[Approximation of mathematical scanning simulation data and clinical results f radiofrequency ablation of perimitral atrial flutter. Condition of existence of perimitral atrial flutter].

AIM: 1) to create Perimitral Atrial Flutter (PMAFL) model and estimate theoretical probability of elimination of perimital reetntry using left atrial geometry two-dimensional mathematical modeling and ablative formatting; 2) to compare clinical results of PMAFL ablation by means of mitral vs inferioseptal isthmus ablation and mathematical modeling data. MATERIAL AND METHODS: Clinical phase. Study was conducted on 24 pts (6 women, 57.1 ± 9.3 years) with PMAFL. Initially RF-lesions delivered in LA in the MI (endocardial approach to MI). Distal CS roof ablation (epicardial approach to MI) was a second step. As a third step linear RF-lessions of the inferioseptal isthmus (ISI)- from right pulmonary vein ostium to mitral annulus was performed (endocardial approach to ISI). As a fourth step RF-applications applied inside the proximal CS roof (epicardial approach to ISI). Mathematical phase. As the first step numeric reconstruction of the autowave process in excitable tissues of the left atrium was performed. Fitzhugh-Nagumo equation was used for simulation to enabled us to take into account the electrical inhomogeneity of the atria (pulmonary vein ostia). A special scanning method was used for calculating characteristics of autowave processes in a two-dimensional mathematical model of the atrium. As the second step simulation of linear ablation formatting which linked PV ostia and active medium boundaries (corresponding to mitral and inferioseptal isthmus ablation lines) was performed. RESULTS: Clinical phase. Left MI endocardial RFA terminated PMAFL in 6 cases, increased CL without changes of atrial hierarchy activation in 2 cases, and transformed PMAFL to AFib in 2 cases. Distal CS ablation terminated PMAFL in 2 pts. Endocardial ISI ablation of associated with SR restoration in 2 cases and increasing of PMAFL CL in 5 cases. Proximal CS-roof ablation terminated PMAFL in 12 pts. Follow up was 26.7 ± 12.4 mos. Endocardial and epicardial MI approach terminated PMAFL in 8 pts (36%). RFA of endocardial 39nd epicardial aspects of the ISI restored SR in 12 pts (64%) (p< 0.05). MATHEMATICAL PHASE: There are three definite conditions of PMAFL existing: 1) Initial autowave spreading between superior PV and boundary of medium (corresponding to patent conduction between superior PV ostia and mitral annulus); 2) Non-active medium existing between four PV ostia (corresponding to PV isolation after index ablation); 3) Refractory characteristics of medium (corresponding to posterior wall of LA) and medium between PV ostia and boundaries (corresponding to isthmus zones) have to differ each other. The linear ablation patterns (from PV ostia to boundary of medium) suppress PAMFL in two-dimensional mathematical modeling of the left atrium. CONCLUSION: There are definite conditions of PAMFL simulation by means autowave processing in a 2-D active medium using scanning algorithm. Those conditions may consistent with certain EP characteristics of LA after index ablation clinical results of PAMFL ablation.

[Microvascular angina].

Microvascular angina is a rather widely spread disease which is associated with high rate of unfavorable outcomes and substantial economical cost of examination and treatment. However problems of noninvasive diagnostics of the disease have not been entirely solved as well as clear-cut algorithm of management has not been elaborated. We present in this paper consideration of contemporary aspects of etiology, pathogenesis, clinical course, diagnosis, and treatment of microvascular angina in accordance with European recommendations on management of patients with stable ischemic heart disease.

[Matrix metalloproteinases and hypertrophic cardiomyopathy].

Prognosis of patients with hypertrophic cardiomyopathy (HCMP) to a great extent is determined by clinical variant of the disease. As the system of matrix metalloproteinases (MMPs) plays an important role in development and progression of the processes of fibroformation and tissue remodeling polymorphisms of modifier genes regulating its components can influence clinical course of HCMP. Among possible markers of prognostication of the course of cardiovascular diseases the role of MMPs and their tissue inhibitors has been discussed. With the aim of studying effects of MMPs on the course of HCMP we conducted this investigation in which we included 58 patients and a group of healthy volunteers (control group) with comparable sex and age. In all participants (n=112) we determined polymorphism of MMP-3 - rs3025058 and markers of fibroformation (MMP-3, TIMP-1, TIMP-2, and collagen IV). We found that unfavorable allele variant MMP-3 1171 was associated with hypertrophy of interventricular septum. We also established that levels of TIMP-1 in the group of patients with HCMP were significantly lowered in comparison with those in control group. Concentration of marker MMP-3 was elevated in the group of patients with variant "atrial fibrillation" compared with groups of stable course and progressing course. We revealed medium degree reverse correlation between MMP-3 marker and thickness of left ventricular posterior wall and direct correlation of this parameter with coefficient of asymmetry. Polymorphism MMP-3 - 1171 produced an impact on the level of TIMP-1 marker. The data obtained by us confirm effect of the system of MMPs on formation of hypertrophic remodeling of the heart in HCMP.

[Renin-angiotensin-aldosterone system in hypertrophic cardiomyopathy].

Keeping in mind an important role of renin-angiotensin aldosterone system (RAS) in developing of cardiac remodeling and fibrosis, genetic polymorphisms coding its components could have influence with clinical variants of the course. Biomarkers could appear predictors of adverse. To examine the contribution of the RAS to developing of different hypertrophic cardiomyopathy (HCM) clinical variants of the course we studied 58 patients with HCM and controls comparable by age and gender. All patients were genotyped of gene polymorphisms CMA1 A(-1903)G rs1800875, AGTM235T rs699, AGTR1 A1166C rs5186, CYP11B2-344 T/C rs1799998. Angiotensin-converting enzyme (ACE) and angiotensin II (AII) levels were measured in 40 patients with HCM and 39 controls. We found out that AII were significantly decreased in patients with HCM than in healthy controls. The positive correlation between AII and left ventricle posterior wall (LVPW) were detected. Severity of heart hypertrophy were associated with pejorative genotype of AGT M235T polymorphism and CMA1 A(-1903) polymorphism. Significant association between the AG genotype of CMA1 A(-1903) polymorphism and angina class II-III and ventricular extrasystole of high gradation was observed. Our data not only support the hypothesis that RAAS polymorphisms may influence phenotype, but also allow for create new approaches to possible predicting adverse outcomes.

[Effect of 6-month therapy with perindopril A on structural-functional state of arterial vascular bed in patients with chronic heart failure].

UNLABELLED: In patients with chronic heart failure (CHF) endothelial dysfunction of large vessels is an independent predictor of repeated hospitalizations because of CHF aggravation and cardiac death. OBJECTIVE: To evaluate the effect of perindopril A (5-10 mg/day) on endothelial function of large vessels in patients with CHF. MATERIAL AND METHODS: The study included 30 patients with NYHA class II-III CHF aged 45-70 years. Patients took perindopril A 5-10 mg for 6 months. Patients underwent 24-h BP monitoring, assessment of endothelium vasodilation. RESULTS: In the end of period of treatment hypotensive effect and improvement of endothelial function of large vessels were achieved. We observed increase of flow-mediated vasodilation (FMD) measured by high-frequency ultrasound of brachial artery after reactive hyperemia: FMD1 4.25 (3.9; 4.8) vs FMD2 6.8 (5.1; 7.4), p = 0.003) and enhancement of pulse wave amplitude estimated by photoplethysmography (shear phase - SF): SF1 6.62 (2.4; 8.7) vs SF2 7.36 (3.8; 10.2) (p = 0.003).

[Hypertrophic cardiomyopathy -- modern state of the problem. Issues of epidemiology and nomenclature, genetics and pathophysiology, variants of course and differential diagnosis].

The problem of the study of hypertrophic cardiomyopathy (HCM) has preserved its actuality because of high prevalence (1:500), risk of sudden cardiac death (SCD) in individuals of young able-bodied age. Subject of great interest appear problems of search for additional clinical, instrumental and genetic markers, environmental factors which are capable to influence formation of a clinical variant of HCM course, risk of SCD, and prognosis of HCM. Important problem requiring further study appears to be molecular genetic characteristic of the disease. Integrated nomenclature of various forms and variants of course of HCM is essential for elaboration of tactics of management of patients and assessment of results of multicenter trials.

[Long-term results of radiofrequency catheter ablation of long-lasting persistent atrial fibrillation: five years of follow-up].

AIM: To evaluate long-term results of radiofrequency catheter ablation (RFA) vs. rate-control strategy in patients with long-lasting persistent atrial fibrillation (AF) METHODS: We assessed 5-years results in 66 patients (53.3+/-12.3 years old, 8 women) with long-lasting persistent AF who underwent RFA (ablation group), as well as in age-gender-AF duration-matched patients who were treated with rate-control strategy (rate-control group).The ablation strategy consisted of wide-area circumferential lines around pulmonary veins, roof lines and extensive RFA of the left atrial substrate modification using a three-dimensional mapping system. Incidence of sinus rhythm (SR) maintenance, death, stroke, myocardial infarction (MI), worsening of heart failure (NYHA) were evaluated after 5 years of follow-up. RESULTS: After 5 years of follow up SR was present in 38 (56%) of 42 who were under follow up patients of ablation group and all patients had AF in rate-control group (95% CI 0.02247-0.3598; p=0.0001). Seventeen (27%) patients of ablation group continued to take atniarrhythmic drugs. 29 (44%) patients of ablation group vs. 48 (73%) patients of rate-control group received warfarin (95% CI 0.442-1.1; p=0.046) at five years of follow up. After five years of follow up the incidence of MI, stroke, worsening of heart failure functional class, and death in the ablation/rate-control groups were 0%/7.5% (95% CI 0.05247-0.30898; p=0,006), 0%/9% (95% CI 0.08903-0.32561; p=0.001), 6%/25% (95% CI 0.147-0.894; p=0.006), and 0.02%/0%, respectively. CONCLUSIONS: In patients with long-lasting persistent AF ablation strategy results in stable SR in the majority of patients, and decreased incidence of cardiovascular events compared with rate-control strategy during up to 5 years of follow-up.

[Prediction of severe cardiac complications with the help of myocardial perfusion scintigraphy in patients with residual chronic total occlusion after percutaneous coronary interventions].

Aim of the study was assessment of prognostic value of exercise myocardial perfusion scintigraphy in patients with stable and unstable angina in whom revascularization by percutaneous coronary intervention (PCI) was incomplete and at least one chronic total coronary artery occlusion (CTO) remained after PCI. Between March 2002 and December 2007 569 consecutive patients with multivessel lesions were subjected to SPECT imaging of myocardial perfusion after incomplete revascularization of the myocardium by PCI. At least 1 residual CTO was found in 129 patients (79% men, mean age 64+/-8 years). Primary outcomes were defined as cardiac death or myocardial infarction. Secondary outcomes were registered in 10 (7.9%) and 15 (11.9%) patients, respectively, with moderate and large transitory disturbances of perfusion. Logarithimic range criterion was statistically significant in patients distributed to groups by total estimation of rest in relation to cardiac complications. Univariate and multivariate Cox proportional hazards regression analysis gave additional important information for prediction of severe and nonsignificant cardiac complications when scintigraphic data were added to angiographic and clinical data, left ventricular ejection fraction, and results of treadmill test. Early monitoring with the use of myocardial scintigraphy by SPECT method is associated with increasing prognostic value relative to severe cardiac complications in patients subjected to incomplete revascularization by PCI, and having at least one residual chronic total occlusion.

[Comparative assessment of risk factors and hospital results in male and female patients underwent to coronary artery bypass surgery].

There are controversial data on relatively unfavorable effect of female gender on postoperative mortality of patients underwent to coronary artery bypass grafting (CABG). In order to assess risk factors and hospital outcomes after elective CABG we studied retrospectively data on patients who had undergone CABG in Sani Konuogly medical center (Gasiatep, Turkey) during the period from March 2002 to March 2010. For elimination of unfavorable effect of old age we included into analysis data from patients younger than 65 years. In accordance with study aim all patients (n=2692) were divided into two gender groups 1966 men (mean age 54,01 years) and 726 women (mean age 54.35 years). Diabetes (48.3 and 26.9%; p=0.0001), arterial hypertension (76.6 and 28.4%; p=0.00001), and obesity (50 42%; p=0.03) were more frequent among women while smoking (44.5 and 10.3%; p=0.0001), hyperlipidemia (37.6 and 21.5%; p=0.0002), and history of myocardial infarction (31.3 and 17.3%; p=0.06) were more often registered among men. Mortality was insignificantly higher in women (1.6 and 0.9%; p=0.06). Perioperative Q-wave myocardial infarction was more frequent among men than among women (1.5 and 0.4% respectively; p=0.04). It is necessary to conduct prospective well controlled study for exclusion of gender influences on perioperative outcomes in patients subjected to CABG .

[Contemporary trends of genetic analysis in hypertrophic cardiomyopathy].

Subject of great interest of contemporary scientific community is a search for additional genetic and environmental factors which are capable to influence formation of a clinical variant of the course of hypertrophic cardiomyopathy (HCMP). It has been shown by many works that besides mutations in genes of sarcomere proteins clinical course of HCMP is also affected by modifier genes of the cardiovascular system such as association of polymorphisms RAAS, sympathoadrenal system, NO-synthase, endothelin system, and system of blood coagulation. Attempts have been made to study effects of these polymorphisms on formation of clinical variant of HCMP course and to search for associations with development of unfavorable variants.

[Comparison of effectiveness of radiofrequency catheter ablation of left arterial isthmuses for treatment of postablational perimitral atrial flutter].

AIM: To compare results of radiofrequency (RF) ablation (A) of mitral and inferior septal isthmuses in the left atrium for the treatment of perimitral atrial flutter (AF) in patients with atrial fibrillation previously subjected to RF isolation of pulmonary veins and modification of the left atrial anatomical arrhythmia substrate. MATERIAL AND METHODS: We treated 20 patients (3 women, mean age 57.1+/-9.3 years) with recurrent postablational perimitral AF verified by 3-dimensional reconstruction of left and right atrial activation by nonfluoroscopic mapping and pacing techniques of entrainment into tachycardia cycle. At first stage RFA was carried out in the region of mitral isthmus (its endocardial parts). At second stage RFA was performed in the region of coronary sinus (CS) roof (epicardial portions of the mitral isthmus). At the third stage RFA influences were applied in the region of inferior septal isthmus (endocardial portions of the inferioseptal isthmus). At the fourth stage RFA was applied in the region of roof of proximal CS (epicardial portions of inferioseptal isthmus). RESULTS: Application of RF influences to endocardial parts of the mitral isthmus resulted in sinus rhythm (SR) restoration in 6 cases. Change of length of the tachycardia cycle was noted in 5cases. SR restoration was observed after RFA in the region of the roof of distal CS in 3 cases and change of length of the tachycardia cycle was noted in 2 more cases. RFA of epicardial parts of the inferioseptal isthmus resulted in SR restoration in 3 cases and in increase of atypical AF cycle length in 6 cases. In 12 cases SR was restored during RFA application in the region of the roof of proximal CS parts. RF influences in the region of endocardial (stage 1) and epicardial (stage 2) parts of the mitral isthmus resulted in SR restoration in 9 cases while continuation of RFA in the region of endocardial (stage 3) and epicardial (stage 4) parts of the inferioseptal isthmus led to SR restoration in the remaining 15 cases (p<0.05). CONCLUSION: RFA of endocardial and epicardial parts of the inferioseptal isthmus significantly more often led to termination of perimitral atypical AF in patients previously operated because of atrial fibrillation.

[Remodeling of vascular bed in patients with arterial hypertension: possibilities of diagnostics and correction].

Arterial hypertension determines the remodeling of the vascular bed at all levels, resulting in a high risk of developing cardiovascular complications. Recent studies performed on the basis of evidence-based medicine, demonstrated the high efficiency of the combination drug therapy with perindopril and amlodipine in preventing such complications. This may be due to the positive influence of a fixed combination of these drugs on the parameters of the state of the microcirculatory level of the vascular bed.

[Comparison of the effectiveness of pulmonary veins isolation vs linear radiofrequency ablation in paroxysmal atrial fibrillation patients using either mathematical scanning or clinical approach].

AIM: to compare clinical results of linear ablation vs. PVI approach in patients with paroxysmal AF and to estimate theoretical probability of 4-waves re-entry to eliminate as a results of the both ablative techniques formatting by means left atrial geometry two-dimensional mathematical modeling. MATERIAL AND METHODS: Clinical phase. Study was conducted on 20 pts (6 women, 51,4±13,6 years of age) with paroxysmal AF underwent index RFA. All pts were divided into two age-sex-arrhythmia history duration-antiarrhythmic drugs (AAD)-matched groups. The first group consisted of 10 pts (3 women, mean age - 51,1±11,9, history of arrhythmia - 3,2±1,2 years) in whom ablation strategy consisted of PVI using LASSO technique. The second group concluded of 10 pts (3 women, mean age - 51,1±12,9, history of arrhythmia- 3,1±1,1 years) in whom ablation strategy consisted of wide-area circumferential lines application around pulmonary veins, combined to roof line and mitral isthmus RFA using three-dimensional mapping system. Mathematical phase. As the first step numeric reconstruction of the autowave process in excitable tissues of the left atrium and the simulation of AF was performed. Fitzhugh-Nagumo equation was used for simulation to enabled us to take into account the electrical inhomogeneity of the atria (pulmonary vein ostia). A special scanning method was used for calculating characteristics of autowave processes in a two-dimensional mathematical model of the atrium. As the second step simulation of circular (corresponding to LASSO approach) and linear ablation (corresponding to 3D approach) was performed. RESULTS: Clinical phase. There were no complications associated with RFA. 7 pts of the first group vs 4 pts of the second subgroup had early recurrences of arrhythmia. AAD free sinus rhythm incidence in the first/second groups was 80%/20% at 12 months respectively (p=0,003). Mathematical phase. While circular LASSO-like ablation pattern was used, there was no elimination of 4-waves re-entry turning around the pulmonary veins ostia and vortex waves caused by them in a distributed two-dimensional atrial medium after time period equal to the re-entry period. Thus, the circular ablation formatting does not affect peripulmonary veins re-entry and, therefore, does not suppress AF. In contrast, linear ablation patterns suppress arrhythmias caused by 4-waves re-entry in two-dimensional mathematical modeling of the left atrium. CONCLUSION: Mathematical approach using linear ablation to simulate suppressed 4-waves re-entry more effectively comparing to PVI only. Clinical results are consistent with ablation formatting data obtained by means of 4-waves re-entry simulation in a two-dimensional mathematical modeling of the left atrium.

[Two years experience of the use of a penetration catheter (Tornus) recanalization during percutaneous coronary interventions on chronic total occlusions].

We included in this study 43 patients chronic total occlusions (CTO) subjected percutaneous coronary interventions (PCI) with the use of penetration catheter (Tornus) in 2009-2010. Penetration catheter was applied only in those cases when it was not possible to introduce low profile coronary dilatation catheter into the site of occlusion. After penetration of CTO by a guide wire a channel was formed by a manually rotated penetration catheter. The Tornus catheter was successfully passed into distal part of an artery in 81.4% of cases. In other.

[Echocardiographic parameters in patients with Wolf-Parkinson-White syndrome before and during one year after radiofrequency catheter ablation of accessory atrioventricular junction].

We present in this paper results of assessment of morphofunctional state of myocardium in patients with the Wolf-Parkinson-White syndrome before and during one year after radiofrequency catheter ablation (RFA) of accessory atrioventricular junction (AAVJ) and comparison of them with analogous parameters of the group of healthy volunteers as well as in dependence on electrophysiological properties of AAVJ and its localization. One hundred sixty patients took part in the conducted study: main group comprised 160 patients (80.7%) with WPW syndrome (114 men [81.4%], 26 women [18.6%], mean age 39.5+/-15.3 years), comparison group comprised 20 practically healthy persons (15 men [75.0%], 5 women [25%], mean age 41.9+/-5.3 years). All main group patients were subjected to endocardial electrophysiological investigation and RFA of AAVJ. Transthoracic echocardiography (EchoCG) was carried out in patients of main group before and in 2, 6, and 12 months after operation of RFA of AAVJ, and once in control group. Analysis of parameters of central hemodynamics according to data of transthoracic EchoCG in patients with WPW syndrome before RFA of AAVJ demonstrated that before conduct of operative intervention no significant differences were revealed in the studied parameters compared with analogous characteristics of the clinical comparison group. During whole period of dynamic observation (2, 6, and 12 months after fulfilled RFA of AAVJ) in patients with WPW syndrome the studied parameters of central hemodynamics did not undergo substantial changes compared with initial characteristics. We failed to establish significant differences of EchoCG parameters in patients with WPW syndrome in dependence on electrophysiological properties of AAVJ (concealed, manifest) and on AAVJ localization (right, left, septal). According to EchoCG data in patients with WPW syndrome so called "minor" anomalies of development of connective tissue of the heart were diagnosed in 69 (49.3%) patients while in control group - in 2 (10%) patients.

[Parameters of central hemodynamics in patients with typical atrial flutter before and after radiofrequency catheter ablation].

We present here results of dynamic assessment of morphofunctional state of the myocardium by the method of transthoracic echocardiography (EchoCG) in patients with paroxysmal and chronic forms of typical atrial flutter (AF) before and during one year after radiofrequency catheter ablation (RFA) of cavo-tricuspid isthmus, and comparison of them with analogous parameters in a group of healthy volunteers. Eighty six patients participated in the study. Group 1 comprised 48 patients suffering from paroxysmal form of typical AF including 42 (87.5%) men, 6 (12.5%) women (mean age 50.9+/-18.1 years). Group 2 consisted of 18 patients with permanent form of typical AF including 16 (88.9%) men and 2 (11.1%) women (mean age 53.6+/-9.4 years). The group of clinical comparison comprised 20 practically healthy persons (mean age 41.9+/-5.3 years) without structural pathology from the side of cardiovascular system including 15 (75.0%) men and 5 (25.0%) women. All group 1 and 2 patients were subjected to RFA of typical AF. In patients of groups 1 and 2 EchoCG was carried out before and in 2, 6, and 12 months after operation of RFA, in control group--once. Analysis of parameters of central hemodynamicas in patients with typical AF detected significantly lowered values of characteristics of myocardial contractile function compared with the group of practically healthy subjects. But these parameters did not differ significantly between patients with different variants of clinical course of arrhythmia. It was established that in patients with typical AF in 2 months after conduct of procedure significant improvement of myocardial inotropic function and diminishment of dimensions of cardiac chambers was noted. In 6 months after fulfilled RFA values of investigated parameters approximated analogous parameters in the group of clinical comparison.

[Comparative analysis of antioxidant activity of nebivolol in patients with chronic heart failure with and without concomitant type 2 diabetes].

UNLABELLED: Consistent neurohormonal activation of sympatho-adrenal system in patients with chronic heart failure (CHF) and hyperglycemia contributes to development of oxidative stress--one of the most important pathogenetic mechanisms of endothelial dysfunction. PURPOSE: To study the impact of nebivolol concerning modification of clinical and hemodynamic indicators and parameters of oxidative stress in patients with CHF and with or without concomitant diabetes mellitus type 2 (DM2). MATERIAL: Nebivolol was used in complex therapy of CHF in 82 patients, suffering from NYHA class I - III CHF (EF < 50%) of ischemic genesis with or without comorbid DM2, average age 63.2 +/- 8.2 years. RESULTS: After 8 months of therapy significant improvement of clinical status was observed in both groups, tolerance to physical activity increased (significant reduction of average class of CHF in the group with DM2 from 2.5 +/- 0.58 to 2.125 +/- 0.71, p = 0.001, and in the second group from 2.3 +/- 0.5 to 1.9 +/- 0.4, p = 0.01). We also noted in both groups increase of plasma oxidative resistance (reduction of intensity of fast flash in lipid peroxidation h from 7 to 6 mm, p = 0.016, and from 8 to 6 mm, p = 0.03, respectively) and increase of antioxidant plasma protection (increase of SH-groups from 154.19 to 182.4 mmol/1, p = 0.00035, and from 176 to 205, p = 0.004, respectively). CONCLUSION: Nebivolol is a modern neurohormonal modulator, which contributes to reverse evolution of oxidative changes in patients with CHF and hyperglycemia.

[Pulmonary arterial hypertension: changing approaches to management].

The review is devoted to different aspects of pulmonary arterial hypertension (PAH); new classification of PAH is published in 2010. There are idiopathic PAH and PAH associated with other diseases. Current guidelines recommend to treat PAH only after the verification of diagnosis with right heart catheterization and acute tests with vasodilators. Patients-reactors should be treated with calcium antagonists. The following drugs related to one of three categories should be used in PAH: (1) prostanoids (epoprostenol, iloprost et al.); (2) blockers of endothelin receptors (bosentan, ambrisentan, sitaxsentan); (3) phosphodiesterase 5 type inhibitors (sildenafil, tadalafil et al.) In majority of cases the combined treatment is used, usually the combination of bosentan and sildenafil is used.