Effects of multikinase inhibitors on pressure overload-induced right ventricular remodeling

Background

Little is known about the effects of current PAH therapies and receptor tyrosine kinase inhibitors on heart remodeling. We sought to investigate the effects of the multikinase inhibitors sunitinib (PDGFR-, VEGFR- and KIT-inhibitor) and sorafenib (raf1/b-, VEGFR-, PDGFR-inhibitor) on pressure overload induced right ventricular (RV) remodeling.

Methods

We investigated the effects of the kinase inhibitors on hemodynamics and remodeling in rats subjected either to monocrotaline (MCT)-induced PH or to surgical pulmonary artery banding (PAB). MCT rats were treated from days 21 to 35 with either vehicle, sunitinib (1 mg/kg, 5 mg/kg and 10 mg/kg/day) or sorafenib (10 mg/kg/day). PAB rats were treated with vehicle, sunitinib (10 mg/kg/day) or sorafenib (10 mg/kg/day) from days 7 to 21. RV function and remodeling were determined using echocardiography, invasive hemodynamic measurement and histomorphometry.

Results

Treatment with both sorafenib and sunitinib decreased right ventricular systolic pressure, pulmonary vascular remodeling, RV hypertrophy and fibrosis in MCT rats. This was associated with an improvement of RV function. Importantly, after PAB, both compounds reversed RV chamber and cellular hypertrophy, reduced RV interstitial and perivascular fibrosis, and improved RV function.

Conclusion

We demonstrated that sunitinib and sorafenib reversed RV remodeling and significantly improved RV function measured via a range of invasive and non-invasive cardiopulmonary endpoints in experimental models of RV hypertrophy.     

Tissue Doppler imaging in systemic sclerosis: A 3-year longitudinal study

Objectives

To investigate by standard echocardiography and pulsed-tissue Doppler imaging (TDI) the course of systemic sclerosis (SSc) heart disease and its correlation with epidemiological, clinical, and serological features of the disease and drug treatment.

Methods

A total of 74 consecutive patients (69 females, between the ages of 19 and 71 years, and disease duration 1–43 years) and 71 controls underwent cardiac assessment at baseline and at 3-year follow-up.

Results

At baseline, compared to controls, patients showed post-Bonferroni correction, impaired left (LV) and right ventricular (RV) diastolic function (E_m/A_m 0.85 ± 0.4 vs 1.5 ± 0.7, p = 0.0003; E_t/A_t 0.9 ± 0.3 vs 1.3 ± 0.4, p = 0.0003), subtle LV and RV systolic dysfunction (S_m 13.7 ± 2.7 vs 15.4 ± 3.2 cm/s, p = 0.031; S_t < 11.5 cm/s in 16/74 patients vs 0 controls, p = 0.0031), and higher pulmonary artery systolic pressure (sPAP) (26.1 ± 6.0 vs 24.1 ± 5.1, p = 0.040). At 3-year follow-up, SSc patients showed a further deterioration of biventricular diastolic and systolic function and a further sPAP increase. At multiple regression analysis of baseline data, E_m/A_m < 1 was detected in 55/74 patients vs 25/71 controls (p < 0.0001) and was associated with age (p = 0.030); E_t/A_t < 1 was detected in 16/74 patients vs 7/71 controls (p < 0.0001), was associated with NYHA class ≥ II (p = 0.033), late capillaroscopic pattern (p = 0.029), and a baseline cardiac Medsger severity score ≥ 1 (p = 0.029). TDI evidence of new abnormalities in RV and/or LV diastolic function was associated with a baseline cardiac Medsger severity score ≥ 1 (p = 0.01). Neither diastolic or systolic abnormalities nor sPAP changes correlated with treatment.

Conclusions

Our study confirms that SSc patients exhibit biventricular systolic and diastolic dysfunction and increased sPAP and reveals further deterioration at 3-year follow-up.     

Prevalence and severity of ventricular dysfunction in patients with HIV-related pulmonary arterial hypertension

Objectives

To evaluate the occurrence of ventricular systolic dysfunction in human immunodeficiency virus (HIV)-related pulmonary arterial hypertension (PAH).

Background

Patients with HIV-related PAH may develop ventricular systolic dysfunction both as a consequence of PAH progression or of the myocardial involvement from the HIV infection itself.

Methods

Cardiac magnetic resonance imaging was applied to measure ejection fraction for the left ventricle and the right ventricle in patients with HIV-related PAH (n = 27) and in patients with PAH from other aetiologies (n = 115).

Results

In HIV-related PAH, ejection fraction values were lower and a higher proportion of patients presented with an advanced stage of ventricular dysfunction (55% vs. 25%; p = 0.009). In a multivariate model, PAH related to HIV infection remained independently associated with advanced ventricular dysfunction (p = 0.011).

Conclusions

Patients with HIV-related PAH have more prevalent and severe ventricular systolic dysfunction compared to patients with PAH from other aetiologies.     

Percutaneous pulmonary valve replacement after different duration of free pulmonary regurgitation in a porcine model: Effects on the right ventricle

Background

Free pulmonary regurgitation (PR) after surgical correction of Tetralogy of Fallot (ToF) with transannular patching can lead to irreversible right ventricular (RV) failure. However, the optimal timing of valve replacement is still debated.

Methods and results

Thirty six pigs were included in the study. Twenty one pigs had a bare metal stent placed in the pulmonary annulus inducing free PR and 9 animals served as control. Six animals died prematurely due to procedural complications. The 21 animals were divided into 3 groups with differential duration of PR (1, 2, 3 months, respectively) after which PPVR was performed. After 1 month with competent valve the animals were euthanized. Cardiac magnetic resonance (CMR) and right heart catheterization were performed serially. Free PR led to severe dilation of the RV in all three groups compared to matched controls (p < 0.001). Final RV volume after one month with competent pulmonary valve was modeled. Increase in RV volume from baseline to valve replacement (ΔRV) was the only predictor of RV recovery (p < 0.001) and increases in ΔRV beyond 120 mL/m2 were predictive of very low probability of recovery. A total of 5 animals did not recover.

Conclusions

Recovery of right ventricular function after free PR by treatment with PPVR was successful in the majority of animals. Increases in RV volume during PR were the only predictor of non-recovery after PPVR and duration of PR did not in itself predict treatment success.     

Acute hemodynamic response of infused fasudil in patients with pulmonary arterial hypertension: A randomized,controlled, crossover study

Background

The Rho-kinase pathway has been shown to be involved in the pathogenesis of PAH. As yet, however, the acute effects of the Rho-kinase inhibitor fasudil have not been compared with established pulmonary selective vasodilators in patients with PAH. We compared the acute effects of intravenous fasudil with inhaled iloprost in patients with pulmonary arterial hypertension (PAH).

Methods

Using a crossover design, 50 patients with PAH (idiopathic PAH, PAH associated with repaired left-to-right cardiac shunts, or connective tissue disease) were randomized to iloprost inhalation (5 μg) and intravenous fasudil (30 mg over 30 min). Hemodynamic data were collected at baseline and during acute drug exposure.

Results

Comparable decreases were observed in mean pulmonary artery pressure (− 4.6 ± 4.3 mm Hg vs. − 4.8 ± 4.2 mm Hg) and pulmonary vascular resistance (− 3.0 ± 3.0 Wood U vs. − 2.2 ± 2.7 Wood U) with fasudil infusion and iloprost inhalation, respectively, during acute challenge. However, fasudil infusion resulted in a more pronounced increase in mean cardiac output and mixed venous oxygen saturation compared with iloprost inhalation (13.7 ± 17.1% vs. 6.9 ± 15.0%; p = 0.044 and 4.5 ± 5.3% vs. 2.7 ± 8.2%; p = 0.044, respectively). Whereas inhaled iloprost resulted in a non-significant increase in mean systemic arterial oxygen saturation (0.8 ± 3.6%), infused fasudil resulted in a non-significant reduction (− 0.6 ± 1.1%).

Conclusion

Infused fasudil improved pulmonary hemodynamics in patients with PAH without significant toxicity.     

Ferric carboxymaltose improves exercise capacity and quality of life in patients with pulmonary arterial hypertension and iron deficiency: A pilot study

Background

Pulmonary arterial hypertension (PAH) is a progressive condition harboring a poor prognosis. Iron deficiency in PAH correlates with disease severity and mortality. While replacement therapy may be beneficial, dietary iron absorption is impaired in PAH patients by hepcidin, a key regulatory protein of iron homoeostasis. We therefore assessed the therapeutic potential and safety of intravenous iron supplementation in patients with PAH and iron deficiency.

Methods

20 patients with PAH and iron deficiency, who were on stable targeted PAH therapy, received a single infusion of ≤ 1000 mg ferric carboxymaltose. All patients were assessed at baseline and two months after iron treatment. Exercise capacity was evaluated based on the 6-minute-walking distance (6MWD), and quality of life (QoL) was assessed by the SF-36 questionnaire (100 point scale). The effects were compared to 20 matched patients with stable PAH without iron deficiency who did not receive ferric carboxymaltose.

Results

In iron deficient patients, iron supplementation led to a marked improvement of iron status (serum iron 5.7 ± 0.4 to 11.1 ± 1.1 μmol/L, ferritin 29.3 ± 6.3 to 145.2 ± 25.4 μg/L, transferrin saturation 7.5 ± 0.7 to 19.3 ± 2.3%, all p ≤ 0.001). Iron-deficient patients receiving ferric carboxymaltose showed a significant increase of the 6MWD from 346.5 ± 28.3 to 374.0 ± 25.5 m (p = 0.007), whereas no significant changes were found in the control group not receiving iron supplementation (6MWD 389.9 ± 25.3 to 379.6 ± 26.2 m; n.s.), resulting in a net increase in the 6MWD of 37.8 m (p = 0.003). This was associated with an improvement in QoL (SF-36 score from 44.3 ± 3.7 to 50.6 ± 3.6; p = 0.01). Only minimal side-effects were reported.

Conclusions

These data indicate that parenteral iron supplementation with ferric carboxymaltose significantly improves exercise capacity and QoL and is well tolerated in patients with PAH and iron deficiency, and when administered in addition to targeted PAH therapies. Our results provide proof of concept for further studies evaluating the potential of iron as an adjunct in PAH treatment on a larger scale.     

Macitentan treatment retards the progression of established pulmonary arterial hypertension in an animal model

Background

Macitentan is a new endothelin receptor antagonist that is used to treat pulmonary arterial hypertension in humans. Treatment of established pulmonary hypertension with macitentan was studied using the monocrotaline model of pulmonary hypertension.

Methods

Three groups of rats were created (n = 12): control (CON: macitentan only), monocrotaline (MCT: monocrotaline only) and macitentan (MACI: macitentan and monocrotaline). Monocrotaline (60 mg/kg) was injected in the MCT and MACI groups on day 0; volume matched saline was injected in the CON groups. Macitentan therapy (30 mg/kg/day) was commenced on day 11 in the CON and MACI groups. Serial echocardiography and ECGs were performed. The rats were sacrificed if they showed clinical deterioration.

Results

The MCT and MACI rats showed signs of pulmonary hypertension by day 7 (maximum pulmonary velocity, CON 1.15 ± 0.15 m/s vs MCT 1.04 ± 0.10 m/s vs MACI 0.99 ± 0.18 m/s; p < 0.05). Both the MCT and MACI groups developed pulmonary hypertension, but this was less severe in the MACI group (day 21 pulmonary artery acceleration time, MCT 17.55 ± 1.56 ms vs MACI 22.55 ± 1.00 ms; pulmonary artery deceleration, MCT 34.72 ± 3.72 m/s² vs MACI 17.30 ± 1.89 m/s²; p < 0.05). Right ventricular hypertrophy and QT interval increases were more pronounced in MCT than MACI (right ventricle wall thickness, MCT 0.13 ± 0.1 cm vs MACI 0.10 ± 0.1 cm; QT interval, MCT 85 ± 13 ms vs MACI 71 ± 14 ms; p < 0.05). Survival benefit was not seen in the MACI group (p = 0.50).

Conclusions

Macitentan treatment improves haemodynamic parameters in established pulmonary hypertension. Further research is required to see if earlier introduction of macitentan has greater effects.     

5-year serial follow-up of clinical condition and ventricular function in patients after repair of tetralogy of Fallot

Objective

To study the changes over time in biventricular size and function, and clinical parameters in patients after repair of tetralogy of Fallot (TOF) without subsequent pulmonary valve replacement (PVR).

Methods

We prospectively included 78 non-PVR patients (age 20(6–60)years at baseline), who were studied twice with a 5-year interval. Patients underwent magnetic resonance imaging for assessment of biventricular size and function. Exercise testing and electrocardiography were performed to determine peak oxygen uptake (peak VO₂) and QRS duration. N-terminal prohormone brain natriuretic peptide (NT-proBNP) was assessed additionally.

Results

Pulmonary regurgitation (PR), right ventricular (RV) volumes and QRS duration increased during 5-year follow-up (RV end-diastolic volume (EDV) 130 ± 30 ml/m² to 138 ± 34 ml/m²; QRS 132 ± 27 msec to 139 ± 27 msec); peak VO₂ decreased (96 ± 19% to 91 ± 17%). RV ejection fraction, RV effective stroke volume (eff.SV), and NT-proBNP levels remained unchanged. The slope of RVEDV increase was 1.6 ± 3.0 ml/m²/year, and depended on RVeff.SV, not on RVEDV, at baseline. Increase in RVEDV correlated with increase in QRS duration over time (r = 0.28, p = 0.016), and with decrease in RV mass/EDV ratio over time (r = − 0.42, p < 0.001), not with decrease in peak VO₂. In subgroup analysis, patients with larger RVs at baseline showed larger increase in PR during follow-up and larger decrease in NYHA class over time.

Conclusions

In TOF patients with moderate RV dilatation, RVEDV increased by 1.6 ± 3.0 ml/m²/year, irrespective of RV size at baseline, but depended on RVeff.SV at baseline. Despite limited progression in RV size, unfavourable changes occurred during 5 years follow-up, which suggests there is a need for close follow-up.     

Cardiac cachexia is associated with right ventricular failure and liver dysfunction

Background

The mechanisms involved in cardiac cachexia remain poorly understood. We examined the association of right ventricular (RV) and hepatic dysfunction with cardiac cachexia.

Methods

We prospectively enrolled 118 patients with left ventricular ejection fraction (LVEF) ≤ 40%, which were subgrouped as follows: New York Heart Association (NYHA) class II (n = 59), NYHA class III without cachexia (n = 41) and NYHA class III with cachexia (n = 18). All patients underwent blood collection, echocardiography and exercise testing.

Results

Reduced systolic RV function (tricuspid annular plane systolic excursion [TAPSE] ≤ 15 mm), was present in 80% of cachectic patients. When comparing NYHA class II patients vs. non-cachectic and cachectic NYHA class III patients we found a stepwise decrease in systolic RV function (TAPSE 19 [16–23] vs. 16 [13–19] vs. 14 [9–15] mm, respectively; p < 0.001) and an increase in right atrial pressure (RAP; > 10 mm Hg: 6.8 vs. 27.5 vs. 75.0%, respectively; p < 0.001), indicating a higher degree of congestive right HF in cardiac cachexia. Systolic and diastolic function of the left ventricle did not differ between non-cachectic and cachectic patients in NYHA class III. Serum alkaline phosphatase and direct bilirubin correlated with TAPSE and RAP, and were highest in cachectic patients (all p ≤ 0.002), suggesting cholestatic dysfunction due to liver congestion. In multivariable regression analysis, RV dysfunction, cholestatic liver parameters and albumin were independently associated with the presence of cardiac cachexia.

Conclusion

Patients with cardiac cachexia display a more pronounced degree of right HF, cholestatic liver dysfunction and hypoalbuminemia compared to non-cachectic patients of similar LVEF and NYHA class.     

Circulating biomarkers of collagen type I metabolism mark the right ventricular fibrosis and adverse markers of clinical outcome in adults with repaired tetralogy of Fallot

Background

Right ventricular (RV) fibrosis is common in patients with repaired tetralogy of Fallot (rTOF). Although accumulating evidence indicates the role of circulating biomarkers of collagen metabolism in left ventricular fibrosis, rTOF data are lacking. This study examined the expression profile and clinical relevance of circulating biomarkers of collagen type I metabolism in rTOF patients.

Methods

Serum biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I, PICP), degradation (carboxy-terminal telopeptide of collagen type I, CITP), and enzymes regulating collagen degradation (matrix metalloproteinases, and type I tissue inhibitor, TIMP-1) were measured in 70 rTOF and 91 control adults. All patients had complete clinical data and received cardiovascular magnetic resonance scans with late gadolinium enhancement (LGE).

Results

Compared to the controls, rTOF patients had higher PICP levels (p < 0.001), PICP:CITP ratios (p < 0.001), and TIMP-1 concentrations (p < 0.001). Increasing PICP levels correlated with higher RV LGE scores (r = 0.427, p < 0.001), lower VO₂max (r = − 0.428, p = 0.002), and larger RV volumes. Furthermore, stepwise multivariate linear regression analysis identified RV end-diastolic volume index > 150 mL/m² (β = 40.52, p = 0.016), RV LGE score (β = 3.94, p = 0.008), and age (β = − 1.77, p = 0.011) as independent correlates of circulating PICP levels.

Conclusions

Patients with rTOF exhibited a profibrotic state with excessive collagen type I synthesis and dysregulated degradation. Elevated circulating PICP levels might reflect RV fibrosis, and link to adverse markers of clinical outcome.     

A proposal for a new scoring system in the prediction of catheter ablation outcomes: Promising results from the Turkish Cryoablation Registry

Background

Although cryoballoon based catheter ablation is an effective therapeutic option in atrial fibrillation (AF), a significant amount of patients failed to remain in sinus rhythm at long term follow-up. Appropriate selection of patients for catheter ablation reduces unnecessary interventions and prevents complications related with catheter ablation. The purpose of our study is to propose a new scoring system in the prediction of recurrence after AF ablation with cryoballoon.

Method

A total of 236 patients (54% male, age 54.6 ± 10.45 years and 79.6% paroxysmal) with symptomatic AF underwent an index cryoablation. The first 3 months after AF ablation is defined as blanking period. Predictors of AF recurrence after cryoablation were analyzed with multivariate Cox regression analysis. BASE-AF₂ score [acronym stands for Body mass index > 28 kg/m² (1); Atrial dilatation > 40 mm (1); current Smoking (1); Early recurrence (1); duration of AF history > 6 years (1) and non-paroxysmal type (1) of AF] is identified by the total number of significant predictors of recurrence in each patient (range = 0–6).

Results

At median 20 (range: 12–30) months follow-up, 74.5% of the patients were free from AF recurrence. Of these patients, 64 (27.1%) patients had a BASE-AF₂ score of ≥ 3. Patients with AF recurrence had a higher mean BASE-AF₂ score (3.27 ± 0.82 vs. 1.1 ± 0.95, p < 0.001) compared to patients without AF recurrence. ROC analysis showed that a BASE-AF₂ score of ≥ 3 well predicted AF recurrence with a sensitivity of 80.8% and a specificity of 91.6% (AUC = 0.94; 95% CI: 0.89–0.97, p < 0.001). A BASE-AF₂ score of ≥ 3 was found to be an independent predictor of AF recurrence (HR: 3.34, 95% CI: 2.34–4.76, p = 0.001).

Conclusion

BASE-AF₂, which was identified as a new scoring system, has well predicted AF recurrence and could be helpful in selecting appropriate patients for interventional strategy.     

Adverse impact of chronic subpulmonary left ventricular pacing on systemic right ventricular function in patients with congenitally corrected transposition of the great arteries

Background

Patients with congenitally corrected transposition of the great arteries (ccTGA) are at high risk of heart block requiring subpulmonary left ventricular (LV) pacing. Long-term right ventricular (RV) pacing in congenitally normal hearts is associated with LV dysfunction. We examined the effects of univentricular subpulmonary LV pacing on the systemic RV in a ccTGA cohort.

Methods

ccTGA patients with two echocardiographic studies at least 6 months apart were included. Records of 52 patients, 22 with pacing, were retrospectively reviewed. Seven patients with biventricular pacing were included for comparison.

Results

The LV-Paced Group experienced deterioration in the RV fractional area change (RVFAC) (28.7 ± 10.0 vs. 21.9 ± 9.1%; P = 0.003), systemic atrioventricular valve regurgitation (P = 0.019) and RV dilatation (end-diastolic area 32.7 ± 8.7 vs. 37.2 ± 9.0 cm²; P = 0.004). There was a corresponding deterioration in NYHA class (P = 0.013). Multivariate Cox regression analysis showed that pacing was an independent predictor of deteriorating RV function and RV dilation (hazard ratio 2.7(10–7.0) and 4.7(1.1–20.6) respectively). None of these parameters changed significantly in the Un-paced Group. The CRT Group showed improvement in RVFAC (22.0% to 30.7% (P = 0.030) and NYHA class (P = 0.030), despite having lower baseline RVFAC (22.0 ± 5.7 vs. 31 ± 9.7%; P = 0.025) and greater dyssynchrony (RV total isovolumic time 13.4 ± 2.1 vs. 9.3 ± 4.2 s/min; P = 0.016) when compared to the Un-Paced Group.

Conclusions

Univentricular subpulmonary LV pacing in patients with ccTGA predicted deterioration in RV function and RV dilatation over time associated with deteriorating NYHA class. Alternative primary pacing strategies such as biventricular pacing may need consideration in this vulnerable group already highly prone to mortality from systemic RV failure.     

Longitudinal strain curves in the RV free wall differ in morphology in patients with pulmonary hypertension compared to controls

Background

Previous studies using speckle tracking-derived strain for quantification of right ventricular (RV) function in pulmonary hypertension (PHT) have focused on the magnitude of global and regional peak longitudinal systolic strains (PLSS) and systolic strain-related indices of dyssynchrony. The aim of our study was to investigate the pattern of RV contraction and relaxation with the use of the contour and timing of strain and velocity curves in PHT.

Methods

The study population consisted of thirty‐seven patients with PHT (45 ± 18 years, 16 women) and thirty‐seven controls. A complete two-dimensional echo with speckle-tracking-derived longitudinal strain of the basal RV free wall and interventricular septum (IVS) was performed and the cycle length-corrected time to PLSS (SST) and time from PLSS to 50% of PLSS (systolic strain half time—SSHT) in both regions were calculated.

Results

Patients with PHT had significantly reduced PLSS (− 24.9 ± 2.0% vs − 43.2 ± 3.0%, p < 0.001) and increased SST (0.47 ± 0.02 vs 0.39 ± 0.02, p = 0.043) and SSHT (0.22 ± 0.02 vs 0.16 ± 0.02, p = 0.047) in the basal RV free wall compared to controls. Furthermore, peak systolic velocities were observed earlier in the cardiac cycle in both regions in patients with PHT compared to controls.

Conclusions

Longitudinal strain curves in the RV free wall reach peak values later in the cardiac cycle and return slower towards the baseline in PHT. Furthermore, peak systolic velocities are observed earlier in the cardiac cycle in both the basal RV free wall and the basal IVS. The above observations effectively illustrate changes in patterns of RV contraction and relaxation caused by PHT.     

Associations between N-terminal pro-B-type natriuretic peptide and cardiac function in adults with corrected tetralogy of Fallot

Background

Amino-terminal B-type natriuretic peptide (NT-proBNP) may detect early cardiac dysfunction in adults with tetralogy of Fallot (ToF) late after corrective surgery. We aimed to determine the value of NT-proBNP in adults with ToF and establish its relationship with echocardiography and exercise capacity.

Methods and results

NT-proBNP measurement, electrocardiography and detailed 2D-echocardiography were performed on the same day in 177 consecutive adults with ToF (mean age 34.6 ± 11.8 years, 58% male, 89% NYHA I, 29.3 ± 8.5 years after surgical correction). Thirty-eight percent of the patients also underwent a cardiopulmonary-exercise test. Median NT-proBNP was 16 [IQR 6.7–33.6] pmol/L, and was elevated in 55%. NT-proBNP correlated with right ventricular (RV) dilatation (r = 0.271, p < 0.001) and RV systolic dysfunction (r = − 0.195, p = 0.022), but more strongly with LV systolic dysfunction (r = − 0.367, p < 0.001), which was present in 69 patients (39%). Moderate or severe pulmonary regurgitation was not associated with higher NT-proBNP. Tricuspid and pulmonary regurgitation peak velocities correlated with NT-proBNP (r = 0.305, p < 0.001 and r = 0.186, p = 0.045, respectively). LV twist was measured with speckle-tracking echocardiography in 71 patients. An abnormal LV twist (20 patients, 28%) was associated with elevated NT-proBNP (p = 0.030). No relationship between NT-proBNP and exercise capacity was found.

Conclusions

NT-proBNP levels are elevated in more than 50% of adults with corrected ToF, while they are in stable clinical condition. Higher NT-proBNP is most strongly associated with elevated pulmonary pressures, and with LV dysfunction rather than RV dysfunction. NT-proBNP has the potential to become routine examination in patients with ToF to monitor ventricular function and may be used for timely detection of clinical deterioration.     

Evaluation of the right ventricle: Comparison of gated blood-pool single photon electron computed tomography and echocardiography with cardiac magnetic resonance

Background

The evaluation of the right ventricle (RV) is a challenge; as a result six transthoracic echocardiography (TTE) parameters have been suggested. While gated blood-pool single photon electron computed tomography (GBPS) is a promising technique, there is currently no completely automated and validated processing software available clinically. Consequently, cardiac magnetic resonance (CMR) imaging remains the gold standard for RV assessment. We aimed to compare RV evaluation by GBPS and TTE to CMR.

Methods

Fifty-eight patients underwent CMR, GBPS and TTE for RV assessment, including volumes, RVEF and TTE's indices of RV function (fractional area change (FAC), RV myocardial performance index by pulsed wave Doppler (MPI-PWD) and tissue Doppler (MPI-TDI) and tricuspid annular plane systolic excursion (TAPSE) by M-Mode and tissue Doppler (TAPSE-TDI)). GBPS was performed using both a commercial (QBS) and the Montreal Heart Institute (MHI) proprietary software.

Results

Nuclear medicine derived volumes quantification showed very good correlations with CMR, for RV end-diastolic (r = 0.84 and 0.77, all p < 0.001) and end-systolic (r = 0.82 and 0.67, all p < 0.001) volumes by MHI and QBS software respectively. RVEF showed a significant correlation with CMR in patients with RVEF ≤ 45% (r = 0.54, p = 0.029 and r = 0.55, p = 0.028, by MHI and QBS respectively). Among TTE parameters, only FAC and MPI-TDI were significantly correlated with CMR-RVEF, mainly for RVEF ≤ 45% (r = 0.63, p = 0.011 and r = 0.58, p = 0.046).

Conclusions

GBPS, both with MHI and QBS software, exhibited significant correlations with CMR for evaluation of the RV (volumes and decreased RVEF estimation). Among TTE's parameters, only FAC and MPI-TDI showed significant correlation with CMR with RVEF ≤ 45%.     

Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients

Background

The double-blind phase of the EARLY study of bosentan remains the only randomized controlled trial of a PAH-targeted therapy in World Health Organization functional class (FC) II patients. We report on the efficacy, safety, disease worsening, survival and prognostic factors in mildly symptomatic pulmonary arterial hypertension (PAH) patients treated with bosentan in the open-label extension phase of the EARLY study.

Methods

Exploratory efficacy outcomes included 6-minute walk distance (6MWD) and WHO FC. Adverse events were recorded. Kaplan–Meier analysis was used to estimate time to first PAH worsening event (death, initiation of intravenous or subcutaneous prostanoids, atrial septostomy or lung transplantation) and survival. Cox regression analysis determined factors prognostic of survival.

Results

Median exposure to bosentan (n = 173) was 51 months. At the end of the bosentan-treatment assessment period, 77.8% of patients were in WHO FC I/II. Adverse events led to discontinuation of bosentan in 20.2% of patients. Aminotransferase elevations > 3 × upper limit of normal occurred in 16.8%. Four-year PAH-event-free survival and survival were 79.5% (95% confidence intervals [95% CI] 73.4, 85.6) and 84.8% [95% CI 79.4, 90.2], respectively. Low 6MWD, low mixed venous oxygenation, high N-terminal pro hormone of brain natriuretic peptide levels and PAH associated with connective tissue disease were associated with a higher risk of death.

Conclusions

The majority of patients exposed to long-term bosentan maintained or improved their functional class. Approximately 20% of the patients discontinued treatment because of adverse events, which were most commonly PAH worsening and elevated liver enzymes.     

Estudio de la repetición del pentanucleótido CCTTT en el gen de la sintasa inducible del óxido nítrico en pacientes con hipertensión arterial pulmonar

Introduction

One of the pathways involved in pulmonary arterial hypertension (PAH) is the nitric oxide (NO) pathway. A polymorphism in the inducible NO synthase (NOS2) gene has been described, consisting of the CCTTT pentanucleotide repeat, which causes a reduction in NO production. The aim of this study was to determine if this polymorphism increases susceptibility to developing PAH.

Methods

Sixty four patients with a diagnosis of PAH groups i and iv and 50 healthy controls were compared. DNA genotyping of the samples for this polymorphism was performed using PCR. The distribution between both groups was compared and correlated with clinical and haemodynamic parameters and therapeutic response.

Results

A significantly different distribution was observed in the number of repeats between patients and controls (P < .0001). When the samples were categorised by short forms (both alleles with less than 12 repeats) and long forms (≥ 12 repeats), it was observed that the former had an almost 4-fold risk of developing PAH (odds ratio: 3.83; 95% CI: 1.19-12.32, P = .024). There were no differences between the most common types of PAH, either in therapeutic response or survival. There was no correlation between haemodynamic parameters and the number of repeats in the patients, and only a weak correlation with systolic PAH.

Conclusions

There are significant differences in the distribution of the NOS2 promotor CCTTT polymorphism between patients with PAH and the healthy population. A minor CCTTT pentanucleotide repeat in the NOS2 gene may increase the risk of developing PAH.     

Efectos protectores del aceite de Nigella sativa en la lesión pulmonar inducida por hiperoxia

Background

Oxygen-induced lung injury is believed to lead to the development of bronchopulmonary dysplasia in premature infants. We have evaluated the beneficial effects of Nigella sativa oil (NSO) on rats with hyperoxia-induced lung injury.

Methods

Thirty newborn Sprague-Dawley rats were randomly divided into 3 groups as hyperoxia (95% O₂), hyperoxia + NSO and control (21% O₂). Pups in the hyperoxia + NSO group were administered intraperitoneal NSO at a dose of 4 ml/kg daily during the study period. Histopathologic, immunochemical, and biochemical evaluations (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], malonaldehyde [MDA] and myeloperoxidase [MPO]) were performed.

Results

In the histopathologic and immunochemical evaluation, severity of lung damage was significantly lower in the hyperoxia + NOS group (P < .05). Tissue GSH-Px and SOD levels were significantly preserved, and MDA, MPO levels were significantly lower in the hyperoxia + NSO group (P < .05).

Conclusion

NSO significantly reduced the severity of lung damage due to hyperoxia.     

Current epoprostenol use in patients with severe idiopathic,heritable or anorexigen-associated pulmonary arterial hypertension: Data from the French pulmonary hypertension registry

Objectives

The current use of intravenous epoprostenol in patients with severe idiopathic, heritable or anorexigen-use associated pulmonary arterial hypertension (IHA-PAH) was investigated.

Methods

This observational study evaluated newly diagnosed (≤ 1 year) patients with IHA-PAH, enrolled in the French pulmonary hypertension (PH) registry between 2006 and 2010 and treated with epoprostenol. Among 209 consecutive patients receiving epoprostenol for the treatment of severe PH, 78 had IHA-PAH, including 43 patients naïve of previous PAH-specific treatment.

Results

After 4 months of epoprostenol therapy, improvement was observed for treatment naïve patients (n = 43) and for patients who had received previous PAH-specific therapy (n = 35): NYHA functional class improved in 79% and 44% of these patients, respectively, 6-minute walk distance increased by 146 (p < 0.0001) and 41 m (p = 0.03), cardiac index increased by 1.2 (p < 0.0001) and 0.5 L·min^− 1·m^− 2 (p = 0.006), and pulmonary vascular resistance decreased by 700 (p < 0.0001) and 299 dyn·s·cm^− 5 (p = 0.009). In the treatment-naïve patient group, upfront combination of epoprostenol and oral PAH therapy tended to be more beneficial compared with epoprostenol monotherapy and was associated with improvement in cardiac index (p = 0.03).The observed 1- and 3-year survival estimates from epoprostenol initiation were 84% and 69%, respectively. The highest survival rates were observed for treatment-naïve patients receiving upfront combination of epoprostenol and oral PAH therapy (92% and 88% at 1 and 3 years, respectively).

Conclusions

First-line therapy with epoprostenol, especially when combined with oral PAH treatment, was associated with a substantial improvement in clinical and hemodynamic status and favorable survival estimates in patients with severe IHA-PAH.     

Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure

Background

Pulmonary arterial hypertension (PAH) after shunt closure is associated with a poor prognosis. The aim of this study was to assess retrospectively the hemodynamics of patients developing PAH after shunt closure.

Methods

Hemodynamic data obtained by right heart catheterization (RHC) performed at baseline and after shunt closure were analyzed.

Results

Twenty-two patients, 13 with atrial septal defect (ASD), 6 with ventricular septal defect (VSD), 1 with patent ductus arteriosus, 1 with both ASD and VSD, and 1 with complete atrio-ventricular canal have been considered. The mean age at closure was 25.3 ± 20.1 years (range of 3 months to 56.7 years), and the mean age at PAH diagnosis was 37.0 ± 20.8 years (range of 5 to 61.2 years). The time delay between shunt closure and PAH diagnosis was 140.2 ± 100.2 months. At baseline RHC, hemodynamic data were as follows: pulmonary vascular resistance (PVR) of 8.6 ± 2.6 Wood units, PVR index (PVRi) of 10.1 ± 2.7 Wood units ∗ m², mean pulmonary arterial pressure of 43.7 ± 9.7 mm Hg, PVR to systemic vascular resistance ratio (PVR/SVR) of 0.70 ± 0.23, and Qp/Qs of 1.6 ± 0.4. In particular, 18/22 (81%) had PVR ≥ 5 Wood units, 21/22 (95%) PVRi ≥ 6 Wood units ∗ m², 21/22 (95%) PVR/SVR ≥ 0.33, and 11/22 (50%) Qp/Qs ≤ 1.5. During the follow-up, 5/22 (22%) patients died and one patient underwent successful double lung transplantation.

Conclusions

High baseline values of PVR (≥ 5 Wood units), PVRi (≥ 6 Wood units ∗ m²) and PVR/SVR (≥ 0.33) are common findings in patients who develop PAH late after shunt closure. Large prospective clinical trials are needed to establish the safe limits for shunt closure.