**6. Therapeutic approaches involving ANS in the heart**

By understanding the mechanism of influence of the anatomy and physiology of the ANS heart and its influence on various heart abnormalities, we can determine the appropriate therapeutic approaches. Therapeutic approaches in neurocardiology fall into two focuses: (1) applying novel treatment and (2) interaction of non-drug and multiple drugs treatments. Patients with cardiomyopathy are suggested to have increased sympathetic innervation and decreased parasympathetic innervation; therefore, interventions aiming to reduce sympathetic tone and thereby increasing parasympathetic tone are beneficial to reduce the susceptibility of ventricular arrhythmia sudden cardiac death. Some options of approaches include the following options [4].

### **6.1 Selective sympathetic blockade**

Multiple studies have shown that in patients with heart failure, pharmacologically inhibition of sympathetic activity may reduce the risk of sudden cardiac death. Current pharmacological therapies include β-blockers (β-receptor antagonist) and angiotensin-converting enzyme inhibitors (ACE-I), which are the mainstay approaches for early hypertension and other cardiovascular disease associated with dysautonomia [22]. Surgical techniques, for instance, sympathectomy, reduce the risk of comorbidities in patients with hypertension and reduce the incidence of ventricular arrhythmia [22].

## **6.2 Cardiac autonomics modulation therapies**

Pharmacological therapies such as β-blockers, ACE-I, angiotensin receptor blockers (ARB), aldosterone antagonists, and statins are proven to decrease the risk of sudden cardiac death in patients with ischemic cardiomyopathy. In addition, these drugs also provide modulations of the ANS by decreasing sympathetic activity and increasing parasympathetic activity. Through baroreflex, Angiotensin II decreases vagal bradycardia. This effect can be reversed with ACEI and ARB by increasing parasympathetic output to the heart. In an experimental study using rat models with ischemic cardiomyopathy, aldosterone antagonist and ACEI showed a decrease of myocardial NE content, demonstrating an antisympathetic effect. Statin therapies show several mechanisms in normalizing sympathetic activity and cardiovascular reflex regulation, such as increased baroreceptor sensitivity for heart rate control, reducing angiotensin II-induced sympathetic responses, decreasing baseline of renal sympathetic activity, and downregulating mRNA and protein expression of Angiotensin II type I receptors as well as NADP oxidase subunits of the heart [4].

### **6.3 Resynchronization therapy**

Biventricular pacing has been suggested to improve hemodynamic status in patients with intraventricular conduction delay and reduced ejection fraction and decreased sympathetic tone in patients with hypertension, thus shifting the autonomic balance of the heart to a less sympathetic more parasympathetic profile [4]. Proper cardiac resynchronization therapy (CRT), in the short term, results in left ventricular systolic function improvement and mitral regurgitation reduction, providing a more optimal ventricular filling. Over a more extended period, CRT promotes left ventricular reverse remodeling, leading to significant functional capacity, survival, and quality of life improvements [23].

## **6.4 Parasympathetic function mortality and cardiovascular risk**

Several measurements that can be used to index parasympathetic function/activity include resting heart rate, heart rate recovery (heart rate decrease following termination of exercise), heart rate variability, and baroreflex sensitivity (the responsiveness of the cardiovascular system to blood pressure changes). Several studies have shown that reduced parasympathetic function is associated with mortality and leads to risk factors for cardiovascular diseases. Those risk factors include biological factors such as hypertension, diabetes, abnormal cholesterol; lifestyle factors such as tobacco use, physical inactivity, and overweight; and non-modifiable factors such as age and family history [4].
