Impact of First-Line Sildenafil Monotreatment for Pulmonary Arterial Hypertension

Yanagisawa, Ryoji; Kataoka, Masaharu; Tanaka, Hiroki; Kawakami, Takashi; Tamura, Yuichi; Fukuda, Keiichi; Yoshino, Hideaki; Satoh, Tsuyoshi

doi:10.1253/circj.cj-11-1192

Cited by 15 publications

(6 citation statements)

References 31 publications

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“…Clinical data are supporting the benefits of this treatment in terms of improvement of symptoms, exercise capacity, haemodynamics, and possible outcome [21]. However, it is still unclear whether sildenafil affects microvascular injury via mechanisms that are independent from or additional to vasodilation.…”

Section: Discussionmentioning

confidence: 98%

Novel Mechanisms of Sildenafil in Pulmonary Hypertension Involving Cytokines/Chemokines, MAP Kinases and Akt

et al. 2014

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Pulmonary arterial hypertension (PH) is associated with high mortality due to right ventricular failure and hypoxia, therefore to understand the mechanism by which pulmonary vascular remodeling initiates these processes is very important. We used a well-characterized monocrotaline (MCT)-induced rat PH model, and analyzed lung morphology, expression of cytokines, mitogen-activated protein kinase (MAPK) phosphorylation, and phosphatidylinositol 3-kinase-Akt (PI-3k-Akt) pathway and nuclear factor (NF)-κB activation in order to elucidate the mechanisms by which sildenafil's protective effect in PH is exerted. Besides its protective effect on lung morphology, sildenafil suppressed multiple cytokines involved in neutrophil and mononuclear cells recruitment including cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2α/β, tissue inhibitor of metalloproteinase (TIMP)-1, interleukin (IL)-1α, lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1α, and MIP-3α. NF-κB activation and phosphorylation were also attenuated by sildenafil. Furthermore, sildenafil reduced extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK activation while enhanced activation of the cytoprotective Akt pathway in PH. These data suggest a beneficial effect of sildenafil on inflammatory and kinase signaling mechanisms that substantially contribute to its protective effects, and may have potential implications in designing future therapeutic strategies in the treatment of pulmonary hypertension.

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Section: Discussionmentioning

confidence: 98%

Novel Mechanisms of Sildenafil in Pulmonary Hypertension Involving Cytokines/Chemokines, MAP Kinases and Akt

et al. 2014

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“…The current standard for assessing exercise capacity in PAH is the 6MWT; clinical trials in Japan have adopted the 6MWT as the primary endpoint. 22, 23 The 6MWT, however, is time-limited, which may constrain its validity as a true measure of exercise capacity. According to the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) study, when the dose of sildenafil increased, the mean pulmonary artery pressure decreased significantly.…”

Section: Advantages Of Swt Over 6mwt For Pah Patientsmentioning

confidence: 99%

Incremental Shuttle Walk Test as a Valuable Assessment of Exercise Performance in Patients With Pulmonary Arterial Hypertension

Irisawa

Takeuchi

Inui

et al. 2014

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp chievement of reliable results in clinical trials requires an accurate assessment technique. Many clinical trials investigating pulmonary arterial hypertension (PAH) have used the 6-min walk test (6MWT) as a clinical endpoint. Measurement of peak oxygen consumption (pV O2) and oxygen consumption at anaerobic threshold (V O2 at AT) via indirect calorimetry provides an objective, reliable and non-invasive technique to assess exercise tolerance in patients with various cardiac diseases. Furthermore, V O2 at AT describes the highest V O2 that the patient can sustain without developing lactic acidosis, and appears to be an independent marker of PAH severity. 1 In the Sitaxsentan Therapy for Pulmonary Arterial Hypertension (STRIDE-1) study, pV O2 was adopted as the clinical endpoint. 2 Measurement of pV O2, however, requires sophisticated equipment, laboratory facilities, and highly trained personnel. As a result, this test is not widely used and is often confined to large hospitals or research centers. These tests are also expensive and time-consuming, and may not be practical for frequent assessments or large groups of patients. Because of these limitations, field exercise tests such as the submaximal 6MWT have been developed as inexpensive and simple alternative measures of exercise tolerance. 3 The 6MWT measures the distance a patient can voluntarily traverse in a 6-min period. The test protocol, however, is selfpaced, difficult to standardize, and potentially influenced by motivation and encouragement. In addition, the 6MWT has only a moderate correlation with pV O2, 4 and is not a reliable predictor of mortality in patients with congestive heart failure. 5 The development of a simple objective field test that is more highly predictive of pV O2 and easily standardized and used is therefore desirable for patients with PAH.An incremental, externally paced 10-m shuttle walk test (SWT) has been developed for patients with chronic airway limitation. This test is highly reliable and reproducible after only 1 practice walk. 6 In contrast, the 6MWT requires at least 2 practice trials to obtain reliable results. 3 Most importantly, SWT performance relates strongly to pV O2 (r=0.88) in patients with chronic airway limitation, 7 and a strong relationship Background: Nearly all clinical trials investigating patients with pulmonary arterial hypertension (PAH) have used the 6-min walk test (6MWT) to evaluate exercise tolerance. The incremental shuttle walk test (SWT), however, has been proposed as a more valid and reproducible alternative to the 6MWT in the evaluation of exercise tolerance in patients with chronic obstructive pulmonary disease. The efficacy of SWT in clinical practice to evaluate the exercise capacity of patients with PAH was investigated.

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“…Yanagisawa et al added epoprostenol therapy to the treatment regimen of several patients during the first 12 weeks in their study. 10 It is clear that there were non-responders and poor responders to sildenafil, and additional therapy was required. They obviously carefully followed up patients on sildenafil monotreatment with repeated evaluation of clinical status and response to treatment and, if needed, initiated combination therapy at appropriate times.…”

Section: Article P 1245mentioning

confidence: 99%

How Long Can We Leave Patients With Pulmonary Arterial Hypertension on Oral Drug Monotreatment?

Ogawa

Matsubara

2012

Circ J

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Impact of First-Line Sildenafil Monotreatment for Pulmonary Arterial Hypertension

Cited by 15 publications

References 31 publications

Novel Mechanisms of Sildenafil in Pulmonary Hypertension Involving Cytokines/Chemokines, MAP Kinases and Akt

Novel Mechanisms of Sildenafil in Pulmonary Hypertension Involving Cytokines/Chemokines, MAP Kinases and Akt

Incremental Shuttle Walk Test as a Valuable Assessment of Exercise Performance in Patients With Pulmonary Arterial Hypertension

How Long Can We Leave Patients With Pulmonary Arterial Hypertension on Oral Drug Monotreatment?

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