[Clinical guidelines for the diagnosis and treatment of pulmonary hypertension].

Pulmonary hypertension (PH) is a group of diseases characterized by progressive increases in pulmonary vascular resistance and pulmonary artery pressure, which results in right ventricular heart failure and sudden death. Based on the current version of the guidelines for PH diagnosis and treatment, adopted by the experts of the European Society of Cardiology and the European Respiratory Society in 2009, and on the data of Russian and foreign clinical trials, the Russian experts elaborated clinical guidelines for PH in 2013. The latter consider the current classifications of PH, the specific features of its pathogenesis, and its diagnostic algorithm. The section dealing with drugs for maintenance therapy discusses data on the use of oral anticoagulants, diuretics, cardiac glycosides, and oxygen therapy. PH-specific therapy includes calcium antagonists, prostanoids, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Surgical procedures for PH involve atrial septostomy, thromboendartectomy, and lung or heart-lung transplantation. A treatment algorithm is proposed for PH patients. The current medicinal approaches using specific therapy agents and their combinations offer new promises for the effective treatment of patients with PH and improve its prognosis.

[Pulmonary hypertension in Russia: the first results of the national register].

AIM: To investigate the demographic and clinical characteristics of patients with pulmonary hypertension (PH) and chronic thromboembolic pulmonary hypertension (CTEPH), regions of their residence, the specific features of diagnosis and drug therapy, and the patients' survival within the framework of a multicenter open-label prospective study. SUBJECTS AND METHODS: The study enrolled patients over 18 years of age with PH classified as Group 1 (PH) and Group 4 (CTEPH). The follow-up was made in 9 expert centers of Russia on January 1 to February 28, 2014. The data of patients with PH and CTEPH were electronically entered at the register website: www.pul-hyp.medibase.ru. RESULTS: The study included 242 patients (183 women and 59 men) from 44 regions of the Russian Federation. PH of different etiologies was present in 79.3%, including 43.8% with idiopathic PH, 28.5% with congenital heart disease-associated PH, 6.2% with diffuse connective tissue-associated PH, 0.8% with hereditary PH; 20.7% were diagnosed with CTEPH. The patients' mean age at the inclusion in the register was 43.2 ± 15.8 years; the median PH duration was 4.4 years (1.4 to 10.6%). The distance covered during a 6-minute walk test was 395.2?111.1 m; the Borg dyspnea index was 3.4 ± 1.4 scores and the functional class was 2.5 ± 0.8. After right cardiac catheterization, the mean pulmonary artery pressure was 53.1 ± 19.5 mm Hg; cardiac output, 3.8 ± 1.2 l/ min; cardiac index, 2.1 ± 0.6 l/min/m2; pulmonary vascular resistance, 1105 ± 677.6 dyn·sec/cm5. A positive acute pharmacological test was seen in 16.3% of the patients. The most common comorbidity was erosive ulcerative lesion of the gastrointestinal tract (23.5%), hypertension (16.9%), and obesity (16.5%). 66% of the patients received PH-specific therapy: sildenafil (51.6%), bosentan (20.9%), or iloprost (7%); 7.4% of the patients were observed within the framework of clinical trials, 17.7% received combined therapy for PH: 16.3 and 1.4% had dual- or triple-component therapy, respectively; 55.8% of the patients took calcium antagonists, 61.4% had diuretics, 85.6% had antithrombotic drugs. The survival rates were 98% in the first year of the follow-up and 90.1% by the end of 2013. CONCLUSION: The formation of a national register of patients with PH and CTEPH makes it possible to introduce current approaches to diagnosing and treating the patients of this category and to evaluate the efficiency and quality of rendered medical care and will contribute to the estimation of required health care volumes and the expenditure of public health resources.

[Effect of bosentan on the clinical status and cellular immunity of patients with idiopathic pulmonary hypertension].

AIM: To study the effect of bosentan on the clinical status and cellular immunity of patients with idiopathic pulmonary hypertension (IPH). SUBJECTS AND METHODS: The study enrolled 35 patients with Functional Class (FC) II and IV IPH who had received conventional therapy for 3 months. All the patients took bosentan 125 mg/day for 4 weeks. Then they were randomized to have bosentan 125 or 250 mg/day (Groups 1 and 2). FC was assessed and 6-minute walk test (6MWT), transthoracic echocardiography (EchoCG), and right heart catheterization (RHC) were performed at baseline and after 12 weeks. Peripheral blood lymphocytes were immunophenotyped and the functional activity of neutrophils was determined by their ability to absorb latex particles at baseline and following 3 and 12 weeks. RESULTS: After 12 weeks of treatment, both groups showed a statistically significant increase in the distance covered during the 6MWT. The Borg index and FC also decreased statistically significantly. EchoCG demonstrated a statistically significant reduction in systolic pulmonary artery pressure (SPAP) in Group 1; and in Group 2, SPAP was lower at baseline and remained substantially unchanged (it statistically significantly decreased as evidenced by RHC). Bosentan statistically significantly diminished pulmonary vascular resistance in both groups. No adverse reactions were noted. At baseline, the patients showed a statistically significant elevation in NKT-like lymphocytes up to 10.79 +/- 6.2%. The other indicators of peripheral blood lymphocyte phenotyping did not exceed the normal range. The count of NKT-like lymphocytes remained significantly above the normal levels throughout the follow-up in both groups and slightly dropped in Group 1 patients only after 12 weeks of treatment. In Group 2, the level of CD3+CD25+ lymphocytes rose as compared to the normal levels at 3 and 12 weeks of treatment. At 3 weeks of treatment, there was a statistically significant difference between the groups in phagocytic number. CONCLUSION: Bosentan treatment statistically significantly improves the clinical status of patients with IPH and it is characterized by good tolerability. Bosentan does not exceed the normal count of peripheral blood NKT-like lymphocytes, but it has a direct or indirect positive effect on the B-lymphocytic component of the immune system in patients with IPH.

[Diagnostic capabilities of single-photon emission computed tomography/computed tomography in the evaluation of perfusion disorders in pulmonary hypertension].

OBJECTIVE: to study the diagnostic capabilities of single-photon emission computed tomography/computed tomography (SPECT/ CT) in the evaluation of lung perfusion in pulmonary hypertension (PH). SUBJECT AND METHODS: Ten patients with pulmonary hypertension were examined. Its diagnosis was verified in accordance with the Russian guidelines for the diagnosis and treatment of PH, by conducting a set of studies involving right heart catheterization. CT angiopulmonography was carried out in all the patients. At the same time all the patients underwent a radiological study on a combined SPECT/CT scanner with the intravenous injection of the radiotracer 9mTc-MAA (technetium-99m-labelled macroaggregated albumin) with an activity of 2-4 mCi. RESULTS: CT-angiopulmonography revealed no thrombi in the pulmonary artery lumen in 7 patients and confirmed the diagnosis of pulmonary thromboembolism (PTE) at the level of segmental vessels in 3. SPECT/CT examination identified 5 cases of non-thromboembolic PH and 5 cases of PTE with consideration for SPECT perfusion defects and no visible lung tissue (fibrous or other) changes on a CT scan. It should be noted that the 5 patients diagnosed as having PTE included 2 patients in whom PTE had not previously been diagnosed at CT angiopulmonography. This may be due to that this technique cannot always clearly visualize thrombi in the pulmonary vessel lumen at a subsegmental level. CONCLUSION: The inivestigations have indicated that, by clearly ivisualizing pulmonary aanatomy, morphology, and function, combined SPECT/CT imaging is a valuable diagnostic tool in detecting lung pathology.

[Possibilities of rational combination antihypertensive therapy: results of HEMERA international clinical trial].

AIM: To evaluate the efficiency and safety of two treatment regimens using ramipril or losartan in combination with hydrochlorothiazide (HCT) and amlodipine in grade 1-2 arterial hypertension (AH). SUBJECTS AND METHODS: The prospective, international, multicenter, randomized, open-label, controlled trial with parallel groups included 347 AH patients in Russia (n = 166), Croatia, and Ukraine. The follow-up was 12 weeks in patients not receiving antihypertensive therapy (AHT) and 13 weeks in those who had previously received AHT with regard to a washout period. The basis for two treatment regimens was ramipril or losartan. If no target blood pressure (BP) was achieved, amlodipine or HCT was added at week 4 and a third antihypertensive drug (AHD) was used 8 weeks later. RESULTS: At the inclusion, clinical BP was 157.64/95.5 mm Hg in 332 (61%) AH patients aged 55.9 +/- 11 years. At week 4 of monotherapy with ramipil 5 mg or losartan 50 mg, BP was reduced to 141.9/87.4 mm Hg. Addition of a second AHD further lowered BP to 131.8/81.9 mm Hg (to 127.6/79.7 at 12 weeks of treatment; p < 0.001). After 4 weeks of treatment with ramipril 5 mg or losartan 50 mg, 35% of the patients achieved target BP. At weeks 8 and 12, double or triple AHT increased the number of patients achieving the target level up to 75 and 94%, respectively. When losartan was used as monotherapy, about one third of the patients achieved target BP; 20 and 22% of the patients required the addition of a second AHD (HCT and amlodipine, respectively). Only 10% of the patients needed to take a combination of three AHDs. Nearly one third of the patients achieved target BP during monotherapy with losartan or ramipril. Double AHT involving ramipril or losartan in combination with the diuretic or amlodipine was used in 18 and 20% and in 22 and 24% of the patients, respectively. 28 and 19% of the patients received triple therapy including ramipril or losartan, amlodipine, and HCT. The most common adverse reactions were dizziness (2.4%), fatigue (1.8%), and coughing (1.2%). CONCLUSION: In the patients with grades 1-2 AH, the treatment regimens using basic therapy with ramipril or losartan proved to be highly effective and allowed target BP to be achieved in 94% of cases. Both treatment regimens were comparable in view of safety; slight side effects occurred rarely (in less than 2.5% of the patients) and required that the treatment should not be discontinued.

[Possibilities of using levosimendan in patients with idiopathic pulmonary hypertension].

AIM: To evaluate the efficiency and safety of intravenous infusion of levosimendan in patients with idiopathic pulmonary hypertension (IPH) and its clinical, hemodynamic, and neurohumoral effects. SUBJECTS AND METHODS: The study included 9 patients (mean age 31.8 +/- 8.7 years) with Functional Class III and IV IPH and severe right ventricular failure (RVF). Levosimendan was administered as dropwise intravenous infusion. The patients' general condition, blood pressure, heart rate, and 6-minute walk test results were assessed at baseline and 24 hours after levosimendan infusion, and then following 12 weeks. The time course of changes in blood neurohumoral mediators was determined and transthoracic echocardiography performed. RESULTS: At 24 hours after initiation of levosimendan infusion, there were substantial reductions in pulmonary artery systolic pressure, mean pulmonary artery pressure, mean right atrial pressure, and pulmonary vascular resistance. There was a significant increase in exercise tolerance. The blood exhibited lower norepinephrine and NT-proBNP and higher epinephrine concentrations. At 12 weeks after termination of levosimendan infusion, the improved functional status was preserved in the patients with IPH. There were no noticeable changes in the achieved key hemodynamic parameters. Only one patient needed re-administration of the drug 12 weeks later. The achieved changes in vasoactive mediators were retained 12 weeks following levosimendan infusion. Levosimendan treatment was not followed by clinically relevant adverse reactions requiring infusion termination and therapy discontinuation. CONCLUSION: 24-hour intravenous levosimendan infusion in patents with FC III-IV IPH and severe RVF causes positive changes in the key hemodynamic parameters and neurohumoral status of the patients and promotes stabilization in those with IPH at 12-week follow-up.

[Use of nebivolol in patients with idiopathic pulmonary hypertension: results of the pilot study].

AIM: To study the impact of 24-week therapy with nebivolol in a dose of 5 mg/day on the clinical and functional status of patients with idiopathic pulmonary hypertension (IPH), echocardiographic parameters, and blood levels of vasoactive mediators and nitric oxide (NO) metabolite. SUBJECTS AND METHODS: During continuous standard therapy comprising dihydropyridine calcium antagonists, warfarin, and diuretics, 12 patients with IPH and functional class (FC) II-III received nebivolol in a dose of 5 mg/day for 24 weeks. According to the data of right heart catheterization, all the patients had a positive acute pharmacological test with a vasodilator (NO). Six-minute walk test (6'WT), estimation of the Borg dyspnea index (BDI) and FC, transthoracic echocardiography (EchoCG), and measurements of the levels of NO metabolites, endothelin-1, (ET-1), thromboxane B2 (TxB2), and 6-keto-prostaglandin F1alpha (6-ketoPG F1alpha) were done at baseline and after 12 and 24 weeks of the therapy. RESULTS: Following 24-week nebivolol treatment, there was a statistically significant increase in 6'WT distance (from 473 +/- 47.6 to 516.7 +/- 58.4 m; p < 0.0001) and a drop in BDI (from 3.4 +/- 2.2 to 1.1 +/- 0.7; p < 0.05) and FC (from 2.9 +/- 0.4 to 1.7 +/- 0.2; p < 0.05). Doppler EchoCG showed that pulmonary artery systolic pressure statistically significantly decreased (91.6 +/- 30 to 78.3 +/- 39 mm Hg; p = 0.05) at 12 weeks and slightly increased up to 83.2 +/- 32.4 mm Hg at 24 weeks. After 24-week treatment, the anteroposterior dimensions of the right ventricle (RV) statistically significantly reduced (from 4.4 +/- 0.6 to 3.8 +/- 1.2 cm; p < 0.05). The other EchoCG parameters remained substantially unchanged. There was a statistically reduction in the level of ET-1 (from 2.99 +/- 1.1 to 2.17 +/- 0.8 micromol/l; p < 0.05). The concentrations of 6-ketoPG Fla, TxB2, and NO metabolite remained substantially unchanged at 24 weeks of treatment with nebivolol. There were no adverse reactions requiring that the dose of the drug be discontinued or reduced. Heart rate tended to be lower at a 24-week follow-up. All the patients continued taking nebivolol after completion of the study. CONCLUSION: Therapy with nebivolol in a dose of 5 mg/day for 24 weeks led to a significant functional improvement in the patients with IPH and reductions in RV dimensions and blood ET-1 levels. The therapy did not cause adverse reactions.

[Changes in orthogonal ECG in hypertensive patients taking different antihypertensive therapy].

AIM: To ascertain changes in orthogonal ECG in hypertensive patients taking different antihypertensive treatment. MATERIAL AND METHODS: Orthogonal ECG parameters and those of 24-h blood pressure monitoring (BPM) were examined before and after antihypertensive treatment with different drugs in 95 hypertensive patients aged 47 +/- 1 years. Of them, 14 patients received trandolapril+verapamil SR for 2 months, 13 patients--candesartan for 3 months, 25 patients--ramipril for 5 months, 26 patients--carvedilol for 4 months, 10 patients--atenolol for 8 months, 7 patients--doxasozine for 5 months. RESULTS: 24-h BPM parameters improved in all the groups. Initially, conventional ECG evidence on left ventricular hypertrophy was not seen in 86% patients. Dynamics of orthogonal ECG showed that parameters which increase in left ventricular hypertrophy decrease in response to treatment in patients with baseline values above the median. Parameters G and Gx, which in left ventricular hypertrophy diminish, rise significantly in patients with baseline values under median due to therapy. Treatment with impact on renin-angiotensin system reduced voltage parameters of orthogonal ECG, improved G characterizing repolarisation. Treatment with adrenoreceptors blockers reduced IADI. CONCLUSION: The analysis of parameters of orthogonal ECG reveals positive dynamics in response to treatment in patients with insignificant changes on ECG in short follow-up. Drugs of different groups change different parameters of orthogonal ECG.

[Tissue myocardial Doppler echocardiographic evaluation of right ventricle function and the level of natriuretic peptides in patients with pulmonary hypertension of various etiologies].

AIM: To study structural and functional changes of the right ventricle (RV) in patients with pulmonary hypertension (PH) of various etiologies and to assess an association of these changes with the levels of natriuretic peptides (NP). SUBJECTS AND METHODS: The study enrolled 102 patients with PH (29 with idiopathic PH (IPH), 15 with PH in the presence of chronic pulmonary thromboembolism (PTE), 18 with HP associated with scleroderma systematica (SS), 13 with PH in the presence of chronic obstructive pulmonary disease (COPD), 15 with PH associated with congenital heart disease, 12 with residual PH and a control group of 21 healthy volunteers. Conventional echocardiography (EchoCG) and tissue myocardial Doppler (TMD) EchoCG were performed. The plasma levels of brain NP (BNP) and atrial NP were measured. RESULTS: Conventional EchoCG revealed the most significant remodeling of the heart and pulmonary artery in patients IPH and the least one in those with COPD. TMD findings suggest that RV diastolic function was most and less significantly impaired in patients with IPH and in those with COPD, respectively, and corresponded to the level of NT-proBNP in patients with PH. In patients with PTE with SS, RV diastolic dysfunction (DD) dominated over systolic ones, the functional class and the level of NT-proBNP being comparable with those in patients with ILH. TMD could reveal RV DD in a larger proportion of patients with PH (in all groups) than could Doppler EchoCG. The ratio of the maximum RV early filling velocity to RV tricuspid valve (TV) ring peak movement rate in early diastole (TV E/EM) corresponded to the levels of NP and the magnitude of cardiac remodeling in patients with PH. ROC analysis revealed the intrinsic separating values of TV E/Em from the mitral ring (MR E/Em) which allowed the patients with higher NT-proBNP levels to be identified with a high sensitivity and a high specificity. An aggregate of factors, such as age, right atrial volume, and PA systolic pressure as shown by conventional EchCG and TMD readings, identified patients with PH and elevated NT-proBNP with 73.3% sensitivity and 90.7% specificity. CONCLUSION: TMD has advantages over conventional EchoCG in the detection of RV DD associated with elevated NP levels in patients with PH.

[Using nonselective endothelin receptor antagonist in idiopathic pulmonary hypertension].

Idiopathic (primary) pulmonary hypertension (IPH) is a rare disease of unknown etiology, which is characterized by elevated pulmonary artery pressure, increased total pulmonary vascular resistance, frequently a malignant course with evolving right ventricular decompensation, and a fatal outcome. The diagnosis of IPH is established on the increments in the mean resting and exercise pulmonary artery trunk pressure by more than 25 and more than 30 mm Hg at rest and during exercise, respectively, with a normal pulmonary artery wedge pressure. Endothelin receptor antagonists (ERA) are one of the effective classes of drugs for the treatment of patients with IPH. Bosentan is the first drug from the ERA class that blocks the receptors of both types and that has been recommended by the WHO to treat patients with functional class II-IV pulmonary hypertension. The described case demonstrates the possibility of concomitantly using bosentan in a female patient with IPH shortly after ineffective treatment with a calcium antagonist.

[Diagnosis and treatment of pulmonary heart before and after hospitalization]. / Diagnostika i lechenie legochnogo serdtsa na dogospital'nom i gospital'nom étapakh.

Prevalence of pulmonary heart among patients with cardiovascular pathology is 5%. Clinical picture of pulmonary heart comprises symptoms of underlying disease and signs of pulmonary and cardiac failure. The following instrumental methods of investigation are very helpful for diagnosis of pulmonary heart: chest roentgenography, electrocardiography, echocardiography, pulmonary function testing, computer tomography. Pulmonary heart should be diagnosed during ambulatory examination. Hospitalization of patients with pulmonary heart is dictated by severity of clinical condition or presence of diagnostic problems. Radionuclide pulmonary scintigraphy, pulmonary angiography, right heart catheterization, lung biopsy can be carried out in hospital. Treatment should be directed at underlying disease, lowering of pulmonary artery pressure, alleviation of respiratory and cardiac failure.

[The use of aspirin in patients with primary pulmonary hypertension]. / Primenenie aspirina u bol'nykh s pervichnoi legochnoi gipertoniei.

AIM: To investigate aspirin efficacy in patients with primary pulmonary hypertension (PPH) after a course of prostaglandin E-1 (PE) treatment. MATERIALS AND METHODS: 12 PPH patients (mean age 35.7 +/- 2.5 years) having the disease for 6.7 +/- 1.1 years were assigned to a 6-month course of aspirin treatment in a dose 100 mg/day in combination with calcium antagonist isradipin. All the patients have previously undergone 21-day PE treatment (vasaprostan). Before and after the treatment, the patients were examined clinically and biochemically. RESULTS: As shown by ECG, chest x-ray, bicycle exercise, aspirin used in combination with isradipin led to stabilization of the disease. Platelet aggregation also remained stable, thromboxan B2 and endothelin-1 levels went down. Low doses of aspirin allowed to avoid side effects typical for this drug. CONCLUSION: Use of aspirin in a dose 100 mg/day in combination with calcium antagonists to treat primary pulmonary hypertension is justified.

[Activity of renin-angiotensin-aldosterone system (RAAS) and vasopressin level in patients with primary pulmonary hypertension]. / Aktivnost' renin-angiotenzin-al'dosteronovoi sistemy i uroven' vazopressina u patsientov s pervichnoi legochnoi gipertoniei.

AIM: Assessment of RAAS and vasopressin in patients with primary pulmonary hypertension (PPH). MATERIALS AND METHODS: Activity of plasma renin (APR), angiotensin-converting enzyme (ACE), plasma levels of angiotensin II (AII) and vasopressin (VP), serum concentration of aldosteron (AS) were measured by radioimmunoassay and enzyme immunoassay in 21 PPH patients with circulatory failure (age 34.7 +/- 2.1 years), 11 patients with NYHA functional class II-III, 10 with class IV, and 10 control subjects (age 29.8 +/- 1.5 years). RESULTS: Compared to controls, 21 PPH patients had elevated RAAS parameters: APR up to 3.52 ng/ml/h (p < 0.05), activity of ACE up to 43.13 units, AII level up to 33.93 ng/ml (p < 0.01), AS up to 468.86 ng/ml (p < 0.01), VP up to 5.26 ng/ml (p < 0.001). Circulatory failure progression resulted in activation of all the RAAS components. This and VP activation was the greatest in PPH patients with ACE > 5 ng/ml/h. PPH patients with mean pressure in the pulmonary artery higher than 60 mm Hg demonstrated higher ARP, AS, VP, AII, ACE than those who had this pressure under 60 mm Hg. CONCLUSION: PPH patients display a noticeable activation of RAAS and VP. This activation seems to be secondary as the changes increase with elevation of the pressure in the pulmonary artery and aggravation of circulatory insufficiency. Plasma renin activity determines the degree of RAAS activation as a whole. The discovered activation of RAAS in PPH gives grounds for doubts in the validity of using ACE inhibitors in the treatment of PPH.