Theoretical aspect of effective antiarrhythmic therapy: Ventricular arrhythmia and drugs that prolong Action Potential Duration (APD)

Abstract Background Therapeutic hypothermia (TH) increases the risk of ventricular arrhythmia (VA) by prolonging action potential duration (APD) and steepening the APD restitution (APDR). The calcium sensitizer levosimendan, a medication for heart failure treatment, has been reported to shorten APD by enhancing ATP-sensitive K current and affect the APDR. Purpose We hypothesized that levosimendan might shorten the already prolonged APD particularly at long pacing cycle length (PCL), thus decreases the maximal slope of APDR, and prevent VA during TH. Methods Langendorff-perfused isolated rabbit hearts were subjected to 15-min TH (30°C) followed by 30-min treatment with levosimendan (0.5 μM, n=9) or vehicle (n=8). Using an optical mapping system, APD was evaluated by S1 pacing and APDR curve was plotted using APD70 versus diastolic interval. Ventricular fibrillation (VF) inducibility was evaluated by burst pacing for 30 s at the shortest PCL that achieved 1:1 ventricular capture. Results The APD was shortened from 259±8 ms at TH to 241±18 ms after levosimendan infusion at long PCL of 400 ms (p=0.024). However, at short PCL of 280 ms, the APD was not changed before (194±19) and after (188±23) levosimendan during TH (p=0.61). Levosimendan decreases the maximal slope of APDR curve from 1.99±0.65 at TH to 1.41±0.32 after adding levosimendan (p=0.034). The VF inducibility was decreased by levosimendan from 39±30% at 30°C to 14±12% with levosimendan (p=0.023). In control hearts, the maximal slope of APDR (p=0.75) and VF inducibility (p=0.12) were not changed by vehicle during TH. Conclusion Levosimendan might protect the hearts against VA during TH by shortening APD at long PCL and flattening the APDR. Enhancing ATP-sensitive K current with levosimendan during TH might be a novel approach to prevent VA during TH. Funding Acknowledgement Type of funding source: None

Download Full-text

Concurrent increases in post-pacing action potential duration and contractility predict occurrence of ventricular arrhythmia

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s00424-020-02445-7 ◽

2020 ◽

Vol 472 (12) ◽

pp. 1783-1791

Author(s):

Chih-Min Liu ◽

Feng-Zhi Lin ◽

Yao-Chang Chen ◽

Yung-Kuo Lin ◽

Yen-Yu Lu ◽

...

Keyword(s):

Ventricular Arrhythmia ◽

Action Potential ◽

Action Potential Duration

Download Full-text

Anti‐Inflammatory and Antiarrhythmic Effects of Beta Blocker in a Rat Model of Rheumatoid Arthritis

Journal of the American Heart Association ◽

10.1161/jaha.120.016084 ◽

2020 ◽

Vol 9 (18) ◽

Cited By ~ 1

Author(s):

Ting‐Tse Lin ◽

Yen‐Ling Sung ◽

Jhen‐Yang Syu ◽

Kia‐Yuan Lin ◽

Hung‐Jui Hsu ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Ventricular Arrhythmia ◽

Action Potential ◽

Action Potential Duration ◽

Cardiac Fibrosis ◽

Optical Mapping ◽

Ex Vivo ◽

Electrical Remodeling ◽

Propranolol Treatment ◽

Anti Inflammatory

Background Patients with rheumatoid arthritis are at twice the risk of ventricular arrhythmia and sudden cardiac death as the general population. We hypothesize that β‐blocker treatment of rheumatoid arthritis is antiarrhythmic by producing synergistic anticatecholaminergic and anti‐inflammatory effects. Methods and Results Collagen‐induced arthritis (CIA) was induced in Lewis rats by immunization with type II collagen in Freund's incomplete adjuvant. The treatment with propranolol (4 mg/kg) started on the first day of immunization. We evaluated the ventricular vulnerability to ventricular arrhythmia using in vivo programmed stimulation and performed ex vivo optical mapping to measure the electrical remodeling of the heart. The ventricular tissue was further processed for immunohistochemical staining and protein array analysis. The assessment of ventricular vulnerability showed that the number and duration of the induced ventricular arrhythmia episodes were increased in CIA rats, which were improved with propranolol treatment. The sympathovagal index and the plasma level of catecholamines significantly increased in CIA rats, whereas the use of propranolol attenuated sympathetic hyperactivity. In the optical mapping study, electrical remodeling, characterized by prolonged action potential duration, slow conduction velocity, and steepened action‐potential duration restitution, were noted in CIA rats and reversed in the propranolol‐treatment group. The propranolol treatment was associated with decreases in paw thickness, fewer inflammatory cell infiltrations in the heart, reduced levels of cardiac inflammatory cytokines, and less cardiac fibrosis as compared with the CIA group. Conclusions CIA increased ventricular arrhythmia vulnerability through sympathetic hyperinnervation and proarrhythmic ventricular electrophysiological remodeling. Treatment with propranolol in CIA rats was both anti‐inflammatory and antiarrhythmic.

Download Full-text