May Measurement Month 2017 in Russia: hypertension treatment and control-Europe

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative by the International Society of Hypertension aimed at raising awareness of high BP and to act as a temporary solution to the lack of screening programs worldwide. The most recent publication compared data from three surveys performed in Russian population aged 25-64 showed that the prevalence of hypertension increased by approximately 20% from 2003 to 2013. This study presents screening data collected in 2017 though the MMM17 initiative in Russia. An opportunistic cross-sectional survey of volunteers aged ≥18 was carried out in May 2017 in 19 Russian cities. Blood pressure measurement, the definition of hypertension, and statistical analysis followed the standard MMM protocol. The recruitment of MMM17 participants in Russia occurred in shopping malls, colleges and universities, supermarkets, business centres, parks, and squares. Russian young cardiologists as an official section of Russian Society of Cardiology was actively involved. A total of 5660 individuals were screened. After multiple imputation, 2709 (47.9%) had hypertension. Of individuals not receiving antihypertensive medication, 753 (20.3%) were hypertensive. Of individuals receiving antihypertensive medication, 1094 (55.9%) had uncontrolled BP. Comparing with the worldwide results of MMM17 screening, Russian participants had a higher proportion of hypertension, comparable antihypertensive prescription rate, and worse hypertension control. Thus, the MMM17 project appears to be an important step in evaluating hypertension burden in Russia and emphasizes the further need to improve hypertension awareness, treatment, and control

ИННОВАЦИЯ В МЕДИКАМЕНТОЗНОМ ЛЕЧЕНИИ ПАЦИЕНТОВ С ЛЕГОЧНОЙ АРТЕРИАЛЬНОЙ ГИПЕРТЕНЗИЕЙ И НЕОПЕРАБЕЛЬНОЙ, ПЕРСИСТИРУЮЩЕЙ/ РЕЗИДУАЛЬНОЙ ФОРМАМИ ХРОНИЧЕСКОЙ ТРОМБОЭМБОЛИЧЕСКОЙ ЛЕГОЧНОЙ ГИПЕРТЕНЗИИ: СТИМУЛЯТОР РАСТВОРИМОЙ ГУАНИЛАТЦИКЛАЗЫ – РИОЦИГУАТ

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are diseases, diagnosed at a late stage with functional class III or IV according to World health organization (WHO). PAH and CTEPH leads to severe right heart failureand ultimately, death. The modern researches aim at exploring the potential therapeutic targets, as at developing new drugs that can affect the previously set target. Riociguat is the first in a new class of soluble guanylatecyclase stimulators. The analysis of main researches, which reflect the evidence of riociguat efficiacy and safety in patients with PAH and inoperable, persistent/recurrent CTEPH, is presented in this rewiew.Легочная артериальная гипертензия (ЛАГ) и хроническая тромбоэмболическая легочная гипертензия (ХТЭЛГ ) являются заболеваниями, чаще всего диагностируемыми на поздней стадии, с функциональным классом (ФК) легочной гипертензии III или IV по классификации Всемирной организации здравоохранения (ВОЗ), и приводящими к тяжелой правожелудочковой недостаточности с последующим летальным исходом. Cовременные исследования направлены на изучение фундаментальных терапевтических мишеней и на создание новых лекарственных препаратов, воздействующих на ранее установленные мишени. Риоцигуат – первый представитель нового класса лекарственных препаратов-стимуляторов растворимой гуанилатциклазы (рГЦ ). В обзоре проводится анализ основных исследований, в которых оценивалась эффективность/безопасность риоцигуата у пациентов с Л АГ и неоперабельной, персистирующей/резидульной формами ХТЭЛГ

ASPECTS OF MODERN COMBINATION SPECIFIC THERAPY OF PULMONARY ARTERIAL HYPERTENSION: THE PROS AND CONS

The treatment algorithm for pulmonary arterial hypertension (PAH) includes three main stages: general measures; induction drug therapy; combined drug therapy and intervention  methods  for patients  who fail to respond adequately  to induction therapy. The specific therapy includes endothelin receptor antagonists  (ARE), prostanoids, phosphodiesterase type 5 inhibitor (PT5I) and soluble guanylate cyclase stimulators (rGCS). The combined specific therapy, which means the simultaneous  use of more than one class of specific drugs, is an attractive approach, taking into account the malignancy and complexity of PAH pathogenesis, and the successful experience  in using medication combinations in the treatment of systemic arterial hypertension  and heart failure. The article shows that down to recent times the issues  of necessity and timeliness of the combined PAH-specific therapy, and the choice of rational combinations, require further study. The COMPASS-2 randomized study did not prove that the adding bosentan to the stable sildenafil therapy is more effective than sildenafil monotherapy, and extends  the time to the development  of the first morbidity event/ mortality in PAH patients. The meta-analysis  of H.l. Liu et al. showed that the monotherapy leads to a significant reduction in mortality in patients with PAH, improvement of functional and hemodynamic status compared with the placebo or standard therapy. The combined therapy is associated  with a significant improvement in functional and hemodynamic status, but the mortality of patients did not decrease reliably compared with the monotherapy. The combined therapy is associated with a significant increase in cancellation frequency due to adverse effects as compared with the monotherapy.The concept  of the advantage  of rGC stimulants  over PT5I was studied  in an international multicentre  open-label  IIIb phase  RESPITE (Riociguatum Сlinical Effects Studied in Patients With Insufficient Treatment Response  to PDE5) study of the safety and efficacy of the transition from the PT5I therapy to riociguatum therapy in patients with PAH who did not achieve the treatment goals when using PT5I. The study included patients with functional capacity III (WHO),  a distance of 165–440 m in the 6-min walk distance (6MWD), cardiac index <3.0  l/min/m2, pulmonary vascular resistance>  400  dyne*s *cm-5, the average pressure in the pulmonary artery > 30  Hg mm despite receiving stable doses  of sildenafil in the highest  dose of 80 mg 3 times a day or tadalafil in the highest  dose of 40 mg 1 once a day. A part of patients also received an endothelin  receptor antagonist  (ERA). The clinical endpoints included changes in 6MWD, hemodynamics from baseline  to Week 24  of therapy, WHO FC, the NT-proBNP levels,  the quality of life evaluation, and % patients  developing  clinical worsening from baseline to Week 12 and 24 of therapy.After cancellation of PDE5i, the patients received riociguat. The interim analysis of the study showed that 50% of patients had improved to WHO FC II from III, increased 6MWD from 353  ± 78 to 392  ± 112  m (n = 25); improved hemodynamic parameters and NT-proBNP levels by Week 24, which may indicate that patients with an insufficient response  to PDE5i therapy may benefit  from a transition to riociguat. This approach should be further investigated,  as suggested by 2016 Russian Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension

New perspectives in pulmonary arterial hypertension treatment: 2009 European recommendations

Pulmonary arterial hypertension (PAH) is one of the most severe cardiovascular disorders. It is characterised by progressing clinical course, right ventricular failure development, and very poor prognosis. In September 2009, the European Society of Cardiology and the European Respiratory Society released a new revision of clinical recommendations on pulmonary hypertension (PH) diagnostics and treatment. The recommendations review the evidence for supportive therapy (oral anticoagulants, diuretics, digitalis medications, and oxygen), specific therapy (calcium antagonists, prostanoids, endothelin receptor antagonists, and phosphodiesterase 5 inhibitors), and surgery. Modern pharmaceutical approaches, including specific therapy medications and their combinations, could increase the effectiveness of PH treatment and improve PH prognosis. The meta-analysis of 23 randomised trials demonstrated that in PAH patients, specific therapy (mean duration 14,3 weeks) decreased mortality and hospitalisation rates by 43% and 61%, respectively. In other countries, specific therapy medications are included into targeted treatment programs. In Russia, only bosentan is officially recommended for PAH treatment, while the registration of inhaled iloprost and sildenafil citrate is expected in the nearest future

INHALED NITRIC OXIDE: CLINICAL EFFECTS AND INFLUENCE ON THE PROFILE OF INFLAMMATORY MARKERS IN PATIENTS WITH IDIOPATHIC PULMONARY HYPERTENSION

Aim. To study the effect of treatment with inhaled nitric oxide (iNO) on the clinical status of patients with idiopathic pulmonary hypertension (IPH), and the profile of proinflammatory cytokines in peripheral blood. Material and methods. Patients with IPH (n=48) were included into the study. Evaluation of the IPH functional class (FC), the 6-minute walk test (6MWT) with the assessment of the Borg index, echocardiography , laboratory tests [blood count, evaluation of high-sensitivity C-reactive protein (hsCRP), interleukins (IL), interferon-γ (INFγ), tumor necrosis factor a (TNFa), macrophage inflammatory protein a (MIP1 a), soluble adhesion molecules (sICAM-1, sVCAM-1) in peripheral blood] were performed at baseline and on day 21 of iNO therapy course. The iNO course 40 ppm during 5 hours a day for 21 days was carried out additionally to the standard IPH therapy under the toxicity control by the PrinterNOx (England). Results. Increase in exercise tolerance, improvement of IPH FC (from 3.35±0.52 to 2.71±0.56; p=0.008), reduction in systolic pulmonary artery pressure (SPAP) by Doppler echocardiography (from 96.23±23.65 to 82.36±20.92 mmHg; p<0.05) were found in IPH patients as a result of iNo therapy. The significance of inflammation in IPH pathogenesis was confirmed due to assessment of the initial levels of proinflammatory cytokines. iNO therapy resulted in significant decrease in proinflammatory cytokines-IL-1β, IL-6, IL-8, TNFa levels. iNO induced significant dynamics of IL-1β and sVCAM in patients with IPH FC II. It reduced IL-8 and TNFa and increase INFγ (p<0.05) in patients with IPH FC III-IV. Changes in IL-1β and sVCAM levels (ΔIL-1β and ΔsVCAM) by the 21 day of iNO therapy in comparison with these at baseline correlated with ΔSPAP , and ΔIL-6 correlated with ΔFC and Δ6MWT distance (30.5 [21.0; 53.0] m; p<0.001). This allows considering these indicators as markers of iNO treatment efficacy. Conclusions. 21-day iNO therapy in IPH patients resulted in significant improvement of functional status, reduce SPAP and caused the positive dynamics of proinflammatory cytokines blood levels

INHALED NITRIC OXIDE: CLINICAL EFFECTS AND INFLUENCE ON THE PROFILE OF INFLAMMATORY MARKERS IN PATIENTS WITH IDIOPATHIC PULMONARY HYPERTENSION

Aim. To study the effect of treatment with inhaled nitric oxide (iNO) on the clinical status of patients with idiopathic pulmonary hypertension (IPH), and the profile of proinflammatory cytokines in peripheral blood. Material and methods. Patients with IPH (n=48) were included into the study. Evaluation of the IPH functional class (FC), the 6-minute walk test (6MWT) with the assessment of the Borg index, echocardiography , laboratory tests [blood count, evaluation of high-sensitivity C-reactive protein (hsCRP), interleukins (IL), interferon-γ (INFγ), tumor necrosis factor a (TNFa), macrophage inflammatory protein a (MIP1 a), soluble adhesion molecules (sICAM-1, sVCAM-1) in peripheral blood] were performed at baseline and on day 21 of iNO therapy course. The iNO course 40 ppm during 5 hours a day for 21 days was carried out additionally to the standard IPH therapy under the toxicity control by the PrinterNOx (England). Results. Increase in exercise tolerance, improvement of IPH FC (from 3.35±0.52 to 2.71±0.56; p=0.008), reduction in systolic pulmonary artery pressure (SPAP) by Doppler echocardiography (from 96.23±23.65 to 82.36±20.92 mmHg; p&lt;0.05) were found in IPH patients as a result of iNo therapy. The significance of inflammation in IPH pathogenesis was confirmed due to assessment of the initial levels of proinflammatory cytokines. iNO therapy resulted in significant decrease in proinflammatory cytokines-IL-1β, IL-6, IL-8, TNFa levels. iNO induced significant dynamics of IL-1β and sVCAM in patients with IPH FC II. It reduced IL-8 and TNFa and increase INFγ (p&lt;0.05) in patients with IPH FC III-IV. Changes in IL-1β and sVCAM levels (ΔIL-1β and ΔsVCAM) by the 21 day of iNO therapy in comparison with these at baseline correlated with ΔSPAP , and ΔIL-6 correlated with ΔFC and Δ6MWT distance (30.5 [21.0; 53.0] m; p&lt;0.001). This allows considering these indicators as markers of iNO treatment efficacy. Conclusions. 21-day iNO therapy in IPH patients resulted in significant improvement of functional status, reduce SPAP and caused the positive dynamics of proinflammatory cytokines blood levels.</p

Heart and pulmonary artery remodeling association with various levels of natriuretic peptides and renin-angiotensin-aldosterone system activation in patients with pulmonary hypertension of various etiology

Aim. To study the associations between heart and pulmonary artery (PA) remodeling severity, according to echocardiography data, natriuretic peptide (NUP) levels, and renin-angiotensin-aldosterone system (RAAS) activation among patients with pulmonary hypertension (PH) of various etiology.Material and methods. The study involved 111 patients with PH, including 30 subjects with idiopathic PH (IPH), 16with chronic PA thromboembolia (PATE), 19 with systemic scleroderma (SS), 15 with chronic obstructive pulmonary disease (COPD), 18 with congenital heart disease (CHD), 13 with residual PH (RPH), as well as 21 healthy controls. In all participants, echocardiography, EchoCG (Vivid 7, GE, USA) and measurement of plasma brain and atrial NUP, angiotensin II (AT II) and plasma renin activity (PRA) were performed.Results. Significant increase in NUP levels was observed in all subgroups, especially in those with PATE and IPH. RAAS activation was detected in all subgroups excluding those with COPD, being maximal in SS subgroup. In all subgroups, dilatation of right heart chambers and PA trunk, as well as decrease in right ventricular (RV) ejection fraction (EF), was observed. Heart remodeling severity was maximal in subjects with IPH, CHD, and PATE, and minimal - in those with SS and COPD, which is consistent with PA systolic pressure and RVEF levels in respective subgroups.Conclusion. Heart remodeling was observed in all PH patients, being maximal in IPH, CHD, and PATE subgroups. Elevated NUP level, registered in all PH subjects, was highest in PATE and IPH subgroups. Significantly increased levels of PRA and AT II were observed in SS, IPH, and PATE individuals, with maximal RAAS activation among SS patients

Clinical and Instrumental Characteristics of Newly Diagnosed Patients with Various Forms of Pulmonary Hypertension according to the Russian National Registry

Aim. To study demographic and clinical characteristics and to give a comparative description of the functional and hemodynamic status, profile of concomitant pathology in patients with various forms of pulmonary arterial hypertension (PAH), and chronic thromboembolic pulmonary hypertension (CTEPH) according to the Russian National Registry. Methods. During the period from January 01, 2012, till January 01, 2019, 1105 patients aged >18 years with verified diagnosis of PAH and CTEPH, who were subsequently observed at 15 PH expert centers of the Russian Federation in the 52 provinces, are included in the Russian registry on the basis of the Federal State Budgetary Institution of Cardiology of the Ministry of Healthcare of Russia. All newly diagnosed patients (n=727) were entered into the registry database (NCT03707561). A comparative analysis of demographic and clinical characteristics, profile of concomitant pathology, and parameters of a comprehensive examination of patients was performed. Results. Among newly diagnosed patients, 67% had PAH and 28.3% had CTEPH. In the PAH group, 40.9% of patients had idiopathic arterial PAH (IPAH), 36.6% had PAH associated with simple congenital heart disease (PAH-CHD), 19.3% had PAH associated with systemic connective tissue disease (PAH-CTD), 1.8% had portal pulmonary hypertension (PoPH), 0.6% had PAH associated with HIV infection (PAH-HIV), 0.4% had heritable PAH (HPAH), and 0.4% had drug/toxin-induced PAH. At the time of diagnosis, PAH patients were younger than patients with CTEPH (45.2±14.9; 52.6±15.3 years, respectively) (p<0.05). At the time of diagnosis, 71% PAH and 77% CTEPH patients had WHO FC III/IV. Mean (±SD) 6MWD was significantly less in CTEPH vs. the PAH group 331.3±110.3 vs. 361.8±135.7 m (p=0.0006). Echo data showed a comparable sPAP between groups; CTEPH population had a more pronounced increase in the area of the right atrium (SRA) (24 [20; 32] cm2 and 19 [15; 26] cm2, respectively), and a significant decrease in FAC (24.7 [22, 4; 29.0] and 29.0 [23.0; 31.0] %, respectively) as compared to the PAH group. RHC showed a comparable increase of sPAP and mPAP in PAH and CTEPH groups. 15.2% of patients with IPAH and HPAH demonstrated positive results in the acute vasoreactivity testing. CTEPH patients were more often obese and suffered from arterial hypertension and right heart failure. Deep venous thrombosis was significantly more often observed in patients with CTEPH (53%). The most common concomitant pathology was erosive-ulcerative lesion of the stomach/duodenum, less often of the esophagus (23.5% and 44.5%, respectively). Conclusion. According to the Russian registry in patients with PAH and IPAH, the diagnosis is established at a younger age in comparison with the European registries. CTEPH patients are characterized by more severe functional status, pronounced signs of right heart failure taking into account the older age and the spectrum of comorbid pathology, which limits the possibility of surgical treatment. An increase in the number of expert centers participating in the registry is the key to improving early diagnosis of PH and optimal follow-up according to common standards in order to timely optimize therapy and reduce mortality of patients