Advances in targeted therapy for chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by unresolved thrombi in the pulmonary arteries and microvasculopathy in nonoccluded areas. If left untreated, progressive pulmonary hypertension will induce right heart failure and, finally, death. Currently, pulmonary endarterectomy (PEA) remains the only method that has the potential to cure CTEPH. Unfortunately, up to 40% of patients are ineligible for this procedure for various reasons. In recent years, refined balloon pulmonary angioplasty (BPA) has become an alternative option for inoperable CTEPH patients, and it may be another curative treatment in the future, particularly in combination with prior PEA. Nevertheless, 23% of patients still suffer from persistent PH after BPA. Given that CTEPH shares many similarities with idiopathic pulmonary arterial hypertension (PAH), targeted drugs developed for PAH are also attractive options for CTEPH, especially for inoperable or persistent/recurrent CTEPH patients. To date, riociguat, macitentan, and subcutaneous treprostinil are the only drugs proven by randomized control trials to be capable of improving the exercise capacity (6-min walking distance) of CTEPH patients. In this review, we summarize the achievements and unresolved problems of PAH-targeted therapy for CTEPH over the last decade.

[Treatment of pulmonary arterial hypertension]. / Tratamiento de la hipertensión arterial pulmonar.

Treatment of pulmonary arterial hypertension has achieved significant progress over the past 20 years. Currently, 3 groups of drugs have proven useful for the treatment of this disease: endothelin receptor antagonist, phosphodiesterase inhibitors and prostacyclin and its analogues. It is recommended to initiate treatment with one of these drugs, the choice depending on the initial severity of patient disease and the preferences of the treating physician. When the patient does not have a satisfactory response, new drugs acting at a different pathway are most commonly added. At this time, considering referral for lung transplantation could be an alternative. Most experts recommend grouping maximum experience in what is known as expert centers. Treatment has led to better survival in these patients, but there is still a long way to cure this life-threatening disease.

Development of a prostacyclin-agonist-eluting aortic stent graft enhancing biological attachment to the aortic wall.

OBJECTIVES: Stent graft-related complications, including endoleaks and graft migration, are partly attributed to insufficient graft attachment to the aortic wall. ONO-1301, a stable synthetic prostacyclin agonist, reportedly reorganizes extracellular matrices, enhancing tissue healing. We hypothesized that ONO-1301-eluting stent grafts may strengthen graft attachment to the aortic wall. METHODS: Polylactic acid polymer-conjugated ONO-1301, which releases ONO-1301 into adjacent tissues over 3 months (ONO(+) group), or polylactic acid polymer only (ONO(-) group) was coated onto the stent graft and placed in the descending thoracic aorta of canines weighing 16 to 20 kg under fluoroscopic guidance. Examinations occurred at 1, 2, or 3 months postoperatively (n = 6 for each time point and group). RESULTS: ONO-1301 aortic-wall concentrations were within the effective range even at 3 months. The maximal load for tearing the graft from the aortic wall ex vivo was significantly greater in the ONO(+) group than in the ONO(-) group (117.1%±44.4%, 133.9%±23.2%, and 119.9%±13.5% at 1, 2, and 3 months, respectively; P=.0007). Immunohistochemical examination revealed abundant α-smooth muscle actin-positive cells in the neointima in both groups. The fibrotic area between the graft and the aortic wall was significantly larger (P<.0001), and migrating cells into the graft fabric were significantly greater (P=.0003) in the ONO(+) group than in the ONO(-) group. CONCLUSIONS: In canines, the ONO-1301-eluting stent graft enhanced tissue reorganization and improved the attachment between the graft and the aortic wall. This new device may be useful in preventing inadequate graft attachment to the aortic wall.

Impact of cardiac support device combined with slow-release prostacyclin agonist in a canine ischemic cardiomyopathy model.

BACKGROUND: The cardiac support device supports the heart and mechanically reduces left ventricular (LV) diastolic wall stress. Although it has been shown to halt LV remodeling in dilated cardiomyopathy, its therapeutic efficacy is limited by its lack of biological effects. In contrast, the slow-release synthetic prostacyclin agonist ONO-1301 enhances reversal of LV remodeling through biological mechanisms such as angiogenesis and attenuation of fibrosis. We therefore hypothesized that ONO-1301 plus a cardiac support device might be beneficial for the treatment of ischemic cardiomyopathy. METHODS: Twenty-four dogs with induced anterior wall infarction were assigned randomly to 1 of 4 groups at 1 week postinfarction as follows: cardiac support device alone, cardiac support device plus ONO-1301 (hybrid therapy), ONO-1301 alone, or sham control. RESULTS: At 8 weeks post-infarction, LV wall stress was reduced significantly in the hybrid therapy group compared with the other groups. Myocardial blood flow, measured by positron emission tomography, and vascular density were significantly higher in the hybrid therapy group compared with the cardiac support device alone and sham groups. The hybrid therapy group also showed the least interstitial fibrosis, the greatest recovery of LV systolic and diastolic functions, assessed by multidetector computed tomography and cardiac catheterization, and the lowest plasma N-terminal pro-B-type natriuretic peptide levels (P < .05). CONCLUSIONS: The combination of a cardiac support device and the prostacyclin agonist ONO-1301 elicited a greater reversal of LV remodeling than either treatment alone, suggesting the potential of this hybrid therapy for the clinical treatment of ischemia-induced heart failure.

Effect of antioxidants on the stability of ONO-1301, a novel long-acting prostacyclin agonist, loaded in PLGA microspheres.

The purpose of this study was to investigate the physicochemical stability of ONO-1301 in poly(lactide-co-glycolide) microspheres (PLGA MS) under storage for 28 days in the absence or presence of butylated hydroxytoluene (BHT) or α-tocopherol as antioxidant. First, we observed the hydrolysed product: (i) in acidic solution and oxidized product and (ii) in PLGA MS under storage in HPLC study, each structure was determined by liquid chromatography-nuclear magnetic resonance/mass spectrometry. Second, ONO-1301-loaded PLGA MS containing 10% BHT was shown to be superior to ONO-1301-loaded PLGA MS without BHT, in the standpoint of the stability under storage or in vitro drug-release test, and AUC(0-28) following subcutaneous injection in rats. Finally, ONO-1301-loaded PLGA MS with 10% BHT were demonstrated to be significantly more effective than ONO-1301-loaded PLGA MS without BHT in a murine sponge model of angiogenesis. In conclusion, BHT is an effective antioxidant on the stability of ONO-1301 in PLGA MS under storage.

Management of end-stage sarcoidosis: pulmonary hypertension and lung transplantation.

Sarcoidosis is not only a multisystem, but also a multinational disease that is prevalent throughout the world, including Europe, the USA and Japan. Lung involvement in sarcoidosis is seemingly invariable, with up to 95% of patients manifesting some form of pulmonary disease during the course of their lifetime. The natural history of sarcoidosis in the lung is quite variable and spans the spectrum from spontaneous resolution to advanced fibrocystic disease in ~5% of cases. Advanced sarcoidosis will be the subject of this review with a special focus on pulmonary hypertension and lung transplantation as a last-resort treatment option for some patients with end-stage disease.

Local delivery of synthetic prostacycline agonist augments collateral growth and improves cardiac function in a swine chronic cardiac ischemia model.

AIMS: It was reported that administration of angiogenic growth factors can augment collateral growth in ischemic tissues. It is assumed that angiogenic effects of cell transplantation may be mainly mediated by secretion of angiogenic cytokines. We tested feasibility of clinical use of ONO-1301, a synthetic small molecule that stimulates secretion of growth factors from various cell types, to treat patients with chronic myocardial ischemia. MAIN METHODS: Effects of ONO-1301 on fibroblasts and endothelial cells were evaluated in vitro. We examined the efficacy of local delivery of ONO-1301 in models of rat hindlimb ischemia and swine chronic ischemic myocardium. KEY FINDINGS: ONO-1301 stimulated hepatocyte growth factor secretion from human fibroblasts. ONO-1301 promoted vascular-like tube formation by endothelial cells in vitro. Direct injection of a slow-release form of ONO-1301 (SR-ONO) to rat hindlimb ischemic muscle enhanced perfusion recovery. In a swine cardiac ischemia model, direct injection of SR-ONO into the ischemic myocardium significantly augmented collateral formation (SR-ONO vs. control; 1.7+/-0.2 vs. 1.0+/-0.2 Rentrop score), with improved local ventricular wall motion, reduced enlargement of left ventricular diastolic volume (49.5+/-1.9 mL vs. 59.7+/-4.2 mL) and increased cardiac index (4.2+/-0.1 vs. 3.4+/-0.2 L/min/m(2)). Histological analysis revealed that SR-ONO suppressed fibrosis in ischemic tissue (collagen volume fraction; 7.5+/-1.1% vs. 12.8+/-2.2%) and enhanced neovascularization (capillary density, 275.6 vs. 159.3/mm(2); arterioles 36.6 vs. 25.5 /mm(2)). SIGNIFICANCE: Local delivery of SR-ONO might be effective for therapeutic angiogenesis and propose that local administration of slow-release of synthetic small molecules represents new strategy for therapeutic angiogenesis.

Treatment of pediatric pulmonary hypertension.

Pulmonary hypertension was once thought to be a rare condition and only managed in specialized centers. Now however, with the advent of echocardiography, it is found in many clinical scenarios, in the neonate with chronic lung disease, in the acute setting in the intensive care unit, in connective tissue disease and in cardiology pre- and postoperatively. We have a better understanding of the pathological process and have a range of medication which is starting to be able to palliate this previously fatal condition. This review describes the areas that are known in this condition and those that are less familiar. The basic physiology behind pulmonary hypertension and pulmonary vascular disease is explained. The histopathologic process and the various diagnostic tools are described and are followed by the current and future therapy at our disposal.

Prostacyclin analogues: prevention of cardiovascular diseases.

Prostacyclin (PGI(2)) inhibits platelet aggregation and vasoconstriction. PGI(2) synthase (PGIS), a catalyst of PGI(2) formation from prostaglandin H2, is widely distributed and predominantly found in vascular endothelial and smooth muscle cells. Vane et al. first discovered PGI(2) in 1976, for which they received the Nobel Prize in medicine and physiology in 1982. However, the later discovery of nitric oxide (NO), which also resulted in a Nobel Prize for the scientists involved, led to less attention being focused on PGI(2). The reason for this is somewhat perplexing and may have been due to the lack of information on how to correctly use PGI(2). Current findings suggest that researchers concentrated too much effort on the therapeutic effects of PGI(2), while largely ignoring the potential for preventative effects. In addition, PGI(2) was shown to be effective against diseases in some studies but was without effect in others. The present paper contains a review of PGI(2) and PGIS, in addition to an examination of the relationship between PGIS gene mutations and cardiovascular diseases. PGI(2) analogues that can be used in the prevention of cardiovascular diseases are also discussed.