Oxymatrine prevents hypoxia- and monocrotaline-induced pulmonary hypertension in rats

Pulmonary hypertension is a progressive disease characterized by marked pulmonary arterial remodeling and increased vascular resistance. Inflammation and oxidative stress promote the development of pulmonary hypertension. Oxymatrine, one of the main active components of the Chinese herb Sophora flavescens Ait. (Kushen), plays anti-inflammatory and antioxidant protective roles, which effects on pulmonary arteries remain unclear. This study aimed to investigate the effects of oxymatrine on pulmonary hypertension development. Sprague–Dawley rats were exposed to hypoxia for 28 days or injected with monocrotaline, to develop pulmonary hypertension, along with administration of oxymatrine (50 mg/kg/day). Hemodynamics and pulmonary arterial remodeling data from the rats were then obtained. The antiproliferative effect of oxymatrine was verified by in vitro assays. The inflammatory cytokine mRNA levels and leukocyte and T cell accumulation in lung tissue were detected. The antioxidative effects of oxymatrine were explored in vitro. Our study shows that oxymatrine treatment attenuated right-ventricular systolic pressure and pulmonary arterial remodeling induced by hypoxia or monocrotaline and inhibited proliferation of pulmonary arterial smooth muscle cells (PASMCs). Increased expression of inflammatory cytokine mRNA and accumulation of leukocytes and T cells around the pulmonary arteries were suppressed with oxymatrine administration. Under hypoxic conditions, oxymatrine significantly upregulated Nrf2 and antioxidant protein SOD1 and HO-1 expression, but downregulated hydroperoxide levels in PASMCs. In summary, this study indicates that oxymatrine may prevent pulmonary hypertension through its antiproliferative, anti-inflammatory, and antioxidant effects, thus providing a promising pharmacological avenue for treating pulmonary hypertension.     

Up-regulation of hexokinase1 in the right ventricle of monocrotaline induced pulmonary hypertension

Background

Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with a glycolytic shift during heart metabolism. An increase in glycolytic metabolism can be detected in the right ventricle during PAH. Expression levels of glycolysis genes in the right ventricle during glycolysis that occur in monocrotaline (MCT)-induced pulmonary hypertension (PH) remain unknown.

Methods

PH was induced by a single subcutaneous injection of MCT (50 mg/kg) into rats, eventually causing right heart failure. Concurrently, a control group was injected with normal saline. The MCT-PH rats were randomly divided into three groups according to MCT treatment: MCT-2 week, 3 week, and 4 week groups (MCT-2w, 3w, 4w). At the end of the study, hemodynamics and right ventricular hypertrophy were compared among experimental groups. Expression of key glycolytic candidate genes was screened in the right ventricle.

Results

We observed an increase in mean pulmonary arterial pressure, right ventricular systolic pressure and right ventricular hypertrophy index three weeks following MCT injection. Alterations in the morphology and structure of right ventricular myocardial cells, as well as the pulmonary vasculature were observed. Expression of hexokinase 1 (HK1) mRNA began to increase in the right ventricle of the MCT-3w group and MCT-4w group, while the expression of lactate dehydrogenase A (LDHA) was elevated in the right ventricle of the MCT-4w group. Hexokinase 2(HK2), pyruvate dehydrogenase complex α1 (PDHα1), and LDHA mRNA expression showed no changes in the right ventricle. HK1 mRNA expression was further confirmed by HK1 protein expression and immunohistochemical analyses. All findings underlie the glycolytic phenotype in the right ventricle.

Conclusions

There was an increase in the protein and mRNA expression of hexokinase-1 (HK1) three and four weeks after the injection of monocrotaline in the right ventricle, intervention of HK1 may be amenable to therapeutic intervention.     

Fasudil dichloroacetate (FDCA), an orally available agent with potent therapeutic efficiency on monocrotaline-induced pulmonary arterial hypertension rats

Given the therapeutic efficacy of fasudil hydrochloride (F) and dichloroacetate (DCA) on pulmonary arterial hypertension (PAH), a new salt fasudil dichloroacetate (FDCA) was designed, synthesized and biologically evaluated. FDCA exhibited comparable ROCK II inhibitory activity relative to fasudil hydrochloride, and suppressed the expression of TNF-α and IL-6 in both PDGF-BB and hypoxia-treated pulmonary arterial smooth muscle cells (PASMCs) and endothelial cells (PAECs). Significantly, FDCA lowered mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), and decreased right ventricular hypertrophy (RVH) in monocrotaline (MCT)-induced PAH rats. Meanwhile, FDCA remarkably decreased pulmonary artery medial thickness (PAMT) and hyperplasia, restoring the elasticity of elastic fiber, reduced cardiac hypertrophy, and attenuated fibrosis of heart and lung. Collectively, FDCA exhibited triple activities of pulmonary vasodilation, vascular remodeling inhibition and RVH inhibition, suggesting that it may be a promising agent for PAH intervention.     

脂肪干细胞移植对野百合碱诱发的肺动脉高压大鼠肺动脉压的量效和时效作用

目的探索脂肪干细胞（ADSC）移植治疗野百合碱（MCT）诱导的肺动脉高压（PAH）大鼠的适宜细胞数和干预时间。 方法（1）MCT的建模时效和量效：雄性SD大鼠48只分为正常对照组,20 mg/kg、30 mg/kg、40 mg/kg MCT组分别予腹腔注射生理盐水、MCT 20 mg/kg、30 mg/kg、40 mg/kg,4和8周后,右心室插管法检测平均肺动脉压（mPAP）,称重法计算右心室肥厚指数（RVHI）。（2）ADSC的治疗量效作用：雄性SD大鼠分别予腹腔注射MCT（30只）和生理盐水（30只）,1周后通过颈静脉注射分别移植0.5×10⁶、1.0×10⁶、3.0×10⁶、5.0×10⁶ADSC,其他组予等量生理盐水。移植3周后检测mPAP和RVHI。（3）ADSC的治疗时效作用：雄性SD大鼠30只,分别注射40 mg/kg MCT（24只）和生理盐水（6只）。MCT腹腔注射1 d,1、2周后分别移植1.0×10⁶个ADSC。MCT注射4周后检测mPAP和RVHI。多组间比较采用单因素或双因素方差分析,两两比较采用LSD检验。 结果（1）腹腔注射4周后,30 mg/ kg或40 mg/kg MCT组mPAP和RVHI均升高[mPAP值（24.89±3.31）mmHg,（27.19±2.11）mmHg比（15.80±0.42）mmHg,差异有统计学意义（P均< 0.05）;RVHI值0.42±0.06,0.47±0.04比0.25±0.02,差异有统计学意义（P均< 0.05）]。8周后,20 mg/kg或30 mg/ kg MCT组mPAP和RVHI均恢复正常,而40 mg/kg MCT组大鼠全部死亡。（2）40 mg/ kg MCT诱导的PAH大鼠mPAP和RVHI均升高。移植1.0×10⁶个ADSC可降低PAH大鼠的mPAP[（17.24±0.66）mmHg比（27.19±1.73）mmHg,P < 0.05]。移植0.5×10⁶、3.0×10⁶、5.0× 10⁶个ADSC不能降低PAH大鼠的mPAP和RVHI。（3）MCT腹腔注射1周和2周后,移植1.0×10⁶个ADSC可降低PAH大鼠的mPAP。 结论40 mg/kg MCT造模4周可建立稳定的PAH大鼠模型;造模1或2周后移植1.0×10⁶个ADSC能有效降低PAH大鼠的mPAP。     

Inflammatory cytokines in pulmonary hypertension

Pulmonary hypertension is an “umbrella term” used for a spectrum of entities resulting in an elevation of the pulmonary arterial pressure. Clinical symptoms include dyspnea and fatigue which in the absence of adequate therapeutic intervention may lead to progressive right heart failure and death. The pathogenesis of pulmonary hypertension is characterized by three major processes including vasoconstriction, vascular remodeling and microthrombotic events. In addition accumulating evidence point to a cytokine driven inflammatory process as a major contributor to the development of pulmonary hypertension.This review summarizes the latest clinical and experimental developments in inflammation associated with pulmonary hypertension with special focus on Interleukin-6, and its role in vascular remodeling in pulmonary hypertension.     

The regulatory effect of hydrogen sulfide on hypoxic pulmonary hypertension in rats

Hypoxic pulmonary hypertension (HPH) is an important pathophysiological process. The mechanism of HPH is still not fully understood. Recent studies showed that hydrogen sulfide (H(2)S) could relax vascular smooth muscles and inhibit the proliferation of cultured vascular smooth muscle cells. Our study showed that both the gene expression of cystathionine gamma-lyase (CSE), one of the H(2)S generating enzymes, and the activity of CSE were suppressed in lung tissues during HPH. And the plasma level of H(2)S was decreased during HPH. Exogenous supply of H(2)S could increase the plasma level of H(2)S, enhance CSE activity, and up-regulate CSE gene expression in lung tissue. At the same time, exogenous supply of H(2)S could oppose the elevation of pulmonary arterial pressure and lessen the pulmonary vascular structure remodeling during HPH. The results showed that endogenous H(2)S system was involved and exogenous H(2)S could exert beneficial effect on the pathogenesis of HPH.     

Chronic thromboembolic pulmonary hypertension

Chronic pulmonary thromboembolic disease is an important cause of severe pulmonary hypertension, and as such is associated with significant morbidity and mortality. The prognosis of this condition reflects the degree of associated right ventricular dysfunction, with predictable mortality related to the severity of the underlying pulmonary hypertension. Left untreated, the prognosis is poor. Pulmonary endarterectomy is the treatment of choice to relieve pulmonary artery obstruction in patients with chronic thromboembolic pulmonary hypertension and has been remarkably successful. Advances in surgical techniques along with the introduction of pulmonary hypertension-specific medication provide therapeutic options for the majority of patients afflicted with the disease. However, a substantial number of patients are not candidates for pulmonary endarterectomy due to either distal pulmonary vascular obstruction or significant comorbidities. Therefore, careful selection of surgical candidates in expert centres is paramount. The current review focuses on the diagnostic approach to chronic thromboembolic pulmonary hypertension and the available surgical and medical therapeutic options.

Electronic supplementary material

The online version of this article (doi:10.1007/s12471-014-0592-2) contains supplementary material, which is available to authorized users.     

Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats

Hill, Nicholas S., Rod R. Warburton, Linda Pietras, andJames R. Klinger. Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats.J. Appl. Physiol. 83(4):1209-1215, 1997.Endothelin-1 (ET-1), a potent vasoactive andmitogenic peptide, has been implicated in the pathogenesis ofseveral forms of pulmonary hypertension. We hypothesized thatnonspecific blockade of ET receptors would blunt the development ofmonocrotaline (MCT)-induced pulmonary hypertension in rats. Asingle dose of the nonspecific ET blocker bosentan (100 mg/kg) given tointact rats by gavage completely blocked the pulmonary vasoconstrictoractions of Big ET-1 and partially blunted hypoxic pulmonaryvasoconstriction. After 3 wk, MCT-injected (105 mg/kg sc) rats gavagedonce daily with bosentan (200 mg/kg) had lower right ventricular (RV)systolic pressure (RVSP), RV-to-body weight (RV/BW) andRV-to-left ventricular (LV) plus septal (S) weight [RV/(LV+S)] ratiosand less percent medial thickness of small pulmonary arteries thancontrol MCT-injected rats. Lower dose bosentan (100 mg/kg) had noeffect on these parameters after MCT or saline injection. Bosentanraised plasma ET-1 levels but had no effect on lung ET-1 levels.Bosentan (200 mg/kg) also had no effect on wet-to-dry lung weightratios 6 days after MCT injection. When given during the last 10 days,but not the first 11 days of a 3-wk period after MCT injection,bosentan reduced RV/(LV+S) compared with MCT-injected controls. Weconclude that ET-1 contributes to the pathogenesis of MCT-inducedpulmonary hypertension and acts mainly during the later inflammatoryrather than the acute injury phase after injection.

     

A novel adipocytokine,omentin, inhibits monocrotaline-induced pulmonary arterial hypertension in rats

Omentin is a novel adipocytokine mainly expressed in visceral rather than subcutaneous adipose tissue. Several epidemiological studies demonstrated the negative relationship between blood omentin level and occurrence of obesity, type 2 diabetes and hypertension. Increases of inflammatory responses, contractile reactivity and structural remodeling of vascular wall contribute to hypertension development. Our in vitro studies previously demonstrated that omentin inhibited those hypertension-related pathological processes. In addition, our in vivo study demonstrated that intravenously injected omentin acutely inhibited agonists-induced increases of blood pressure in rats. However, the chronic effects of omentin on hypertension development are not determined. In the present study, we tested the hypothesis that chronic omentin treatment may inhibit pulmonary arterial (PA) hypertension (PAH). PAH was induced by a single intraperitoneal injection of monocrotaline (MCT: 60 mg/kg) to rats. Omentin (18 μg/kg/day) was intraperitoneally treated for 14 days. Chronic omentin treatment inhibited MCT-induced increases in PA pressure. Omentin inhibited MCT-induced right ventricular hypertrophy as well as increase of lung to body weight ratio. Histologically, omentin inhibited MCT-induced PA hyperplasia. Further, omentin inhibited the impairment of both endothelium-dependent and -independent relaxations mediated by acetylcholine and sodium nitroprusside, respectively. In conclusion, we for the first time demonstrate that chronic omentin treatment inhibits MCT-induced PAH in rats via inhibiting vascular structural remodeling and abnormal contractile reactivity.     

Clinical worsening after pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension

Introduction

Pulmonary endarterectomy (PEA) is the most effective treatment for chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study is to evaluate long-term survival and freedom from clinical worsening after PEA.

Methods

All patients who underwent PEA in our hospital between May 2000 and August 2009 were included. Follow-up parameters were all-cause mortality and time to clinical worsening, defined as a combination of death, need for pulmonary hypertension-specific medication or 15% decrease in six-minute walk distance without improvement in functional class. The Cox proportional hazard regression was used to identify predictors.

Results

Seventy-four consecutive patients (mean age 55.9 ± 13.8 years, 51% female) underwent PEA. Prior to surgery, 55 patients were in NYHA functional class III or higher. The mean pulmonary artery pressure was 41.3 ± 11.9 mmHg with a mean pulmonary vascular resistance of 521 ± 264 dyn·s·cm⁻⁵ (range 279–1331 dyn·s·cm⁻⁵). Five patients (6.8%) died in-hospital. Out of hospital, 5 out of 69 patients (7.2%) died during a median follow-up of 3.7 ± 2.2 years [range 0.1–8.5 years]). The one- and five-year survival rates were 93% and 89%, respectively. During follow-up, clinical worsening occurred in 13 out of 69 patients (18.8%). The one- and five-year rates of freedom from clinical worsening were 94% and 72%, respectively. The baseline NT-pro BNP level tended to be a predictor for occurrence of clinical worsening.

Conclusion

Pulmonary endarterectomy is associated with good long-term survival in patients with CTEPH. However, clinical worsening occurred in a substantial number of patients at long-term follow-up.     

Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats

Background

Mast cells (MCs) are implicated in inflammation and tissue remodeling. Accumulation of lung MCs is described in pulmonary hypertension (PH); however, whether MC degranulation and c-kit, a tyrosine kinase receptor critically involved in MC biology, contribute to the pathogenesis and progression of PH has not been fully explored.

Methods

Pulmonary MCs of idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline-injected rats (MCT-rats) were examined by histochemistry and morphometry. Effects of the specific c-kit inhibitor PLX and MC stabilizer cromolyn sodium salt (CSS) were investigated in MCT-rats both by the preventive and therapeutic approaches. Hemodynamic and right ventricular hypertrophy measurements, pulmonary vascular morphometry and analysis of pulmonary MC localization/counts/activation were performed in animal model studies.

Results

There was a prevalence of pulmonary MCs in IPAH patients and MCT-rats as compared to the donors and healthy rats, respectively. Notably, the perivascular MCs were increased and a majority of them were degranulated in lungs of IPAH patients and MCT-rats (p < 0.05 versus donor and control, respectively). In MCT-rats, the pharmacological inhibitions of MC degranulation and c-kit with CSS and PLX, respectively by a preventive approach (treatment from day 1 to 21 of MCT-injection) significantly attenuated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved. However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling.

Conclusions

The accumulation and activation of perivascular MCs in the lungs are the histopathological features present in clinical (IPAH patients) and experimental (MCT-rats) PH. Moreover, the accumulation and activation of MCs in the lungs contribute to the development of PH in MCT-rats. Our findings reveal an important pathophysiological insight into the role of MCs in the pathogenesis of PH in MCT- rats.     

Determinants of an elevated pulmonary arterial pressure in patients with pulmonary arterial hypertension

Given the difficulty of diagnosing early-stage pulmonary arterial hypertension (PAH) due to the lack of signs and symptoms, and the risk of an open lung biopsy, the precise pathological features of presymptomatic stage lung tissue remain unknown. It has been suggested that the maximum elevation of the mean pulmonary arterial pressure (P_pa) is achieved during the early symptomatic stage, indicating that the elevation of the mean P_pa is primarily driven by the pulmonary vascular tone and/or some degree of pulmonary vascular remodeling completed during this stage. Recently, the examination of a rat model of severe PAH suggested that the severe PAH may be primarily determined by the presence of intimal lesions and/or the vascular tone in the early stage. Human data seem to indicate that intimal lesions are essential for the severely increased pulmonary arterial blood pressure in the late stage of the disease.However, many questions remain. For instance, how does the pulmonary hemodynamics change during the course of the disease, and what drives the development of severe PAH? Although it is generally acknowledged that both pulmonary vascular remodeling and the vascular tone are important determinants of an elevated pulmonary arterial pressure, which is the root cause of the time-dependent progression of the disease? Here we review the recent histopathological concepts of PAH with respect to the progression of the lung vascular disease.     

吸入乙酰半胱氨酸对博莱霉素导致的大鼠肺纤维化的影响

目的:研究N-乙酰半胱氨酸(NAC)雾化吸入对于博莱霉素(BLM)导致的大鼠肺纤维化的影响作用。方法:取清洁SD大鼠100只,平均分为10小组,1小组为对照组,其余每3小组为一组,分别为模型组,防治组,治疗组,通过在大鼠气管中注入BLM的方法来制造大鼠肺纤维化模型,防治组在造模前的7天以及造模后的7天内,治疗组在造模后的7天内,分别给予NAC雾化吸入治疗。在成功造模后的第7天、14天、28天,每组处死1小组大鼠,取出病理组织,通过免疫组化方法来观察肺组织纤维化的程度。研究NAC对大鼠肺纤维化的影响。结果:与模型组对比,防治组和治疗组在纤维化程度上明显较轻(P0.05)。结论:吸入NAC对于博莱霉素导致的大鼠肺纤维化有明显的抑制作用,而且防治组疗效明显好于治疗组。既提前7天用药,效果更明显,大鼠获益更多。     

Anxiety and depression disorders in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

Background

The objective of this prospective study was to assess the prevalence of anxiety and depression disorders and their association with quality of life (QoL), clinical parameters and survival in patients with pulmonary hypertension (PH).

Methods

We prospectively assessed 158 patients invasively diagnosed with pulmonary arterial hypertension (n = 138) and inoperable chronic thromboembolic PH (n = 20) by clinical measures including quality of life (QoL, SF-36 questionnaire), cardiopulmonary exercise testing and six minute walking distance and by questionnaires for depression (PHQ-9) and anxiety (GAD-7). According to the results of the clinical examination and the questionnaires for mental disorders (MD) patients were classified into two groups, 1) with moderate to severe MD (n = 36, 22,8%), and 2) with mild or no MD (n = 122). Patients were followed for a median of 2.7 years. Investigators of QoL, SF-36 were blinded to the clinical data.

Results

At baseline the 2 groups did not differ in their severity of PH or exercise capacity. Patients with moderate to severe MD (group 1) had a significantly lower QoL shown in all subscales of SF-36 (p < 0.002). QoL impairment significantly correlated with the severity of depression (p < 0.001) and anxiety (p < 0.05). During follow-up period 32 patients died and 3 were lost to follow-up. There was no significant difference between groups regarding survival. Only 8% of the patients with MD received psychopharmacological treatment.

Conclusion

Anxiety and depression were frequently diagnosed in our patients and significantly correlated with quality of life, but not with long term survival. Further prospective studies are needed to confirm the results.     

Interleukin 1 bioactivity in the lungs of rats with monocrotaline-induced pulmonary hypertension

A single subcutaneous injection of monocrotaline in rats provokes lung injury, inflammation, and progressive pulmonary hypertension. The specific mediators of the lung injury and inflammation and the relation of these events to the ensuing hypertensive pulmonary vascular disease are not understood. Since the monokine interleukin 1 (IL-1) has been implicated in acute inflammatory reactions, the present study tested the hypotheses that monocrotaline promotes the appearance of IL-1 in the bronchoalveolar spaces of treated rats and that accumulation of the monokine coincides temporally with development of lung injury, inflammation, and/or pulmonary hypertension. As expected, monocrotaline administration was associated with an early phase of pulmonary edema, manifest at Day 7 post-treatment as an increase in the lung wet-to-dry weight ratio, followed at Day 14 post-treatment by development of pulmonary hypertension as evidenced by progressive right ventricular hypertrophy. Lung inflammation also was present at Days 14 and 21 after monocrotaline as indicated by the accumulation of leukocytes in the bronchoalveolar lavage fluid and by an increase in the lung tissue activity of the granulocyte-specific enzyme myeloperoxidase. Interleukin 1, bioassayed in bronchoalveolar lavage fluid using the standard D10 T-cell assay system, was increased slightly at Day 4 postmonocrotaline, returned to baseline at Day 7, and was markedly elevated at Days 14 and 21 after monocrotaline treatment. These observations indicate that increases in the bronchoalveolar lavage fluid content of IL-1 bioactivity are temporally related to the evolution of monocrotaline-induced lung injury, inflammation, and pulmonary hypertension and suggest that the monokine may play a pathogenetic role in these events.     

MRI model-based non-invasive differential diagnosis in pulmonary hypertension

Pulmonary hypertension(PH) is a disorder characterised by increased mean pulmonary arterial pressure. Currently, the diagnosis of PH relies upon measurements taken during invasive right heart catheterisation (RHC). This paper describes a process to derive diagnostic parameters using only non-invasive methods based upon MRI imaging alone.     

Pregnancy in women with pulmonary hypertension

Women with pulmonary hypertension have a high risk of morbidity and mortality during pregnancy. The inability to increase cardiac output leads to heart failure while further risks are introduced with hypercoagulability and decrease in systemic vascular resistance. There is no proof that new advanced therapies for pulmonary hypertension decrease the risk, though some promising results have been reported. However, pregnancy should still be regarded as contraindicated in women with pulmonary hypertension. When pregnancy occurs and termination is declined, pregnancy and delivery should be managed by multidisciplinary services with experience in the management of both pulmonary hypertension and high-risk pregnancies.     

Sharp increase in density of pulmonary and pericardial mast cells in monocrotaline-induced pulmonary hypertension in rats

Multifunctional granular mast cells (MCs) are involved in various pathological processes. The response of the MC population in the myocardium, pericardium, and lungs to pulmonary hypertension (PH) has been studied 8 weeks after the injection of monocrotaline. Five intact and five experimental rats were used. The density of MCs of different degrees of maturity was estimated in paraffin sections stained with Alcian blue and Safranin. The expression of PH was estimated by functional parameters using an echocardiogram and morphological markers. The MC density in the myocardium of intact and experimental rats was relatively low, i.e., 2–4 cells/mm². In the pericardia of intact rats, the MC density was 14 times higher than in the myocardia and increased by a factor of three in PH. In the myocardia and pericardia of intact and experimental rats, mature, Safranin-positive cells predominated (70–80%). In the lungs of intact rats, the MC density was about 30 cells/mm² and 98% of the cells were immature Alcian-positive cells. In lungs of rats with PH the mean density of MCs increased 5.6 times. In lungs of rats with severe pathologies, mature Safranin-positive cells appeared. The highest number of MCs in lungs was found in rats with distinctly pronounced disorders of myocardial function and marked histolological damages of myocardium and lung. The findings show the active reaction of the MC population to monocrotaline-induced PH, which stimulates the migration of immature MCs to the pericardium and lungs from the outside. The connection of cellular mechanisms of the development of PH with the function of MCs is not yet clear; however, the results of the present work indicate the important role of MCs in the pathogenesis of PH.     

A low resting heart rate at diagnosis predicts favourable long-term outcome in pulmonary arterial and chronic thromboembolic pulmonary hypertension. A prospective observational study

Background

A low resting heart rate (HR) is prognostically favourable in healthy individuals and in patients with left heart disease. In this study we investigated the impact of HR at diagnosis on long-term outcome in patients with differently classified precapillary pulmonary hypertension (pPH).

Methods

pPH patients diagnosed as pulmonary arterial (PAH) or inoperable chronic thromboembolic pulmonary hypertension (CTEPH) were registered and regularly followed at our centre Baseline characteristics and events defined as either death or lung transplantation were noted. The prognostic value of HR was analysed using Kaplan Meier estimates, live tables and Cox regression.

Results

206 patients with PAH (148) and inoperable CTEPH (58) were included. The median HR was 82 bpm. pPH with a HR below 82 bpm had a significantly longer overall event-free survival (2409 vs.1332 days, p = .000). This advantage was similarly found if PAH and CTEPH were analysed separately. Although a lower HR was associated with a better hemodynamic and functional class, HR was a strong and independent prognostic marker for transplant free survival even if corrected for age, sex, hemodynamics and functional status.

Conclusion

We show that resting HR at diagnosis is a strong and independent long-term prognostic marker in PAH and CTEPH. Whether reducing HR by pharmacological agents would improve outcome in pPH has to be assessed by future trials with high attention to safety.