Medical Public Number: yigemed
Author Zhang Tianxin
Heart failure, referred to as heart failure, refers to a group of clinical syndromes in which ventricular filling and impaired ejection function are caused by abnormal cardiac structure or function, which ultimately leads to a decrease in ventricular pumping function. Cardiovascular diseases such as myocardial infarction, ischemia, hypertension or hereditary cardiomyopathy can lead to heart failure through the development of the end stage, with a high mortality rate and a very poor prognosis. Heart failure has become one of the problems affecting global health and has gradually increased with the aging process. Although significant progress has been made in the treatment of heart failure medications, the mortality rate within five years after the diagnosis of the disease has been found to be as high as 50%. At present, traditional medical treatment has been listed as the standard treatment for heart failure, but the treatment of heart failure is not only to improve symptoms, but more importantly to prevent and delay the development of ventricular remodeling.
Traditional anti-heart failure drugs
The ultimate goal of heart failure treatment is to reduce risk factors, improve heart failure symptoms, slow disease progression and improve survival rate. Traditional anti-heart failure drugs include beta blockers, diuretics, and renin angiotensin aldosterone system (RAAS) antagonists. Beta blockers inhibit heart failure caused by excessive release of catecholamines (such as shortness of breath, elevated blood pressure or weakness) by inhibiting chronic activation of the sympathetic nervous system. Diuretics are high blood pressure and heart failure. The main therapeutic drugs can rapidly improve the symptoms and signs of heart failure patients. RAAS system antagonists play an important role in the normal development of the cardiovascular system, functional homeostasis, maintenance of electrolyte balance and regulation of blood pressure.
New anti-heart failure drugs
2.1 New anti-heart failure drugs for pathophysiological characteristics
2.1.1 Angiotensin Receptor-enkephalinase inhibitor (LCZ696)
The most promising drug in the treatment of heart failure is a combination of valsartan (RAAS system antagonist) and enkephalin. A drug that acts as a peptidase inhibitor, sacubitril, which is commonly referred to as ARNi (angiotensin receptor-enkephalinase inhibitor). ARNi drugs are a novel neuro-endocrine inhibitor that acts as a dual blocker and is mainly used to inhibit the adverse effects of RAAS while preventing peptide degradation. A recent study of the ARNi drug LCZ696 showed that this class of drugs can improve heart failure patients and disease progression better than the traditional ACEI drug enalapril; the risk of sudden death is greatly reduced. In addition, the proportion of patients hospitalized with heart failure treated with LCZ696 was significantly lower, and the rate of treatment for intensive anti-heart failure was also significantly reduced. LCZ696 is well tolerated, but it can cause kidney damage, hyperkalemia, cough, and also increase the risk of hypotension. Although the incidence of these adverse reactions is extremely low, it continues to attract the attention of clinical researchers. Although more and more people are beginning to pay attention to its less adverse reactions, the drug-related research still provides very strong evidence for our clinical use of ARNi drugs.
2.1.2 Non-steroidal mineralocorticoid receptor antagonism (Finerenone)
A non-steroidal MRAs, the official name is BAY94-8862. From a phase IIa clinical study, Finerenone, like spironolactone, significantly reduced NT-proBNP levels in patients with chronic heart failure with reduced ejection fraction and patients with renal insufficiency, and more importantly, reduced hyperkalemia The incidence of symptoms and the deterioration of renal function. In addition, in patients with chronic heart failure with reduced ejection fraction, patients with type 2 diabetes, and/or patients with chronic kidney disease, the effects of Finerenone and eplerenone are similar, which can significantly reduce the level of NT-proBNP, but it can also be moderately reduced. The patient’s mortality rate and cardiovascular admission rate . A phase III clinical trial is currently being planned to evaluate the clinical value of Finerenone and eplerenone in the treatment of patients with chronic heart failure and diabetic nephropathy.
2.2 New anti-heart failure drugs acting on the heart β-adrenergic signaling pathway
In patients with heart failure, the activity and expression level of G protein-coupled receptor kinase 2 (GRK2) is significantly increased, which can promote the progression of heart failure by inactivating and down-regulating the adrenergic signaling pathway, and ultimately impair myocardial contractility. Promotes the death of cardiomyocytes. Inhibition of GRK2 by the use of important regulatory gene therapy methods can significantly improve the functional and morphological parameters of preclinical animal heart failure models. Recently, paroxetine has been shown to have both inhibitory effects of GRK2 as an antidepressant. The antidepressant was applied to the mouse model after myocardial infarction for 2 weeks, and it was found that the cardiac function was significantly improved, myocardial fibrosis was reduced, and the left ventricular structure was effectively preserved. In addition, paroxetine is more effective in the treatment of heart failure than the current traditional therapeutic drug beta blocker. After 2 weeks of treatment, the drug function is still maintained. However, it is still not considered that this kind of special medicine can be used in patients with heart failure, because the dose of heart failure treatment is often increased compared with the conventional medication. However, this study at least indicates that this small molecule GRK2 inhibitor is a potential drug for the treatment of heart failure.
2.2.2 M119 and Gallein
Other small molecule drugs acting on GRK2-Gβγ also include M119 and Gallein. In the acute mouse heart failure model caused by chronic β-ARs stimulation by the isoproterenol micro-osmotic pump, we were treated with M119 at the onset of heart failure. We found that the heart function of the mice was significantly improved, and the left ventricular wall thickness was improved. Significant normalization, marked reduction in cardiac hypertrophy, marked reduction in myocardial fibrosis and a marked decrease in the expression of GRK2. The complex gallein and M119 have the same effect, but their chemical composition is more stable, which has been shown to inhibit the heart failure process in pre-heart failure animal models. A clinically relevant study showed that administration of gallein in a heart failure model of pressure overload mice can significantly improve survival, preserve cardiac function, reduce cardiac hypertrophy, reduce myocardial fibrosis, and reduce the release of adrenaline catecholamines and reduce inflammatory markers. s level. Based on a comprehensive study of small animal heart failure models, we found that small molecule GRK2-Gβγ inhibitors can significantly improve cardiac function and inhibit heart failure progression. However, before such small molecule inhibitors are applied to clinical research, a large number of animal model related studies still need to be systematically carried out to continuously provide strong evidence.
Ivabradine is a current-specific selective inhibitor of sinus node, which can reduce sinus rhythm The patient’s heart rate, without affecting its myocardial contractility and atrioventricular conduction, can be applied to patients with heart failure who cannot tolerate beta blockers. On February 9, 2012, the European Medicines Regulatory Agency formally approved ivabradine for the treatment of chronic heart failure with concurrent systolic dysfunction. The basis for this indication was approved by the SHIFT study. The SHIFT study used the morbidity and mortality rate of patients with chronic heart failure to study the end point. A total of 6555 patients with moderate to severe heart failure with a heart rate greater than 70 beats/min in 37 countries were followed up for an average of 23 months. The addition of ivabradine to the treatment showed a significant reduction in mortality and hospitalization risk in patients with chronic heart failure. The clinical efficacy of ivabradine is considerable and has been used more and more widely in clinical practice. However, there are also corresponding adverse reactions, such as blurred vision, visual hallucinations and visual disturbances, but these adverse reactions are reversible reactions and will not affect the normal life of patients.
Heart failure is the end stage of development of many cardiovascular diseases, with high mortality and poor prognosis. It is a major treatment difficulty in clinical practice. Medical workers have not only paid attention to the improvement of symptoms in patients with heart failure, but also paid more attention to the long-term prognosis of such patients. The treatment aims to improve the quality of life of patients and improve the survival rate and mortality. In recent years, rapid progress has been made in the treatment of chronic heart failure. With the continuous development and introduction of new anti-heart failure drugs and medical technology, we have seen the dawn of treating chronic heart failure, but still need a lot of clinical research. To confirm, the future has a long way to go.