I. Overview
Pulmonary hypertension belongs to pulmonary hypertension, the first major category of PH, and refers to a pathophysiological state in which pulmonary artery pressure rises above the normal range and pulmonary vascular resistance increases progressively under certain circumstances, eventually manifesting as right heart failure.PAH is defined as a pulmonary artery pressure at sea level conditions that is higher than 25 mmHg at rest or >30 mmHg during exercise, while the pulmonary capillary wedge pressure should be < 15 mmHg.
Many factors are involved in the pathophysiological process of PAH, including vasoconstriction, pulmonary vascular proliferation and remodeling, and thrombosis. Among them, studies at the molecular level suggest a key role for endothelial dysfunction again. Decreased vasodilator production and increased expression of contractile substances not only lead to sustained vasoconstriction, but also promote pulmonary vascular smooth muscle proliferation and pulmonary vascular remodeling. Three signaling pathways are now thought to have important roles in the imbalance of vasoactive substances in PAH.
(1) prostacyclin pathway ;
(2) Nitric oxide (NO) pathway;
(3) endothelin-1 pathway. The above signaling pathways provide targets for various specific drug therapies. Figure Therapeutic targets for pulmonary arterial hypertension.
PAH has a complex etiology and is poorly understood by clinicians, and its misdiagnosis rate has been high, and its treatment is difficult with a poor prognosis. In recent years, PAH research has progressed rapidly, but without treatment, the median survival rate of patients is generally 2 to 3 years from the diagnosis of idiopathic pulmonary hypertension, according to NIH statistics. None of the existing treatments can cure this serious disease, but advances in targeted therapies can help improve symptoms, improve patients’ quality of life, and extend life expectancy to some extent: the five-year survival rate for patients after treatment can be >50%.
II. Targeted therapy for PAH
The conventional treatments for PAH include oxygen, diuretics, calcium antagonists, anticoagulant therapy, digitalis therapy, etc. Most of these treatments have been validated in large-scale randomized controlled clinical trials, and there are some clinical misconceptions.
New targeted drugs for the treatment of PAH are now progressing rapidly, and specific treatment must be given to patients with negative acute vasodilator tests. Prostacyclin and its analogs, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors are all options.
1.Endothelin receptor antagonists
Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor and smooth muscle cell pro-secretor, which can cause pulmonary vasoconstriction and transitional hyperplasia causing pulmonary hypertension. the effect of ET-1 is mediated by the ETA-established ETB receptor.
Bosentan is a non-selective endothelin receptor antagonist that competitively inhibits the binding of ET-1 to ET-A receptors and ET-B receptors, thereby blocking the action of ET-1. Bosentan significantly improves 6 min walking distance and hemodynamics and prolongs survival time. It is indicated for the treatment of patients with functional class II-IV idiopathic pulmonary hypertension, congenital heart disease-associated pulmonary hypertension, and connective tissue disease-associated pulmonary hypertension.
The current recommended usage is an initial dose of 62.5 mgbid for 4 weeks with subsequent 125 mgbid maintenance therapy. Bosentan is the treatment of choice for cardiac class III pulmonary hypertension according to the European American recommended treatment guidelines. Because bosentan has the potential for adverse effects of liver damage, it is recommended that liver function be monitored at least once a month during treatment. If the increase of transaminases is less than or equal to 3 times the high limit of normal value, the drug can be continued for observation; between 3 and 5 times, the drug can be continued at half the dose or suspended and liver function monitored every 2 weeks, and then used again when transaminases return to normal; between 5 and 8 times, the drug is suspended and liver function monitored every 2 weeks, and then considered to be used again when transaminases return to normal; when it reaches 8 times or more, it needs to be stopped and No longer consider re-dosing.
The selective ET-A receptor antagonists sitaxsentan and ambesentan are currently available in Europe and the United States, and have been shown to be safe and effective in patients with pulmonary arterial hypertension in preliminary clinical studies. Due to the short duration of application, it is unclear whether selective ET-A receptor antagonists are better than non-selective drugs.
2. Prostacyclin and structural analogues
The earliest drug available for the treatment of pulmonary hypertension is FLOLAN, which is an endogenous prostacyclin. Long-term intravenous application of epoprostenol has shown significant efficacy in patients with moderate to severe PAH. It is still the treatment of choice for patients with class IV cardiac function, but is not currently available in China. In addition, this drug is expensive, complicated to use (including long-term indwelling catheter, drug to be deployed when used, operation of infusion pump, etc.), and has more adverse effects.
The dose of iloprost per inhalation should vary from person to person and requires an acute pulmonary vasodilation test to evaluate. Long-term application of the drug can reduce pulmonary artery pressure and pulmonary vascular resistance, improve exercise tolerance, and improve quality of life. Pediatric patients have poor compliance and generally do not use this drug. Common adverse effects of inhaled iloprost include cough, headache, congestion, and individually may cause fever. In addition, the prostacyclin class of drugs has been approved for marketing abroad, such as travoprost and beprostadine. In particular, the long-term efficacy of treprostinil has been recognized by foreign doctors.
It is worth emphasizing the difference and connection between prostaglandin E1 (PGB1) and prostaglandin I2 (PGI2), both of which are metabolites of arachidonic acid and both have powerful vasodilating effects. PGI2, also known as prostacyclin, has a stronger vasodilating effect on the pulmonary vasculature than the pulmonary circulation, and is the drug of choice for the treatment of pulmonary hypertension.
3.Phosphodiesterase inhibitors
Pulmonary arterial hypertension patients with damaged pulmonary artery endothelium and decreased NO synthesis, supplemental NO is an ideal target therapy, but the dose control is difficult to operate, especially in the domestic temporary can not be achieved.
NO directly activates soluble guanylate cyclase (cGMP), which activates cGMP enzymes to open potassium channels and inhibit calcium inward flow, resulting in lower intracellular calcium concentration and relaxation of pulmonary vascular smooth muscle. Thus the diastolic effect of NO is dependent on the ability to increase and maintain the level of cGMP in vascular smooth muscle cells. In contrast, cGMP degradation is mainly dependent on phosphodiesterase 5 (PDE5), and PDE-5 inhibitors can prevent cGMP degradation at this point, increase the intracellular concentration of cGMP, and exert its vasodilatory effect. Meanwhile, the high expression of PDE-5 in pulmonary vascular smooth muscle is the molecular basis for the application of selective PDE5 inhibitors in the treatment of pulmonary hypertension.
Sildenafil and vardenafil have been marketed as PDE-5 inhibitors, among which sildenafil has been added to the indications of pulmonary hypertension abroad, and is a potent and highly selective PDE-5 inhibitor that can improve exercise tolerance, functional class and hemodynamics in patients with pulmonary hypertension. Adverse effects of sildenafil include headache, flushing, dyspepsia, and rhinorrhea.
Vardenafil, a new PDE-5 inhibitor, has also shown good efficacy in clinical trials in China. The effect of vardenafil on PDE5 inhibition is 20 times that of sildenafil, and the price is cheaper than sildenafil, but there are few international studies on it, and only small-scale studies suggest that it may be beneficial to patients with pulmonary hypertension. Long-term results need to be further studied.
4.Other new targeted therapies
(1) Statins
Basic and clinical studies have found that statins can reduce or even reverse pulmonary vascular remodeling and pulmonary arterial hypertension. The possible mechanisms include promoting NO and PGI2 production, inhibiting ET-1, angiotensin-II and thromboxane A2 (TXA2), reducing inflammatory response, and inhibiting thrombus formation in small pulmonary vessels. Clinical studies of simvastatin in the treatment of pulmonary arterial hypertension have initially confirmed its beneficial effects. Statins are relatively inexpensive and widely used in clinical practice, and may have good prospects for application in the treatment of patients with IPAH, but the results of large clinical trials are still lacking.
(2) Gene therapy
McMurtry et al. found that pulmonary artery survivin gene was overexpressed in six patients with idiopathic pulmonary hypertension, and gene therapy with inhaled adenovirus-carried survivin mutants in rats with wild lilybine-induced pulmonary hypertension reduced pulmonary vascular resistance, right ventricular hypertrophy and pulmonary artery mesenteric hypertrophy. In vitro and in vivo experiments showed that inhibition of survivin induced apoptosis and decreased proliferation of pulmonary artery smooth muscle cells, so inhibition of inappropriate expression of survivin in patients with pulmonary hypertension would be a new strategy for targeted treatment of pulmonary hypertension.
(3)Vasoactive intestinal peptide
VIP was originally a neuropeptide acting as a neurotransmitter and is now considered an effective vasodilator in the somatopulmonary circulation.Petkov et al. found that patients with idiopathic pulmonary hypertension were deficient in VIP in plasma and lung tissue, and that alternative treatment with this kinase substantially improved hemodynamic and prognostic parameters in patients without adverse effects. In the eight patients studied, VIP was able to reduce mean pulmonary artery pressure and increase cardiac output and mixed venous oxygen saturation. Therefore, VIP may become a new wedge for targeted therapy.
III. Combination therapy
According to the pathogenesis of pulmonary hypertension, the combination of drugs targeting different therapeutic targets will become a more effective treatment option for pulmonary hypertension. Some drugs such as PDE inhibitors can enhance and prolong the effect of other drugs such as prostacyclin. The goal of combination therapy is to fully utilize the effects of various drugs and minimize the occurrence of adverse effects. Current combination regimens often combine any two or three of iloprost, sildenafil and bosentan. Most experts currently recommend the combination of PDE-5 inhibitors and bosentan for the long-term treatment of patients. For patients with acute right heart failure and severe heart failure, a short-term combination of iloprost and a PDE-5 inhibitor may be considered, but note that this regimen is not suitable for long-term application.
Few large clinical trials have been completed to evaluate combination therapy, but promising results have been obtained in animal studies.