Patent Publication Number: US-2015073288-A1

Title: Method and apparatus to control conduction through the heart to treat cardiac conditions

Description:
RELATED APPLICATION 
     This application is related to, and claims the benefit of, provisionally-filed U.S. Patent Application Ser. No. 60/464,767 filed Apr. 23, 2003, and U.S. patent application Ser. No. 10/798,613 filed Mar. 11, 2004 entitled “System for the Delivery of a Biologic Therapy with Device Monitoring and Back-Up”, which are incorporated herein by reference in their entirety. This application is also related to, and claims the benefit of, provisionally-filed U.S. Patent Application Ser. No. 60/684,658, filed May 26, 2005. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates generally to cardiovascular therapies and, more particularly, to control of conduction through the heart. 
     BACKGROUND OF THE INVENTION 
     Cardiac conditions such as supraventricular arrhythmias (SVA) or chronic heart block are treated with device therapies, drug therapies, or a combination thereof. Device therapies typically involve implantable medical devices (IMDs). IMDs are effective except with some patients that experience SVA or chronic heart block. One such example relates to implantable pulse generators (IPGs) or implantable cardioverter-defibrillators (ICDs) that deliver electrical stimulation to the vagal nerve plexes located in the heart. Stimulation of vagal nerve plexes enhances parasympathetic input to the atrioventricular (AV) node and subsequently slows AV nodal conduction and ventricular rate. While this therapy operates acutely, tachyphylaxis may occur. Tachyphylaxis is a rapidly decreasing response to a drug or physiologically active agent after administration of a few doses. Additionally, vagal stimulation may induce atrial arrhythmias. 
     Combined device and drug therapies are costly. One such therapy relates to ventricular rate sensors of an IMD that rely on a sensor-based algorithm to regulate the delivery of drugs. In this case, drugs are typically taken orally on a daily basis regardless of the existence of atrial fibrillation (AF) or inadequate ventricular rate in a heart. A daily dosage is problematic for some patients. For example, some patients are excessively bradycardiac while in sinus rhythm and experience an elevated ventricular rate in AF. To address this problem, a pacemaker is implanted to detect “drug induced brady” conditions and to control the rate of drug delivery. Pacemakers increase patients&#39; costs. 
     Drug therapies also have drawbacks. Drugs are delivered through systemic circulation of a patient. Examples of systemic drug delivery include oral, intravenous, subcutaneous, or transdermal delivery methods. Since systemic drug delivery introduces drugs to all organs and tissue, non-targeted organs or tissue may exhibit drug toxicity. Drug toxicity concerns limit the dosage that is administered to a patient. Limiting a dosage may reduce the effectiveness of the drug. Systemic drug delivery may also cause side effects in the patient, which reduces tolerability or effectiveness of drugs. For example, drugs that slow down AV nodal conduction may cause side effects such as sinus bradycardia, congestive heart failure, fatigue, or constipation. 
     Some gene therapies claim to chronically transfect AV nodal tissue with specific genes to control conduction rate through the AV node. However, it is unclear whether these gene therapies adequately control titration of an agent to achieve therapeutic goals. Consequently, gene therapy may result in uncontrollable or inadequate AV nodal rate. It is therefore desirable to have therapies that overcome the limitations described above. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The present invention will become more fully understood from the detailed description and the accompanying drawings, wherein: 
         FIG. 1  is a block diagram of an exemplary system to control conduction through a heart; 
         FIG. 2  is a partial perspective view of an exemplary medical device that delivers therapeutic agent to myocardial tissue of a patient; 
         FIG. 3  is a flow diagram of a method to detect cardiac conditions; 
         FIG. 4  is a flow diagram of a method to treat cardiac conditions when a patient has low physical activity; 
         FIG. 5  is a flow diagram of a method to treat cardiac conditions when a patient has increased physical activity; 
         FIGS. 6A-6B  are flow diagrams of a method to control atrial ventricular conduction time; 
         FIG. 7  is a flow diagram of a method to detect cardiac conditions; 
         FIG. 8  is a flow diagram of a method to treat cardiac conditions; 
         FIG. 9  is a flow diagram of a method to treat cardiac conditions based upon patient activity; 
         FIG. 10A  is a bar diagram in which ventricular rate is controlled; 
         FIG. 10B  is a electrocardiogram in which ventricular rate is controlled; 
         FIG. 10C  is a block diagram of  FIG. 10B  in which ventricular rate is controlled; and 
         FIG. 10D  is a bar diagram of reversible increase of AH and AV intervals during continuous administration of an agent. 
     
    
    
     DETAILED DESCRIPTION OF THE EMBODIMENTS 
     The following description of embodiments is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses. For purposes of clarity, similar reference numbers are used in the drawings to identify similar elements. 
     The present invention is directed to control of conduction through a heart. This is accomplished, in part, by monitoring delivery of an agent (e.g. drug, biologic, drug/biologic, etc.) to a target area through a closed loop feedback system. Closed loop feedback systems typically relate to implantable medical devices (IMDs). An IMD includes a first and a second lead. The distal end of the first lead is inserted into or around the target area (e.g. atrialventricular (AV) nodal area etc.). The first lead then delivers the agent to the target area. The IMD monitors the electrical response from the heart by accessing data via an electrode at a distal end of a second lead. Adjustments are made to the amount of agent delivered based upon the sensed electrical response from the heart by accessing data. In this manner, a patient&#39;s ventricular rate is maintained at an optimal level. 
     A variety of cardiovascular conditions are treated through control of AV conduction time. For example, the present invention treats paroxysmal chronic supraventricular arrhythmias (i.e. atrial fibrillation, atrial flutter, atrial tachycardia, supraventricular tachycardia). Additionally, chronic heart block (i.e. chronic atrial fibrillation (AF) conditions, chronic AV block conditions) is also treated through the control of the ventricular rate or atrialventricular conduction time. Episodic periods of AF with fast ventricular response are also managed. Furthermore, the present invention improves the treatment and management of atrial bradyarrhythmias. 
     The present invention also improves treatment of cardiovascular conditions. For example, drug dosages are reduced by five to twenty fold. Additionally, low or undetectable systemic plasma concentrations are obtained. Elimination or diminution is achieved for non-cardiac and cardiac side effects (e.g. ventricular proarrhythmia etc.). Non-orally bioavailable drugs can be administered. Greater efficacy or duration of action is obtained. Episodic drug delivery decreases the risk for drug toxicity and complication. Episodic delivery also increases the time periods between drug replacement in the implantable drug delivery arrhythmia management system. A synergistic effect may be obtained in combination with electrical stimulation therapies. 
       FIG. 1  depicts a block diagram of system  10  that treats cardiac conditions (e.g. supraventricular arrhythmias, chronic heart block etc.) by monitoring the effectiveness of an agent delivered to myocardial tissue. System  10  includes IMD  12 , one or more leads  20   a - 20   c , and agent reservoir  30 . A detailed example of an IMD  12  may be seen with respect to a U.S. patent application Ser. No. 10/465,351 filed on Jun. 19, 2003, and assigned to the assignee of the present invention, the disclosure, in relevant part, is incorporated by reference. Exemplary IMDs  12  include an IPG to provide a pacing function, an ICD to provide shocks, a monitoring implant to record various cardiac performance characteristics, or a device that combines these functions. 
     Leads  20   a - 20   c , which extend from IMD  12 , are inserted into or around the myocardial tissue. For example, distal end of lead  20   a  is in the right atrium, distal end of lead  20   b  is in the right ventricle, and distal end of lead  20   c  is in or in close proximity to the AV node. Leads  20   a - 20   c  include electrodes to sense data related to cardiovascular variables or parameters. Lead  20   c  also includes a delivery line (not shown) that allows delivery of the agent to the myocardial tissue. An agent delivery system  30 , coupled to lead  20   c  via conductive line  21 , contains and pumps the desired agent (e.g. drug, biologic agent, drug/biologic agent, genetic material etc.) to the myocardial tissue. Line  21  is a coaxial line that includes a conductive line (e.g. wire) and an agent delivery line (not shown). 
     An exemplary catheter  18  to deliver therapeutic agent to tissue is depicted in  FIG. 2 . Catheter  18  includes a catheter body  19 , lead  20   c  and a fluid container  50 . Lead  20   c  comprises a lead body  22 , one or more electrodes  24 , and an anchoring mechanism  34 . Lead body  22  has a proximal end  35 , a distal end  36 , and a lumen therebetween. Anchoring mechanism  34  (e.g. a fixed screw etc.), disposed near distal tip  25  of lead  20   c , is configured to secure lead  20   c  to the myocardial tissue (e.g. AV nodal tissue etc.). Ideally, lead  20   c  is affixed in or around the triangle of Koch of the myocardial tissue. Fluid container  50  interconnects agent delivery system  30  with the myocardial tissue. Fluid container  50  is guided through lead  20   c  and is either removed after the procedure or left in place. Distal tip  55  of fluid container  50  either contacts the myocardial tissue or is forced into the myocardial tissue. 
     System  10  operates as a closed loop feedback system. For example, IMD  12  signals agent delivery system  30  over line  21  to deliver an agent to myocardial tissue. Exemplary agents include calcium channel antagonists, beta-adrenergic antagonists, digitalis-derived drugs, purinergic agents (e.g. adenosine compound, etc.), parasympathetic agents, (e.g. acetylcholine-like compounds, etc.), local anesthetics, adrenergic agonists or other suitable material. In response to signals from IMD  12 , agent delivery system  30  pumps agent via a pump (not shown) through lead  20   c . The agent is delivered through the fluid container  50  and into or onto the myocardial tissue. The agent regulates AV nodal conduction. For example, the agent controls the speed at which a depolarization wavefront passes from the atrium to the ventricule. In the case of supraventricular tachycardias (SVT), the speed of the depolarization wavefront is decreased. In contrast, the speed of the depolarization wavefront is increased for AV nodal block. Sensed data is then transmitted over one or more leads  20   a - 20   c  via their respective electrodes  24  to IMD  12 . Based upon the sensed data, IMD  12  then determines whether an adjustment of the agent dosage is required. If an adjustment is required, IMD  12  signals agent delivery system  30  to increase, decrease, or stop agent delivery. 
     FIGS.  3  through  6 A- 6 B generally depict an embodiment to monitor the effect of an agent on myocardial tissue and then, if necessary, adjust the agent dosage. These operations are embodied in computer instructions that are stored in memory (e.g. RAM) and executed on the microprocessor of IMD  12 .  FIG. 3  specifically relates to monitoring for cardiac conditions. At operation  100 , a patient&#39;s heart rate is sensed through the electrode(s) of one or more leads  20   a - 20   c . At block  110 , a determination is made as to whether an arrhythmia is occurring. If arrhythmia is not detected, system  10  continues to sense data related to the heart rate at block  100 . Alternatively, if an arrhythmia is detected, the ventricular rate is sensed by one or more of electrodes of leads  20   a - 20   c  at block  120 . At block  130 , a determination is made as to whether an elevated ventricular response is occurring. An undetected elevated ventricular response causes system  10  to return to block  120  to continue to sense data related to ventricular rate. If an elevated ventricular response is detected, the patient&#39;s level of activity is sensed at block  140 . At block  150 , a determination is made as to whether the patient is at rest. If the patient is at rest, the operation goes to block  300  of  FIG. 5 . In contrast, if the patient is at rest, the operation goes to block  200  of  FIG. 4 . 
       FIG. 4  is a flow diagram depicting a method to treat a patient for cardiovascaular conditions while in an inactive physical state (i.e. rest state). Generally, blocks  300 - 340  relate to treatment of a high ventricular rate; blocks  350 - 380  relate to maintaining a desirable ventricular rate; and blocks  410 - 480  relate to treatment of a low ventricular rate. At block  300 , agent delivery to a target area (e.g. AV nodal area, etc.) occurs. At block  310 , a determination is made as to whether a high ventricular rate is occurring. Typically, a high ventricular rate is greater than 80 beats per minute (BPM). However, age, pre-existing disease, pre-existing physiological sinus heart rate (if available) and other factors are considered by the physician when programming the ventricular heart rate levels. If high ventricular rate data is sensed from the electrical activity of the myocardial tissue, IMD  12  signals agent delivery system  30  to increase the agent dosage level at block  320 . The elevated dosage level is also referred to as a first dosage level. A determination is then made as to whether the ventricular rate is within the desired range after the administration of the first dosage level at block  330 . A desired ventricular rate range is typically greater than 60 BPM and less than 80 BPM. If the ventricular rate is not within the desired range after a certain time period, the agent is administered at another elevated dosage level at block  320 . For example, if the ventricular rate exceeds 100 bpm for over 5 minutes at rest while a drug is administered at a given dosage X, then dosage X is increased 10-200% until the ventricular rate is within the desired range. Alternatively, if the ventricular rate is determined to be within the desired range, delivery of the agent in its current dosage is continued at block  340 . 
     If it is determined that a high ventricular rate does not exist at block  310 , the operation turns to maintenance of a desired ventricular rate. A determination is made as to whether the ventricular rate is within a desired range at block  350 . If the ventricular rate is below the desired ventricular rate, delivery of the agent is stopped at block  400 . If the ventricular rate is within the desired range, the agent is continuously delivered in its current dosage at block  360 . A determination is then made as to whether the arrhythmia has stopped at block  370 . If the arrhythmia has ceased, the agent is continuously delivered at its current dosage to the target area at block  300 . If not, a determination is made as to whether the heart rate is too low at block  375 . If the heart rate is not too low, delivery of the agent is stopped at block  380  and system  10  returns to monitoring cardiovascular conditions at block  100  of  FIG. 3 . If the heart rate is too low, a pacing operation is implemented at operation  420 . 
     Blocks  400 - 480  generally relate to treatment of a low ventricular rate. At block  400 , delivery of the agent is stopped for low range ventricular rate (e.g. typically less than 60 BPM). At block  410 , a determination is made as to whether pacing is required. If pacing is required, pacing is performed at block  420  by one of the leads  20   a - 20   c . At block  430 , the heart rate is monitored. At block  450 , a determination is made as to whether the heart rate is too low. If the heart rate is too low, the operation makes a determination as to whether pacing is required at block  410 . If the heart rate is not too low, a determination is made as to whether the heart rate is too high at block  460 . If the heart rate is too high, the operation goes to block  310  to determine whether a high ventricular rate exists. If the heart rate is not too high, the agent is administered at a certain dosage level at block  470 . For example, if the heart rate is at 160 bpm during exercise, then the AVN blocker drug such as calcium channel blocker agent (e.g. verapamil etc.) is continuously delivered. A determination is then made at block  480  as to whether the arrhythmia has stopped. If the arrhythmia has stopped, delivery of the agent is stopped at block  380 . If the arrhythmia has not stopped, the agent is delivered at a certain dosage level at block  470 . This dosage level is referred to as a second dosage level. 
       FIG. 5  is a flow diagram that depicts treatment of a cardiac condition based upon the activity of a patient instead of ventricular rate. At block  500 , agent delivery to a target area (e.g. AV nodal area, etc.) occurs. At block  505 , a determination is made as to whether a patient exhibits high physical activity. U.S. patent application Ser. No. 10/465,351, incorporated by reference, in relevant part, briefly describes sensors for activity. 
     Typically, high physical activity is determined by increased activity of these sensors (e.g. motion sensor, etc). If high physical activity data is sensed from the electrical activity of the myocardial tissue, IMD  12  signals agent delivery system  30  to increase the agent dosage level at block  510 . The elevated dosage level is also referred to as a first dosage level. A determination is then made as to whether the patient, who is experiencing high physical activity, nevertheless maintains the heart beat within a desired range after the administration of the first dosage level at block  515 . If the heart rate is not within the desired range within a certain time period, the agent is administered at another elevated dosage level at block  510 . For example, the patient has a ventricular rate of 180 bpm at a given dosage level X, then this dosage level is increased by 10-200%. Alternatively, if the heart rate is determined to be within the desired range, delivery of the agent in its current dosage is continued at block  520 . 
     If it is determined that a high physical activity does not exist at block  505 , the operation turns to medium level of physical activity operations. A determination is made as to whether medium physical activity is occurring at block  525 . If the ventricular rate is below the desired ventricular rate, delivery of the agent is stopped at block  550 . If medium physical activity is occurring, the agent is continuously delivered in its current dosage at block  530 . A determination is then made as to whether the arrhythmia has stopped at block  535 . If the arrhythmia has ceased, the agent is continuously delivered at its current dosage to the target area at block  500 . If not, a determination is made as to whether the heart rate is too low at block  540 . If the heart rate is not too low, delivery of the agent is stopped at block  545  and the system returns to monitoring cardiovascular conditions at block  100  of  FIG. 3 . 
     Blocks  550 - 585  generally relate to treatment of a patient during low physical activity. At block  550 , delivery of the agent is stopped for low range ventricular rate (e.g. less than 60 BPM). At block  555 , a determination is made as to whether pacing is required. If pacing is required, pacing is performed at block  560  by one of the leads  20   a - 20   c . At block  565 , the heart rate is monitored. At block  570 , a determination is made as to whether the heart rate is too low. If the heart rate is too low, the operation makes a determination as to whether pacing is required at block  555 . If the heart rate is not too low, a determination is made as to whether the heart rate is too high at block  575 . If the heart rate is too high, the operation goes to block  505  to determine whether a high physical activity exists. If the heart rate is not too high, the agent is administered at a certain dosage level at block  580 . For example, a calcium blocking agent may be delivered if the ventricular heart rate is 160 beats per minute. A determination is then made at block  585  as to whether the arrhythmia has stopped. If the arrhythmia has stopped, delivery of the agent is stopped at block  545 . If the arrhythmia has not stopped, the agent is delivered at a certain dosage level at block  580 . This dosage level is referred to as a second dosage level. 
       FIGS. 6A and 6B  depict operations to control AV conduction time. At block  700 , the heart rate is sensed by system  10 . At block  710 , AV conduction time is monitored. At block  720 , a determination is made as to whether AV conduction time too high. If AV conduction time is not too high, the operation loops back to block  710  to monitor AV conduction time. Alternatively, if AV conduction time is too high, agent is delivered to the target area at block  730 . At block  740 , a determination is made as to whether AV conduction time is lower than 100 microseconds. If AV conduction time is not lower than 100 milliseconds) (ms), a determination is then made at block  780  as to whether AV conduction time is less than 250 ms. In contrast, if AV conduction time is lower than 100 ms, agent delivery is stopped at block  750 . At block  760 , AV conduction time is monitored. At block  770 , a determination is made as to whether AV conduction time is greater than 100 ms. If AV conduction time is not greater than 100 ms, system  10  loops back to block  760  to monitor AV conduction time. Alternatively, if AV conduction time is greater than 100 ms, the agent is delivered to the target area at block  730 . 
     Turning now to block  780 , a determination is made as to whether AV conduction time is less than 250 ms. If AV conduction time is less than 250 ms, delivery of the agent continues at its current dosage at block  790 . 
     At block  810 , a determination is made as to whether AV block III is occurring in the patient. If it is not present, agent delivery continues at a specified dosage at block  820 . The heart rate is monitored and appropriate action is taken if a cardiac condition is detected at block  825 . Optionally, control of system  10  returns to block  700 . In contrast, if AV block III is occurring, a determination is made as to whether pacing is required at block  830 . If pacing is required, a pacing operation is implemented at block  840 . The patient&#39;s heart rate is monitored at block  850 . A determination is made as to whether the heart rate is too low at block  860 . At block  865 , the heart rate is monitored and appropriate action is taken if a cardiac condition is detected. Optionally, control of system  10  returns to block  700 . 
       FIGS. 7-9  illustrate another embodiment to control conduction through a heart.  FIG. 7  depicts operations that determine whether a therapeutic algorithm or a pacing algorithm are implemented. At block  900 , the heart rate of a patient is sensed. At block  910 , a determination is made as to whether atrial arrhythmia is detected. If no atrial arrhythmia is detected, any therapy is stopped at operation  915  and the system returns to sensing the heart rate at block  900 . If atrial arrhythmia is detected, the patient&#39;s level of activity is sensed at block  920 . At block  930 , the heart rate is determined. At operation  940 , a determination is made as to whether an elevated ventricular response is present. If so, the therapeutic algorithm is implemented at operation  950  and the operations in  FIG. 8  are then followed. If an elevated ventricular response is not detected, a determination is made as to whether a low ventricular response is present at block  960 . If so, a standard pacing algorithm is implemented at operation  970  and the operations of  FIG. 9  are implemented. However, if a low ventricular response is not detected, control of the algorithm returns to the start operation. 
       FIG. 8  is a flow diagram related to administration of a therapeutic agent taking into consideration a patient&#39;s level of physical activity. At operation  1000 , an agent is delivered to the target area (e.g. triangle of Koch area). At operation  1010 , a determination is made as to whether a condition is satisfied. Exemplary conditions include the elapsed time from which the agent was delivered to the target area, variables related to AF, slope of heart rate change, or other suitable conditions. If the condition is not satisfied, control of the operation returns to block  1000  in which the agent continues delivery. In contrast, if the condition is satisfied, the patient&#39;s level of activity is checked at block  1015 . A determination is then made as to whether a low heart range is present at block  1020 . If a low heart range is present, a determination is made as to whether a minimum dosage level is being applied to patient at block  1030 . If the minimum dosage level is being used, delivery of the agent at target area is stopped at block  1040  and control of the algorithm returns to block  100 . In contrast, if a minimum dosage level is not present, the agent dosage is decreased at operation  1032  to control of system  10  then turns to block  1000 . 
     If a low heart range is not present in the patient, a determination is then made at block  1022  as whether a normal heart range is present. If the normal heart range is occurring, agent dosage is maintained at block  1024  and control of system  10  returns to block  1000 . If a normal heart range is not present in the patient, a determination is made as to whether the patient is being administered at maximum agent dosage level at block  1028 . If not, agent dosage is increased at block  1029  and control of system  10  returns to block  1000 . In comparison, if the patient is at the maximum dosage level, a patient alert is sent to the physician at block  1026  and control of the algorithm returns to block  1000  at operation  1049 . 
       FIG. 9  relates to checking patient&#39;s level of activity. At operation  1100 , the heart rate of the patient is sensed. At block  1110 , a determination is made as to whether atrial arrhythmia is occurring. If not, any applicable therapy is stopped at block  1115  and control of system  10  returns to sensing the heart rate at  1100 . If atrial arrhythmia is detected, the patient&#39;s level of activity is sensed using an activity sensor at block  1120 . A determination is made as to the patient&#39;s heart rate at block  1130 . At block  1140 , a determination is made as to whether an elevated ventricular response is present. At block  1150 , if there is an elevated ventricular response, control of the algorithm returns to block  1020 . In contrast, if an elevated ventricular response is not present, a determination is made as to whether a low ventricular response is occurring in the patient at block  1060 . A standard pacing algorithm is implemented at block  1170  if a low ventricular response is present. In contrast, if the patient lacks a low ventricular response, control of the operation returns to the start of the algorithm. 
       FIGS. 10A-10D  represent in vivo experimental data obtained from anesthetized animals based upon features of the claimed invention. Specifically, this data demonstrates that local drug delivery directly into the AVN region effectively controls ventricular rate during AF without producing systemic effects and toxicity. This study evaluated the effect of locally administered acetylcholine (ACH) on AVN conduction and refractoriness properties during sinus rhythm and AF. Canines (n=7) were anesthetized, and instrumented to assess atrial and ventricular electrophysiology as well as arterial blood pressure. A custom drug delivery catheter was fixed into the AVN region using a combination of standard electrophysiological mapping techniques and image guided therapy via a cardiac navigation system. Its location was confirmed by delivering an ACH test dose and resultant complete, but fully reversible heart block in all 7 animals. As noted from data presented below in Table 1, the duration of AV block administered via direct AVN injection was substantially longer than for intravenous administration of the identical dose. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 AV Block III duration and overall AV Block duration for  
               
               
                 direct AVN Bolus injection vs. Intravenous Bolus injection. 
               
            
           
           
               
               
               
            
               
                   
                 Direct AVN Bolus 
                 Intravenous Bolus 
               
               
                   
                 (n = 6) 
                 (n = 5) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Overall AV Block duration* (min) 
                 41.19 ± 27.14 
                 0.31 ± 0.43 
               
               
                 AV Block III duration (min) 
                 12.30 ± 4.72 
                 0.00 ± 0.00 
               
               
                   
               
               
                 *Duration of AV block I, II and III 
               
            
           
         
       
     
     Subsequently, incremental doses of ACH starting at 10 ug/min were infused into the AVN until complete atrioventricular heart block (AVB) was observed. ACH produced AVB in a dose dependent manner. During electrically induced AF, the ventricular rates decreased from 182±32 to 77±28 beats per minutes (bpm) (acetylcholine dosage inducing first degree AVB; p&lt;0.05) and to 28±8 bpm (third degree AVB; p&lt;0.05) ( FIG. 10A ). Raw data obtained during electrically induced AF are shown in  FIG. 10B  during and without drug administration. At the first degree AVB dose, AVN effective refractory period (ERP) at a pacing cycle length of 400 milliseconds (msec) increased from 186±37 msec to 282±33 msec (p=0.06), and Wenckebach cycle length from 271±29 msec to 378±58 msec (p&lt;0.05) ( FIG. 10C ). In addition, ACH dose producing first AVB prolonged AV, PR and AH intervals, whereas PP intervals, HV intervals and blood pressure remained unchanged, demonstrating a local effect ( FIG. 10D ). Observed effects were fully reversible within 20 minutes after stopping ACH infusion. From this in vivo data, local ACH delivery into the AVN region successfully increased AVN refractoriness and significantly decreased ventricular rate response during electrically induced AF in a dose related fashion. These effects occurred without significant systemic effects and were rapidly reversible within minutes. This may represent a novel drug delivery therapy whereby direct AVN drug delivery is monitored and controlled to maintain an optimal ventricular rate during AF events. 
     The present invention has numerous applications. For example, while the figures relate to AF, other types of cardiac conditions may be treated by this process. For example, AV block may rely on the embodiment presented in  FIGS. 7-9 . To illustrate, blocks  1020  and  1028  may be switched with each other. Additionally, the blocks that describe “atrial arrhythmia” are switched to AV block. The rest of the blocks remain unchanged. The description of the invention is merely exemplary in nature and, thus, variations that do not depart from the gist of the invention are intended to be within the scope of the invention. Such variations are not to be regarded as a departure from the spirit and scope of the invention.