Recently, there have been online rumors about some recovered COVID-19 "positive" patients who started intense exercise shortly after recovery and then suddenly died due to myocarditis. Myocarditis is an inflammatory lesion occurring in the myocardium, and the most common cause of myocarditis is virus. Currently, it is known that more than 30 viruses can cause myocardial damage, including the familiar influenza virus, and of course, the novel coronavirus is one of them. However, most myocarditis has a good prognosis and can be cured. The combination of direct viral damage and cardiac damage caused by the host immune response is the pathophysiology of COVID-related myocarditis. COVID-related myocarditis diseases are divided into three types: acute, chronic, or fulminant. Among them, fulminant myocarditis is a sudden and severe disease that can lead to acute heart failure, cardiogenic shock, and life-threatening arrhythmias.
Heart failure (HF) is a complex clinical syndrome caused by the progression of various heart diseases to a severe stage, often accompanied by symptoms such as dyspnea, fluid retention, and reduced exercise tolerance. It has become the leading cause of death worldwide. Currently, there are many drugs used in the treatment of heart failure, such as angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and diuretics, which have been widely used in clinical practice. However, the therapeutic effect is limited, so people are still committed to discovering new therapeutic drugs or new uses of drugs.
Traditional Anti-HF Drugs
The traditional drugs for treating HF include ACEI, ARB, beta-blockers, aldosterone receptor blockers, diuretics, nitrates, positive inotropic agents, and vasodilators. Among them, the combination of ACEI (or ARB), beta-blockers, and aldosterone receptor blockers can effectively improve the prognosis of patients, which is known as the "golden triangle" of HF treatment.
Commonly used RAAS inhibitors include ACEI and ARB. ACEI can inhibit the activity of angiotensin-converting enzyme and block the conversion of Ang I to Ang II. Captopril and enalapril are commonly used ACEI drugs in clinical practice. However, since they can inhibit the metabolism of bradykinin, they may cause adverse reactions such as dry cough. Therefore, for patients who are intolerant to ACEI, ARB needs to be used, such as candesartan and telmisartan. ARB can selectively block the binding of Ang II to AT1 receptors and inhibit the release of aldosterone. The effect of ARB on improving heart function is similar to ACEI, but it does not affect the metabolism of bradykinin. Although it lacks the protective effect of bradykinin on the body, it can reduce the incidence of adverse reactions such as dry cough.
β-blockers antagonize the stimulatory effects of catecholamines by occupying β-receptors, effectively reducing heart rate and protecting myocardial cells. New β-blockers, such as metoprolol and bisoprolol, can improve endothelial function by enhancing arterial vasodilation and reducing monocyte adhesion and migration. They can also reduce the number and activity of inflammatory cells, which is beneficial for metabolism and can be used for the prevention of atherosclerosis, with fewer adverse reactions.
Diuretics are the only drugs that can effectively eliminate fluid retention. Traditional diuretics are divided into loop diuretics and thiazide diuretics, which control water and sodium retention by inhibiting renal tubular reabsorption. The new diuretic tolvaptan is a highly selective vasopressin V2 receptor antagonist that can reduce the expression of aquaporin 2, thereby preventing water reabsorption in the collecting duct, increasing urine output, and has the effect of water excretion without sodium excretion. It does not lead to electrolyte imbalances such as hypokalemia and hyponatremia, nor deterioration of renal function, and is more effective for HF patients with hyponatremia.
Nitrate drugs (such as nitroglycerin) are commonly used vasodilators in clinical practice. After activation, they generate NO, which can activate soluble guanylate cyclase, increase cGMP-dependent kinase/cyclic nucleotide-gated ion channels, reduce intracellular free Ca2+, and desensitize smooth muscle cells to Ca2+, causing vasodilation and rapid relief of symptoms. However, continuous use can easily lead to drug resistance, resulting in reduced efficacy, dysfunction of vascular endothelial cells, and even enlargement of myocardial infarction area. Therefore, the rational clinical application of nitrate drugs is particularly important.
Nicorandil is a drug with dual effects of opening ATP-sensitive potassium ion channels and similar to nitrates. It can reduce the risk of complications associated with interventional therapy and also improve symptoms and blood flow in patients with acute HF.
Positive inotropic drugs include digitalis and non-digitalis drugs. Digitalis drugs, by inhibiting the Na+/K+-ATP enzyme on the myocardial cell membrane, can increase intracellular Na+ levels, thereby promoting Na+/Ca2+ exchange, increasing intracellular Ca2+ levels, and enhancing myocardial contractility. At the same time, they can inhibit renal Na+/K+-ATP enzyme and parasympathetic afferent nerves, suppressing renin secretion, renal tubular reabsorption of sodium, and sympathetic excitability, thus exerting an anti-heart failure effect. Digoxin is a digitalis positive inotropic drug that does not increase the mortality rate of HF patients with long-term use, and is recommended for patients who still have HF symptoms despite using other anti-HF drugs. Currently, long-term use of non-digitalis positive inotropic drugs for HF treatment is not recommended. Milrinone is a phosphodiesterase inhibitor with vasodilator and cardiotonic effects. By inhibiting phosphodiesterase, it increases the concentration of adenosine phosphate in myocardial cells, increases calcium concentration, and enhances myocardial contractility. It can be used for patients who are not suitable for catecholamines. Sodium nitroprusside is a commonly used vasodilator that can evenly dilate blood vessels throughout the body, with rapid onset. It can improve left ventricular compliance, reduce myocardial oxygen consumption and afterload, and alleviate symptoms of left HF in a short time. It can be used in combination with various drugs. Clinical studies have shown that sodium nitroprusside combined with dopamine, acetylstrophanthin, and other positive inotropic drugs can effectively relieve acute HF symptoms, improve lung function, and reduce pulmonary edema.
New Anti-HF Drugs
1. Sodium-Glucose Cotransporter 2 (SGLT-2) Inhibitors
Sodium-glucose cotransporters are primarily distributed in the small intestine, myocardial cells, and renal tubular epithelial cells, among which SGLT-2 is located in the S1 segment of the proximal tubules in the kidney. It is a transporter with low affinity but high transport capacity, accounting for the reabsorption of 80% to 90% of the glucose filtered by the glomerulus. Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are a new class of oral antidiabetic drugs. Their primary mechanism of action is to inhibit the reabsorption of glucose in the proximal tubules of the kidneys, thereby increasing urinary glucose excretion and lowering blood glucose levels. Recent research has found that in addition to preventing the kidneys from reabsorbing glucose, SGLT-2 inhibitors also promote the excretion of sodium in urine. This osmotic diuresis effect reduces plasma volume, lowers blood pressure, and decreases preload and afterload on the heart, thus relieving vascular wall stress and improving myocardial diastolic function. Therefore, SGLT-2 inhibitors can improve heart failure symptoms and cardiac function. The improvement of hemodynamics by SGLT-2 inhibitors is one of the important mechanisms for their benefits in heart failure. This dual mechanism of glucose and sodium excretion enables SGLT-2 inhibitors to inherently possess the ability to lower blood sugar and reduce the risk of heart failure. In recent years, with the accumulation of evidence on the cardiovascular benefits of SGLT-2 inhibitors, they have been shown to significantly reduce the risk of hospitalization for heart failure in patients with type 2 diabetes, regardless of whether they have a high risk of heart failure or a history of heart failure.
2. Angiotensin Receptor-Neprilysin Inhibitor
Angiotensin receptor-neprilysin inhibitor is a novel drug for the treatment of heart failure. It has a dual role of inhibiting neprilysin degradation and antagonizing angiotensin II receptors. Currently, there is increasing evidence of its application in heart failure with reduced ejection fraction (HFrEF), and it has been considered the preferred choice for HFrEF in heart failure-related guidelines, expert recommendations, or consensus.
Sacubitril is a prodrug of neprilysin inhibitor, which is decomposed into neprilysin inhibitor sacubitrilat (LBQ657) by carboxylesterase in the liver. This inhibits the degradation of natriuretic peptides by neprilysin, exerting vasodilator, increasing glomerular filtration rate, natriuretic, and diuretic effects. Valsartan inhibits the renin-angiotensin-aldosterone system (RAAS) by inhibiting angiotensin II type 1 (AT1) receptors. Sacubitril valsartan sodium is rapidly decomposed in the body after oral administration, has a high binding rate to plasma proteins, has a limited degree of penetration through the blood-brain barrier, and can be excreted through both liver and kidney channels. Cytochrome P450 enzymes (CYP450) rarely mediate the metabolism of sacubitril and valsartan, so their combination with drugs that affect CYP450 does not affect the pharmacokinetics of sacubitril valsartan sodium. Bioequivalence test results show that valsartan in sacubitril valsartan sodium has higher bioavailability compared to valsartan alone.
3. Myocardial Myosin Activator
Omecamtiv mecarbil (OM) is a novel, selective, and specific myocardial myosin activator. Myocardial myosin is a cytoskeletal motor protein in myocardial cells that directly converts chemical energy into mechanical force to enable myocardial contraction, enabling the heart to perform its normal contractile function. OM selectively activates the S1 subunit of myocardial myosin by binding to the catalytic region of myosin ATPase, accelerating the enzymatic cycle of actin, enhancing ATP conversion, and accelerating the actin-myosin cycle, resulting in stronger myocardial contractility and improved cardiac function. This differs from traditional drugs that increase intracellular calcium levels to exert positive inotropic effects. Preclinical studies have shown that myocardial myosin activators can increase myocardial contractility without affecting myocardial intracellular calcium concentration or myocardial oxygen consumption. In animal models, OM can reduce peripheral vascular resistance, mean left arterial pressure, and left ventricular end-diastolic pressure. Preclinical and clinical data indicate that OM can improve cardiac function, reduce ventricular wall stress, reverse ventricular remodeling, and promote sympathetic nervous system attenuation.
4. Novel Soluble Guanylate Cyclase (sGC) Agonist
Guanylate cyclase is primarily located in the cell membrane and cytoplasm, existing in a soluble form within the cytoplasm. The biological messenger NO can activate the soluble guanylate cyclase (sGC) - cyclic guanosine monophosphate (cGMP) signaling pathway. The NO-sGC-cGMP signaling pathway plays an important role in vasodilation, anti-proliferation of vascular smooth muscle cells, and anti-platelet aggregation. After NO is produced by the vascular endothelium, it further stimulates the production of cGMP mediated by sGC. The myocardial endothelium is sensitive to NO and can regulate contractile and relaxant functions by increasing intracellular cGMP levels. Vericiguat is the world's first soluble guanylate cyclase agonist drug developed for the treatment of chronic heart failure patients and was approved by the FDA in January 2021 for the treatment of cardiac insufficiency.
5. Mineralocorticoid Receptor Antagonist (MRA)
MRA is one of the cornerstones in the treatment of chronic heart failure. Finerenone, a novel highly selective non-steroidal MRA, has shown promising results in the treatment of cardiovascular diseases and kidney diseases, with numerous advantages compared to traditional steroidal MRAs. Finerenone differs from steroidal MRAs in terms of tissue distribution, mineralocorticoid receptor (MR) binding, cofactor recruitment, and downstream gene expression, effectively blocking inflammation, fibrosis, and adverse cardiovascular and kidney events mediated by excessive MR activation.
As a highly selective non-steroidal MRA, finerenone possesses high specificity and does not exhibit L-type calcium channel activity, with no significant impact on 65 different enzymes and ion channels. Clinical studies have fully demonstrated the cardiorenal protective effects of finerenone in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). For patients with T2DM and CKD of varying severity, finerenone provides benefits, and its cardiovascular benefits are not affected by the baseline levels of eGFR or UACR. Currently, finerenone has been successfully launched in the United States and is expected to be available in China soon, benefiting more patients with T2DM and CKD, and providing more options for patients with heart failure.
References
[1] Yang Jiuliang. Research Progress on New Drugs for the Treatment of Heart Failure [J]. Medical Theory and Practice, 2021, 34(11): 1830-1832. DOI: 10.19381/j.issn.1001-7585.2021.11.010.
[2] Li Meng, Lei Shuai, Zhang Chenping, Li Yuhua, Wei Xinzheng, Shan Qingyun, Hu Huiyuan, Hao Liying. Research Progress in Drug Treatment for Heart Failure [J]. Journal of China Medical University, 2022, 51(05): 455-458.
[3] Peng Juan, Fan Linlin, Li Ranyi, Li Xiaoyu, Lv Qianzhou, Zou Yunceng. Research Progress in Drug Treatment for Heart Failure [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(04): 373-381.
About the Author
Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.
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