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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.

Background: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) require lifelong treatment. The aim of the present study was to investigate adherence to disease-specific treatment in patients with PAH or CTEPH.

Methods: The study comprised an adult population diagnosed with PAH (n=384) or CTEPH (n=187) alive in 2016-2017. The study utilised three registries: the Swedish PAH registry, the National Board of Health and Welfare, and Statistics Sweden. Withdrawals from pharmacies of disease-specific oral treatments were studied. Adherence was assessed as: 1) Number of days covered defined as the difference between the total number of daily dosages dispensed and the total number of days covered; and 2) Manual assessment by two persons that independently reviewed each patient's prescription fill history to detect anomalies or patterns of deteriorating or improving adherence over time.

Results: The mean age was 61 +/- 16 years, 61% were female and mean time since diagnosis was 4.6 years. Adherence was 62% using the Number of days covered method and 66% by the Manual assessment method. Drug-specific adherence varied from 91% for riociguat to 60% for sildenafil. Good adherence was associated with shorter time since diagnosis in patients with PAH and with lower number of concomitant other chronic treatments in patients with CTEPH. Age, sex, socioeconomic status or number of pulmonary hypertension (PH) treatments were not associated with adherence.

Conclusion: Adherence to oral disease-specific treatment was 60-66% and associated with time since diagnosis and number of concomitant chronic treatments. Sex, age or socioeconomic factors did not affect adherence.

OBJECTIVE: Endothelial function, including the nitric oxide (NO)-pathway, has previously been extensively investigated in heart failure (HF). In contrast, studies are lacking on the NO pathway after heart transplantation (HT). We therefore investigated substances in the NO pathway prior to and after HT in relation to hemodynamic parameters.

DESIGN: 12 patients (median age 50.0 yrs, 2 females), heart transplanted between June 2012 and February 2014, evaluated at our hemodynamic lab, at rest, prior to HT, as well as four weeks and six months after HT were included. All patients had normal left ventricular function post-operatively and none had post-operative pulmonary hypertension or acute cellular rejection requiring therapy at the evaluations. Plasma concentrations of ADMA, SDMA, L-Arginine, L-Ornithine and L-Citrulline were analyzed at each evaluation.

RESULTS: In comparison to controls, the plasma L-Arginine concentration was low and ADMA high in HF patients, resulting in low L-Arginine/ADMA-ratio pre-HT. Already four weeks after HT L-Arginine was normalized whereas ADMA remained high. Consequently the L-Arginine/ADMA-ratio improved, but did not normalize. The biomarkers remained unchanged at the six-month evaluation and the L-Arginine/ADMA-ratio correlated inversely to pulmonary vascular resistance (PVR) six months post-HT.

CONCLUSIONS: Plasma L-Arginine concentrations normalize after HT. However, as ADMA is unchanged, the L-Arginine/ADMA-ratio remained low and correlated inversely to PVR. Together these findings suggest that (i) the L-Arginine/ADMA-ratio may be an indicator of pulmonary vascular tone after HT, and that (ii) NO-dependent endothelial function is partly restored after HT. Considering the good postoperative outcome, the biomarker levels may be considered "normal" after HT.

Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance of vasoactive substances and remodeling of pulmonary vasculature. Nitric oxide, formed from l-arginine, is essential for homeostasis and smooth muscle cell relaxation in PAH. Our aim was to compare plasma concentrations of l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) in PAH compared to left ventricular systolic dysfunction (LVSD) and healthy subjects. This was an observational, multicenter study comparing 21 patients with PAH to 14 patients with LVSD and 27 healthy subjects. Physical examinations were obtained and blood samples were collected. Plasma levels of ADMA, SDMA, l-arginine, l-ornithine, and l-citrulline were analyzed using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Plasma levels of ADMA and SDMA were higher, whereas l-arginine and l-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p < 0.001). Patients with PAH also had lower levels of l-arginine than patients with LVSD (p < 0.05). l-Arginine correlated to 6 min walking distance (6MWD) (r _s = 0.58, p = 0.006) and l-arginine/ADMA correlated to WHO functional class (r _s = −0.46, p = 0.043) in PAH. In conclusion, l-arginine levels were significantly lower in treatment naïve PAH patients compared to patients with LVSD. Furthermore, l-arginine correlated with 6MWD in PAH. l-arginine may provide useful information in differentiating PAH from LVSD.

Background: Pulmonary hypertension (PH) is a rare condition characterized by endothelial dysfunction and vascular remodelling, leading to increased pulmonary vascular resistance (PVR) and right ventricular heart failure. Endothelial dysfunction is associated with an imbalance between vasoconstrictor compounds, such as endothelin and thromboxane A2, and vasodilator compounds, such as prostacyclin and nitric oxide (NO). Asymmetric dimethylarginine (ADMA), a methyl derivate of L-arginine, inhibits synthesis of NO. Vardenafil, a phosphodiesterase type 5 inhibitor (PDE5-inhibitors), causes vasodilation through the NO/cGMP pathway.

Aim: This thesis investigates the pharmacological effects and diagnostic utility of vardenafil in PH patients. In addition, to evaluate the change of L-arginine and dimethylarginines before and during PAHspecific therapy in PAH patients compared to patients with left ventricular heart failure (LVHF) and healthy subjects.

Methods: The pharmacokinetics and hemodynamic effects of vardenafil were examined during right heart catheterization (RHC) in 16 PH patients and plasma concentrations were measured for up to nine hours after oral administration. In 20 PH patients, acute vasoreactivity test with vardenafil was performed during RHC. Hemodynamic responses were recorded, responders were defined and followed for up to seven years. Additionally, plasma ADMA, symmetric dimethylarginine (SDMA), L-arginine, L-citrulline and L-ornithine levels before and after PAH drug treatment were monitored in 21 PAH patients and compared to values measured in 14 LVHF patients and 27 healthy subjects.

Results: Vardenafil concentrations increased rapidly to maximum plasma concentration (tmax 1h) and elimination half-life was 3.4 h. Patients co-medicated with bosentan had reduced vardenafil concentration. Significant acute hemodynamic responses were observed for mean pulmonary artery pressure (mPAP) (p<0.001), pulmonary vascular resistance (PVR) (p<0.001), cardiac output (CO) (p=0.015), cardiac index (CI) (p=0.010), systemic vascular resistance (SVR) (p<0.001) and PVR/SVR (p=0.002) and were related to plasma vardenafil concentrations. PAH patients had significantly higher ADMA and SDMA levels and significantly lower L-arginine levels and L-arginine/ADMA ratio compared with healthy subjects (p<0.001). L-arginine was also lower in PAH patients compared to patients with LVHF (p<0.05). WHO functional class and six minutes walking distance (6MWD) correlated to Larginine and L-arginine/ADMA ratio in PAH at baseline (p<0.05). At follow-up, patients on mono- or combinationtherapy with endothelin receptor antagonists (ERA) had lower ADMA levels than patients without ERA (p<0.05). In contrast, patients on PDE5-inhibitors had higher ADMA levels compared to patients without PDE5-inhibitors (p<0.05).

Conclusion: Vardenafil is safe in acute vasoreactivity test in PH patients. Cardiopulmonary hemodynamic response was related to plasma drug concentrations. There was a high inter-individual variability of vardenafil pharmacokinetics and co-medication with bosentan caused a pharmacokinetic drug interaction. Baseline L-arginine and dimethylarginines levels were different in PAH patients compared to LVHF patients and healthy controls. PAH-specific treatment influenced L-arginine and dimethylarginines. Our data suggest that L-arginine might be useful for differentiating PAH from LVHF, and L-arginine/ADMA ratios were related to the severity of PAH and might be useful for follow-up evaluations of PAH patients.

PURPOSE: 

Acute vasodilator testing is recommended in patients with pulmonary arterial hypertension to identify individuals who may benefit from long-term treatment with oral calcium channel blockers. The aim of this study was to investigate the use of vardenafil in acute vasoreactivity testing compared to adenosine.

METHODS: 

A total of 20 patients eligible for right heart catheterisation were enrolled. Acute vasoreactivity testing was carried out with intravenous (iv) adenosine (n = 18) followed by oral vardenafil (n = 20). Haemodynamic responses were recorded at baseline and after 60 min (vardenafil). Responders were defined according to consensus guideline criteria.

RESULTS: 

Both vardenafil and adenosine significantly decreased mean pulmonary arterial pressure (mPAP, p < 0.001 and p = 0.026, respectively) and pulmonary vascular resistance (p < 0.001 and p > 0.001, respectively), and significantly increased cardiac output (p = 0.001 and p = 0.005, respectively). Vardenafil reduced mPAP more than adenosine (p = 0.044), while adenosine resulted in higher responses of cardiac index (p = 0.009) and pulmonary arterial oxygen saturation (p = 0.042). Acute adverse reactions were common with adenosine, while no side effects were observed after a single oral dose vardenafil. Vardenafil identified five responders (out of 20), while adenosine identified three responders (out of 18). During a 7-year follow-up, vardenafil responders had significantly lower NT-proBNP levels compared to non-responders.

CONCLUSIONS: 

Vardenafil may be safely used for acute vasoreactivity testing in patients with PH. A single oral dose of vardenafil is better tolerated than iv adenosine and may identify additional responders who could benefit from long-term vasodilator treatment.

OBJECTIVE: We investigated whether vardenafil, a phosphodiesterase-5 inhibitor, alters plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and arginine.

PATIENTS AND METHODS: ADMA, SDMA, and arginine were measured (0-540min) in 12 patients with pulmonary hypertension after a single oral dose of vardenafil. Invasive hemodynamic data were collected at baseline and after 60min.

RESULTS: A reduction in ADMA was observed at 30 and 45min with a median change of -11.1% (P=0.021) and -12.5% (P=0.002). SDMA decreased with a median -5.3% change (P=0.032) at 45min. An increase in arginine, median 40.3% (P=0.002), 45.0% (P=0.010), and 77.1% (P=0.008) was observed at 120, 300, and 540min respectively. An increase in the arginine/ADMA ratio, median 11.7% (P=0.012), 32.5% (P=0.003), 26.5% (P=0.021), 33% (P=0.007), 48.5% (P=0.007), and 63.1% (P=0.008) was observed at 15, 45, 60, 120, 300, and 540min respectively. There was a positive correlation between vardenafil exposure and the percent change in the arginine/ADMA ratio from baseline to 540min (r=0.80; P=0.01). A correlation between baseline mean right atrial pressure (mRAP) and baseline ADMA (r=0.65; P=0.023), and baseline SDMA (r=0.61; P=0.035) was observed. A correlation between the baseline arginine/ADMA ratio and baseline cardiac output (CO) (r=0.59; P=0.045) and baseline cardiac index (CI) (r=0.61; P=0.036) was observed. Baseline arginine/ADMA ratio correlated with baseline mRAP (r=-0.79; P=0.002). A correlation between change (0-60min) in CI and change in arginine (r=0.77; P=0.003) as well as change in the arginine/ADMA ratio (r=0.61; P=0.037) was observed.

CONCLUSIONS: Vardenafil induced changes in ADMA, SDMA, arginine, and the arginine/ADMA ratio in patients with PH. An increase in arginine and the arginine/ADMA ratio was associated with improvement in CI.

To evaluate the pharmacokinetic parameters of a single oral dose of vardenafil in patients with pulmonary hypertension (PH). Sixteen patients with PH received vardenafil in single oral doses (20, 10 or 5 mg), and repeated blood sampling for up to 9 h was performed. Vardenafil plasma concentration was determined using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using model-independent analysis. The plasma vardenafil concentration increased rapidly and exhibited a median time to maximum plasma concentration (t(max)) of 1 h and a mean elimination half-life (t(1/2)) of 3.4 h. The geometric mean and standard deviation of (1) the peak plasma concentration (C-max) was 21.4 +/- 1.7 mu g/L, (2) the normalized C-max (C-max,C- norm) 79.1 +/- 1.6 g/L, (3) the area under the time-concentration curve (AUC) 71.5 +/- 1.6 mu g center dot h/L and (4) the normalized AUC (AUC(norm)) 261.6 A +/- 1.7 g center dot h/L. Patients co-medicated with bosentan reached t(max) later and had a 90% reduction of C-max, C-max,C- norm, AUC and AUC(norm). The pharmacokinetic profile of vardenafil overall revealed considerable inter-individual variability in patients with PH. Co-medication with bosentan resulted in a pharmacokinetic drug interaction, leading to significantly decreased plasma concentrations of vardenafil. Therapeutic drug monitoring for individual dose optimization may be warranted.