Patent Publication Number: US-11033744-B2

Title: System for electrical therapeutic stimulation-based treatment of Brugada syndrome

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     This non-provisional patent application is a continuation of U.S. Pat. No. 10,335,600, issued Dec. 3, 2019, the disclosures of which is incorporated by reference. 
     FIELD 
     This application relates in general to treatment of cardiac rhythm disorders and, in particular, to a system for electrical therapeutic stimulation-based treatment of Brugada syndrome. 
     BACKGROUND 
     Brugada syndrome is a distinct form of genetically-determined idiopathic cardiac arrhythmia syndrome that can lead to syncope, cardiac arrest and sudden cardiac death (SCD). The syndrome is a genetic form of cardiac rhythm disorder caused by an inherited ion channelopathy. Brugada syndrome has been observed in the electrocardiograms of otherwise healthy young individuals without evidence of structural heart disease who are of Southeast Asian descent. Men are eight to ten times more likely to suffer Brugada syndrome. The syndrome has an autosomal-dominant pattern of transmission in about half of the familial cases observed and primarily affects Southeast Asian men, especially Thai and Laotian, in the 30-50 year age range, with a median age of 41 years. 
     The prognosis in Brugada syndrome is poor. Although the exact incidence of SCD due to Brugada syndrome is unknown, the magnitude of the problem has been estimated to range from 180,000 to 450,000 deaths annually in the United States alone. Further, about 2.5% of all cardiac arrest cases in which the patient showed no clinically identifiable cardiac abnormalities have been attributed to Brugada syndrome. The syndrome also accounts for 4% to 12% of all SCDs in genetically pre-disposed individuals, and a 40% mortality rate has been observed in symptomatic patients at two to three years follow up, with a 2% to 4% mortality rate in asymptomatic patients. During electrophysiologic studies (EPS), asymptomatic patients with induced ventricular tachycardia (VT) or ventricular fibrillation (VF) exhibited four times more SCD than non-inducible patients. 
     The cause of death in Brugada syndrome is due to VF, yet the precise mechanism underlying the electrocardiographic changes observed in symptomatic patients having Brugada syndrome is unknown. Pathologically, in 20% of observed cases, the syndrome has been associated with mutations in SCN5A gene expression, located in chromosome 3, which encodes for sodium ion channel transport to cell membranes of cardiac myocytes. Loss-of-function mutations in this gene have been theorized to lead to a failure of the action potential dome to develop, that in turn causes persistent ST segment elevation. The clinical events observed coincident to the electrocardiographic markers of Brugada syndrome, from syncope to VT to VF to SCD, are triggered by polymorphic ventricular arrhythmias, whose mechanism could be a Phase 2 reentry in the area around the right ventricular outflow tract. 
     Conventional approaches to treating Brugada syndrome focus on preventing or ameliorating VT and VF. For instance, implantable cardiac rhythm management devices, particularly automatic implantable cardioverter-defibrillator (ICDs), and, to a lesser extent, transiently-introduced electrophysiology catheters, apply a therapy based on the reversion of already-established polymorphic arrhythmias, such as described in Lee et al., “Prevention of Ventricular Fibrillation by Pacing in a Man with Brugada Syndrome,” J. Cardiovasc. Electrophysiol., Vol. 11, pp. 935-937 (August 2000), the disclosure of which is incorporated by reference. Similarly, Quinidine-based pharmaceutical therapies have also been used to effectively prevent VF induction and suppress spontaneous arrhythmias. Finally, surgical interventions through ablation at the right ventricular outflow tract level have been explored. Notwithstanding, these approaches constitute aggressive interventions and are impracticable to use on the large population that is theorized to have the Brugada syndrome, as only a small percentage will develop VT or VF, or experience cardiac arrest or SCD. 
     Therefore, a need remains for an approach to proactively treating the conduction and activation problems underlying the Brugada syndrome, rather than focusing on only avoiding or alleviating the deleterious sequelae of the syndrome. 
     SUMMARY 
     Brugada syndrome and related forms of ion channelopathies, including ventricular asynchrony of contraction, originate in the region near the His bundle or para-Hisian regions of the heart. Manifestations of Brugada syndrome can be corrected by delivering endocardial electrical stimulation coincident to the activation wave front propagated from the atrioventricular (AV) node. 
     In one embodiment, a system for electrical therapeutic stimulation-based treatment of Brugada syndrome is provided. The system includes a cardiac pacing device including a pulse generator and a pair of pacing electrodes electrically coupled to the pulse generator via an endocardial lead and positioned in one of a region near the His bundle and a para-Hisian region of a patient&#39;s heart, the pulse generator configured to deliver electrical therapeutic stimulation through the pair of pacing electrodes substantially coincident to propagation of an activation wave front proceeding from the atrioventricular node of the patient&#39;s heart; and a diagnostic module operatively coupled to the pulse generator and configured to sense via at least one sensing electrode physiology indicative of a presence of Brugada syndrome in the patient, the diagnostic module further configured to control the pulse generator in delivering the electrical therapeutic stimulation in response to the presence of Brugada syndrome, wherein the physiology indicative of a presence of Brugada syndrome includes an electrocardiogram that exhibits an ST segment elevation in the anterior precordial (V 1 , V 2 , V 3 ) leads with QRS complexes exhibiting an image of right bundle branch block in the right precordial leads and an elevation at the J point. 
     In a further embodiment, a cardiac rhythm management system for treating Brugada syndrome is provided. The system includes an endocardial lead comprising a pair of pacing electrodes and at least one sensing electrode both on a distal end that has been positioned in one of a region near the His bundle and a para-Hisian region of a patient&#39;s heart; and a cardiac rhythm management device comprised in a hermetically-sealed biocompatible housing and further including: a sensing amplifier electrically coupled to the endocardial lead and configured to detect through the at least one sensing electrode propagation of an activation wave front proceeding from the atrioventricular node; a pulse generator electrically coupled to the endocardial lead and configured to deliver electrical therapeutic stimulation under programmed parametric control, the pulse generator further configured to deliver the electrical therapeutic stimulation through the pair of pacing electrodes substantially coincident to the activation wave front as detected by the sensing amplifier; and a diagnostic module operatively coupled to the pulse generator and the sensing amplifier and configured to sense via the at least one sensing electrode physiology indicative of a presence of Brugada syndrome in the patient, the diagnostic module further configured to control the pulse generator in delivering the electrical therapeutic stimulation in response to the presence of Brugada syndrome, wherein the physiology indicative of a presence of Brugada syndrome includes an electrocardiogram that exhibits an ST segment elevation in the anterior precordial (V 1 , V 2 , V 3 ) leads with QRS complexes exhibiting an image of right bundle branch block in the right precordial leads and an elevation at the J point. 
     In a still further embodiment, a catheter-based cardiac rhythm management system for treating Brugada syndrome is provided. The system includes an electrophysiology catheter configured to be transiently-introduced into the heart of a patient and including a plurality of electrodes on a distal end; a sensing amplifier electrically coupled to the electrophysiology catheter and configured to detect through the electrodes propagation of an activation wave front proceeding from the atrioventricular node; and a pulse generator electrically coupled to the electrophysiology catheter and configured to deliver electrical therapeutic stimulation under programmed parametric control through the electrodes via the electrophysiology catheter when distally positioned in one of a region near the His bundle and a para-Hisian region of a patient&#39;s heart, the pulse generator further configured to deliver electrical therapeutic stimulation through the electrodes substantially coincident to the activation wave front as detected by the sensing amplifier; and a diagnostic module operatively coupled to the pulse generator and the sensing amplifier and configured to sense via at least one of the electrodes physiology indicative of a presence of Brugada syndrome in the patient, the diagnostic module further configured to control the pulse generator in delivering the electrical therapeutic stimulation in response to the presence of Brugada syndrome, wherein the physiology indicative of a presence of Brugada syndrome includes an electrocardiogram that exhibits an ST segment elevation in the anterior precordial (V 1 , V 2 , V 3 ) leads with QRS complexes exhibiting an image of right bundle branch block in the right precordial leads and an elevation at the J point. 
     Still other embodiments will become readily apparent to those skilled in the art from the following detailed description, wherein are described embodiments by way of illustrating the best mode contemplated. As will be realized, other and different embodiments are possible and the embodiments&#39; several details are capable of modifications in various obvious respects, all without departing from their spirit and the scope. Accordingly, the drawings and detailed description are to be regarded as illustrative in nature and not as restrictive. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a front anatomical diagram showing placement of an implantable cardiac rhythm management device in a male patient for treating Brugada syndrome, in accordance with one embodiment. 
         FIGS. 2 and 3  are graphs showing, by way of example, 12-lead electrocardiograms for patients exhibiting Brugada syndrome. 
         FIG. 4  is a flow diagram showing a method for treating Brugada syndrome through triggered pacing in accordance with one embodiment. 
         FIG. 5  is a flow diagram showing a method for treating Brugada syndrome through optimized atrioventricular nodal pacing in accordance with a further embodiment. 
         FIG. 6  is a flow diagram showing a method  100  for selecting an algorithm for detecting Brugada syndrome for use in conjunction with the methods of  FIGS. 4 and 5 . 
         FIGS. 7A-B ,  8 A-B and  9 A-B are graphs respectively showing, by way of example, 12-lead electrocardiograms for patients exhibiting Brugada syndrome following treatment through the methods of  FIGS. 4 and 5 . 
         FIG. 10  is a flow diagram showing a method  100  for sensing QRS width for use in conjunction with the methods of  FIGS. 4 and 5 . 
         FIG. 11  is a functional block diagram showing a computer-implemented system for treating Brugada syndrome, in accordance with a further embodiment. 
     
    
    
     DETAILED DESCRIPTION 
     Implantable cardiac rhythm management (CRM) devices include pacemakers, implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. CRM devices and, to a lesser extent, transiently-introduced electrophysiology catheters, such as used to induce ventricular arrhythmias during electrophysiologic studies (EPS), currently provide the only effective means for treating the sequelae VT and VF triggered by the syndrome and thereby help to prevent SCD. However, these devices focus on preventing or ameliorating VT and VF, rather than directly addressing the elimination of the electrocardiographic pattern typical of Brugada syndrome and related forms of channelopathies and cardiac asynchrony disorders. 
     Conventional arrhythmia management using CRM devices is episode-focused. Changes in heart rhythm are monitored by a CRM device as arrhythmic episodes potentially requiring therapy to convert, mitigate, or interrupt the dysrhythmia. Pacemakers, for instance, manage bradycardia, which is an abnormally slow or irregular heartbeat, by delivering pacing stimuli to restore normal sinus rhythm through electrodes provided on endocardial pacing leads. Implantable cardioverter defibrillators (ICDs) treat tachycardia, which are abnormally fast and life threatening heart rhythms, through high energy cardioversion, defibrillation shocks, or anti-tachycardia pacing. 
     Brugada syndrome, as well as other forms of conduction problems that start in the His and para-Hisian regions, such as ventricular asynchrony of contraction, can be corrected by actively stimulating those regions of the heart as the activation wave front coming from the atrioventricular (AV) node enters using an implantable CRM device.  FIG. 1  is a front anatomical diagram showing placement of an implantable CRM device  19  in a male patient  10  for treating Brugada syndrome, in accordance with one embodiment. Depending upon type, CRM devices can provide therapeutic electrical stimuli for up to three chambers of the heart. Single-chamber CRM devices rely on one endocardial lead attached to either the right atrium or right ventricle, while dual-chamber CRM devices utilize a pair of endocardial leads attached to the right atrium and right ventricle. Triple-chamber CRM devices use endocardial leads in the right atrium and right ventricle and coronary venous leads in the left ventricle. 
     The implantable CRM device  19  is preferably at least a dual-chamber CRM device that is surgically implanted subcutaneously in the patient&#39;s pectoral region or other suitable location in situ. A pair of dual-chamber endocardial leads  19  are guided through the left subclavian vein (not shown) and superior vena cava  18  into the right atrium  12  and right ventricle  13  of the heart  11  for providing cardiac physiological monitoring within and for delivering electrical therapy to the patient&#39;s heart  11 . For the sake of clarity, the endocardial leads  19  are shown leading directly into the heart  11 , although different placement and orientation may be used during actual implantation. Other forms of CRM may require placement of endocardial leads in the left atrium  14  or left ventricle  15  of the heart  11 . For the sake of completeness, two endocardial leads  21 ,  22  are shown, although only the endocardial lead  21  and its pacing electrodes  23  that are distally located in the region near the His bundle  16  or para-Hisian region  17  are directly addressed in the delivery of pacing therapy for treating Brugada syndrome. 
     In the general sense, electrical stimuli can be delivered through pacing electrodes  23 ,  25  respectively on the distal ends of each of the endocardial leads  21 ,  22 , although only the pacing electrodes  23  that are distally located in the region near the His bundle  16  or the para-Hisian region  17  are of interest herein. By way of example, the pacing electrodes  23 ,  25  are bipolar electrodes, but the pacing electrodes could also be unipolar or tripolar. In a further embodiment, the endocardial leads  21 ,  22  can also respectively include sensing electrodes  24 ,  26  located near their distal ends for monitoring physiology indicative of a presence of Brugada syndrome. In a still further embodiment, the pacing electrodes  23 ,  25  could be alternatively re-purposed to sense physiology between deliveries of electrical stimuli. 
     The implantable CRM device  19  also encloses operational circuitry within a hermetically-sealed housing  28 , which generally includes control circuitry  27 ; inductive transducer  28 ; oscillator  29 ; wireless transceiver  30 ; memory  31 ; and power source  32 , which provides a finite power supply for the operational circuitry. The control circuitry  27  implements the implantable CRM device&#39;s functionality and controls pulse generator output circuitry  33  for delivering electrical stimulation therapy through the pacing electrodes  23 ,  25  to the heart  11 , and sensing amplifiers  34  for monitoring cardiac physiology in the heart  11  through the sensing electrodes  24 ,  26 . The transducer  28  provides inductive signal conversion to enable remote parametric programming of the implantable CRM device  19  and stored physiologic data offload from the memory  31  through an external programmer or similar inductively-coupled device, as further described infra with reference to  FIG. 11 . The oscillator  29  regulates internal CRM device operation by controlling timing. The wireless transceiver  30  enables wireless communications with an external computer or similar wirelessly-interfaced device, as also further described infra with reference to  FIG. 11 . Finally, the memory  31  stores monitored cardiac physiology, such as the patient&#39;s monitored physiometry; environmental data, for instance, ambient temperature or time of day; and parametric information, including programming, status, and device operational characteristics for the implantable CRM device  19  proper. The parametric information can include pacing parameters, including electrical stimuli waveform, voltage, amplitude, phase, pulse width, rate, inter-pulse delay, pacing duration, inter-pacing delay, and so forth. Still other kinds of parametric information and pacing parameters are possible. 
     Brugada syndrome is a genetic disease characterized by abnormal electrocardiogram findings and an increased risk of cardiac arrest and SCD, such as described in Braunwald, “Heart Disease—A Textbook of Cardiovascular Medicine,” p. 904 (8 th  ed. 2008), the disclosure of which is incorporated by reference.  FIGS. 2 and 3  are graphs respectively showing, by way of example, 12-lead electrocardiograms  40 ,  50  for patients exhibiting Brugada syndrome. The syndrome is primarily characterized by an electrocardiogram  40 ,  50 , or similar temporally-captured cardiac cycle physiology, that exhibits an ST segment elevation in the anterior precordial (V 1 , V 2 , V 3 ) leads with QRS complexes exhibiting an image of right bundle branch block in the right precordial leads and an elevation at the J point, which are respectively indicated by boxes  41 ,  51 . In general, the electrocardiogram pattern can be of three types, Type 1 with coved-type ST segment, Type 2 with saddleback ST segment and Type 3 with ST segment elevated less than 1 mm. 
     Clinically, a QRS duration in lead V 2  longer than 90 msec combined with an inferolateral J wave or horizontal ST segment morphology following the J wave can serve as predictors of cardiac events for purposes of treating Brugada syndrome. Referring back to  FIG. 1 , Brugada syndrome, as well as other forms of related conduction problems, can be corrected by actively stimulating the region near the His bundle  16  or the para-Hisian region  17 . Two forms of pacing are used. In the first form, electrical stimulation is triggered by the direct early detection of the arrival of an activation wave front from the AV node  36  to the His bundle  16  or para-Hisian regions  17  of the patient&#39;s heart  11 , as further described infra with reference to  FIG. 4 . In the second form, electrical stimulation is triggered by an atrial activity, which can be sensed in lieu of or in addition to His or para-Hisian events, as further described infra with reference to  FIG. 5 . 
     Empirically, the electrocardiographic pattern characteristic of Brugada syndrome can be eliminated by using an ample combination of pacing sites and electrical stimulation amplitudes around the region near the His bundle  16  or in the para-Hisian region  17 , on either the right atrial and right ventricular sides of the tricuspid valve  35 , or in some combination thereof. A virtual pacing electrode, when applied to the right region of the septum, allows the Brugada syndrome electrocardiographic pattern to be normalized and the conduction and activation abnormalities that created the pattern to be corrected. In one embodiment, the endocardial lead  21  is guided through the tricuspid valve  35  and the pacing electrodes  23  are placed in the para-Hisian region  17  towards the right ventricular outflow tract, such as described in Nakagawa et al., “Para-Hisian pacing: Useful clinical technique to differentiate retrograde conduction between accessory atrioventricular pathways and atrioventricular nodal pathways,” Heart Rhythm, Vol. 2(6), pp. 667-72 (June 2005), the disclosure of which is incorporated by reference. In a further embodiment, the pacing electrodes  23  are placed in the region near the His bundle  16  at a point near the AV septum, superior to the tricuspid valve  35 , such as described in Deshmukh et al., “Permanent, Direct His-Bundle Pacing,” Circulation, Vol. 101, pp. 869-977 (2000), the disclosure of which is incorporated by reference. 
     Empirically, these pacing locations have been found to deliver optimum stimulation therapy when using an implanted endocardial pacing lead  21  or, in a further embodiment, when using an transiently-introduced electrophysiology catheter (not shown). The pulse generator  33  delivers a ventricular pacing output of at least two single-phase superimposed waveforms of opposite polarity with respect to an indifferent (reference) electrode (not shown). The indifferent electrode could be located as a third electrode in a tripolar lead, an exposed metallic surface on the implantable CRM device&#39;s housing  28 , an electrode connected to the implantable CRM device  19  proper, or other type of reference voltage lead. A pulse generator and single-phase superimposed waveforms of opposite polarity as used to bypass a conduction defect causing an asynchronous contraction of the heart, such as described in U.S. Patent App. Pub. No. 2012/0053651, the disclosure of which is incorporated by reference, could be used as the implantable CRM device  19 . 
     The stimulation of either the region near the His bundle  16  or the para-Hisian region  17  achieves two simultaneous ends. Three pacing modes are available, (a) dedicated DDD pacing (always ON) with a short AV interval, (b) on-demand according to QRS width (the latter parameter can be automatically triggered when QRS is wider than 100 msec), and (c) on-demand according to QRS width, manually compared with an averaging template. There is a programmable pacing duration, whose window is also programmable from three to ten beats. The modes enable the QRS width to be analyzed and the proper type of pacing provided, as further described infra with reference to  FIG. 10 . 
     In a further embodiment, as Brugada syndrome is not present at all times, but instead appears and disappears as the conditions of the patient change, the presence of the Brugada syndrome electrocardiographic pattern can be sensed in an algorithmic way that enables stimulation delivery only when necessary, after an appropriate AV interval; ventricular stimulation is triggered upon the sensing of the atrial depolarization followed by a waiting period that constitutes the longest practicable interval that avoids bringing back the Brugada syndrome electrocardiographic pattern. 
     The twofold aim of detecting the presence of Brugada syndrome and bypassing the syndrome&#39;s defects can be provided by delivering cardiac episode-focused stimuli in the region near the His bundle  16  or para-Hisian region  17 .  FIG. 4  is a flow diagram showing a method  60  for treating Brugada syndrome through triggered pacing in accordance with one embodiment. The method  60  provides an algorithm for initiation of the pacing device, informing the physician of incorrect lead position, as appropriate, optimizing the pacing voltage, and deciding on whether to continue the ventricular stimulation upon the presence of Brugada syndrome physiology. The method  60  is operable on an implantable CRM device  19  under programmatic control, such as program code executable as a series of process or method modules or steps by the device&#39;s control circuitry, as described supra with reference to  FIG. 1 . 
     In a further embodiment, in addition to providing pacing through the pacing electrodes  23  in the region near the His bundle  16  or para-Hisian region  17 , the implantable CRM device  19  can also wirelessly communicate with an external electrocardiographic system, as further described infra with reference to  FIG. 11 , which can sense whether the physiology indicative of the presence of Brugada syndrome is exhibited in the patient&#39;s electrocardiogram. By collaborating with the external electrocardiographic system, energy consumption of the implantable CRM device  19  can be minimized by limiting the amount of ventricular pacing delivered to the patient  10 . The external electrocardiographic system helps the implantable CRM device  19  to avoid situations of creating a propagation wave front with inferior hemodynamic and functional efficacy in comparison to a normal propagation wave front, for instance, due to less than optimum lead positioning. In a still further embodiment, the method  60  is operable on a transiently-introduced electrophysiology catheter, in conjunction with an external pulse generator, such as used to induce ventricular arrhythmias during EPS. 
     As an initial step, the patient&#39;s physiology is monitored to detect the presence of Brugada syndrome (step  61 ). Detection can be performed by first sensing cardiac physiology through the sensing amplifiers  34  and then providing the physiology to the external electrocardiographic system, as further described infra with reference to  FIG. 11 , which algorithmically identifies physiology indicative of a presence of Brugada syndrome in the patient  10 . Alternatively, the detection can be performed by the sensing amplifiers  34  and the control circuitry of the implantable CRM device  19 . If the syndrome is not present (step  62 ), no further action need be undertaken and, at later points in time, the presence of Brugada syndrome is again repeatedly detected (step  61 ). 
     Upon a finding of the presence of Brugada syndrome in the patient  10  (step  62 ), the patient&#39;s physiology is monitored to detect an event, specifically, propagation of an activation wave front proceeding from the AV node  36  of the patient&#39;s heart, either in region near the His bundle  16  or para-Hisian region  17  (step  63 ), as applicable. The detection can be performed by the sensing amplifiers  34  and the control circuitry of the implantable CRM device  19 . If present (step  64 ), electrical stimulation therapy is delivered from the pulse generator output circuitry  33  (step  65 ), which initiates pacing at an AV delay triggered by atrial event sensing in the region near the His bundle  16  or para-Hisian region  17 , or 50 msec, whichever is lower, at a pacing amplitude of about 1.2 times threshold. If detection is being performed using a transiently-introduced electrophysiology catheter, the same catheter can also be used to stimulate the region. Pacing is timed to be delivered substantially coincident to the arrival of the atrial event to the His bundle  16  or para-Hisian region  17 . A few microseconds delay can occur between the arrival of the activation wave front and the initiation of delivery of electrical stimulation to the region. However, from the standpoint of cardiac myocytes, the delay is de minimus and the electrical stimulation is received simultaneously as part of the activation wave front timed to the waveform of the atrial activation. 
     Pacing continues for a predetermined period of time. The pacing will be maintained for 80 to 99% of the time, as physician-programmable due to its patient dependence, to enable for windows of time with no pacing, to verify if the pattern remains in the absence of pacing or that the syndrome has satisfactorily resolved due to a favorable change in the substrate of the patient&#39;s heart. Pacing is continued for a therapy interval that the health care personnel adjusts to the actual clinical substrate of the patient being treated. In the rare case of a patient in which the Brugada syndrome resolves in a spontaneous manner, the health care personnel may program a long interval, whereas a short interval may be more appropriate for a patient in which Brugada syndrome manifestations tend to appear for only brief periods of time. 
     During pacing, the patient&#39;s physiology is periodically monitored to detect the presence of Brugada syndrome (step  66 ), in the same manner described supra, which also confirms that the pacing amplitude of 1.2 times threshold is sufficient to suppress the Brugada syndrome manifestations. If the syndrome is still present (step  67 ), the pacing amplitude is increased (step  70 ) until a programmable maximum amplitude of 15 to 30 volts is reached, in which case the physician is advised to review the position of the lead. Thus, if the maximum allowable pacing amplitude has been reached (step  71 ), a problem likely exists and a change in ventricular pacing lead position is indicated (step  72 ), after which pacing stops (step  69 ) and the method ends. 
     Otherwise, if the syndrome is not present, yet the predetermined period of time for pacing has not yet expired (step  68 ), the patient&#39;s physiology is again monitored to detect the presence of Brugada syndrome (step  66 ), as described supra. However, if the predetermined period of time for pacing has expired (step  68 ), pacing is stopped (step  69 ) and the method ends. 
     The foregoing method relied on the direct early detection of the arrival of the activation wave front to the region near the His bundle  16  or para-Hisian region  17 . Alternatively, atrial activity can be sensed in lieu of or in addition to His or para-Hisian events.  FIG. 5  is a flow diagram showing a method  80  for treating Brugada syndrome through optimized atrioventricular nodal pacing in accordance with a further embodiment. The method  80  provides an algorithm for initiation of the pacing device, informing the physician of incorrect lead position, as appropriate, optimizing AV delay and pacing voltage, and deciding on whether to continue the ventricular stimulation upon the presence of Brugada syndrome physiology. The method  80  is operable on an implantable CRM device  19  under programmatic control, in wireless communication with an external electrocardiographic system, or on a transiently-introduced electrophysiology catheter, in conjunction with an external pulse generator, as described supra. 
     Parts of the method are the same as performed for the direct early activation wave front detection method. Thus, as an initial step, the patient&#39;s physiology is monitored to detect the presence of Brugada syndrome (step  81 ). Detection can be performed by first sensing cardiac physiology through the sensing amplifiers  34  and then providing the physiology to the external electrocardiographic system, which algorithmically identifies physiology indicative of a presence of Brugada syndrome in the patient  10 . Alternatively, the detection can be performed by the sensing amplifiers  34  and the control circuitry of the implantable CRM device  19 . If the syndrome is not present (step  82 ), no further action need be undertaken and, at later points in time, the presence of Brugada syndrome is again repeatedly detected (step  81 ). 
     Upon a finding of the presence of Brugada syndrome in the patient  10  (step  82 ), the patient&#39;s physiology is monitored to detect an atrial activation event (step  83 ). The detection can be performed by the sensing amplifiers  34  and the control circuitry of the implantable CRM device  19 . If an atrial activation event is detected (step  84 ), electrical stimulation therapy is delivered from the pulse generator output circuitry  33  (step  85 ), which initiates pacing at an AV delay triggered by the atrial activity sensing; atrial pacing, where the patient  10  requires atrial pacing, that is equal to 50% of the previous interval between atrial and ventricular sensing; or 50 msec, whichever is lower, at a pacing amplitude of about 1.2 times threshold. Pacing continues for a predetermined period of time. 
     During pacing, the patient&#39;s physiology is periodically monitored to detect the presence of Brugada syndrome (step  86 ), in the same manner described supra, which also confirms that the pacing amplitude of 1.2 times threshold is sufficient to suppress the Brugada syndrome manifestations. If the syndrome is still present (step  87 ), the pacing amplitude is increased (step  95 ) until a programmable maximum amplitude of 15 to 30 volts is reached, in which case the physician is advised to review the position of the lead. Thus, if the maximum allowable pacing amplitude has been reached (step  96 ), a problem likely exists and a change in ventricular pacing lead position is indicated (step  97 ), after which pacing stops (step  94 ) and the method ends. 
     Once the lowest voltage at which the manifestations of Brugada syndrome are removed has been found, the atrioventricular AV delay is increased. The delay between atrial activation events is optimized to reflect the longest AV delay permitted without affecting the reappearance of the Brugada syndrome manifestations. The AV delay is fine-tuned by continually monitoring the patient&#39;s physiology to detect the presence of Brugada syndrome. Otherwise, if the syndrome is not present (step  87 ), the AV delay is increased (step  88 ). The AV delay is slowly increased in steps of one to 20 msecs, with 5 msecs being preferable, until the Brugada syndrome electrocardiographic pattern reappears. Following a period of pacing, the patient&#39;s physiology is once again monitored to detect the presence of Brugada syndrome (step  89 ), in the same manner described supra. If the syndrome is no longer present (step  90 ) and the maximum AV delay has not yet been reached (step  91 ), the AV delay is again increased (step  88 ). However, if the maximum AV delay has been reached without affecting the reappearance of the Brugada syndrome manifestations (step  91 ), the AV delay is shorted back to the previous AV delay (step  92 ) and pacing is continued for a therapy interval that the health care personnel adjusts to the actual clinical substrate of the patient  10  being treated. Using the longest AV delay that still removes the undesired effects of Brugada syndrome ensures that the optimal preload will be minimally affected by the stimulation, thus maintaining near normal hemodynamics in the heart. The pacing will be maintained for 80 to 99% of the time, as physician-programmable due to its patient dependence, to enable for windows of time with no pacing, to verify if the pattern remains in the absence of pacing or that the syndrome has satisfactorily resolved due to a favorable change in the substrate of the patient&#39;s heart. 
     If the predetermined period of time for pacing has expired (step  93 ), pacing is stopped (step  94 ) and the method ends. 
     As battery technology improves and processing power becomes less expensive in terms of cost and battery life, the algorithm to detect the presence of the Brugada syndrome electrocardiographic pattern could be internally implemented as part of the control circuitry of the implantable CRM device  19 .  FIG. 6  is a flow diagram showing a method  100  for selecting an algorithm for detecting Brugada syndrome for use in conjunction with the methods of  FIGS. 4 and 5 . To select an appropriate Brugada syndrome detection algorithm, the patient&#39;s physiology would first be evaluated (step  101 ), then compared to against a set of stored predefined algorithms (step  102 ). A new algorithm specific to the patient could be created from the physiology (step  105 ) if desired (step  104 ). Depending upon the cost tradeoffs of development, production, maintenance, regulatory compliance, and other factors at the time of production, an individualized algorithm could be created that maps for each patient the changes in the intracardiac electrocardiographic patterns that are detected with the implanted sensing electrodes  24 ,  26  to the presence or absence of the Brugada syndrome electrocardiographic pattern as registered by an external electrocardiographic system. Otherwise, a best matching detection algorithm could be chosen for the patient  10  (step  105 ), whether a standard “one size fits all” algorithm, an algorithm selected from a set of generic algorithms to cover different classes of patients, or other suitable form of detection algorithm. 
     Once selected, the detection algorithm can be provided to the implantable CRM device  19  (step  106 ), or to an external electrocardiographic system, external sensor, or programmer, if detection of Brugada syndrome is being performed transiently, such as during EPS. During use, the device will match the electrographic differences detected by the sensing electrodes  24 ,  26  with the Brugada syndrome electrocardiographic pattern specified in the detection algorithm for the patient  10 . 
     In a still further embodiment, an individualized algorithm could be developed directly from the patient&#39;s physiology and automatically uploaded into the device used for Brugada syndrome detection. This approach would have the advantage of not limiting the set of parameters that would need to be adjusted to ensure an univocal match between the Brugada syndrome electrocardiographic pattern, as detected by an external ECG system, and by the internal algorithm in the implantable CRM device  19 , or external device, as applicable. In addition, advances in signal processing would enable continual creation of improved detection algorithms, even after the device has already been implanted in the patient  10 . Still other ways to formulate Brugada syndrome detection algorithms and to equip an implantable CRM device  19  or external device are possible. 
     The precise mechanism by which Brugada syndrome causes arrhythmias is unknown, but has been theorized to be due to transmural depolarization dispersion or transepicardial repolarization dispersion, which can lead to reentrant VTs in Phase 2. Brugada syndrome is characterized by alterations in several ion channels, and, in particular, changes in the sodium ion channel with overexpression of cardiac transient outward potassium current. These changes are mainly expressed in the epicardium with higher endo-to-epi repolarization gradients that facilitate the re-entry mechanisms in polymorphic cells. 
     The cardiac stimulation delivered by the implantable CRM device  19 , or external device, as applicable, used in treating Brugada syndrome compensates for electrical shifts in the balance of the voltage-dependent sodium, potassium and, eventually, calcium ion channels by applying a relatively intense electrical field. This electrical field facilitates normalizing those channelopathies, after which the electrocardiographic signs of Brugada syndrome disappear, along with the specter of its sudden death manifestation. To enable the following physician or health care provider to verify the disappearance of the electrocardiographic manifestations of Brugada syndrome, the cardiac stimulation must not be allowed to produce alterations in the electrocardiogram that could mask the signs typical of Brugada syndrome, for instance, the left ventricular bundle block image of right ventricular apical pacing. The normal conduction through the His-Purkinje system produces a fast, sequential, synchronous depolarization of the myocardial fibers, making the ventricular contraction more efficient. Consequently, the region near the His bundle  16  and the para-Hisian region  17  are ideal pacing sites for maintaining a normal activation pattern and enabling the verification of the disappearance of the Brugada syndrome electrocardiographic pattern. 
     A foregoing approach allows the generation of an activation wave front with near-normal ventricular depolarization and narrow QRS complexes in patients that already exhibit narrow basal QRS complexes. This type of activation wave front is well suited to eliminating the typical electrocardiographic signs of Brugada syndrome. Near-physiologic stimulation is delivered substantially simultaneously to atrial activation by using a “virtual electrode” that allows the creation of a stimulation field far stronger than a conventional electrode, which can correct the depolarization and conduction abnormalities present in Brugada syndrome. Moreover, this stronger stimulation field entrains areas that are farther away from the actual pacing site and can thereby overcome conduction disturbances. Thus, the use of this “virtual electrode” facilitates locating the pacing electrodes  23  in a location, specifically, the region near the His bundle  16  or para-Hisian region  17 , that allows the health care operator to correct and effectively eliminate the Brugada syndrome electrocardiographic pattern, thereby obviating the need to perform complex electrophysiologic mapping procedures to define the stimulation site. 
     As delivered through the pacing electrodes  23 , the high-energy stimulation at septal level modifies the electrocardiographic pattern in leads V 1 , V 2 , V 3  through a “homogenizer effect” over the transmural epicardium/endocardium voltage gradient by acting on the involved voltage-dependent ionic channels and restoring an adequate epicardium/endocardium voltage ratio. There is also a homogenizing effect on the epicardium/endocardium repolarization dispersion, as well as in the intraepicardiac dispersion. The efficacy of the stimulation herein provided is theorized to be based on the fundamentally voltage-dependence, and consequently the “virtual electrode effect” at septum level, of the ionic sodium and potassium cellular channels. The stimulation could be modifying the altered charges in the epicardium area of the right ventricular outflow tract, which is close to the pacing sites used, that is, the region near the His bundle  16  and the para-Hisian region  17  of the heart  11 . Alternatively, the “virtual electrode effect” may simply be due to the increase in the initial depolarization voltage, correcting and activating a small number (about one percent) of “slow” sodium channels, consequently eliminating the overexpression of the potassium current (Ito) evident in the electrocardiogram by elimination of the Brugada syndrome-typical pattern in leads V 1 , V 2 , V 3 . Last, a “tsunami effect” that modifies all the currents, including those of sodium, potassium and calcium in its various forms, may be triggered through the pacing and thus preventing reentry in Phase 2. 
     The waveforms and amplitudes used in the electrical stimulation delivered through the foregoing methods described supra with reference to  FIGS. 4 and 5 , by the implantable CRM device  19 , or external device, as applicable, has been verified through clinical experiments to bypass the activation and conduction problems underlying the Brugada syndrome electrocardiographic pattern.  FIGS. 7A-B ,  8 A-B and  9 A-B are graphs respectively showing, by way of example, 12-lead electrocardiograms for patients exhibiting Brugada syndrome following treatment through the methods of  FIGS. 4 and 5 . Referring first to  FIGS. 7A-B , the patient exhibiting manifestations of Brugada syndrome, as described supra with reference to  FIG. 1 , has undergone pacing in the para-Hsian region  17 . Following therapy, several differences in cardiac profile can be noted, including a change of axis and elimination of left anterior fascicular block (box  1 ), a change in pattern in lead augmented vector right (aVR) (box  2 ), a disappearance of Brugada syndrome pattern in leads V 1  and V 2  (box  3 ), and a post-pacing reappearance of the syndrome&#39;s manifestations. No changes in J point or T wave in lead V 3  are exhibited. 
     Referring next to  FIGS. 8A-B , the patient exhibiting manifestations of Brugada syndrome, as described supra with reference to  FIG. 2 , has undergone pacing in the septal para-Hsian region  17 . Following therapy, a change in pattern in aVR and a disappearance of Brugada syndrome pattern in leads V 1  and V 2  can be observed. 
     Finally, referring to  FIGS. 9A-B , the same patient has again undergone pacing in the septal para-Hsian region  17 . Following therapy, as before, a change in pattern in aVR (box  1 ) and a disappearance of Brugada syndrome pattern in leads V 1  and V 2  can be observed, as well as a partial reapparition (boxes  2 - 3 ) after a few beats and morphology the same as presented pre-pacing. No changes in J point or T wave in lead V 3  are exhibited (box  4 ). 
     The three pacing modes enable the QRS width to be analyzed and the proper type of pacing provided.  FIG. 10  is a flow diagram showing a method  100  for sensing QRS width for use in conjunction with the methods of  FIGS. 4 and 5 . The implantable CRM device  19  has at least three programmable parameters for pacing, which are para-Hisian, apex, or both para-Hisian and apex, and at least two values that reflect changes in the QRS width, which are coil-to-coil and ring-to-distal coil (programmable). 
     First, if Brugada syndrome QRS width sensing is not enabled (step  101 ), sensing and pacing are provided as for a DDD CRT device (step  102 ). Otherwise, if Brugada syndrome QRS width sensing is enabled (step  101 ) and the device is set to automatic mode (step  104 ), the QRS width is measured (step  104 ). If the QRS width is less than 100 msec (step  105 ), pacing for a short AV interval is provided (step  107 ). Otherwise, if the QRS width is equal to or greater than 100 msec (step  105 ), the QRS duration is sensed (step  106 ). If the device is not set to automatic mode (step  104 ), a manual adjustment template is used (step  108 ). If a Brugada syndrome pattern is apparent (step  109 ), pacing for a short AV interval is provided (step  107 ). Otherwise, if a Brugada syndrome pattern is not apparent (step  109 ), the QRS width is sensed (step  110 ). 
     The pacing therapy can be delivered wholly in situ via an implantable CRM device  19  that performs sensing, detection algorithm analysis and pacing. Alternatively, the implantable CRM device  19  could be remotely coupled to an external electrocardiographic system that would collaboratively perform select aspects of the end-to-end treatment regime.  FIG. 11  is a functional block diagram showing a computer-implemented system  130  for treating Brugada syndrome, in accordance with a further embodiment. The system  130  includes an external electrocardiograph machine  133 , conventional external programmer  131  and an external computer  136 . Other components are also possible. 
     The external electrocardiograph machine  133 , or similar device, can capture an electrocardiogram of the patient  10  at different points of the pacing therapy, as described supra, which can be used to identify physiology indicative of a presence of Brugada syndrome in the patient. The external electrocardiograph machine  133  can be a conventional electrocardiograph machine that uses a set of twelve precordial leads  134  (shown as a single across-the-chest “strap” for the sake of simplicity) to record an electrocardiogram. In a further embodiment, the external electrocardiograph machine  133  relies on the implantable CRM device  19  to temporally capture cardiac cycle physiology, which is then interpreted by either the external electrocardiograph machine  133  or an external computer  136 , as described infra, into an electrocardiogram or similar form of temporal mapping of the cardiac cycle physiology. 
     The conventional external programmer  131 , or similar device, can remotely communicate with the implantable CRM device  19  using an inductive (or wireless) communications channel to enable remote parametric programming of and stored physiologic data offload from the device. The programmer  131  includes a physically-connected programmer wand  132 , which is placed by health care personnel over the patient&#39;s pectoral region above the implantable CRM device  19  to initiate and carry out programmer-to-CRM device communications. 
     The external computer  136 , or similar device, can be wirelessly (or inductively) interfaced to the implantable CRM device  12 . The external computer  136  receives cardiac cycle physiology, as recorded by the implantable CRM device  12  via the wireless communications channel. Alternatively, cardiac cycle physiology or, equivalently, electrocardiograms, can be retrieved by the external computer  136  from the external electrocardiograph machine  133 , or other source. The external computer  136  algorithmically identifies physiology indicative of a presence of Brugada syndrome in the patient  10 . In addition, the external computer  136  can create an individualized algorithm for each patient  10  that maps the changes in the intracardiac electrocardiographic patterns that are detected with the implanted sensing electrodes  24 ,  26  to the presence or absence of the Brugada syndrome electrocardiographic pattern as registered in the cardiac cycle physiology or electrocardiograms. 
     Finally, the system  130  can include a centralized server  137  coupled to a database  138  within which patient data, such as the electrocardiograms and algorithms, are stored. The external electrocardiograph machine  133 , external programmer  131 , and the external computer  136  can interface with the centralized server  137  through a network  135 , such as a publicly available wide area network, including the Internet. Other forms of remote server interfacing are possible. 
     In a yet further embodiment, the system  130  can be adapted for use in EPS, whereby a transiently-introduced electrophysiology catheter (not shown) serves the functions of the implantable CRM device  19 , which can either be temporarily rendered inoperable or be absent from the patient  10  altogether. 
     While the invention has been particularly shown and described as referenced to the embodiments thereof, those skilled in the art will understand that the foregoing and other changes in form and detail may be made therein without departing from the spirit and scope.