Early risk prediction in idiopathic versus connective tissue disease-associated pulmonary arterial hypertension: call for a refined assessment.

Despite systematic screening and improved treatment strategies, the prognosis remains worse in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) compared to patients with idiopathic/hereditary pulmonary arterial hypertension (IPAH). We aimed to investigate differences in clinical characteristics, outcome and performance of the European Society of Cardiology (ESC)/ European Respiratory Society (ERS) risk stratification tool in these patient groups. This retrospective analysis included incident patients with CTD-PAH (n=197, of which 64 had interstitial lung disease, ILD) or IPAH (n=305) enrolled in the Swedish PAH Register (SPAHR) 2008-2019. Patients were classified as low, intermediate or high risk at baseline, according to the "SPAHR-equation". One-year survival, stratified by type of PAH, was investigated by Cox proportional regression. At baseline, CTD-PAH patients had lower diffusing capacity for carbon monoxide and lower haemoglobin but, at the same time, lower N-terminal prohormone-brain natriuretic peptide, longer 6 min walk distance, better haemodynamics and more often a low-risk profile. No difference in age, World Health Organisation functional class (WHO-FC) or renal function between groups was found. One-year survival rates were 75, 82 and 83% in patients with CTD-PAH with ILD, CTD-PAH without ILD and IPAH, respectively. The 1-year mortality rates for low-, intermediate- and high-risk groups in the whole cohort were 0, 18 and 34% (p<0.001), respectively. Corresponding percentages for CTD-PAH with ILD, CTD-PAH without ILD and IPAH patients were: 0, 26, 67% (p=0.008); 0, 19, 39% (p=0.004); and 0, 16, 29% (p=0.001), respectively. The ESC/ERS risk assessment tool accurately identified low-risk patients but underestimated the 1-year mortality rate of CTD-PAH and IPAH patients assessed as having intermediate risk at diagnosis.

Predicting mortality during long-term follow-up in pulmonary arterial hypertension.

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. 386 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-intermediate 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.

Risk stratification in chronic thromboembolic pulmonary hypertension predicts survival.

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.

Clinical outcome and functional characteristics of patients with asymptomatic low-flow low-gradient severe aortic stenosis with preserved ejection fraction are closer to high-gradient severe than to moderate aortic stenosis.

Asymptomatic "paradoxic" severe low-flow low-gradient aortic stenosis with preserved ejection fraction (PAS) constitutes a challenging condition where the optimal management and follow-up remain elusive. We evaluated the clinical outcome in patients with PAS as compared to asymptomatic patients with moderate (MAS) or classical severe aortic stenosis (CAS). Consecutive asymptomatic moderate or severe aortic stenosis patients without concomitant other heart or lung disease (n = 121) were invited. Participants (n = 74) were assigned to three subgroups with regard to degree of aortic stenosis: MAS (n = 25), CAS (n = 22) and PAS (n = 27). Echocardiographic parameters at baseline and clinical outcome data after > 3 years of follow-up time were obtained. Patients with PAS had the smallest stroke volumes and the highest relative wall thickness (p < 0.05). Left ventricular mass index was highest in subjects with CAS, followed closely by PAS and eventually MAS subjects. Whereas ejection fraction was similar amongst the subgroups, a stepwise decrease in global longitudinal left ventricular strain with increasing degree of aortic stenosis was observed, with CAS patients displaying the lowest mean global longitudinal strain, followed by PAS and MAS. A trend towards increasing mortality rate by increasing degree of stenosis was observed. Patients with CAS underwent aortic valve replacement surgery more frequently than both PAS and MAS (p < 0.001). These data suggest that echocardiographic parameters and clinical outcome in patients with PAS bear closer resemblance to CAS than to MAS, but management of PAS is more conservative than in CAS.

Opioid receptor agonist Eribis peptide 94 reduces infarct size in different porcine models for myocardial ischaemia and reperfusion.

Eribis peptide 94 (EP 94) is a novel enkephalin analog, thought to interact with the µ- and δ-opioid receptors. The purpose of the present study was to examine the cardioprotective potential of EP 94 in two clinically relevant porcine models of myocardial ischaemia and reperfusion, and to investigate if such an effect is associated with an increased expression of endothelial nitric oxide synthase (eNOS). Forty-one anesthetized pigs underwent 40min of coronary occlusion followed by 4h of reperfusion. In Protocol I, balloon occlusion of the left anterior descending artery was performed with concurrent intravenous administration of (A) vehicle (n=7), (B) EP 94 (1ug/kg) after 5, 12, 19 and 26min of ischaemia (n=4) or (C) EP 94 (1ug/kg) after 26, 33, 40min of ischaemia (n=6). In Protocol II, open-chest pigs were administered (D) vehicle (n=6) or (E) 0.2ug/kg/min of EP 94 (n=6) through an intracoronary infusion into the jeopardized myocardium, started after 30min of ischaemia and maintained for 15min. The hearts were stained and the protein content of eNOS measured. EP 94 reduces infarct size when administered both early and late during ischaemia compared with vehicle (infarct size group A 61.6±2%, group B 50.2±3% and group C 49.2±2%, respectively, P<0.05), as well as when infused intracoronary (infarct size group D 82.2±3.9% and group E 61.2±2.5% respectively, P<0.01). Phosphorylated eNOS Ser(1177) in relation to total eNOS was significantly increased in the group administered EP 94, indicating activation of nitric oxide production.

Glucagon-like peptide-1 (7-36) amide prevents the accumulation of pyruvate and lactate in the ischemic and non-ischemic porcine myocardium.

Glucagon-like peptide-1 (7-36) amide (GLP-1) has been studied as a treatment option in diabetic patients. We investigated the effect of recombinant GLP-1 infusion on hemodynamic parameters, myocardial metabolism, and infarct size during normoxic conditions as well as during ischemia and reperfusion using an open-chest porcine heart model. In the presence of rGLP-1, interstitial levels of pyruvate and lactate decreased during ischemia and reperfusion both in ischemic and non-ischemic tissue. Moreover, rGLP-1 infusion resulted in increased plasma insulin levels and decreased blood glucose levels. Neither hemodynamic variables nor the consequent infarct size were influenced by rGLP-1 infusion. We conclude that rGLP-1 altered myocardial glucose utilization during ischemia and reperfusion. It did not exert any untoward hemodynamic effects.

8'-aminoguanosine inclusion results in enhanced efflux of taurine in preconditioned ischemic myocardium.

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.