Atrial Fibrillation and Cardioversion Drugs

Abstract

The heart is constantly and harmoniously alternating contractions and diastolic activities, and these mechanical activities are stimulated by the heart’s electrical activity. Atrial fibrillation results in changes to atrial myocytes, with early but potentially reversible alteration in ion channels. Atrial fibrillation is one of the arrhythmias characterized by mechanical dysfunction caused by uncoordinated contraction of atrium, and it is also the most common and serious arrhythmia in clinical practice, which can cause serious complications, such as hemodynamic changes and cerebral embolism. Therefore, cardioversion drugs have become a research hotspot in the field of arrhythmia. Medical treatment of atrial fibrillation includes cardioversion, control of ventricular rate, and anticoagulation. This chapter focuses on drug cardioversion.

1. Introduction

The heart is constantly and harmoniously alternating contractions and diastolic activities, and these mechanical activities are stimulated by the heart’s electrical activity. Atrial fibrillation results in changes to atrial myocytes, with early but potentially reversible alteration in ion channels. Later changes include structural remodeling with myocyte degeneration, myocardial fibrosis, left atrial enlargement, and heterogeneity of conduction [1]. The heart’s electrical activity originates the sinus node, and the impulses are conducted to the right and left atrium, then to the atrioventricular node, and finally to the ventricular muscle along atrioventricular bundle, left and right bundle branches, and the Purkinje fiber network (shown in Figure 1). Cardiac arrhythmia occurs when the activity of the entire heart becomes too fast, too slow, or irregular or the sequence of activities of each part is disordered. Arrhythmias are classified in a wide variety of categories. According to its occurrence principle, it can be divided into two categories: abnormal impulse origin and abnormal impulse conduction. According to the site of origin, it can be divided into sinus, atrial, atrioventricular junction, and ventricular arrhythmia. According to the speed of heart rate during arrhythmia, it can be divided into fast and slow arrhythmia. Some scholars also propose to divide arrhythmias into two categories: benign and malignant, or lethal, potentially fatal and benign.

Figure 1.

Electrical activity of the heart.

2. Tachyarrhythmias

Tachyarrhythmias include premature atrial beats, atrial tachycardia (atrial tachycardia), atrial flutter (atrial flutter), and atrial fibrillation. Atrial fibrillation is the most common clinically significant arrhythmia, often associated with structural heart disease. Its prevalence increases with age and will continue to increase over the next 30 years, especially in countries with medium sociodemographic indices, becoming one of the greatest epidemic and public health challenges. Atrial fibrillation may cause hemodynamic disturbances and thromboembolic events. It has been reported that the prevalence of atrial fibrillation in the general population is 0.4 to 1.0%, the prevalence of people over 60 years old is 2–4%, and the incidence of elderly people over 80 years old can reach 8–10% [2]. When atrial fibrillation occurs, the auxiliary pump effect of the atria is lost, which reduces the cardiac output by 15–30%. This chapter mainly focuses on the pathogenesis of atrial fibrillation and its cardioversion drugs.

2.1 Epidemiology of atrial fibrillation

The number of cases of atrial fibrillation worldwide was estimated at 37.6 million in 2017 and is expected to increase by more than 60% by 2050 [3, 4]. According to the 2010 Global Burden of Disease Study by Chung et al., it is estimated that at least 33 million people worldwide had atrial fibrillation as of 2010, and data analysis showed that from 1990 to 2010, the prevalence and incidence of atrial fibrillation in both men and women after age adjustment increased significantly [4]. The prevalence of atrial fibrillation in Europe is also high, with studies showing that there will be about 9 million cases by 2016, and the number of patients with atrial fibrillation in Europe will increase significantly in the next few decades and may even increase 1-fold between 2010 ~ 2060 [4].

2.2 Causes of atrial fibrillation

There are many causes of atrial fibrillation, mainly coronary heart disease and myocardial diseases in developed countries, and rheumatic valvular heart disease in developing countries. A small percentage of atrial fibrillations with no clear causes is called isolated or idiopathic atrial fibrillation. Common causes are as follows:

1. Hypertension Patients with AF typically have other concomitant cardiovascular risk factors—hypertension being one of the commonly associated conditions with a prevalence of up to 90% in major clinical trials of AF [5]. The occurrence of atrial fibrillation is related to the abnormal electrophysiological of hypertrophic myocardium, hypertrophic myocardial ischemia, and hypertrophic myocardial fibrosis caused. Because of myocardial hypertrophy and fibrosis, decreased ventricular compliance and increased atrial pressure, thereby atrial fibrillation was induced by atrial electrophysiology disorder.

2. Coronary heart disease In coronary angiography shows that there is 0.6 to 0.8% of atrial fibrillation in obvious coronary artery stenosis, and atrial fibrillation in acute myocardial infarction accounted for 10 ~ 15%.

3. Rheumatic heart disease remains a common cause of atrial fibrillation, particularly mitral stenosis with insufficiency. Among them, 41% of patients with mitral stenosis have atrial fibrillation, and aortic valve lesions have a small chance of atrial fibrillation. The average age at which patients develop atrial fibrillation is about 37 years, mostly women.

4. Heart disease of pulmonary origin The incidence of atrial fibrillation in lung disease is reported as 4–5%. Paroxysmal causes are related to recurrent pulmonary infections, chronic hypoxia, acidosis, and electrolyte abnormalities.

5. Congenital heart disease In congenital heart disease, atrial fibrillation is seen in cases when atrial septal defect is present.

6. Cardiomyopathy Atrial fibrillation can occur in various types of cardiomyopathies, and the incidence is between 10–50%, more common in adults, and can also occur in children. Primary congestive cardiomyopathy is predominant, accounting for about 20%.

7. Hyperthyroidism Atrial fibrillation is one of the main symptoms of hyperthyroidism, the incidence of atrial fibrillation in hyperthyroid patients is 15% ~ 20%, and the elderly with hyperthyroidism may have organic damage to the myocardium prone to chronic atrial fibrillation. Atrial fibrillation may be the first presentation in some patients.

8. Preexcitation syndrome also called Wolff-Parkinson-White (WPW). It should be mentioned that preexcitation syndrome and atrial fibrillation are more likely to occur together. The literature reports that the probability of atrial fibrillation and preexcitation syndrome occurring simultaneously is about 12 ~ 18% [6]. The incidence of atrial fibrillation with ventricular preexcitation is generally considered to be age-dependent, rarely in children, and higher in older patients.

2.3 Mechanism of atrial fibrillation

Atrial fibrillation has undergone theories such as “multiple microwave reentry,” “rapid release of impulse foci,” “local venous foci driven with fibrillation-like conduction,” and the recent “pulmonary vein-left atrial reentry.” Single or paired premature atrial beats or tachycardia due to ectopic focal rapid impulse discharge is one of the most common triggers of atrial fibrillation, and multiple wave reentrants are the main mechanism by which atrial fibrillation is maintained.

2.3.1 Myocardial fibrosis

Studies have confirmed that the pathological basis of the pathogenesis of atrial fibrillation is related to myocardial fibrosis and the reduction of atrial muscle tissue content, the left atrium enlarges when atrial fibrillation occurs, aggravates myocardial interstitial fibrosis, reduces the content of healthy atrial muscle tissue and the number of cells, remodeling the extracellular matrix is obvious, and the difference in the refractory period of atrial muscle is significant. The dilated atria activate the RAAS system, which together contributes to the onset and maintenance of atrial fibrillation.

2.3.2 Molecular biological mechanisms

Atrial fibrillation is a progressive condition that begins with paroxysmal and becomes persistent or permanent. Structural and molecular biological changes that occur in the central atrium of the course of the disease are called atrial remodeling. Early changes are manifested as changes in electrophysiology and ion channel characteristics, also known as electro remodeling. Electro remodeling, predominantly reduced L-type calcium channels, predisposes to atrial muscle fibrillation [7]. In the late stage of atrial reconstruction, it is manifested as fibrosis, starch deposition, apoptosis, and other changes in the tissue structure of the atrium, which is called remodeling. Ultrastructural changes in atrial myocytes and fibrosis of the myocardial interstitium, as well as redistribution of collagen fibers, manifested as atrial myocyte hypertrophy, perinuclear glycogen accumulation, atrial myocyte lysis, and changes in atrial connexin at the cellular level. At the molecular level, it is manifested as degradation of structural proteins and contractile proteins, disordered arrangement of slit junction proteins, and degradation of ion channel proteins. Atrial structure remodeling is macroscopically manifested as atrial enlargement.

2.3.3 Molecular genetic mechanism

In 1928, Wolff and White observed that the incidence of atrial fibrillation has a familial tendency to cluster, and there have been reports of familial atrial fibrillation in China since 1979. Seen in: (1) Gene variation on chromosome 11: Chen Yihan et al. [8] reported in the journal science that the S140G mutation of the KCNQ1 gene in a Chinese family line of atrial fibrillation was located, and the KCNQ1 gene was localized in the chromosome 11pl5.5 region. With the application of gene correlation analysis and gene mapping cloning technology, more and more studies have found that the onset of atrial fibrillation is related to the polymorphism of multiple genes. Gai [9] and other scholars found that TIMP2-418G > C gene polymorphisms are associated with the incidence of atrial fibrillation in Han hypertensive heart disease people. CMA1 polymorphisms may be associated with AF, and the rs1800875 GG genotype might be a susceptibility factor for AF in Chinese people [10].

2.3.4 Oxidative stress

In recent years, oxidative stress has been considered to be one of the important mechanisms for the development of atrial fibrillation, and reactive oxygen species (ROS) are produced by oxidative metabolism. The prevalence and incidence of atrial fibrillation have been found to be related to the redox potential of the oxidative stress markers called glutathione and cysteine, with a 10% increase in the prevalence of atrial fibrillation [11]. In addition to the electrical remodeling stimulated by the mechanisms described, ROS have also been demonstrated to contribute to atria structural remodeling. Researchers from Slovakia showed that hydroxyl radicals can alter the myofibrillar protein structure and function, promoting myocardial injury and further contributing to the formation of a fertile substrate for the development of arrhythmias. In addition to the electrical remodeling stimulated by the mechanisms described, ROS have also been demonstrated to contribute to atria structural remodeling. Other studies have shown [12] that RyR2 is oxidized in the atria of patients with chronic atrial fibrillation compared to individuals with sinus rhythm, and changes in RyR2 and production of mitochondrial ROS create a vicious cycle in the development of AF.

2.3.5 Inflammation and atrial fibrillation

Li et al. have found that elevated serum CRP levels are positively correlated with atrial fibrillation [13]. Elevated plasma CRP concentrations have not in themselves been shown to increase the risk of atrial fibrillation, and CCL2 values obtained suggest that inflammation may be the result of AF [14]. Recent studies have shown that the P wave dispersion and hs-CRP levels of paroxysmal atrial fibrillation are significantly higher than those in the control group [15]. In addition, inflammation promotes thrombotic load, stimulates platelet formation, increases thrombin sensitivity, and promotes the transformation of fibrinogen.

3. Clinical symptoms of atrial fibrillation

The clinical manifestations of atrial fibrillation are diverse and can be symptomatic or asymptomatic. This is true even for the same patient. The symptoms of atrial fibrillation depend on a variety of factors, including ventricular rate at the time of attack, cardiac function, concomitant conditions, duration of atrial fibrillation, and sensitivity to perceived symptoms. Most patients experience palpitations, dyspnea, chest pain, thinness, and dizziness. Some people with atrial fibrillation have no symptoms and are only detected during a physical examination or by chance serious complications of atrial fibrillation such as stroke, embolism, or heart failure. Some patients have symptoms of left ventricular dysfunction, which may be secondary to atrial fibrillation with a persistent rapid ventricular rate. Syncope is uncommon but is a serious complication that often suggests sinus node dysfunction and atrioventricular conduction abnormalities or post-thrombosis exfoliation during atrial fibrillation transition.

4. Classification of atrial fibrillation

According to the time and characteristics of the onset, atrial fibrillation can be divided into primary atrial fibrillation, paroxysmal atrial fibrillation, persistent atrial fibrillation, long-term persistent atrial fibrillation, or permanent atrial fibrillation (Eur Heart J 2010, 31: 2369–2429), which is a commonly used classification method in clinical practice.

5. Treatment of atrial fibrillation

Rhythm control and ventricular rate control are the two major strategies for the treatment of atrial fibrillation. Theoretically, it is better to restore and maintain sinus rhythm, but it should be appropriate for individual and disease-specific treatment, and it is necessary to fully weigh the benefits of conversion to patients and the disadvantages of antiarrhythmic drugs. Drugs remain the first-line treatment of choice for controlling heart rhythm and ventricular rate.

The main principles of atrial fibrillation treatment are: (1) try to find the basic causes of atrial fibrillation for treatment, such as correcting heart valve lesions, correcting hypotension, improving heart function, alleviating myocardial ischemia, controlling hyperthyroidism, etc., (2) elimination of predisposing factors, conversion, and maintenance of sinus rhythm, (3) prevention of recurrence, (4) control ventricular rate, and (5) prevent embolic complications, reduce the disability rate, improve the quality of life of patients, and prolong life.

5.1 Treatment of causes

Treatment of the cause of atrial fibrillation is critical, and aggressive treatment of primary heart disease is the easiest way to convert atrial fibrillation to sinus rhythm and maintain it for a long time. Even if the cause cannot be cured, it is important to resolve the hemodynamic abnormality. In cases of coronary heart disease, hypertension, cardiomyopathy, etc., such as improvement of myocardial ischemia, correction of heart failure, good blood pressure control, the chance of atrial fibrillation conversion is increased, and sinus rhythm can be maintained for a long time. In patients with mitral valve stenosis and atrial fibrillation in rheumatic heart disease, many patients are able to maintain sinus rhythm long after cardioversion after surgery to remove the cause.

5.2 Upstream treatment

Drugs for upstream treatment include angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs), aldosterone antagonists, statins, polyunsaturated fatty acid (PUFA), and LCZ696. It can reduce myocardial fibrosis and heterogeneity in the electrical activity of the atrial myocardia. Studies have shown that ACE inhibitors and ARBs can prevent the shortening of the effective refractory period of the atrium, inhibit the early remodeling of the atria [16], and inhibit the occurrence of atrial fibrillation. On the one hand, it may be related to reversal of atrial structural remodeling and electrical remodeling, and inhibition of atrial fibrillation may be achieved through anti-inflammatory and antioxidant effects [17]. Mariscalco G [18] et al. studied 530 patients undergoing cardiac surgery and found that preoperative supplementation with ω-3 PUFA may reduce the incidence of early postoperative AF, but not the incidence of late AF. Studies have shown LCZ696 [19] can simultaneously regulate the natriuretic peptide system and RAAS system, curb the deterioration of heart failure and atrial fibrillation, and combat the pathophysiological changes, such as myocardial remodeling.

5.3 Drug therapy

Medical treatment of atrial fibrillation includes cardioversion, control of ventricular rate, and anticoagulation. This chapter focuses on drug cardioversion.

5.3.1 Drug cardioversion

At present, the drugs commonly used in domestic clinical practice are Class Ic and Class III antiarrhythmic drugs, including Flecainide, Propafenone, Morecizidine, Iblit, vinacalan, dronedarone, ranolazine, and ivabradine.

5.3.1.1 Indications for drug cardioversion

(1) persistent atrial fibrillation is less than half a year, or there is no blood clot in the atrium confirmed by ultrasonography, (2) for patients with paroxysmal atrial fibrillation, it can be treated during the onset of atrial fibrillation or between episodes, and (3) maintain sinus rhythm with drugs after electrical cardioversion.

5.3.1.2 Drug selection

The clinical drug selection principles that should be observed when performing drug reversion in atrial fibrillation are:

1. Paroxysmal atrial fibrillation with or without organic heart disease (but not coronary heart disease and left ventricular hypertrophy) can choose Class Ic antiarrhythmic drugs, such as propafenone, followed by sotalol and ibutilide. If it is still ineffective, amiodarone is an option, but it may also be preferred.

2. Patients with organic heart disease or heart failure: Amiodarone is the drug of choice.

3. Patients with coronary heart disease (including acute myocardial infarction) and atrial fibrillation: Amiodarone should be preferred and sotalol should be selected.

4. Vagus nerve-mediated atrial fibrillation: Amiodarone, amiodarone and flecainide, can also be used.

It should be noted that patients with organic heart disease and atrial fibrillation, especially with coronary heart disease and heart failure, should try to use amiodarone and sotalol, and avoid use the Class Ia (quinidine) and Ic (propafenone) drugs.

The success rate of atrial fibrillation conversion by injecting amiodarone is 34% ~ 69%, and the success rate of oral conversion is 15 ~ 40%, but its clinical application is limited due to its serious side effects.

Intravenous propafenone can convert atrial fibrillation, which has a good effect on recent occurrences, is characterized by fewer adverse reactions, and should be used with caution in patients with organic heart disease.

Recent studies have shown that Ibutilide is a new fast-acting safe class III antiarrhythmic drug with unique ion channel activity. It has intravenous medication that can effectively terminate atrial tachycardia, atrial flutter, and atrial fibrillation, and has the characteristics of fast onset, high efficacy, and fast metabolism. In particular, the success rate of atrial flutter and atrial fibrillation conversion within 2 weeks is significantly higher than that of chronic atrial flutter and atrial fibrillation. Intravenous administration of Ibutilide 1 ~ 2 mg takes effect in 30 to 40 min. Compared with electrical cardioversion, there is no need for anesthesia, which is more convenient and safer to use, and there is no need to adjust the dose for patients with liver and kidney dysfunction. Zhao Jingjing et al. [20] showed that ibutilide combined with radiofrequency ablation has a good therapeutic effect on elderly patients with atrial fibrillation, which can improve the conversion rate after treatment, reduce the recurrence rate after surgery, and reduce the damage to the myocardium. As a novel potassium channel blocker, Ibutilide can inhibit the delayed rectified potassium (Ikr) current that is rapidly activated during repolarization, which is different from other class III antiarrhythmic drugs, Ibutilide also has the effect of promoting slow Na + influx and Ca2+ influx during the plateau phase, counteracting the effect of partial K+ outflow, and prolonging the plateau phase of cardiomyocytes action potential. Prolong the time course of myocardial action potential, prolong the QT interval and effective refractory period, and affect the entire repolarization process. The effect of Ibutilide on the atria is more obvious than that of the ventricle, its effect is 10 times stronger and can extend the effective refractory period of the atrial muscle by 90–110%, Ibutilide will become an important drug for the treatment of atrial tachycardia, atrial flutter, and atrial fibrillation in the future, bringing benefits to patients with atrial arrhythmia. It takes effect about 1 hour after intravenous injection, and its effect of conversion to atrial flutter is better than that of atrial fibrillation. For long-term atrial fibrillation, the literature reports that about 4% of patients develop torsion ventricular tachycardia after injection, and it is more likely to occur in women, so it should be performed under supervision and the post-medication monitoring time should not be less than 5 hours.

At present, quinidine and procainamide are rarely used for conversion, mainly due to their serious adverse effects, and the effect of disopyramide and sotalol conversion to atrial fibrillation is uncertain.

In recent years, new drugs have gradually occupied a certain position in the conversion of atrial fibrillation, such as donedarone and venakalan have a good effect on the conversion of atrial fibrillation.

Dronedarone is a new class III antiarrhythmic drug, its structure is similar to amiodarone, but does not contain iodine, few extracardiac adverse reactions, and the usual dose is 400 mg twice a day. It can reduce the hospitalization rate of cardiovascular disease and arrhythmia mortality rate in patients with atrial fibrillation, but the effectiveness of maintaining sinus rhythm is not as good as amiodarone, guidelines recommend the first-line drug for nonpermanent atrial fibrillation of mild or nonorganic heart disease, but contraindicated in NYHA grade III ~ IV heart failure.

Vernakalant, the first atrial selective atrial fibrillation treatment drug currently on the market, acts on both sodium and potassium channels. The drug is metabolized by the liver pigment P4502D6 isoenzyme, with a half-life of about 4 ~ 8 hours, and is not affected by age, kidney function, and other drugs. The drug has a low incidence of side effects. Vinakalan is currently approved by the European Union for the relapse of adult patients with newly developed atrial fibrillation cardioversion therapy. (onset ≤7 days in nonsurgical patients and ≤ 3 days in postoperative patients).

5.3.2 Combined application of drugs

The combined application of two different antiarrhythmic drugs has an accumulation of effects, a dose reduction, and a decrease in the incidence of adverse reactions, but attention must be paid to their mutual effects. Clinically, β receptor blockers, non-dihydropyridine calcium channel blockers, digoxin, and amiodarone are used to control the ventricular rate of atrial arrhythmias and strive to convert to sinus rhythm. For example, small doses of digitalis combined with β blockers to control the ventricular rate in patients with atrial fibrillation. Amiodarone is safe and effective for atrial arrhythmias in patients with structural heart disease and heart failure due to its weak negative inotropic effect.