WO2008043099A2 - Hybrid pacing system - Google Patents

Abstract

A hybrid pacing system includes an implanted biological pacemaker and an implantable medical device providing pacing stimuli to one or more chambers of the heart. The IMD senses activity produced by the biological pacemaker, and coordinates the pacing stimuli provided by the IMD with the pacing delivered by the biological pacemaker.

Description

HYBRID PACING SYSTEM

BACKGROUND OF THE INVENTION

[0001] In a normal, healthy heart, cardiac contraction is initiated by the spontaneous excitation of the sinoatrial ("SA") node, located in the right atrium. The electrical impulse generated by the SA node travels to the atrioventricular ("AV") node where it is transmitted to the Bundle of His and Purkinje network, which branches in many directions to facilitate simultaneous contraction of the left and right ventricles. In certain disease states, the heart's ability to pace or conduct the electrical impulses for subsequent mechanical contraction properly is compromised.

[0002] Traditionally, various cardiovascular diseases have been managed by drug therapies, device therapies, or a combination of the two. For example, implantable medical devices (IMD's) such as implantable pulse generators (IPG's), pacemakers, and implantable cardioverter defibrillators (ICD) can deliver electrical stimulation to the heart to provide pacing or defibrillation functions. The IMD includes a can or device housing that is implanted subcutaneously with one or more leads extending to an appropriate location within, or external to, the heart. The therapy is generated by circuitry within the device and is transmitted along the lead to an electrode in contact with heart tissue.

[0003] However, certain cardiovascular diseases and conditions such as coronary artery disease, high blood pressure (hypertension), heart attack, diabetes mellitus, cardiomyopathy, heart valve disease, infection of the heart values, congenital heart disease, can and often do lead to heart failure "HF" (sometimes known as congestive heart failure).

[0004] While by itself heart failure is not considered a disease per se, heart failure is a serious, chronic, and complex condition in which the heart's pumping action is compromised. With heart failure, the heart is not operating efficiently and, therefore, must work harder. For example, the heart may pump more frequently to compensate for weaken pumping ability, or the size of its chambers may increase, especially the left ventricle. Hence, significant physical change occurs with heart failure and most notably, the enlargement and thinning of the left ventricle. While biventricular pacing of the heart can benefit HF patients, not all patients can receive optimal therapy as there are often difficulties in LV lead placement.

BRIEF SUMMARY OF THE INVENTION

[0005] A hybrid pacing system achieves pacing by synchronized operation of a biological pacemaker ("biopacer") implanted in the left ventricule of the heart and an implantable medical device for providing pacing stimuli to one or more other chambers of the heart. The IMD synchronizes its operation to sensed signals representing pacing activity of the biopacer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG. 1 is a diagram of a hybrid pacing system for providing biventricular pacing including a left ventricular biopacer and an IMD for providing electrical pacing to the right atrium and right ventricle.

[0007] FIG. 2 is a timing diagram illustrating operation of the hybrid system of FIG. 1 in which left ventricular pacing occurs prior to right ventricular pacing.

[0008] FIG. 3 is a flow chart illustrating operation of the IMD for the timing diagram of FIG. 2.

[0009] FIG. 4 shows a timing diagram for the hybrid system of FIG. 1 when right ventricular pacing precedes left ventricular pacing.

[0010] FIGS. 5A and 5B are flow charts illustrating operation of the IMD for the timing diagram of FIG. 4.

[0011] FIG. 6 is an illustration of a hybrid system in which a biopacer is implanted in the right ventricle, and a IMD provides pacing to the right atrium.

[0012] FIG. 7 shows a timing diagram for operation of the hybrid system of FIG. 6.

[0013] FIG. 8 shows a flow chart for the operation of the hybrid system of FIG. 6 according to the timing diagram of FIG. 7.

[0014] FIG. 9 shows an illustration of a hybrid system in which a biopacer is implanted in the right ventricle, and an IMD provides pacing to the right ventricle.

[0015] FIG. 10 shows a flow chart illustrating how a IPG can operate in concert with a biological pacemaker in the same cardiac chamber, as shown in FIG. 9.

DETAILED DESCRIPTION

[0016] Studies to date have shown that long term heart failure is a common pathology in the population of patients with IMDs for cardiac pacing. For many heart failure patients, it is desirable to have biventricular pacing to restore the synchronization of the contraction of the two ventricles. To achieve biventricular pacing with an IMD, leads must be placed to provide pacing electrodes to the right atrium, the right ventricle, and the left ventricle. However, the placement of the leads and electrodes to the left ventricle can be difficult, and is often limited by the clinical approach chosen.

[0017] More specifically, epicardial lead placement requires chest surgery, which may be contraindicated for some patients. Consequently, left ventricular (LV) leads are typically placed in the coronary vasculature via coronary sinus access. In some cases, however, optimal lead positioning for the LV lead cannot be achieved due to anatomical limitations, as the lead placement is restricted to coronary veins in which a lead can be securely positioned. For example, the coronary vasculature may not reach a particular anatomical position, or the position that can be reached may be surrounded by infarcted tissue so that stimulation delivered by the left side pacing lead will not provide the optimal benefit. Placement of endocardial leads in the left ventricle is also avoided due to its potential for clot formation. As shown in the figures, the hybrid pacing system described herein avoids the need to place a lead in the left ventricle while restoring relative timing of the two ventricles.

[0018] FIG. 1 shows the hybrid pacing system 10, which includes a biological pacemaker 12 also referred to herein as "biopacer" and an IMD 14 synchronized to provide biventriclar pacing to heart H. The biopacer 12 is implanted in a wall of left ventricle LV. The IMD 14 includes housing or can 16, header 18, atrial lead 20, and right ventricular lead 22. Atrial lead 20 extends from header 18 to right atrium RA. Electrode 24 carried at a distal end of atrial lead 20 contacts the wall of right atrium RA. Right ventricular lead 22 includes distal fixation device 26, distal tip electrode 28, and ring electrode 30.

[0019] Biventricular pacing or cardiac resynchronization therapy is achieved by system 10 by pacing right atrium RA, right ventricle RV, and left ventricle LV. IMD 14 provides pacing stimuli to right atrium RA and right ventricle RV. IMD 14 includes, within housing 16, a power source such as a battery, power supply circuitry, sensing and signal processing circuitry, therapy delivery circuitry (which may include pacing as well as cardioversion/defibrillation circuitry), a microprocessor and associated memory, and telemetry circuitry. Atrial stimulation is applied to right atrium RA through lead 20 and electrode 24. Pacing stimulation for right ventricle RV is provided by electrical pulses applied by tip electrode 28 and ring electrode 30. Pacing circuitry within housing 16 generates the pacing pulses delivered through leads 20 and 22 to right atrium RA and right ventricle RV. Electrodes 24, 28, and 30 are also used together with the sensing and signal processing circuitry to derive sense signals representing sensed electrical activity of heart H.

[0020] The biopacer 12 provides pacing for left ventricle LV. As described in more detail below, Biopacer 12 can be formed using genetically engineered vectors or genetically engineered cells or unmodified pacemaker-like cells, which are implanted at a selected location in the wall of left ventricle LV. During initial implantation, a delivery tool, such as a temporary lead or a catheter, is introduced through left atrium LA into left ventricle LV. The delivery tool includes electrodes for sensing electrical activity and delivering pacing stimuli in order to determine the desired location for biopacer 12. When the location has been determined, the genetically engineered viruses or cells are delivered to the myocardium at that location to form a new sinus node. Typically, it takes some time (several weeks to months) after implantation before the transfected cells, the genetically engineered cells or the unmodified pacemaker-like cells reach a state at which biopacer 12 is effective in providing pacing function for the left ventricle LV.

[0021] For biventricular pacing to be effective, the pacing of left ventricle LV and right ventricle RV must be coordinated so that both ventricles contract with the proper timing. If the contractions are not synchronized, the contractions of ventricles LV and RV will cause the septal wall to deflect, and the pumping efficiency of heart H will be degraded.

[0022] FIGS. 2 and 3 illustrate the operation of system 10, and in particular, IMD 14 when pacing of left ventricle LV is required to occur prior to pacing of the right ventricle RV. This is the most common situation for patients requiring a resynchronization therapy.

[0023] In FIG. 2 is a timing diagram showing the operation of system 10. IMD 14 produces stimulation to the right atrium RA and the right ventricle RV, while biopacer 12 generates the LV pulse. The vertical bars labeled as A and RV are either paced or sensed events. [0024] FIG. 3 shows a flow chart illustrating the algorithm governing operation of

IMD 14 to provide the timing of pulses illustrated in FIG. 2. At the start of operation (block 40), IMD 14 sets timer Δt to zero (step 42). IMD 14 then waits for an intrinsic A event to be sensed (step 44).

[0025] If an intrinsic A event occurs before timer Δt reaches a value equal to the time from RV event to the next A event, timer Δt is again reset to zero (step 46). On the other hand, if timer Δt reaches or exceeds the RV to A time (T_RV-_A), IMD 14 delivers an atrial pacing pulse through lead 20 and electrode 24 to right atrium RA (step 48). Once right atrium RA has been paced, timer Δt is set to zero (step 46).

[0026] IMD 14 then waits (step 50) for the LV event to be sensed. In the timing diagram shown in FIG. 2, the LV event is scheduled to occur before the RV event.

[0027] If the LV event is sensed either by RV electrodes 28 and 30 or by RA electrode 24 (step 52), timer Δt is again reset to zero (step 54). IMD 14 then waits for the sensing of an intrinsic RV event by electrodes 28 and 30 (step 56). If the intrinsic RV event is sensed, IMD 14 returns to step 42 and resets timer Δt to zero.

[0028] If an intrinsic RV event is not detected within the ventricle-to-ventricle time period (TJ_LV-RV), IMD 14 generates a pulse which is delivered through lead 22 and electrodes 28 and 30 to pace right ventricle RV (step 58). Once the RV paced event has occurred, timer Δt is reset to zero (step 42).

[0029] FIG. 3 also illustrates a situation where the LV event is not sensed within the

A to RV time (A_A-_RV)- If the LV event is not sensed, the RV pacing pulse is generated (step 58) and timer Δt is reset to zero. The cycle then repeats as illustrated in FIG. 3.

[0030] With the operation as illustrated in FIG. 3, IMD 14 synchronizes the pacing of both right atrium RA and right ventricle RV with respect to sensed LV events produced by biopacer 12. This synchronizes biopacer 12 and IMD 14 in order to provide cardiac ^synchronization therapy.

[0031] As shown in FIG. 3, IMD 14 reacts to sensed LV events, but cannot generate an LV pulse if an LV event is not sensed. IMD 14 may, however, log instances where the LV event is not sensed. That information can then be delivered by telemetry to inform a physician of the missing LV events. This information can then be used to determine whether biopacer 12 is functioning properly.

[0032] FIG. 4 shows a timing diagram in which the order of the RV and LV pulses is reversed from what is shown in FIG. 2. Once again, the LV pulse is generated by biopacer 12. IMD 14 produces the stimulation for right atrium RA and right ventricle RV. The vertical bars labeled A and RV in FIG. 4 represent either paced or sensed events.

[0033] FIGS. 5 A and 5B illustrate the operation of IMD 14 in a situation which cardiac resynchronization therapy requires that the RV pulse lead the LV pulse by a time TRV-LV-

[0034] FIG. 5 A shows the initialization of IMD 14 for the RV first pacing scheme.

At the start of initialization (step 60), IMD 14 initiates ADI pacing of right atrium RA and right ventricle RV (step 62). During ADI pacing, IMD 14 paces right atrium RA, senses dual chambers (i.e., RA and RV), and inhibits pacing upon detection of intrinsic activation.

[0035] IMD 14 measures a time (T_A-_LV) from an A event to an LV event (step 64). It then calculates an A to RV time (T_A-_RV) based upon the measured A-LV time (T_A-_LV), and the desired time between RV and LV events T_RV-_LV (step 66). The initialization process shown in FIG. 5 A is performed periodically in order to maintain synchronization of IMD 14 with biopacer 12.

[0036] FIG. 5B illustrates operation of IMD 14 once initialization has occurred (step

70). Timer Δt is set to zero (step 72), and IMD 14 waits for an intrinsic A event to occur (step 74). IMD 14 has calculated during initialization the time from an A event to RV event (TA-RV)- Since the time from one atrial event to the next (T_A-_A) is a known value, the time from an RV event to the next A event (T_RV-_A) is also a known value. IMD 14 will pace right atrium RA (step 76) if the timer Δt equals or exceeds T_RV-_A- Timer Δt is then set to zero (step 78). If an intrinsic A event is sensed before timer Δt reaches T_RV-_A, the timer Δt is set to zero (step 78).

[0037] IMD 14 then waits (step 80) until Δt equals or exceeds T_A-RV- At that point,

IMD 14 paces right ventricle RV (step 82). [0038] If a ventricular event is sensed representing either an LV pulse generated by biopacer 12 or an intrinsic RV event (step 84), this indicates that synchronization between biopacer 12 and IMD 14 is lost or not established. At step 86, IMD 14 returns to the initialization process shown in FIG. 5A to again measure the T_A-_LV time and recalculate the TA-RV time.

[0039] A loss of synchronization is also indicated if, during the waiting period (step

74), a Far Field R- Wave representing a ventricular event is sensed at RA electrode 24 (step 88). Since wait period 74 normally follows pacing right ventricle RV, it is expected that a Far Field R-Wave representing the LV event should be sensed at approximately the T_RV-_LV time following the RV pace event. At step 90, IMD 14 checks the value of timer Δt when the Far Field R- Wave sense occurred to see whether the value of timer Δt is between T_MIN and TMAX- TMIN is the TRV-LV time minus the minimum tolerance of the T_RV-LV time interval, while TMAX is TRV-LV plus the maximum tolerance on the timer interval.

[0040] If the FFRW sense occurred within the maximum and minimum range of the

TRV time interval, IMD 14 continues to wait for an intrinsic A event or for the T_RV-_A interval to be reached so that a pacing pulse can be delivered to right atrium RA.

[0041] If the FFRW sense event occurs outside of the expected time period, this once again indicates that synchronization between biopacer 12 and IMD 14 has been lost. As a result, IMD 14 returns to the initialization process shown in FIG. 5 A (step 92).

[0042] FIG. 6 shows hybrid system 100, which includes biopacer 102 and IMD 104.

In this embodiment, biopacer 102 is shown implanted in a wall of right ventricle RV. IMD 104, which includes housing 106, header 108, atrial lead 110, and atrial electrode 112, provides electrical pacing to right atrium RA. Operation of IMD 104 is synchronized with biopacer 102 by sensing ventricular events at electrode 112.

[0043] FIG. 7 shows a timing diagram for hybrid system 100. IMD 104 generates stimulation to atrium RA, while biopacer 102 generates a ventricular pulse in right ventricle RV.

[0044] FIG. 8 shows a flow diagram for the algorithm used by IMD 104 in providing synchronized operation with biopacer 102. The process starts (step 130) and IMD 104 waits (step 132) until the Far Field R- Wave is sensed by atrial electrode 112 (step 134). Upon sensing the Far Field R- Wave representing the V event, timer Δt is set to zero (step 136). IMD 104 then waits (step 138) until the timer reaches or exceeds the ventricle-to-atrial time Tv-A- IMD 104 then paces right atrial RA with a pulse delivered through lead 110 and electrode 112. After pacing right atrium RA (step 140), IMD 104 again waits (step 132) for the next Far Field R- Wave to be sensed.

[0045] Although the embodiment shown in FIG. 6 shows biopacer 102 in right ventricle RV, it could also be placed in left ventricle LV, similar to what was shown in FIG. 1. In addition, IMD 104 could provide pacing to left atrium LA, rather than right atrium RA.

[0046] The hybrid system shown in FIG. 6 minimizes the number of endocardial leads. In particular, it avoids the need for a ventricular lead extending through right atrium RA and into right ventricle RV.

[0047] FIG. 9 shows hybrid pacing system 200, which includes biopacer 202 and

IMD 204. Biopacer 202 is implanted in a wall of right ventricle RV. IMD 204 includes housing or can 206, header 208, and right ventricular lead 212. Right ventricular lead 212 includes distal fixation device 216, distal tip electrode 218, and ring electrode 220. In the embodiment shown in FIG. 9, biopacer 202 can serve as a backup mechanism for pacing provided by IMD 204 to right ventricle RV. Conversely, IMD 204 can act as a backup for biopacer 202. In either case, operation of IMD 204 is coordinated with pacing activity of biopacer 202 by sensing pacing activity of biopacer 202.

[0048] FIG. 10 is a flow chart illustrating the coordinated operation of biopacer 202 and IMD 204. The process starts (step 230) and IMD sets timer ΔT to zero (step 232), IMD 204 then waits (234) until an electrical signal is sensed or the minimum escape interval elapses. In this case, in which biopacer 202 and electrodes 218 and 220 are located within right ventricle RV, the electrical signal sensed will typically be an R- wave.

[0049] Upon sensing the electrical signal, timer ΔT is again set to zero (step 2326).

IMD 204 again waits (step 234). If timer exceeds a minimum escape interval, IMD 204 then paces the chamber (in this case right ventricle RV) (step 236). IMD 204 then returns to step 232 to reset timer ΔT to zero, and waits for the next electrical signal to be sensed (step 234). [0050] Although FIG. 9 illustrates an embodiment in which biopacer 202 and pacing lead 212 are both located within right ventricle RV, the same concept can be used in other chambers, such as right atrium RA. The flow chart shown in FIG. 10 would apply to that embodiment, with the electrical signal sensed being a P-wave rather than an R-wave.

[0051] Other embodiments of hybrid pacing systems including coordinated operation of biopacers and IMDs are also possible. For example, in other embodiments biopacers may be implanted in more than one chamber, with a pacing lead from an IMD located in one of the chambers, or in a different chamber. Similarly, hybrid systems including multiple biopacers and multiple pacing leads can also be implemented.

[0052] Although the hybrid pacing systems described in conjunction with the embodiments of FIG. 1 , FIG. 6, and FIG. 9 use electrical sensing of atrial and ventricular events, other types of sensors can also be used. For example, synchronization can also be based, at least in part, upon signals from an accelerometer or a pressure sensor.

[0053] The hybrid pacing system may also include transducers for providing sensory feedback to adjust the LV-RV or RV-LV timing. For example, the feedback can include signals representing dP/dt, absolute pressure, heart sounds, oxygen saturation, blood flow, wall motion and stroke volume measurements. In addition, timing can be adjusted with external echocardiographic guidance or MRI guidance. These feedback inputs can be used to adjust the timing to maximize dP/dt, ejection fraction, stroke volume, or cardiac work as desired. Recently, the concept of introducing a biologic therapy has shown substantial promise. For example, biologic pacing can be achieved by either introducing new pacing cells or altering the chemical structure of existing cells to create or modify a pacing or nodal function. Inducing automaticity in ventricular cells creates a biological pacemaker (biopacer) and the available approaches are many.

[0054] For example, the biopacer can be formed using genetically engineered vectors, such as viral vectors and plasmid vectors. A viral vector can be used to alter ionic currents to convert quiescent cells into cells with rhythmic depolarizations. A vector is delivered to the myocardium, and the transfected cells become the new dominant pacemaker of the heart. [0055] The biological pacemaker (biopacer) may also be formed using genetically engineered cells. In this approach, a cell may be modified genetically to induce automaticity. The genetically engineered cells are then delivered into the myocardium at a desired location to form a new cardiac pacemaker. Moreover, genetically unmodified cells of stem cell origin with a phenotype similar to a nodal cell can be utilized as a biological pacemaker.

[0056] More specifically, as used herein, biological pacemakers include transplantable biological materials, modified or unmodified, to perform pacemaking function similar to quiescent heart muscle cells. The biological materials include, but are not limited to, cells, cell lines and other cellular compositions, vectors or cloning/expression vectors, DNA or RNA including oligos, expressed sequence tags and signal sequences, and proteins including recombinant proteins or proteins purified from biological samples and/or active fragments of proteins. Other transplantable biological materials include siRNA, plasmids, engineered tissue, growth factors and differentiation inducing factors.

[0057] Examples of cell types that can be molecularly modified to perform pace making function include skeletal myoblasts, precursor cells, endothelial cells, differentiated or undifferentiated stem cells, undifferentiated contractile cells, fibroblasts and genetically engineered cells and components of cells, such as genetic material, or a chemoattractant to attract precursor cells as described specifically in US Published Patent Application No. 2006/0149184 at paragraphs [0007], [0029] and [0030] incorporated herein by reference. Stem cells such as spoc cells, cardiomyocytes or their precursors, or mesenchymal stem cells are useful as biological materials as described in Example 3 of US Published Patent Application No. 2005/0058633, paragraphs [0146] and [0147], and in the publication by Potapova, L, et al., Human Mesenchymal Stem Cells as a Gene Delivery System to Create Cardiac Pacemakers, Circulation Research, 94:952-959 (2004) at page 953, paragraph 2, lines 4 to 17, pages 954 & 957 and at page 958, paragraph 2, lines 7 to 21 incorporated herein by reference.

[0058] Molecularly modified cells, including stem cells, altered to exhibit automaticity can be introduced into the left myocardium to form the biological pacemaker as disclosed in various publications including Potapova, L, et al., Human Mesenchymal Stem Cells as a Gene Delivery System to Create Cardiac Pacemakers, Circulation Research, 94:952-959 (2004) at page 953, paragraph 2, lines 4 to 17, pages 954 to 956, page 957, paragraph 4, lines 14 to 23, and page 958, lines 7 to 21, incorporated herein by reference.

[0059] Stem cells therapy includes differentiating stem cells into biological pacemakers as taught in US Published Patent Application No. 2005/0058633, paragraphs [0146] & [0147], incorporated herein by reference, and, in a publication by Choi, Y.H., et al., Cardiac Conduction Through Engineered Tissue, Am J. Pathol., 169: 72-85 (2006) at pages 75-81 incorporated herein by reference.

[0060] Furthermore, genes useful as biopacers include genes encoding dominant negative Kir2, HCN2 and β2 adrenergic receptors, genes encoding channels including Pottasium channels (K+), sodium channels (Na+), T-type calcium channels, and genes encoding a channel or subunit thereof that produces funny current (I_f), polynucleotide sequences encoding Ikr (both subunits: ergl and MiRP),and Iks (both subunits: mink and KvLQTl), Connexins, especially connexin 43, and HCN 1-4 isoforms. See e.g., Miake, J., et al., Biological Pacemaker Created by Gene Transfer, Nature, 419: 132-133 (2004) at pages 132-133, incorporated herein by reference; Potapova L, et al., Human Mesenchymal Stem Cells as a Gene Delivery System to Create Cardiac Pacemakers, Circulation Research 94:952-959 (2004) at page 953, paragraph 2, lines 4 to 17, pages 954 & 957 and on page 958, incorporated herein by reference; Edelberg, J.M., et al., Enhancement of Murine Cardiac Chronotrophy by Molecular Transfer of Human b2 Adrenergic Receptor cDNA, J. Clin Invest. 101:337-343 (1998) at pages 338 to 340 incorporated herein by reference; Qu, J. et al., Expression and Function of a Biological Pacemaker in Canine Heart, Circulation, 107: 1106- 1109 (2003) at pages 1106 to 1108, incorporated herein by reference.

[0061] Alternatively, biopacers may be transplantable engineered tissue as disclosed in a publication by Choi, Y.H., et al., Cardiac Conduction Through Engineered Tissue, Am J. Pathol. 169:72-85 (2006) at pages 78 to 84, incorporated herein by reference. Choi, et al. provide engineered tissue constructs, created from skeletal muscle-derived cells, in rat hearts, to create an alternative AV conduction pathway. These constructs exhibit sustained electrical coupling through persistent expression and function of gap junction proteins. Id. Additionally, Papadaki, M., et al. disclose engineered cardiac tissue created from ventricular cardiac muscle cells, cultured in low-serum conditions, seeded onto polymer scaffolds coated with laminin. These engineered tissue constructs demonstrate electrophysiological properties, such as conduction velocity, similar to levels of neonatal ventricles. See Papadaki, et al., Tissue Engineering of Functional Cardiac Muscle; Molecular, Structural, and Electrophysiological Studies, Am J Physiol, 2001; Hl 68-Hl 78.

[0062] These categories of transplantable biological materials are not always exclusive of one another, and a particular element of biological material may belong to more than one category. Also, the transplanted biological material need not be exclusively biological, but may include an inorganic or engineered material, such as a scaffold to hold biological material. As such, the invention is not limited to the particular materials listed herein.

[0063] Molecular modifications of the transplantable biological material for development of biological pacemakers may be made via gene transfer as disclosed in various publications including, but not limited to: Edelberg, J.M., et al., Enhancement of Murine Cardiac Chronotrophy by Molecular Transfer of Human b2 adrenergic Receptor cDNA, J. Clin Invest. 101 :337-343 (1998) at pages 338 to 340, incorporated herein by reference; Edelberg, J. M., et al., Molecular Enhancement of Porcine Cardiac Chronotropy, Heart, 86:559-562 (2001) at pages 559 to 562, incorporated herein by reference; Miake, J., et al., Biological Pacemaker Created by Gene Transfer, Nature, 419:132-133 (2002) at pages 132- 133, incorporated herein by reference; Plotnikov, A.N., et al., Biological Pacemaker Implanted In Canine Left Bundle Branch Provides Ventricular Escape Rhythms That Have Physiological Acceptable Rates, Circulation 109:506-512 (2004) at pages 507 to 511, incorporated herein by reference; and Qu, J., et al., Expression and Function of a Biological Pacemaker In Canine Heart, Circulation, 107: 1106-1109 (2003) at pages 1106-1109 incorporated herein by reference. Further, molecular modification of the transplantable biological material may be achieved by differentiation of stem cells into biopacers as taught in US Published Patent Application No. 2005/0058633, at paragraphs [0146] and [0147], incorporated herein by reference. [0064] Different methodologies for placing the biological pacemaker in the heart can be applied. These methods include delivering nucleic acid/genes into cardiac cells by utilizing plasmid injections and viral constructs or implanting molecularly modified cells. Alternatively, biological pacers can be formed by stem cell therapy.

[0065] Delivery of the biological pacemaker to the myocardial wall can be achieved by a catheter that is advanced into the ventricular cavity. Using an electrophysiology mapping catheter, one can first stimulate the left ventricle to locate the optimal location for the biopacer where the stimulation captures the left ventricle and causes the contraction of the left ventricle with the desired synchrony with the right ventricle. Afterwards, the same catheter is used to deliver the biological pacemaker to the same location on the left ventricular wall.

[0066] Methods or processes for delivering nucleic acid/genes to cardiac tissue are taught in US Patent No. 6,867,196, at Col. 13, line 21 through Col. 16, line 17, incorporated herein by reference, and published PCT Application No. WO 2005/028024 at paragraphs [0019]-[0049] incorporated herein by reference. Example methods for delivery of DNA to the heart are taught in US patent No. 6,867,196. In one method, nucleic acids combined with transfection reagents, plasmid DNA, or viruses are directly injected into coronary arteries and veins. This is a minimally invasive and clinically viable method for in vivo delivery system of naked nucleic acids. Another method involves the use of , percutaneous transluminal coronary angioplasty (PTCA) catheters to place the genetic material into the coronary venous system from a peripheral vein. For this, double lumen balloon catheters are positioned into coronary veins from peripheral vessels and plasmid DNA solutions are injected under pressure to transfect cardiac muscle cells. A third method uses an injection system that allows for automated regulation of injection speed and volume correlated to the pressure in the injected vessel. Coronary angioplasty catheters are used to simultaneous inject fluids into the selected coronary bed and measure the intracoronary venous hydrostatic pressure during and after injection. For successful delivery of nucleic acid the permeability of a blood vessel needs to be increased. This is achieved by increasing the intravascular hydrostatic pressure. Methods of increasing hydrostatic pressure include rapid (from 1 seconds to 30 minutes) injectionof nucleic acid in solution into the blood vessel, or obstructing the outflow of the injection solution from the tissue for a period of time sufficient to allow delivery of a nucleic acid. Furtherstill, rapid injection combined with obstructing the outflow can also be used as a method of increasing hydrostatic pressure.

[0067] Vectors are nucleic acids originating from a virus, a plasmid, or the cell of an organism into which another nucleic fragment of appropriate size can be integrated without loss of the vectors capacity for self-replication. Vectors introduce nucleic acids into host cells, where it can be reproduced. Examples are plasmids, cosmids, and yeast artificial chromosomes. Vectors are often recombinant molecules containing nucleic acid sequences from several sources. Vectors include viruses, for example adenovirus (an icosahedral (20- sided) virus that contains DNA and there are over 40 different adenovirus varieties, some of which cause respiratory disease), or retrovirus (any virus in the family Retroviridae that has RNA as its nucleic acid and uses the enzyme reverse transcriptase to copy its genome into the DNA and integrate into the host cell's chromosome). Vectors such as adenoviruses, adeno- associated viruses or non- viral vectors can be used to alter the electrophysiological properties of the cardiomyocytes in the left ventricle as disclosed in Miake, J., et al., Biological Pacemaker Created by Gene Transfer, Nature, 419: 132-133 (2002) at pages 132 to 133, incorporated herein by reference.

PROPHETIC EXAMPLE 1 Adenoviral Constructs

[0068] An adenoviral construct of mouse mHCN2 driven by a CMV promoter can be prepared as previously described. See, Qu, J., et al., HCN2 Overexpression In Newborn And Adult Ventricular Myocytes: Distinct Effects On Gating And Excitability, Circ. Res., 2001, 89:E8-E14. A second adenoviral construct containing a mouse HCN2 gene harboring a point mutation, mE324A, can be prepared as described previously. See, Bucchi, A., et al., Wild- Type and Mutant HCN Channels In A Tandem Biological Electronic Cardiac Pacemaker, Circulation., 2006, 114:992-999. PROPHETIC EXAMPLE 2 Canine Studies

[0069] Adult mongrel dogs (Chestnut Ridge Kennels, Chippensburg, PA) can be anesthetized and a custom-modified bipolar 8F steerable catheter (Guidant Corporation) can be used for subendocardial delivery of the adenoviral constructs or saline (as control). An adenoviral construct (AdHCN2 or AdmE324A) or normal saline solution will then be injected at 3 sites identified by electrogram as being in the Left Bundle Branch as described previously. See, Plotnikov, A., N., et al., Biological Pacemaker Implanted In Canine Left Bundle Branch Provides Ventricular Escape Rhythms That Have Physiological Acceptable Rates. Circulation. 2004, 109: 506-512 (2004). The mutant form of the HCN2 gene enables effective separation of the electronic and biologically induced beats.

[0070] An electronic pacemaker (Guidant Discovery II, Flextend lead, Guidant Corp,

Indianapolis, IN) can be implanted in all animals and set at VVI 45 bpm. ECG, 24-hour Holter monitoring, pacemaker log record check, and overdrive pacing at 80 bpm will be performed daily for 14 days. For each dog, the percent electronic and percent biologically induced beats can be calculated daily and then averaged. Results will be reviewed by 2 to 3 independent readers.

[0071] Although the present invention has been described with reference to preferred embodiments, workers skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention.

PROPHETIC EXAMPLE 3

[0072] Implementation of the invention can be accomplished using four components, namely a biological pacing system, endocardial pacing leads, an electronic implantable pacemaker, and a software algorithm governing the operation of the pacemaker. This composite system is described in detail below.

[0073] A biological pacemaker can be formed by using a genetic vector. Specifically, an adenoviral construct of mouse hyperpolarization-activated, cyclic nucleotide-gated HCN2 (mHCN2, GenBank AF211837 - SEQ ID NO: 1) driven by the cytomegalovirus (CMV) promoter, can be prepared by adhering to the good laboratory practices (GLP) procedures. This construct of AdHCN2 can be purified through a plaque assay, amplified to a large stock, and harvested and titrated after CsCl banding for use in the clinical procedure. The targeted titer for the AdHCN2 vector is between 3x10¹¹ ffu/mL and 4x10¹¹ ffu/mL (ffu: focus forming units). For each subject, 2 XlO¹⁰ to 3xlO¹⁰ ffu of virus construct is needed, limiting the volume of the injection to less than 0.1 mL. Construct should be kept frozen at -8O⁰C until the injection procedure.

[0074] Patient with right - left sided cardiac dyssyncrony, determined by QRS width

> 120 msec on surface ECG and confirmed by echocardiography is a candidate for this therapy. A right atrial (RA) and a right ventricular (RV) pacing lead, such as Medtronic CapSure Z Novus models 5554 and 5054 can be placed into the right and left ventricles respectively. Alternatively, a single VDD pacing lead, such as Medtronic model 5038 can be used to access RA and RV simultaneously.

[0075] A left ventricular electrophysiology catheter, such as Medtronic model

STABLEMAPR, can be advanced into the left ventricular cavity. It is preferred to use a steerable delivery catheter, such as Medtronic Attain Deflectable Catheter, in addition to the electrophysiology catheter for the precise positioning of the electrophysiology catheter on the endocardial wall of the left ventricle. A cardiac resyncronization therapy (CRT) device, such as Medtronic InSync Sentry, can be used for the temporary pacing of the right atrium and right ventricle using the leads introduced earlier, and the left ventricle (LV) can be paced via the electrophysiology catheter. Various pacing sites in the left ventricle and various LV-RV pacing delays can be tried to optimize the contraction of the ventricules and to restore the synchrony. The optimal LV pacing location and LV-RV delay can be noted.

[0076] Following the retraction of the left sided catheter, a medical fluid delivery catheter, such as the one described in US patent 7,274,966 can be advanced to the optimal pacing site in the left venctricle. Upto 0.1 mL of the AdHCN2 vector can be delivered to this site to establish the biological pacemaker on the LV wall. Afterwards, all catheters should be removed from the left ventricle, and a dual chamber pacing device, such as Medtronic EnPulse, should be implanted to pace the right atrium and the right ventricle. This pacemaker can be programmed to monitor any autonomous electrophysiological activity in the LV, and follow an algorithm that is similar to the ones shown on Figures 3, 5 or 8 of this application.

[0077] Mouse hyperpolarization-activated, cyclic nucleotide-gated HCN2 - GenBank

AF211837

1 GTGAAGTCTC ATAGATGGGG GCTCATGGTG AGCCAGTTTC TCCACACCCC AACTGGGGCC

61 TGGGGGAGAA GCACCCAGGC CAACCATAAG TGAGTAAGAC AGGCTGGCGA AGTGATGCAC

121 ACCTGTTGGC ACTCTGCAAA GTGGAGTCAG AAGGATCCGT TCAAGGTCAC CCTCAGCACA

181 TACTGACTTC TACAGCCTAT GTCATATGAG CCATTGTCTC CAAAAGACAA AAATAAAATA

241 TAGCCATCCT CCCTGGATGT GCATATGCCA AAGAAΆTTGA GACCCCAGGA AGATGTGCAG

301 TGGACACCCA GGCTGTATGT GTGTAGATCA GAGCCTGAGA CGTCCCTTTA CCTTCAGGTC 361 AGGAAACCCA CAATGCAGAT CCTGGCAGCC AAGGAGTCCA ACTTTGGCTT GCTGAATGCT 421 GTTAGGGCAG CTTCCCCATC TGGTCTATGC CTTCCCTGGC CTGGCCTGGT TCTGACTCAA 481 TTCAAAATAC CCCAGAATCG TGAATAGGAA ATGACTGGTT AGTGTTGGGA GGGCAGGGAA 541 GAGTCTAAAG GAGACCCTTG AAGCAAATGA TTTGGTCCCT AGGGTTATTG GGTTGTTGAT 601 TTATTCGCTT GGTTTTCTAA AGGTCATGAT GAGGTTGTGT ACCTGTGTGT GATGGGGGAG 661 CTATAGGGCT GAACTGAAGT TACAGATGTG TACGATTGAT TAACCGATTG ATCAACCATT 721 GATTAACTGA TTGACAGGGT CTCATCAAGT AGCACTGGTT ACTCTGCAGT TCACTATGAA 781 GATCAGGCTG GCCTCAAACT TAGAGACCCC TCCCAAAGGC TGGGGTTGAA ACTAGAGAGT 841 AGAGAGGGCT CAGCAGTTTA AGAGCATTTA TGGCTCTTGC AGGTGATCTG GGTTTGGTTC 901 CCAGAATCAT TCATAGCTCC AAATCGCTCC AGCTCCAGGG GAATCCAACA CCCTCTTCTG 961 GCTTCGTTAA GGACCATGCT TGCATGTGGT GTACATACAT ACATACATAC ATACATACAT

1021 ACATACATAc ATATATACAT ACATACATAΆ TACATACATA CAGACCGACA GACAGAAAGA

1081 CAAATAAAAT GAGACAAATA CATCTAAAAG ACAAAAACGT AGCTAAATAA GTAAGGACAG 1141 CTCCTGAGTA ATGACACCCA AGGTTGACCT CTGGCTTCTG CACATGCACA CATACACACA 1201 CATACACATC AGCCCTGAGC CACTCACTTA CTGAATATCA GAAAAAAACC TCATGTGTCA 1261 GCATGGACAT GGGGAGACCA GGTAGCCACA GCTAGTTTCT ACTCGTTGAA AGCACCTGGC 1321 TCAGGGCTGG AGAGATGGCT CAGTGGTTAA GAGCACTGAC TGCTCTTCTG AAGGTCCTGA 1381 GTTCAAATCC CAGCAAACAC ATTGTGGCTC ATAACCACCA ATAATGAGGT CTGACGCCCT

1441 CTTCTGGTGC ATCTGAAGCT ACAGTGTACT TAAATTTAAT AATAAATCTT AAAAGAAAAA

1501 GAAGACACCT GGCTCTTTTT AGAATCCTTT GTGAGCCCAA GGGCTGCCTG GCAGAGCAGT 1561 CTCCTGGCAT GGCAGGTCCT CTGCCAGCCA GTAGCCATGC TGCCTCCTCC CCTGCACTCA 1621 ACCACAAGTC CTGGAGCTCT GGCGACCTGC CCAGCTGACA TCTTCCCAGG GTGAACATAA 1681 AAGATCCCCC TTCATCTGGA ACAGGCATGT GCCCTGGGGC GGAGCAGCCT GGCACTGTCA 1741 ACTGTGATGT TCAAAAGTGG AGGCCAGAGG GGTGCCAGGG GCAGCTCCAG AGTCCCCGGG 1801 GTCGGGGCAG CCCATCTGTG TCAGATGAGG GCATGCAGCT GGCATGGCAC ATCCAACATC

1861 ACTGGACACC TACTGTGAGC AGACAGAAGT CATAGCCCCA TTCTTGAGAC ACTCAΆCCAA

1921 TAGCTAAATA TGAGGTCAGG CCAGAAACAG TGAAGGCTGT AGGGACCTTG ATGACCCATA 1981 AAGGGCTGGA AGGGTCCAAG AGAAGTTAAG AGGGACCCAG AAGATCTAAA AGGGTCTAGA 2041 AAGGGTCCAG AAGCATCCAG GGGAGTTTGT AAAAGGTCAG AAGGATTTAA GTGAACTTAG 2101 GGTCCAGGGA AATAAGGGAG AATCTAAGGA TGCCCAGAGG GGACATAAGA AGGTCCCAAG 2161 AGTCTCCTGA ATGAGAACTT TCTTCCCACC AGTTCACAGC TATTCTTCCC CTGTATTTCC 2221 TCCCTTCTCC CCAACATCCT GTCATAAAAT CCTCTCCACT CTTTGGTGAA GAAGGGTGGG 2281 AATTTAGAGT CAGAACTAGT GTCACCTGGC TCCAGCCTCA GGCCACAGCC TTAGGACCCC

2341 CAGGAGCCAA TGTCTCCCCG GACCTGGGGT AAAGTGTGGA ATGTAΆCTGA TGCCTGAGTC

2401 AAGGTGGCAG AGAGTAGGGG TCGGGTATAT GTACAGAGGC AGAAGTTGAA CCAGGATCCC 2461 CTGGAGACCG CTAAGGACTA CCTAACCTGG GATCCTCACT TTTTAAGGGA GAAGTCGCCA 2521 GAAGCCACAG GAGTCTTGCT ACTGTTTTTG TTGCCTGACC ATGCCTCAGT TTCCCCACAA 2581 GTAGGGCTTG GAGATGGGCT GAGATTAGAA CCCAGAATGA TCTCAGCCCT TCTCACAAAT 2641 ATTCATAGGT TTCTGCCTTG GAGGCGGTGA AAGCGACAGA GCCAGAGATA TGGTAGCCTC 2701 CGGGAACACA CTTTTATTAT GGAATCTGCC ACCTTGAACC GAGAAAGGAG TTGGCACCCG 2761 AGGGGTGAGC GTCAGCGGTT GCCCCGCCCG CGGTGTCCTC GAGATCGCGG AGGAACCCCA 2821 GAGTGGACCA GGGCTTGGTC TGCATCGTGC GTCAAGGCAG GGGCCCGCCG GCTGGGCTCT 2881 GTGACCTTGG GTTCGTCCTT GGCCTCAGTT TCCCCCTGGG GAACCGAGCC TGAGCGCATC

2941 TCCAAGGTCT CAAGGGGCTG ACTGACCTTG AGCCTGCTTG CTGGCCAGAG CCTCAGTTTC

3001 CCCATCCATC CCTGTGTGGG GTGAGGGTGG TTCAGGTGGA GGCGGGGCTC CCGCCCCCGC 3061 CCCTCCCCCG CAAGCAGAGG CTCCACCCCC GGCTCCGCCC TCCCTCGGGC TCGGCCGGCG

3121 GCGGCGGCGG CCGCTCCGCT CCGCACTGCC CGGCGCCGCC TCGCCATG (SEQIDNO:!)

Claims

1. A hybrid pacing system comprising: an implanted biological pacemaker for providing pacing to the left ventricle; and an implantable medical device for providing pacing in timed relationship to the pacing of left ventricle based upon sensed activity produced by the biological pacemaker.

2. The system of claim 1, wherein the second heart chamber is an atrium.

3. The system of claim 3, wherein the implantable medical device also provides pacing to a third heart chamber.

4. The system of claim 1, wherein the sensed activity comprises electrical activity representing an atrial or ventricular event.

5. The system of claim 1, wherein the sensed activity comprises at least one of mechanical activity and intracardiac pressure.

6. The system of claim 1, wherein the implantable medical device provides an alert if the sensed activity is indicative of a failure of the biological pacemaker.

7. A hybrid biventricular pacing system comprising: a biological pacemaker for providing left ventricular pacing; and a dual chamber electronic pacemaker for providing right atrial pacing and right ventricular pacing in timed relationship to the left ventricular pacing to maintain a time interval between left ventricular and right ventricular events.

8. The system of claim 7, wherein the electronic pacemaker provides pacing as a function of sensed left ventricular events.

9. The system of claim 7, wherein the electronic pacemaker provides right ventricular pacing at a time interval following the sensed left ventricular events and prior to right atrial events.

10. A method of treating a heart failure condition, the method comprising: implanting a biopacer in a left ventricle; implanting a dual chamber electronic pacemaker; and synchronizing the dual chamber electronic pacemaker to left ventricular sensed events to provide right atrial and right ventricular pacing.

11. For use in conjunction with an implanted biological pacemaker that provides pacing to the left ventricle, an implantable medical device (IMD) that senses pacing activity of the biological pacemaker and provides pacing stimuli in a synchronized relationship to the biological pacemaker based upon the pacing activity sensed.

12. The IMD of claim 11, wherein the sensed pacing activity comprises at least one of mechanical activity and intracardiac pressure.

13. The IMD of claim 11 , wherein the IMD provides an alert if the sensed pacing activity is indicative of a failure of the biological pacemaker.

14. A method of biventricular pacing with coordinated operation of an implantable medical device (IMD) and an implanted biopacer, the method comprising: measuring a time interval (T_A-_LV) from right atrial (RA) event to a sensed left ventricular (LV) event produced by the biopacer; calculating a time interval (T_A-_RV) based upon the measured time interval T_A-_LV and a right ventricle-to-left ventricle time interval T_RV-_LV; and pacing, with the IMD, the right ventricle (RV) as a function of the T_A-_RV time interval.