WO2017122038A1

WO2017122038A1 - Biatrial biphasic stimulation at sub-threshold levels as intervention to treat all types of atrial tachyarhythmias - including atrial fibrillation

Info

Publication number: WO2017122038A1
Application number: PCT/IB2016/000025
Authority: WO
Inventors: Nazmi Krasniqi; Urs Eriksson
Original assignee: Nazmi Krasniqi; Urs Eriksson
Priority date: 2016-01-15
Filing date: 2016-01-15
Publication date: 2017-07-20

Abstract

The present invention relates to a method of biatrial biphasic electric stimulation using an implanted electronic stimulator. In a variety of protocols different combinations of conventional and biphasic electric impulses are applied at sub-threshold levels, i.e. without activating the physiologic conduction system. The electronic cardiac stimulator of the present invention includes multiple electrodes having stimulating and sensing capabilities. Electrodes will be positioned in the right atrial appendage and over the left atrium either at the left posterior atrial wall or within a Vena obliqua atrii sinistri. Insertion of these electrodes into the patient could be accomplished by intravenous or transthoracic access. Location and configuration of these electrodes allow the delivery of sub-threshold levels of electric impulses generating an electric field over the whole atrium. The electric field prevents and reverses pathological structural remodeling of atria in patients with long-lasting and/or persistent atrial tachyarrhythmias.

Description

Background of the invention

1. Field of the Invention

The cardiac device is intended to be inserted in patients with atrial arrhythmias. The invention therefore covers fields of Healt Care Technology, Processors, Medicine, Cardiology and Electrophysiology.

2. Background Information

2.1. Epidemiology and relevance of atrial arrhythmias

Atrial tachyarhythmias (atrial fibrillation, atrial flutter, atrial arrhythmias) are associated with high morbidity and mortality. Atrial fibrilliation, for example, represents the most common type af cardiac arrhythmia (up to 10% of patients > 80 years in developed countries), and significantly contributes to congestive heart failure development, thrombosis, embolization and stroke.

2.2. Pathophysiology of atrial arrhythmias

Atrial arrhythmias are initiated by ectopic beats due to enhanced automaticity, or triggered activity expressed as early or delayed afterpolarization. Ectopic beats encountering anatomical or functional barriers result in micro or macro-reentry of the excitation wavefront with consecutive arrhythmia. Importantly, recurrent arrhythmias initiate a process of structural alteration within the atrium, which in turn results in a vicious cycle of increasing arrhythmia burden and progressive pathological atrial remodeling.

Atrial remodeling is on one hand associated with electric, contractile and structural changes of cardiomyocytes due to specific alterations within intracellular signalling pathways. In turn, alterations of cellular function, and apoptosis promote changes within the extracellular matrix, result in release of proinflammatory cytokines and accumulation of fibroblasts as well as inflammatory cells. In fact, fibrotic processes within the atrium have been recognized as a key factor in changing electric tissue properties affecting physiological propagation of the excitation wavefront. Resulting structural changes further impair normal signal transduction within the atrium and promote self-perpetuation of atral arrhythmias.

2.3. The biological concept underlying the invention

Our invention results from the idea that continuous biatrial stimulation at a sub-threshold level cannot only prevent but also reverse the process of pathological atrial remodeling. Consequently, we anticipate that appropriate biatrial stimulation at subthreshold level will reduce atrial tachyarrhythmia burden and associated morbidity and mortality.

This concept is based (1 ) on our profound experience on cardiomyocyte biology, (2) on insights on effects of atrium only pacing in patients with implanted pacemakers suffering from atrial arrhythmias and, (3) on the mechanistic and biological impact of electric stimulation on cardiomyocytes of failing hearts in patients with Cardiac Resynchronization Therapy. Exact mechanisms on how continuous electric stimulation interferes with pathological, arrhythmia-associated alterations at the cellular and subcellular molecular level are still not entirely understood. Nevertheless, we and others generated a wealth of evidence pointing to a protective effect of electric current on cardiac tissue biology.

In vitro and in vivo data on cardiomyocytes, for example, show that electric current enhances their proliferation, and modulates the expression of metalloproteinases and their inhibitors (Kapeller B., et al. Microcurrent stimulation promotes reverse remodeling in cardiomyocytes. ESC Heart Failure 2016; DOI: 10.1002/ehf2.12080). Thus appropriate electric signals mediate regenerative and antifibrotic properties counteracting adverse mechanisms of pathological atrial remodeling. Intermittent electric activation of cardiomyocytes further results in improved calcium responsiveness of myofilaments as observed in CRT patients (Kirk JA., et al J Clin Invest. 2014; 124(1):129-139. DOI:10.1172/JCI69253). This observation also underlies the concept of cardiac contractility modulation using extracellular electric stimuli delivered through the absolute refractory period (Brunckhorst CB., et al Eur J Heart Failure 2006 8:7-15; Pappone C. et al J Cardiovasc Electrophysiol 2004; 15:418-427). Given the fact that atrial remodeling includes similar morphologic changes as observed in the failing ventricles of patients with heart failure, we strongly believe that biatrial stimulation exerts similar effects in the atrium as cardiac contractility modulation or cardiac resynchronization impose on a failing left heart. Despite a theoretical concern that enhanced availability of Ca⁺ affecting action potential duration could negatively affect automaticity and even trigger atrial fibrillation within the atrium, favorable effects on atrial remodeling should largely outweigh such drawbacks.

Claims

Claims:

1 An implantable electrical cardiac device to perform biatrial stimulation at sub-threshhold levels to treat all types of atrial tachyarhythmias comprising;

a programmable generator and reciever unit

a recorder adapted to record baseline cardiac activity;

a processor adapted to determine whether biphasic stimulation of atria has occurred and to determine whether sub-threshhold stimulation of atria has occurred;

electrodes adapted to stimulate the left and the right atrium during atrial tachyarhythmias and/or during sinus rhythm; wherein, the stimulation procedure includes: pre-intrinsic-capture stimulation at sub-threshold levels with post-intrinsic-capture stimulation at sub-threshold and/or continuous stimulation at sub-threshold levels.

2. The implantable cardiac device of claim 1 , where at least two of the above described electrodes are adapted to be inserted intravenously and/or via transthoracal access into a patient.

3. The implantable cardiac stimulator of claim 1 , wherein one of the electrodes is adapted to be located in the right atrial appendage, and at least one of the electrodes is adapted to be located in the Vena obliqua atrii sinistrii or at the left atrial posterior wall.

4. The implantable cardiac device of claim 1 , wherein each of the electrodes has the same generator.

5. The implantable cardiac device of claim 1 , wherein the electrodes are designed electric energy and sense the electrical signals from the cardias tissue

6. The implantable cardiac device of claim 1 , wherein the electrodes of pacemakers and internal cardiac defibrillators can be used for delivering the pre-intrinsic-capture stimulation at sub-threshold levels with post-intrinsic-capture stimulation at sub-threshold and/or continuous stimulation at sub-threshold levels.

7. The implantable cardiac device of claim 1 , wherein the device and the electrodes can be used as cardiac pacemaker.

8. The cardiac device of claim 1 , which is integrated in cardiac pacemaker and/or internal defibrillator

9. A method to treat all types of atrial tachyarhythmias - including atrial fibrillation using biatrial biphasic electric stimulation at sub-threshold levels

10. The method of claim 8 using electric stimulation at subthreshhold levels

11. The method of claim 8, wherein appropriate electric stimulation of atria mediate regenerative and antifibrotic properties counteracting adverse mechanisms of pathological atrial remodeling

12. The method of claim 8, wherein electric current enhances the proliferation of cardiomycytes, and modulates the expression of metalloproteinases and their inhibitors.

13. The method of claim 8, wherein electric current stimulation modulates the expression of the pro-inflammatory cytokines.

14. The method of claim 8, wherein electric current stimulation enhances Ca²⁺ availability in atria

15. The method of claim 8, wherein the electric current stimulation promotes reverse remodeling in cardiomyocytes of atria.