Efficacy of Varenicline Tartrate in Frequent Premature Ventricular Contractions

Myocardial infarction is the main cause of sudden cardiac death (Sudden cardiac death, SCD) . Frequent ventricular premature beats (referred to as "ventricular premature beats") that occur in patients with myocardial infarction are high-risk ventricular premature beats, which may induce ventricular tachycardia, ventricular flutter, and ventricular fibrillation and other lethal arrhythmias, thereby promoting SCD . In addition, frequent ventricular premature beats can also reduce the contractile function of the heart. How to effectively control frequent ventricular premature beats in the population with myocardial infarction is a major scientific problem that needs to be solved urgently. Regrettably, except for β-blockers (metoprolol, bisoprolol, and carvedilol), all existing anti-arrhythmic drugs may induce new arrhythmias or even lethal arrhythmias, and significantly increase the mortality rate. Therefore, there is an urgent need to explore the efficacy and safety of new anti-arrhythmic drugs in treating frequent ventricular premature beats after myocardial infarction.

The cholinergic system is a complex system that uses acetylcholine as a neurotransmitter to mediate the transmission of nerve electrical signals. It is distributed in the nervous system.The investigators' research found that there is also a complete endogenous cholinergic system in the ventricle, which includes key elements such as acetylcholine neurotransmitter vesicles, acetylcholine transporters, acetylcholine metabolic enzymes, and different subtypes of cholinergic receptors. Importantly, targeted intervention of this endogenous cholinergic system can effectively prevent and treat the above ventricular arrhythmias. This finding reveals a new mode of cardiac electrical pulse propagation, provides a systematic potential intervention target for the prevention and treatment of arrhythmias, and opens up a new direction in the field of arrhythmia research.

Varenicline is a highly selective partial agonist of neuronal nicotinic cholinergic receptors (also known as nicotine receptors), which can highly selectively bind to specific subtypes of neuronal nicotine receptors, stimulate nicotine receptors to produce mild to moderate nicotine-like effects, stimulate a small amount of dopamine release.

The investigators' preclinical research found that varenicline can highly selectively bind to the α₄β₂ nicotine receptors on ventricular cardiomyocytes, induce ventricular cardiomyocytes to produce inward current, increase the conduction velocity of ischemia-reperfusion injured myocardial tissue, while reducing the conduction dispersion in the myocardial injury area, thereby reducing the ventricular premature beats induced by ischemia-reperfusion injury by 90%, reducing the ventricular tachycardia and ventricular fibrillation in the ischemia-reperfusion model of isolated rat hearts by 83%, and reducing the vortex wave reentry in the infarct risk area of the isolated hearts of myocardial infarction rats by 83%. Excitingly, varenicline at the same concentration does not prolong the action potential duration of ventricular cardiomyocytes, does not prolong the QT interval on the electrocardiogram, and does not affect the rhythm, atrioventricular conduction velocity, and ventricular conduction dispersion under the basic state of the heart, suggesting that varenicline may mainly act on the injured myocardial cells under pathological conditions, and play a role in terminating rapid ventricular arrhythmias by increasing the conduction velocity and reducing the dispersion of conduction in the injured myocardial cells.Importantly, the principal investigator of this project has led the research group to carry out an exploratory single-arm clinical study of varenicline in the treatment of frequent ventricular premature beats. Therefore, the investigators plan to carry out a multicenter, randomized, double-blind, placebo-controlled clinical trial of varenicline in the treatment of frequent ventricular premature beats after myocardial infarction to further verify its efficacy and safety.


Eligibility Criteria:
Inclusion Criteria:

1. Aged between 18 and 80 years old (inclusive).
2. Premature ventricular contractions of ≥1000 times/average 24-hour revealed by screening (72-hour Holter monitoring).
3. Definite diagnosis of myocardial infarction for more than 4 weeks, with NYHA Class I-II.
4. Maintained on Metoprolol Succinate Sustained-release Tablets. (If other types of beta-blocker therapy were being used before screening, they must be replaced with Metoprolol Succinate Sustained-release Tablets.)
5. Understand and comply with the study procedures and methods, and sign the informed consent form.

Exclusion Criteria:

1. Myocardial infarction occurring within 4 weeks.
2. NYHA Class III-IV.
3. Use of amiodarone within 1 month before screening.
4. Use of antiarrhythmic drugs, or traditional Chinese medicine, Chinese patent medicine for arrhythmia other than amiodarone within 1 week prior to screening.
5. Sustained ventricular tachycardia, ventricular flutter, or ventricular fibrillation detected during screening (non-sustained ventricular tachycardia does not need to be excluded).
6. Sick sinus syndrome without pacemaker implantation, II-III degree atrioventricular block, or bundle branch block bilateral.
7. Moderate to severe bronchial asthma or severe chronic obstructive pulmonary disease.
8. Severe renal impairment (eGFR less than 30 mL/min/1.73 m²).
9. Hyperthyroidism.
10. Severe sequelae of stroke.
11. Epilepsy, schizophrenia, or depression.
12. Pregnant or breastfeeding women, or those with a positive blood pregnancy test result before randomization.
13. Combined cancer or other diseases, with an expected life expectancy of less than 1 year.
14. Perioperative period of cardiothoracic surgery (1 week before surgery to 2 weeks after surgery).
15. Severe electrolyte disturbance.
16. Digitalis poisoning.
17. Known hypersensitivity to varenicline tartrate tablets or their excipients.
18. History of smoking and cessation for less than 1 year.
19. Individuals taking varenicline tartrate tablets for smoking cessation.
20. Currently participating in other clinical studies.
21. Other conditions making the subjects unsuitable for enrollment as determined by the investigator.