risk group and age. Take home message: The ESC/ERS risk stratification for PAH predicts survival also in CTEPH patients, even when taking PEA into account.

We observed significant correlations between microdialysis probe levels and tissue biopsy levels of energy-related metabolites in both ischaemic and non-ischaemic tissue. These data assess the validity of the microdialysis technique (in the current setting) for studying dynamic changes of myocardial energy metabolism.

We present for the first time concordant energy metabolic and morphometric data in support of IP being a stepwise phenomenon for protection of the ischaemic myocardium. Furthermore, IP resulted in proportionally higher levels of hypoxanthine (relative to inosine) in the ischaemic myocardium, suggesting a different handling of adenine nucleotide breakdown products in the IP myocardium.

The European Society of Cardiology (ESC) and European Respiratory Society (ERS) guideline recommendation of comprehensive risk assessments, which classify patients with pulmonary arterial hypertension (PAH) as having low, intermediate or high mortality risk, has not been evaluated during long-term follow-up in a “real-life” clinical setting. We therefore aimed to investigate the utility of risk assessment in a clinical setting for up to 5 years post diagnosis.Three hundred and eighty-six patients with PAH from the Swedish PAH Registry were included. Risk group (low/intermediate/high) and proportion of low risk variables were investigated at 3-, 4- and 5-year follow-ups after time of diagnosis. In an exploratory analysis, survival rates of patients with low- or high intermediate risk scores were compared.A low risk profile was in multivariate Cox proportional hazards regressions found to be a strong, independent predictor of longer transplant-free survival (p<0.001) at the 3-, 4- and 5-year follow-ups. Also, for the 3-, 4- and 5-year follow-ups, survival rates significantly differed (p<0.001) between the three risk groups. Patients with a greater proportion of low risk variables had better (p<0.001) survival rates. Patients with a high intermediate risk score had worse survival rates (p<0.001) than those with a low intermediate risk score. Results were similar when excluding patients with ≥3 risk factors for heart failure with preserved ejection fraction, atrial fibrillation and/or age >75 years at diagnosis.Our findings suggest that the ESC/ERS guideline strategy for comprehensive risk assessments in PAH is valid also during long-term follow-up in a “real-life” clinical setting.

Attenuated purine levels are characteristic findings of ischemic preconditioning (PC). Lower energy demand in PC myocardium leading to less nucleotide decay is a reasonable explanation. However, experimental data suggest that the activities of the enzymes involved in purine metabolism are increased in PC myocardium. Recently it was suggested that PC favored degradation of exogenous adenosine to inosine successively ending up in enhanced lactate production. This was probably because of the involvement of the hexose monophosphate pathway in the PC ischemic myocardium. This route may therefore be supplementary in energy metabolism as a metabolic flow can be started by adenosine ending up in lactate without initial adenosine 5'-triphosphate (ATP) investment. Purine nucleoside phosphorylase (PNP) is a key enzyme in the proposed metabolic route. In the current study the effect of PNP inhibition (with 8'-aminoguanosine) on myocardial energy metabolism during PC was studied in an open chest porcine heart model using the microdialysis technique. A dose-dependent inhibition of PNP by 8'-aminoguanosine was observed in PC myocardium. This inhibition resulted in an enhanced exodus of taurine reflecting a disturbed energy economy of the cardiomyocytes. Addition of inosine being a true substrate of PNP reversed these changes, which indicated that 8'-aminoguanosine was a competitive inhibitor of PNP. It is concluded that the ischemic PC phenomenon at least partly involves the activated enzyme PNP.

Preconditioning up-regulates a new metabolic pathway (starting with 5'-nucleotidase and ending up with lactate) resulting in ATP formation in the micromolar range on top of another effect terminating in a useful shift in the AK equilibrium reaction in favour of ATP generation in the millimolar range. Although the up-regulation of the purine nucleoside phosphorylase pathway is clearly demonstrated, its biological relevance remains to be proved.

No abstract