Abstract:
This document discusses, among other things, apparatus, systems, and methods for transvascularly stimulation of a nerve or nerve trunk. In an example, an apparatus is configured to transvascularly stimulate a nerve trunk through a blood vessel. The apparatus includes an expandable electrode that is chronically implantable in a blood vessel proximate a nerve trunk. The expandable electrode is configured to abut a predetermined surface area of the vessel wall along a predetermined length of the vessel. An electrical lead is coupled to the expandable electrode. An implantable pulse generator is coupled to the lead and configured to deliver an electrical stimulation signal to the electrode through the lead. In an example method, an electrical signal is delivered from an implanted medical device to an electrode chronically implanted in a blood vessel proximate a nerve trunk to transvascularly deliver neural stimulation from the electrode to the nerve trunk.

Description:
TECHNICAL FIELD 
   This patent document pertains generally to neural stimulation devices and methods, and more particularly, but not by way of limitation, to transvascular neural stimulation devices and methods. 
   BACKGROUND 
   The automatic nervous system (ANS) regulates “involuntary” organs. The ANS includes the sympathetic nervous system and the parasympathetic nervous system. The sympathetic nervous system is affiliated with stress and the “fight or flight response” to emergencies. The parasympathetic nervous system is affiliated with relaxation and the “rest and digest response.” The ANS maintains normal internal function and works with the somatic nervous system. Autonomic balance reflects the relationship between parasympathetic and sympathetic activity. A change in autonomic balance is reflected in changes in heart rate, heart rhythm, contractility, remodeling, inflammation and blood pressure. Changes in autonomic balance can also be seen in other physiological changes, such as changes in abdominal pain, appetite, stamina, emotions, personality, muscle tone, sleep, and allergies, for example. 
   Reduced autonomic balance (increase in sympathetic and decrease in parasympathetic cardiac tone) during heart failure has been shown to be associated with left ventricular dysfunction and increased mortality. Research also indicates that increasing parasympathetic tone and reducing sympathetic tone may protect the myocardium from further remodeling and predisposition to fatal arrhythmias following myocardial infarction. Direct stimulation of the vagal parasympathetic fibers has been shown to reduce heart rate via the sympathetic nervous system. In addition, some research indicates that chronic stimulation of the vagus nerve may be of protective myocardial benefit following cardiac ischemic insult. 
   Some target areas can be difficult to stimulate or isolate. For example, it may be difficult to stimulate a nerve that is located deep in the body or behind an organ. Improved neural stimulation devices are needed. 
   SUMMARY 
   Various aspects of the present subject matter relate to an implantable apparatus. In an example, an apparatus is configured to transvascularly stimulate a nerve trunk through a blood vessel. The apparatus includes an expandable electrode that is chronically implantable in a blood vessel proximate a nerve trunk. The expandable electrode is configured to abut an area of the vessel wall along a length of the vessel. An electrical lead is coupled to the expandable electrode. An implantable pulse generator is coupled to the lead and configured to deliver an electrical stimulation signal to the electrode through the lead. 
   Various aspects of the present subject matter relate to a method. In an example method, an electrical signal is delivered from an implanted medical device to an electrode chronically implanted in a blood vessel proximate a nerve trunk to transvascularly deliver neural stimulation from the electrode to the nerve trunk. 
   This Summary is an overview of some of the teachings of the present application and not intended to be an exclusive or exhaustive treatment of the present subject matter. Further details about the present subject matter are found in the detailed description and appended claims. Other aspects will be apparent to persons skilled in the art upon reading and understanding the following detailed description and viewing the drawings that form a part thereof, each of which are not to be taken in a limiting sense. The scope of the present invention is defined by the appended claims and their equivalents. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
       FIG. 1A  shows a medical device implanted in a patient and leads extending into a heart, according to embodiments of the present subject matter. 
       FIG. 1B  is an illustration of a heart and leads extending into the heart, according to embodiments of the present subject matter. 
       FIGS. 1C and 1D  are illustrations of a heart and related blood vessels. 
       FIG. 1E  is an illustration of blood vessels and nerve trunks. 
       FIGS. 2A and 2B  are illustrations of stimulation targets. 
       FIGS. 2C and 2D  show neural pathways. 
       FIG. 2E  is an illustration of an internal jugular vein near a vagus nerve. 
       FIGS. 3A and 3B  are illustrations of expandable electrodes chronically implanted in a blood vessel. 
       FIG. 4  is a schematic illustration of an implantable system for delivering transvascular stimulation. 
       FIGS. 5 and 6  are flowcharts that illustrate methods of delivering transvascular stimulation. 
   

   DETAILED DESCRIPTION 
   The following detailed description of the present subject matter refers to the accompanying drawings which show, by way of illustration, specific aspects and embodiments in which the present subject matter may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the present subject matter. Other embodiments may be utilized and structural, logical, and electrical changes may be made without departing from the scope of the present subject matter. References to “an”, “one”, or “various” embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. Additionally, the identified embodiments are not necessarily exclusive of each other, as some embodiments may be able to be combined with other embodiments. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope is defined only by the appended claims, along with the full scope of legal equivalents to which such claims are entitled. 
   Overview 
   Referring now to  FIG. 1A , an embodiment of an implantable cardiac device  100  is placed subcutaneously or submuscularly in a patient&#39;s chest with leads  200  extending toward the heart. At least one lead  200  is coupled to an electrode  295  that is placed in a blood vessel and positioned to transvascularly stimulate a nerve on or near the extravascular surface of the vessel. Transvascular stimulation avoids direct contact with nerves during stimulation and reduces problems associated with neural inflammation or injury induced by direct stimulation. Leads can be implanted through the vasculature, thus maintaining the integrity of the thorax. Transvascular stimulation using intravascularly-fed leads provides relatively non-invasive access to anatomical targets and points of innervation in comparison to cuff electrodes. 
     FIGS. 1B-1E  and  FIGS. 2A-2B  illustrate examples of electrode placement.  FIGS. 2B-2C  show neural pathways.  FIGS. 3A-3B  show an example an electrode implanted in a blood vessel.  FIG. 4  shows a schematic representation of an example of an implantable system for delivering transvascular stimulation.  FIGS. 5 and 6  are flow charts that illustrate methods of delivering transvascular stimulation. 
   Electrode Examples 
     FIG. 3A  is shows a cross-section of an example expandable electrode  305  implanted in a blood vessel  310 . In an example, the expandable electrode includes a mesh, at least part of which is electrically conductive. In an example, the expandable electrode is formed from Platinum or Platinum-Iridium. In an embodiment, the expandable electrode  305  is similar to a stent. 
   Referring again to  FIG. 3A , a nerve trunk  320  extends on or near an extravascular surface  325  of the blood vessel  310 . An expandable electrode  305  is implanted at or near a location in the blood vessel where the nerve trunk  320  crosses the blood vessel. In an example, the expandable electrode transmits neural stimulation energy through a predetermined surface area of the wall of a blood vessel. In an example, this predetermined area is about 0.25 to 5 cm 2 . In an example, the expandable electrode has a length L that provides enough surface area that there is at least some flexibility in the placement of the expandable electrode in the vessel with respect to the target nerve. In an example, the length of the expandable electrode is about 0.5 to 2.0 cm. 
   In an example, the entire surface area of the expandable electrode that touches the blood vessel wall is conductive. In an alternative example, at least a part of the surface area of the electrode is non-conductive. For example, an electrode can be formed and positioned to deliver stimulation to through a conductive part of the electrode to a portion  330  ( FIG. 3B ) of a blood vessel that is proximate a nerve. 
     FIG. 3B  shows an end view of the blood vessel and electrode of  FIG. 3A . The expandable electrode has an expanded diameter D (shown in  FIG. 3B ) that is sized for implantation in a blood vessel of a particular size range. In one example, where the electrode is size for implantation in the internal jugular vein, the expanded diameter D is about 0.5 to 1.5 cm, and the length L of the electrode is about 1.0 cm. 
   In an example, the expandable electrode is covered with a drug, such as a drug that prevents occlusion, or a drug that reduces inflammation of the blood vessel near the electrode. 
   The expandable electrode  305  is coupled to a power source that delivers an electrical stimulation. In  FIG. 3A , the illustrated expandable electrode  305  is coupled to a lead  315 . The lead  315  is coupled to an implantable system or device that includes control circuitry, such as the device shown in  FIG. 1  or the system shown in  FIG. 4 . 
   Electrode Placement and Nerve Targets 
   The electrode may be implanted in various locations in the body, including a variety of locations near a trunk or branch of a sympathetic or parasympathetic nerve system. 
   Referring again to the example shown in  FIG. 1A , the location of implanted electrodes  295 ,  296  is denoted by an X. The implanted electrodes  295 ,  296  each transvascularly stimulate a sympathetic nerve or a parasympathetic nerve. In an example, the electrode  295  transvascularly stimulates a peripheral nerve trunk. Examples of a peripheral nerve trunk include the vagus nerve  287 , aortic nerve  288 , and carotid sinus nerve  289 , which are shown in  FIG. 2C . In another example, the electrode  295  stimulates a nerve branch, such as a vagal cardiac branch. 
     FIGS. 1B ,  1 C, and  1 D show examples of blood vessels in which the electrode can be implanted.  FIG. 1B  shows an implantable device  290 , leads  291 ,  292 ,  293  extending into a heart  201  and a superior vena cava  202 , an aortic arch  203 , and a pulmonary artery  204 . Leads extending into the heart are shown as dotted lines. For simplicity, electrodes are denoted with an X. Lead  291  and electrode  298  are inserted in the superior vena cava (SVC)  202 . The electrode  298  is used to transvascularly stimulate a nerve or nerve trunk on or near the SVC  202 . CRM lead  292  is intravascularly inserted through a peripheral vein into the coronary sinus and into the left ventricle. Electrode  299  is implanted in the coronary sinus and coupled to the CRM lead  292 .  FIG. 1B  also shows electrodes  294  and  295 , which are examples of sensing or pacing electrodes located in the right and left ventricles respectively. Physiological data sensed by one or both of the electrodes  294 ,  295  is processed by the device  290 , and a responsive neurostimulation therapy is delivered by one or more of the electrodes  298 ,  299 . 
     FIGS. 1C and 1D  illustrate other bloods vessels on the right side and left side of the heart respectively in which an electrode is implantable.  FIG. 1C  shows the right atrium  267 , right ventricle  268 , sinoatrial node  269 , superior vena cava  202 , inferior vena cava  270 , aorta  271 , right pulmonary veins  272 , and right pulmonary artery  273 .  FIG. 1D  shows the left atrium  275 , left ventricle  276 , right atrium  267 , right ventricle  268 , superior vena cava  202 , inferior vena cava  270 , aorta  271 , right pulmonary veins  272 , left pulmonary vein  277 , right pulmonary artery  273 , and coronary sinus  278 . An electrode can be implanted in one or more of the blood vessels listed above at a location where a nerve, nerve branch, or nerve trunk passes an extravascular surface of the blood vessel. The implanted electrode transvascularly stimulates a nerve, nerve branch, or nerve trunk through the blood vessel. In one example, an electrode is implanted in the SVC  202  near a nerve a vagal nerve trunk. In another example, an electrode is implanted in the coronary sinus  278  near a vagal nerve trunk. 
   In another example, a cardiac fat pad is transvascularly stimulated by an implanted electrode.  FIG. 1C  illustrates a cardiac fat pad  274  between the superior vena cava and aorta.  FIG. 1D  illustrates a cardiac fat pad  279  located proximate to the right cardiac veins and a cardiac fat pad  280  located proximate to the inferior vena cava and left atrium. An electrode implanted in the superior vena cava, aorta, cardiac veins, or inferior vena cava stimulates nerve endings in fat pad  274  or  279 . Nerve endings in the fat pad  280  are stimulated by an electrode located in the coronary sinus. 
   Referring now to  FIG. 1E , in an example, electrodes  131 ,  132 ,  133 ,  134  are implanted at locations in blood vessels near a vagus nerve. Portions of arteries are shown cut-away so that the electrodes are visible in the figure. The aortic arch  116 , pulmonary artery  118 , carotid arteries  124 ,  126  and subclavian arteries  128 ,  130  are shown in  FIG. 1E . The right vagus nerve trunk  120  extends near carotid artery  124  and subclavian artery  128 . The left vagus nerve  122  extends near carotid artery  126  and subclavian artery  130 . Electrode  131  is implanted in carotid artery  124 . The illustrated electrode  131  is an expandable electrode such as a stent. Electrode  132  is implanted in carotid artery  126 . Electrode  133  is implanted in subclavian artery  128 . Electrode  134  is implanted in subclavian artery  130 . Electrode  140  is implanted in the carotid sinus  141  near the carotid sinus nerve  142 . In an example, only one of electrodes  131 ,  132 ,  133 ,  134 ,  140  is implanted in a patient. In another example, two or more electrodes are implanted in a patient and used to transvascularly stimulate a nerve trunk. 
     FIGS. 2A and 2B  provide additional illustrations of nerve target examples near the heart.  FIG. 2A  shows left vagus nerve  250  extending next to a subclavian artery  251 . Various nerves extend around the arch of the aorta  255 . Vagus nerve  250  also extends past the ligamentum arteriosum  256 . The anterior pulmonary plexus  257  crosses the left pulmonary artery  258 . Right vagus nerve  259  extends past a subclavian artery  260  and the cupola of pleura  261 . Cardiac nerves  262  extend past the brachiocephalic trunk  263  near the trachea  264 . Cardiac nerves  262  also extend past the arch of an azygos vein  265  to the right pulmonary artery  273 . In the lower portion of  FIG. 2A  appear the right lung  281 , left lung  282 , esophagus  283 , a lower portion  284  of the left vagus nerve  250 , and a lower portion  285  of the aorta.  FIG. 2B  shows a left phrenic nerve  240  extending past a cupola of pleura  241 , an internal thoracic artery  242 , and left pulmonary artery  258  Vagus nerve  250 , recurrent laryngeal nerves  252 , cardiac nerves  253 , and the anterior pulmonary plexus  257  extend near the left pulmonary artery  258  and ligamentum arteriosum. An expandable electrode, such as a stent, is chronically implantable in the blood vessels shown in  FIG. 2A  or  2 B to transvascularly stimulate a nerve or nerve trunk that extends on or near the blood vessel. In one example, the vagus nerve is transvascularly stimulated from the azygos vein  265  or internal jugular vein. 
     FIGS. 2C and 2D  show nerve pathways.  FIG. 2C  generally illustrates afferent nerves to vasomotor centers. An afferent nerve conveys impulses toward a nerve center. A vasomotor center relates to nerves that dilate and constrict blood vessels to control the size of the blood vessels.  FIG. 2D  generally illustrates efferent nerves from vasomotor centers. An efferent nerve conveys impulses away from a nerve center. Afferent and efferent nerves can be stimulated transvascularly. 
     FIG. 2E  shows the vagus nerve  286  near the internal jugular vein  287 . In an example, the vagus nerve  286  is transvascularly stimulated from the internal jugular vein  287 . A common carotid artery  124  and subclavian artery  128  are also shown in  FIG. 2E . 
   In other examples, nerve trunks innervating other organs, such as the lungs or kidneys are transvascularly stimulated. In an example, an expandable electrode such as a stent is implanted in a blood vessel proximate a nerve or nerve trunk that innervates the lungs or kidneys. 
   Device and System 
   Referring again to the example shown in  FIG. 1A , an implantable device  100  is coupled to a lead  200  that is inserted into a blood vessel and coupled to an electrode  295 . An electrical signal is delivered through the lead  200  to the electrode  295 , which transvascularly stimulates a nerve on an extravascular surface of the blood vessel. The device  100  can optionally also deliver cardiac resynchronization therapy (CRT) through one or more CRT leads that are threaded intravenously into the heart. The CRT leads connect the device  100  to electrodes  300  that are used for sensing or pacing of the atria and/or ventricles. Transvascular stimulation electrode  296  is coupled to a CRT lead. Some embodiments process intrinsic electrical heart signals and deliver a responsive neural stimulation therapy through one of the electrodes  295 ,  296 . An optional satellite unit  110  includes an electrode for neural stimulation and a communication circuit that communicates with the device  100  via a wireless link or conduction through the body. The satellite unit  110  electrode is implanted in a blood vessel, such as an internal jugular vein, to transvascularly stimulate a nerve, such as a vagus nerve, through the wall of the blood vessel. 
     FIG. 4  is a schematic illustration of an example transvascular stimulation system that includes an implantable device  401 , an electrical lead  420  coupled to the implantable device  401 , and an expandable stimulation electrode  425 . The implantable device includes a controller circuit  405 , a memory circuit  410 , a telemetry circuit  415 , and a neural stimulation circuit  435 . The controller circuit  405  is operable on instructions stored in the memory circuit to deliver an electrical stimulation therapy. Therapy is delivered by the neural stimulation circuit  435  through the lead  420  and the electrode  425 . The telemetry circuit  415  allows communication with an external programmer  430 . The illustrated system also includes optional sensor circuitry  440  that is coupled to a lead  445 . The controller circuit  405  processes sensor data from the sensor circuitry and delivers a therapy responsive to the sensor data. 
   Therapies 
   Neural stimulation therapies can be used to treat one or more of a variety of conditions, including but not limited to arrhythmias, heart failure, hypertension, syncope, or orthostatic intolerance. In an example, an efferent peripheral nerve is transvascularly stimulated by an implanted expandable electrode. In another example, an afferent peripheral nerve is stimulated. 
   In an example, electrical stimulation is transvascularly delivered to a parasympathetic nerve to reduce chronotropic, ionotropic, and dromotropic responses in the heart. In a therapy example, electrical stimulation is transvascularly delivered to a parasympathetic nerve trunk during heart failure. In another therapy example, electrical stimulation is transvascularly delivered to a parasympathetic nerve trunk following a myocardial infarction to protect against arrhythmias or prevent cardiac remodeling. 
   Transvascular stimulation of a vagus nerve trunk is used in a number of therapies. In an example, vagal nerve stimulation simultaneously increases parasympathetic tone and decreases sympathetic myocardial tone. In an example, a vagus nerve trunk is transvascularly stimulated following cardiac ischemic insult. Increased sympathetic nervous activity following ischemia often results in increased exposure of the myocardium to epinephrine and norepinephrine. These catecholamines activate intracellular pathways within the myocytes, which lead to myocardial death and fibrosis. This effect is inhibited by stimulation of the parasympathetic nerves, such as vagus nerves. In an example, vagal stimulation from the SVC lowers heart rate, overall blood pressure, and left ventricular pressure. Stimulation of the vagal cardiac nerves following myocardial infarction, or in heart failure patients, can be beneficial in preventing further remodeling and arrhythmogenesis. 
   In other examples, transvascular neural stimulation is used to treat other conditions such as hypertrophic cardiomyopathy (HCM) or neurogenic hypertension, where an increase parasympathetic cardiac tone and reduction in sympathetic cardiac tone is desired. In another example, a bradycardia condition is treated by transvascularly stimulating a sympathetic nerve trunk. In another example, the ionotropic state of the heart is increased by transvascularly stimulating a sympathetic nerve trunk. 
   Methods for Delivering Transvascular Stimulation 
   Referring now to  FIG. 5 , an example method of delivering transvascular neural stimulation includes implanting a medical device, at  505 . At  510 , an electrode is chronically implanted in a blood vessel near a nerve trunk, such as a cardiac peripheral nerve trunk. In an example, the electrode is an expandable electrode, such as a stent. In an example, the expandable electrode has an expanded diameter that is dimensioned to fix the electrode in place by frictional forces. In an example, the expandable electrode includes a drug-eluting coating that prevents occlusion or prevents inflammation of vascular walls or nerves that receives electrical stimulation from the electrode. In an example, the electrode is implanted in a blood vessel at a location where the nerve trunk extends along an extravascular surface of the blood vessel. In an example, the electrode is implanted in a blood vessel near a peripheral nerve trunk. In an example, the peripheral nerve trunk includes a sympathetic or parasympathetic nerve. In an example, the electrode is implanted near a vagal cardiac nerve in a blood vessel such as the SVC, coronary sinus, or an azygos vein. In another example, the electrode is implanted in an internal jugular vein. 
   Returning to  FIG. 5 , at  515 , an electrical signal is delivered from the implanted device to the electrode to transvascularly deliver neural stimulation to a nerve trunk near the blood vessel. In an example, the electrode delivers an electric pulse therapy that is sufficient to elicit depolarization of a target nerve. In an example, the stimulation therapy delivers about 1-10 milliamps of electrical stimulation. In an example, the controller delivers a pulse train of about 10-120 hertz to the electrode. In one example, a pulse train of about 20 hertz is used. In an example, delivery of transvascular neural stimulation near the heart is timed to occur during the cardiac refractory period to prevent fibrillation. 
   In an example, transvascularly stimulating a parasympathetic nerve inhibits cardiac remodeling or delivers an antiarrhythmia therapy following a myocardial infarction. In another example, transvascularly stimulating a sympathetic nerve delivers an antibradycardia therapy. 
     FIG. 6  is a flow chart that illustrates another method. A medical device is implanted at  605 . At  610 , an electrode is chronically implanted in a blood vessel near a nerve trunk. At  615 , a physiologic property is sensed. In an example, an intrinsic electrical heart signal is detected. In another example, blood pressure is detected. At  620 , neural stimulation responsive to the sensed physiologic property is transvascularly delivered through the implanted electrode.