Electrical and Drug Therapy of Arrhythmogenic Heart Diseases

### **Chapter 3**

## ICD for Sudden Cardiac Death Prevention and New Pharmaceutical Treatment Options in Hypertrophic Obstructive Cardiomyopathy

*Antonio da Silva Menezes Junior, Thais Aratak Marques Taia, Camila Cássia Canzi, Ana Lígia Valeriano de Oliveira, Lucas Eduardo Almeida França, Aline Lins da Silva, Matheus Araújo Borges and Guilherme Diniz Prudente*

#### **Abstract**

In humans, hypertrophic cardiomyopathy (HCM) is a heterogeneous cardiac illness typically caused by autosomal dominant sarcomeric gene mutations and characterized by reduced heart's compliance, myofibrillar disarray, and fibrosis of the heart. Areas covered: Although HCM was formerly viewed as a malignant disease entity with few treatment choices, effective management strategies have emerged so that affected individuals may expect to have a normal lifespan without the need for pacing or another type of invasive intervention. Herein, these management strategies are discussed. There is no curative treatment for HCM that reverses or prevents hypertrophy and heart dysfunction. Drug-based therapies aim to alleviate its symptoms and slow disease progression. Mavacamten is a reversible cardiac myosin allosteric modulator with a potential therapeutic effect for obstructive HCM. Mavacamten markedly improved the health status of patients with symptomatic obstructive hypertrophic cardiomyopathy compared with a placebo. In patients with HOCM, the importance of an implantable cardioverter defibrillators (ICD) is to prevent sudden cardiac death (SCD). Approximately 25% of those with HCM suffer from atrial arrhythmias, and the condition is notoriously difficult to manage. Anti-arrhythmic drugs, such as sotalol, amiodarone, and disopyramide, are routinely prescribed. Radiofrequency ablations for atrial fibrillation in patients with HCM have become more common despite their limited effectiveness (about 70% recurrence).

**Keywords:** obstructive hypertrophic cardiomyopathy, implantable cardioverter Desfibrillator, sudden cardiac death, pharmaceutical treatment, prevention

#### **1. Introduction**

In humans, hypertrophic cardiomyopathy (HCM) is a common (1:500 – general population) autosomal dominant inherited cardiovascular disease. It is caused by more than 1400 mutations in 11 or more genes encoding proteins of the cardiac sarcomere. HCM is characterized by left ventricular (LV) hypertrophy, myocardial hypercontractility, and other cardiac abnormalities. Reduced compliance, myofibrillar disarray, and fibrosis are all fenotypes of HCM [1, 2].

Even though HCM was formerly seen as a bleak, unyielding, and malignant disease entity with few treatment choices, the clinical story of the illness has dramatically transformed in recent years. Improved clinical recognition, including benign low-risk subgroups without significant symptoms or disability [3] has led to effective management strategies for major HCM complications, resulting in significantly lower mortality and morbidity rates. Affected individuals have an increased likelihood of achieving normal longevity into their 70s to 90s or even later with good quality of life [3].

Patients with LV dysfunction, obstruction of the left ventricular outflow tract (LVOT), and mitral regurgitation (MR) may have impaired exercise capacity, as well as exertional dyspnea and chest discomfort and syncope. Microvascular dysfunction and subendocardial ischemia are the underlying causes of these symptoms. Septal hypertrophy, as well as issues with the mitral valve and subvalvular apparatus, contribute to systolic anterior motion (SAM) and obstruction of the LVOT, resulting in obstructive HCM (HOCM), as seen in **Table 1**.

#### **2. Implantable defibrillator cardioverter**

Implantable cardioverter defibrillators (ICDs), composed of a defibrillator and electrodes, avoid ventricular arrhythmias and sudden death. The American Heart Association (AHA) and the European Society of Cardiology (ESC) recommend ICDs as a secondary preventive measure for patients with hemodynamically severe ventricular arrhythmias or prior cardiac arrests, as seen in **Table 2** and **Figure 1** [4].

Studies demonstrate that an ICD helps individuals who have had cardiac arrests and slows the progression of HCM by averting sudden death [1, 2]. In patients with HOCM, biventricular implanted cardio defibrillators reduce obstruction in the LVOT, indicating that they improve systolic function in the left ventricle [5].

Thavikulwat et al. studied adult patients with HCM treated with ICD at the Cardiovascular Institute of Bluhm from 2000 to 2013 to assess risk factor profiles, ICD treatment rates, and consequences [4]. During the 5.2-year period, 25 of the 135 patients treated received ICDs. No statistically significant difference was observed between individuals who died suddenly and those who did not undergo ICD therapy. While younger ICD patients received more suitable care, 20% of these patients had insufficient therapy.

Maron et al. [5] studied 486 individuals with high-risk HCM from eight worldwide sites. Among them, 19% received ICD intervention due to ventricular tachycardia or fibrillation. Only one patient died suddenly from ICD failure, while three others died from causes connected to HCM but unrelated to the arrhythmogenic effect. Although anticipation of future shocks increased anxiety, individuals who received any ICD intervention showed no HCM mortality in 1, 5, and 10 years [5]. Notably, ICD was not associated with an increase in mortality, cardiovascular


**Table 1.** *Novel therapeutic targets in hypertrophic cardiomyopathy.*

#### *ICD for Sudden Cardiac Death Prevention and New Pharmaceutical Treatment Options… DOI: http://dx.doi.org/10.5772/intechopen.111637*


*The original source was adapted from the authors. "Ommen SR, Mital S, Burke MA, Day SM, Deswal A, Elliott P, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Vol. 142, Circulation. Lippincott Williams and Wilkins; 2020. p. E533–57."*

#### **Table 2.**

*Eligibility criteria for ICD implementation.*

morbidity, or worsening heart failure. Furthermore, although it causes worry in people who have previously received ICD intervention, it does not significantly affect their psychological well-being [5].

Giraldeau et al., despite studying a small sample, assessed the effectiveness of biventricular stimulation (BiV) in 13 individuals (average age of 55 years) with

*ICD for Sudden Cardiac Death Prevention and New Pharmaceutical Treatment Options… DOI: http://dx.doi.org/10.5772/intechopen.111637*

#### **Figure 1.**

*Risk stratification of SD in HCM. HCM = hypertrophic cardiomyopathy; ICD = implantable cardioverter defibrillator; SD = sudden death; VT = ventricular tachycardia. Source: Maron BJ, Desai MY, Nishimura RA, et al. Management of Hypertrophic Cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2022; 79:390–414. This agreement between Antonio da Silva Menezes junior ("You") and Elsevier ("Elsevier") consists of your license details and the terms and conditions provided by Elsevier and copyright clearance center. License number 5305400128072 license date may 10, 2022.*

HOCM who had undergone 2D transthoracic echocardiography before implantation and were followed for 12 months [6]. The peak gradient in the LVOT was lowered from 80 to 30 mmHg. Displacement curve analysis revealed an inversion of lateral wall movement time in these individuals, with a reduced LVOT gradient. The study concluded that BiV reduces LVL obstruction in patients with HOCM by desynchronizing LV movement and inverting the activation time of the LV wall, without affecting the LV's systolic function [6].

To diagnose, confirm, or stratify the type of hypertrophy present in individuals with HCM, Freitas et al. conducted a multicentric retrospective investigation of 493 patients (58% male; mean age of 46 years) [7]. Their goal was to prove that cardiovascular magnetic resonance imaging and late gadolinium enhancement may be used to stratify risk. The sudden death risk score for HCM and the algorithms of the American College of Cardiology Foundation and the American Association of Cardiology (ACCF/AHA) were used to determine individuals' eligibility for ICDs. During the median 3.4-year follow-up, 12 patients died, 6 had adequate ICD discharges, and 5 had prolonged ventricular tachycardia. Compared to ratings and algorithms, late gadolinium enhancement was the sole independent predictor of outcomes. As people with HCM are more prone to unexpected death, this tool is vital.

Aducci et al. [8] studied 77 patients (45 male, mean age of 46 years) with HCM who received a transvenous ICD. In total, 24 of the patients experienced 49 episodes

#### **Figure 2.**

*Management strategies for HCM. HCM = hypertrophic cardiomyopathy; ICD = implantable cardioverter defibrillator; SD = sudden death; VT = ventricular tachycardia. Source: Maron BJ, Desai MY, Nishimura RA, et al. Management of Hypertrophic Cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2022; 79:390–414. This agreement between Antonio da Silva Menezes junior ("You") and Elsevier ("Elsevier") consists of your license details and the terms and conditions provided by Elsevier and copyright clearance center. License number 5305400128072 license date may 10, 2022.*

of ventricular tachycardia/fibrillation after 67 months. Antitachycardia pacing (ATP) by ICD was successful in 69% of 39 monomorphic ventricular tachycardia (VT) events. However, even with ATP, two episodes of VT occurred. [8]. Thus, although ATP is relatively successful in treating monomorphic VTs in patients with HCM, its optimal treatment rate remains low, and it is typically provided prematurely, raising concerns about arrhythmia induced by ATP [8].

Between June 2014 and May 2016, Maurizi et al. [9] studied 50 patients (34 males; mean age of 40 years; body mass index [BMI] of 25.2) with HCM referred for subcutaneous ICD implantation in primary and secondary preventive centers in seven Italian locations. VT occurred in seven individuals and was cardioverted in two cases. The remaining patients experienced 73 bouts of ventricular fibrillation, with 6% spontaneous conversion. Defibrillation failed in only one patient, who was significantly obese (BMI of 36) and had a maximal LV wall thickness of 25 mm [9].

As reported by the AHA, the 65 J acute defibrillation test with subcutaneous ICD detects and stops VT in 98% of people. Severe obesity is the cause of lone failure (9). These recommendations and/or the ESC's HCM sudden cardiac death (SCD) risk calculator is used to determine if an ICD should be used in a patient at risk for SCD. Late gadolinium enhancement on cardiac magnetic resonance imaging, LV

#### *ICD for Sudden Cardiac Death Prevention and New Pharmaceutical Treatment Options… DOI: http://dx.doi.org/10.5772/intechopen.111637*

systolic dysfunction, and LV apical aneurysm have all been included in an American College of Cardiology (ACC)/AHA risk stratification strategy that has recently shown improved discrimination for SCD or appropriate ICD therapies, as seen in **Figure 2**. However, this much more conservative approach would lead to significantly higher ICD utilization [10–17].

From January 2005 to September 2016, Valzania et al. studied 99 patients (mean age of 53 years) with HCM who received an ICD at Karolinska University Hospital. In follow-up, 12 died from heart failure (HF), 6 from SCD, and 6 from other causes; 20% of the patients demonstrated occlusion of the LVOT due to HOCM, and primary prevention was the top indication for an ICD [10–12].

Apart from septal reduction treatment, people with HCM may expect to have a normal lifespan without the need for pacing, which is indicated only when LVOTO is present. As a result, the subcutaneous implantable cardioverter defibrillator (S-ICD; Boston Scientific, Minneapolis, MN, USA) has become a viable option for both primary and secondary prevention of SCD. Due to the sensing mechanism of the S-ICD's three subcutaneous vectors, QRS and T-wave anomalies in young patients pose constraints—prescreening failure rates for patients with HCM range from 14–38% due to T-waver sensing. However, shocks might still be inappropriate in 8–24% of patients even after proper screening; inappropriate shocks can occur due to factors such as the need for reprogramming and muscle noise due to myopotentials [18]. Therefore, cautious patient selection is required [9, 10].

In patients with HOCM, the importance of an ICD is to avoid SCD (DDD ICD with a lead placed into RVA and programmed short AV-delay). Approximately 25% of those with HCM suffer from atrial arrhythmias, and the condition is notoriously difficult to manage. Anti-arrhythmic drugs, such as sotalol, amiodarone, and disopyramide, are routinely prescribed. Radiofrequency ablations for atrial fibrillation in patients with HCM have become more common despite their limited effectiveness (about 70% recurrence over 3–4 years after a single treatment). Myectomy surgery may be somewhat more successful than surgical ablation at the time of the procedure (recurrence rate of 36–51%), as seen in **Figure 2** [10–13].

#### **3. Novel drugs for HCM**

There is no curative treatment for HCM that reverses or prevents hypertrophy and heart dysfunction, but there are therapeutic options that can generate less progression and greater relief of symptoms. Therefore, drug-based therapies are aimed at alleviating the symptoms associated with HCM and slowing disease progression. Patients with HCM who are symptomatic are generally offered firstline pharmacotherapy with -blockers or nondihydropyridine calcium channel blockers. Disopyramide is effective as an add-on therapy, although it can be poorly tolerated. The inotropic effects of these drugs have been the cornerstone of therapy for decades, reducing SAM/septal contact and LVOT occlusion. However, existing guideline-directed pharmacotherapies were never developed for the treatment of HCM, and lack of evidence. Further, randomized studies have not shown the superiority of any treatment over that of the placebo, based on a small study performed in 1966 [13]. Nonobstructive HCM (noHCM), which accounts for about 30% of all cases of HCM, remains poorly understood and has no recognized disease-modifying therapy. Studies have shown significant disparities in the presentation of HCM between men and women, with the latter being older and more symptomatic at the

time of diagnosis, as well as perhaps having a poorer overall survival rate than the former [14–36].

#### **3.1 Mavacantem and Aficatem (CK-274)**

Mavacantem is a reversible cardiac myosin allosteric modulator that has a potential therapeutic effect for individuals with (HOCM). This modulator demonstrated significant mitigation of hypercontractility, ventricular hypertrophy, myofibrillar disarrangement, and fibrosis in animal models [36–43].

Patients with HCM were treated with mavacamten for 12 weeks, which resulted in a quick and significant decrease in the gradient (LVOT) following exercise in the study participants. Patients with plasma mavacamten concentrations between 350 ng/ mL and 700 ng/mL were more likely to have a VSVE gradient of less than 30 mmHg (the threshold for obstruction in HCM) and less than 50 mmHg (the threshold for consideration of septal reduction therapy) than those with lower values. Such an event is probably due to the fact that mavacamten acts to reduce the formation of actin-myosin cross-bridges, thus generating less systolic and diastolic cross-bridge formation. In addition, it promotes a relaxed energy-saving state that reduces LVOT obstruction [21]. A clinically significant improvement in symptoms, particularly dyspnea, as well as increased effort capacity, was also observed [44, 45]. At the end of the 12-week research, mavacamten lowered the mean gradient of postexercise VSVE from 103 mmHg (standard deviation, 50) at baseline to 19 mmHg (standard deviation, 13; mean change, −89.5 mmHg; 95% confidence interval [CI], −138.3 to - 40.7 mm Hg; P = 0.008). The LVEF at rest was also decreased (mean variation, −15%; CI, −23% to −6%), while peak oxygen consumption rose by an average of 3.5 mL/kg/min (CI 1.2 to 5.9 mL/kg/min) [44–46].

While this modulator was well tolerated by patients at exposures that successfully decreased VSVE obstruction, decreases in LVEF that were greater than those required to alleviate VESV obstruction were shown to be irreversible. Lowered LVEF at higher plasma concentrations and atrial fibrillation (AF) were the most prevalent adverse events conclusively or probably associated with mavacamten use [46].

Several characteristics of HCM were demonstrated by Prondzynski et al. [47], including hypertrophy, myofibrillar disarray, hypercontractility, impaired relaxation, and increased myofilament mass. They also demonstrated that cardiomyocytes derived from human induced pluripotent stem cells and manipulated cardiac tissues recapitulated several characteristics of HCM, including prolongation of the duration of the action potential and increase in myofilament, among others. As a result of these differences, the current density of calcium channel type L was greater in those with HCM than in the control group, as was the duration of the action potential. In addition to the above, this study revealed a novel HCM mutation that was associated with a contractile and electrophysiological phenotype in hiPSC-derived cardiomyocytes [47–57].

It was revealed via the optimization of the indoline compound that aficamten (CK-274), a new cardiac myosin inhibitor, could be developed. Among the most significant advancements in the optimization process was the identification of an Indane analog, which is a molecule that presents an attractive biological profile for the development of therapeutic molecules, in such a way that having a less restricted structure-activity relationship and allowing the fast development of drug-like characteristics. Aficamten was developed to have a predicted human

*ICD for Sudden Cardiac Death Prevention and New Pharmaceutical Treatment Options… DOI: http://dx.doi.org/10.5772/intechopen.111637*

half-life (t1/2) appropriate for once daily (od) dosing, to reach a steady state in less than two weeks, to cause no significant cytochrome P450 induction or inhibition, and to have a broad therapeutic window in vivo with a clear pharmacokinetic/ pharmacodynamic relationship, among other characteristics. Aficamten displayed a human t1/2 that was comparable to projections in the phase I clinical study, and it was able to achieve steady state concentration within the two-week timeframe that had been set [58].

With an estimated human half-life of two weeks and no significant CYP induction or inhibition in preclinical studies, aficamten offers an attractive therapeutic window and a clear PK/PD connection. The large therapeutic window reported in preclinical trials seems to apply to people, supporting the development of aficamten into phase 1 investigations. Aficamten may help reduce cardiac sarcomere hypercontractility, which seems to cause pathological hypertrophy, outflow obstruction, and fibrosis in some hereditary hypertrophic cardiomyopathies [18, 58, 59].

#### **4. Conclusions**

There is no curative treatment for HCM that reverses or prevents hypertrophy and heart dysfunction; therefore, drug-based therapies are aimed at alleviating the symptoms associated with HCM and slowing disease progression. Notably, ICD is beneficial for the prevention of SCD, as it is not associated with an increase in mortality, cardiovascular morbidity, or worsening of HF. While people who have previously experienced some type of ICD intervention express anxiety, it does not significantly affect their psychological well-being.

In certain cases, implanting ICDs is a difficult choice to make, particularly when the available information is insufficient to appropriately classify a patient's risk level. To resolve the doubt, a thorough physician's clinical judgment/intuition and medical reasoning, as well as frank discussions with fully informed patients and families, considering the benefits and limitations of risk stratification and ICDs, may be beneficial. In this approach, the different personal views of patients about sudden death risk and implanted gadgets, as well as opinions from other countries and cultures, are to be considered. The risk of sudden death in HCM is the same for men and women of any race or gender, although ICDs are less often used in minorities than in majority populations.

A successful treatment/prevention of life-threatening ventricular arrhythmias in the HCM population has been proven despite the severe morphology typical of HCM, which often includes large degrees of left ventricular hypertrophy and/or LV outflow tract obstruction. A high incidence of appropriate intervention was seen in studies of individuals judged to be at high risk, both in secondary prevention and in primary prevention, the researchers found. It is even more remarkable that this adequate intervention rate is achieved even considering the young and generally healthy individuals that make up the HCM population.

Because the incidence of SCD in HCM is very low, it is critical to identify individuals who are at high risk of SCD. Traditional risk classification strategies based on clinical risk variables have significant drawbacks and have been shown to overestimate the level of risk. Compared to standard risk prediction models based on bivariate risk variables, a novel risk prediction model that delivers individual 5-year projected risk seems to be better. Preoperative problems seem to be comparable to those associated with the placement of other cardiac devices, but long-term consequences have typically been the focus of research and discussion. Because of their young age at implant and higher frequency of atrial fibrillation, HCM patients are assumed to be more prone to ICD-related issues and inappropriate ICD treatment. However, long-term follow-up evidence on ICD-related complications in general practice is sparse.

## **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Antonio da Silva Menezes Junior\*, Thais Aratak Marques Taia, Camila Cássia Canzi, Ana Lígia Valeriano de Oliveira, Lucas Eduardo Almeida França, Aline Lins da Silva, Matheus Araújo Borges and Guilherme Diniz Prudente Medical and Life School Goiânia, Pontifical Catholic University of Goiás, Goiás, Brazil

\*Address all correspondence to: a.menezes.junior@uol.com.br

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*ICD for Sudden Cardiac Death Prevention and New Pharmaceutical Treatment Options… DOI: http://dx.doi.org/10.5772/intechopen.111637*

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[54] Imori Y, Takano H, Mase H, et al. Bisoprolol transdermal patch for perioperative care of non-cardiac surgery in patients with hypertrophic obstructive cardiomyopathy. BMC Cardiovascular Disorders. 2019;**19**:316-324

[55] Adler A, Fourey D, Weissler-Snir A, et al. Safety of outpatient initiation of disopyramide for obstructive hypertrophic cardiomyopathy patients. Journal of the American Heart Association. 2017;**6**:1-7

[56] de Oliveira GMM. A new look into hypertrophic cardiomyopathy based on clinical evidence. Revista Portuguesa de Cardiologia (English Edition). 2018;**37**:11-13

[57] Jung H, Yang PS, Jang E, et al. Effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation with hypertrophic cardiomyopathy:

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A nationwide cohort study. Chest. 2019;**155**:354-363

[58] Chuang C, Collibee S, Ashcraft L, Wang W, Vander Wal M, Wang X, et al. Discovery of Aficamten (CK-274), a next-generation cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathy. Journal of Medicinal Chemistry. 2021;**64**:14142-14152

[59] Heitner SB, Jacoby D, Lester SJ, et al. Mavacamten treatment for obstructive hypertrophic cardiomyopathy: A clinical trial. Annals of Internal Medicine. 2019;**170**:741-748

#### **Chapter 4**

## Atrial Fibrillation and Cardioversion Drugs

*Taomin Su, Pan Liu, Qin Shi, Yan Wang and Ying Zhou*

#### **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.

**Keywords:** atrial arrhythmias, atrial fibrillation, cardioversion drugs, heart, medical treatment

#### **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

*Atrial Fibrillation and Cardioversion Drugs DOI: http://dx.doi.org/10.5772/intechopen.113163*

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:


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

#### *Atrial Fibrillation and Cardioversion Drugs DOI: http://dx.doi.org/10.5772/intechopen.113163*

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

*Atrial Fibrillation and Cardioversion Drugs DOI: http://dx.doi.org/10.5772/intechopen.113163*

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:


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

#### *Atrial Fibrillation and Cardioversion Drugs DOI: http://dx.doi.org/10.5772/intechopen.113163*

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.

#### **Author details**

Taomin Su1 \*, Pan Liu2 , Qin Shi2 , Yan Wang1 and Ying Zhou1

1 Xuhui Hospital, Fudan University, China

2 Gongli Hospital, Pudong New District, Shanghai, China

\*Address all correspondence to: sutaomin\_2020@sina.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 3
