Patent Application
20100152531
The present invention relates to a device for treating heart failure. More specifically, the invention relates to a cardiac harness that is configured to be fit around at least a portion of a patient's heart and is associated with electrodes attached to a power source for use in defibrillation or pacing. The cardiac harness is further combined with medically beneficial medicaments and a system for delivery of the medicaments so that the beneficial medicaments are controllably released to a patient's heart over an appropriate time horizon. Such a combination will serve to augment and/or extend the efficacy of the cardiac harness and the medicaments used.
Congestive heart failure (“CHF”) is characterized by the failure of the heart to pump blood at sufficient flow rates to meet the metabolic demand of tissues, especially the demand for oxygen. One characteristic of CHF is remodeling of at least portions of a patient's heart. Remodeling involves physical change to the size, shape and thickness of the heart wall. For example, a damaged left ventricle may have some localized thinning and stretching of a portion of the myocardium. The thinned portion of the myocardium often is functionally impaired, and other portions of the myocardium attempt to compensate. As a result, the other portions of the myocardium may expand so that the stroke volume of the ventricle is maintained notwithstanding the impaired zone of the myocardium. Such expansion may cause the left ventricle to assume a somewhat spherical shape.
Cardiac remodeling often subjects the heart wall to increased wall tension or stress, which further impairs the heart's functional performance. Often, the heart wall will dilate further in order to compensate for the impairment caused by such increased stress. Thus, a cycle can result, in which dilation leads to further dilation and greater functional impairment.
Historically, congestive heart failure has been managed with a variety of drugs. Devices have also been used to improve cardiac output. For example, left ventricular assist pumps help the heart to pump blood. Multi-chamber pacing has also been employed to optimally synchronize the beating of the heart chambers to improve cardiac output. Various skeletal muscles, such as the latissimus dorsi, have been used to assist ventricular pumping. Researchers and cardiac surgeons have also experimented with prosthetic “girdles” disposed around the heart. One such design is a prosthetic “sock” or “jacket” that is wrapped around the heart.
Patients suffering from congestive heart failure often are at risk to additional cardiac failures, including cardiac arrhythmias. When such arrhythmias occur, the heart must be shocked to return it to a normal cycle, typically by using a defibrillator. Implantable cardioverter/defibrillators (ICD's) are well known in the art and typically have a lead from the ICD connected to an electrode implanted in the right ventricle. Such electrodes are capable of delivering a defibrillating electrical shock from the ICD to the heart.
Other prior art devices have placed the electrodes on the epicardium at various locations, including on or near the epicardial surface of the right and left heart. These devices also are capable of distributing an electrical current from an implantable cardioverter/defibrillator for purposes of treating ventricular defibrillation or hemodynamically stable or unstable ventricular tachyarrhythmias.
Patients suffering from congestive heart failure may also suffer from cardiac failures, including bradycardia and tachycardia. Such disorders typically are treated by both pacemakers and implantable cardioverter/defibrillators. The pacemaker is a device that paces the heart with timed pacing pulses for use in the treatment of bradycardia, where the ventricular rate is too slow, or to treat cardiac rhythms that are too fast, i.e., anti-tachycardia pacing. As used herein, the term “pacemaker” is any cardiac rhythm management device with a pacing functionality, regardless of any other functions it may perform such as the delivery cardioversion or defibrillation shocks to terminate atrial or ventricular fibrillation. Particular forms and uses for pacing/sensing can be found in U.S. Pat. No. 6,574,506 (Kramer et al.) and U.S. Pat. No. 6,223,079 (Bakels et al.); and U.S. Publication No. 2003/0130702 (Kramer et al.) and U.S. Publication No. 2003/0195575 (Kramer et al.), the entire contents of which are incorporated herein by reference thereto.
In addition, particular forms and uses for cardiac harnesses used for treating CHF and for defibrillating and/or pacing/sensing can be found in U.S. Pat. No. 7,155,295 (Lilip Lau et al.), the entire contents of which is incorporated herein by reference thereto.
In addition to the benefits derived from the cardiac harness disclosed herein, including the electrically active harness (i.e., defibrillation, pacing, sensing), the harness can be used to deliver drugs to the surface of the heart. Many drugs used for heart failure and other cardiac and non-cardiac maladies may have complications and side effects when delivered systemically. Most drugs do not spread out evenly through the body. The drugs may have limited onset and breakdown times when delivered systemically. A variety of body-wide factors may affect the effectiveness of the dose when delivered systemically, including but not limited to, time required to enter blood stream, amount entering bloodstream, and time to leave the bloodstream or be metabolized.
Delivery of appropriate and beneficial medicaments directly to the surface of the heart may allow lower overall doses to be utilized, as the delivery is directly to or near the site of intended impact. As used herein, the term “beneficial medicament” is an agent that assists in the treatment, cure, relief or prevention of disease or disorders of the heart or surrounding tissue. Beneficial medicaments may include one or more therapeutic agents, cellular material, and/or combinations thereof. Any therapeutic compound that affects the heart, coronary vessels, or surrounding tissue may be suitable to use in combination with the cardiac harness.
The present invention solves the problems associated with prior art devices relating to the delivery of beneficial medicaments, such as drugs, from implantable medical devices for the site-specific treatment of cardiac and non-cardiac maladies.
In accordance with the present invention, a cardiac harness is combined with beneficial medicaments and a system for delivery of the medicaments so that the beneficial medicaments are controllably released to a patient's heart over an appropriate time horizon. Such a combination will serve to augment and extend the efficacy of the cardiac harness and the medicaments used.
In one embodiment, a cardiac harness is combined with an mTOR inhibitor delivered locally to one or more specific target areas on or around the heart. In this embodiment, the mTOR inhibitor is delivered directly to the epicardial surface of the heart by the cardiac harness. In another embodiment, a cardiac harness is combined with aldosterone blockade delivered locally to one or more specific target areas on or around the heart. In this embodiment, the aldosterone blockade is used in conjunction with standard care therapies which include the use of ACE inhibitors and β-blockers. The aldosterone blockade has a dose range of 0.1 to 200 mg per day targeted, and the drugs are delivered directly to the epicardial surface of the heart by the cardiac harness. In one embodiment, the pericardium remains intact over the cardiac harness, thereby helping to keep the drugs in contact with the epicardium.
In another embodiment, a polymer material such as, for example, a silicon rubber layer, coats the cardiac harness. The polymer material is then coated with an mTOR inhibitor coating or a non-biodegradable aldosterone blockade coating.
In another embodiment, a polymer material on the cardiac harness is itself impregnated with a beneficial medicament such as an mTOR inhibitor. In this embodiment, over time the mTOR inhibitor elutes directly from the impregnated polymer coating. Alternately, a dielectric coating on the cardiac harness is impregnated with a beneficial medicament such as aldosterone blockade. In this embodiment, the aldosterone blockade elutes directly from the impregnated dielectric coating over time.
In yet another embodiment, a free-standing biodegradable plug or implant is attached to the cardiac harness. In this embodiment, over time the biodegradable beneficial medicament elutes, degrades, and separates itself from the plug or implant.
In another embodiment, the cardiac harness has longitudinal lumens through which the mTOR inhibitor or aldosterone blockade is injected directly onto the epicardial surface of the heart.
The present invention relates to an apparatus and method of preparing a cardiac harness for use in delivering an mTOR inhibitor or aldosterone blockade from the surface of the cardiac harness to a patient's heart. The present invention discloses embodiments and methods for drug delivery that extend the efficacy of the cardiac harness and the beneficial medicament for use in the site-specific treatment of cardiac and non-cardiac maladies. A cardiac harness is disclosed herein, in
The term “cardiac harness” as used herein is a broad term that refers to a device fit onto a patient's heart to apply a compressive force on the heart during at least a portion of the cardiac cycle.
The cardiac harness illustrated in
In the harness illustrated in
With further reference to
In the harness shown in
The undulating spring elements exert a force in resistance to expansion of the heart. Collectively, the force exerted by the spring elements tends toward compressing the heart, thus alleviating wall stresses in the heart as the heart expands. Accordingly, the harness helps to decrease the workload of the heart, enabling the heart to more effectively pump blood through the patient's body and enabling the heart an opportunity to heal itself. It should be understood that several arrangements and configurations of spring members can be used to create a mildly compressive force on the heart to reduce wall stresses. For example, spring members can be disposed over only a portion of the circumference of the heart or the spring members can cover a substantial portion of the heart.
As the heart expands and contracts during diastole and systole, the contractile cells of the myocardium expand and contract. In a diseased heart, the myocardium may expand such that the cells are distressed and lose at least some contractility. Distressed cells are less able to deal with the stresses of expansion and contraction. As such, the effectiveness of heart pumping decreases. Each series of spring hinges of the above cardiac harness embodiments is configured so that as the heart expands during diastole the spring hinges correspondingly will expand, thus storing expansion forces as bending energy in the spring. As such, the stress load on the myocardium is partially relieved by the harness. This reduction in stress helps the myocardium cells to remain healthy and/or regain health. As the heart contracts during systole, the disclosed prior art cardiac harnesses apply a moderate compressive force as the hinge or spring elements release the bending energy developed during expansion allowing the cardiac harness to follow the heart as it contracts and to apply contractile force as well.
Other structural configurations for cardiac harnesses exist, however, but all have drawbacks and do not function optimally to treat CHF and other related diseases or failures. The cardiac harness disclosed herein provides a novel approach to treat CHF and provides electrodes associated with the harness to deliver an electrical shock for defibrillation or a pacing stimulus for resynchronization, or for biventricular pacing/sensing.
A cardiac harness system is disclosed herein for treating the heart. The cardiac harness system couples a cardiac harness for treating the heart coupled with a cardiac rhythm management device. More particularly, the cardiac harness includes rows or undulating strands of spring elements that provide a compressive force on the heart during diastole and systole in order to relieve wall stress pressure on the heart. Associated with the cardiac harness is a cardiac rhythm management device for treating any number of irregularities in heart beat due to, among other reasons, congestive heart failure. Thus, the cardiac rhythm management device associated with the cardiac harness can include one or more of the following: an implantable cardioverter/defibrillator with associated leads and electrodes; a cardiac pacemaker including leads and electrodes used for sensing cardiac function and providing pacing stimuli to treat synchrony of both vessels; and a combined implantable cardioverter/defibrillator and pacemaker, with associated leads and electrodes to provide a defibrillation shock and/or pacing/sensing functions.
The cardiac harness system includes various configurations of panels connected together to at least partially surround the heart and assist the heart during diastole and systole. The cardiac harness system also includes one or more leads having electrodes associated with the cardiac harness and a source of electrical energy supplied to the electrodes for delivering a defibrillating shock or pacing stimuli.
As shown in a flattened configuration in
The undulating strands 22 provide a compressive force on the epicardial surface of the heart thereby relieving wall stress. In particular, the spring elements 23 expand and contract circumferentially as the heart expands and contracts during the diastolic and systolic functions. As the heart expands, the spring elements expand and resist expansion as they continue to open and store expansion forces. During systole, as the heart 10 contracts, the spring elements will contract circumferentially by releasing the stored bending forces thereby assisting in both the diastolic and systolic function.
As just discussed, bending stresses are absorbed by the spring elements 23 during diastole and are stored in the elements as bending energy. During systole, when the heart pumps, the heart muscles contract and the heart becomes smaller. Simultaneously, bending energy stored within the spring elements 23 is at least partially released, thereby providing an assist to the heart during systole. The compressive force exerted on the heart by the spring elements of the harness comprises about 10% to 15% of the mechanical work done as the heart contracts during systole. Although the harness is not intended to replace ventricular pumping, the harness does substantially assist the heart during systole.
The undulating strands 22 can have varying numbers of spring element 23 depending upon the amplitude and pitch of the spring elements. For example, by varying the amplitude of the pitch of the spring elements, the number of undulations per panel will vary as well. It may be desired to increase the amount of compressive force the cardiac harness 20 imparts on the epicardial surface of the heart, therefore panels that have spring elements with lower amplitudes and a shorter pitch, thereby increasing the expansion force imparted by the spring element, are disclosed. In other words, all other factors being constant, a spring element having a relatively lower amplitude will be more rigid and resist opening, thereby storing more bending forces during diastole. Further, if the pitch is smaller, there will be more spring elements per unit of length along the undulating strand, thereby increasing the overall bending force stored during diastole, and released during systole. Other factors that will affect the compressive force imparted by the cardiac harness onto the epicardial surface of the heart include the shape of the spring elements, the diameter and shape of the wire forming the undulating strands, and the material comprising the strands.
As shown in
It is preferred that the undulating strands 22 be continuous as shown in
Associated with the cardiac harness is a cardiac rhythm management device as previously disclosed. Thus, associated with the cardiac harness as shown in
Diseased hearts often have several maladies. One malady that is not uncommon is irregularity in heartbeat caused by irregularities in the electrical stimulation system of the heart. For example, damage from a cardiac infarction can interrupt the electrical signal of the heart. In some instances, implantable devices, such as pacemakers, help to regulate cardiac rhythm and stimulate heart pumping. A problem with the heart's electrical system can sometimes cause the heart to fibrillate. During fibrillation, the heart does not beat normally, and sometimes does not pump adequately. A cardiac defibrillator can be used to restore the heart to normal beating. An external defibrillator typically includes a pair of electrode paddles applied to the patient's chest. The defibrillator generates an electric field between electrodes. An electric current passes through the patient's heart and stimulates the heart's electrical system to help restore the heart to regular pumping.
Sometimes a patient's heart begins fibrillating during heart surgery or other open-chest surgeries. In such instances, a special type of defibrillating device is used. An open-chest defibrillator includes special electrode paddles that are configured to be applied to the heart on opposite sides of the heart. A strong electric field is created between the paddles, and an electric current passes through the heart to defibrillate the heart and restore the heart to regular pumping.
In some patients that are especially vulnerable to fibrillation, an implantable heart defibrillation device may be used. Typically, an implantable heart defibrillation device includes an implantable cardioverter defibrillator (ICD) or a cardiac resynchronization therapy device (CRT-D) which usually has only one electrode positioned in the right ventricle, and the return electrode is the defibrillator housing itself, typically implanted in the pectoral region. Alternatively, an implantable device includes two or more electrodes mounted directly on, in or adjacent the heart wall. If the patient's heart begins fibrillating, these electrodes will generate an electric field therebetween in a manner similar to the other defibrillators discussed above.
Testing has indicated that when defibrillating electrodes are applied external to a heart that is surrounded by a device made of electrically conductive material, at least some of the electrical current disbursed by the electrodes is conducted around the heart by the conductive material, rather than through the heart. Thus, the efficacy of defibrillation is reduced. Accordingly, there are several cardiac harness embodiments that enable defibrillation of the heart and other embodiments disclose means for defibrillating, resynchronization, left ventricular pacing, right ventricular pacing, and biventricular pacing/sensing.
The cardiac harness 20 includes a pair of leads 31 having conductive electrode portions 32 that are spaced apart and which separate panels 21. As shown in
Still referring to
As will be described in more detail, the electrodes 32 have a conductive discharge first surface 38 that is intended to be proximate to or in direct contact with the epicardial surface of the heart, and a conductive discharge second surface 39 that is opposite to the first surface and faces away from the heart surface. As used herein, the term “proximate” is intended to mean that the electrode is positioned near or in direct contact with the outer surface of the heart, such as the epicardial surface of the heart. The first surface and second surface typically will not be covered with the dielectric material 37 so that the bare metal conductive coil can transmit the electrical current from the power source (pulse generator), such as an implantable cardioverter/defibrillator (ICD or CRT-D) 36, to the epicardial surface of the heart. Alternatively, either the first or the second surface may be covered with dielectric material 37 in order to preferentially direct the current through only one surface.
Importantly, the dielectric material 37 used to attach the electrodes 32 to the undulating strands 22 insulates the undulating strands from any electrical current discharged through the conductive metal coils 33 of the electrodes. Further, the dielectric material in this embodiment is flexible so that the electrodes can serve as a seam or hinge to fold the cardiac harness 20 into a lower profile for minimally invasive delivery. Thus, as will be described in more detail (see
Cross sectional views of the leads 31 and the electrode portion 32 are shown in
Referring to
While it is preferred that the cardiac harness 20 be comprised of undulating strands 22 made from a solid wire member, such as a superelastic or shape memory material such as Nitinol, and be insulated from the electrodes 32, it is possible to use some or all of the undulating strands to deliver the electrical shock to the epicardial surface of the heart. For example, as shown in
In contrast to the current conducting undulating strands of
A cardiac harness 20 that can be implanted minimally invasively and be attached to the epicardial surface of the heart, without requiring sutures, clips, screws, glue or other attachment means, is provided. Importantly, the undulating strands 22 may provide relatively high frictional engagement with the epicardial surface, depending on the cross-sectional shape of the strands. For example, in the embodiment disclosed in
In another embodiment as shown in
Still referring to
While the
At present, commercially available implantable cardioverter/defibrillators (ICD's) are capable of delivering approximately thirty to forty joules in order to defibrillate the heart. It is preferred that the electrodes 22 of the cardiac harness 20 of the present invention deliver defibrillating shocks having less than thirty to forty joules. The commercially available ICD's can be modified to provide lower power levels to suit the present invention cardiac harness system with electrodes delivering less than thirty to forty joules of power. As a general rule, one objective of the electrode configuration is to create a uniform current density distribution throughout the myocardium. Therefore, in addition to the number of electrodes used, their size, shape, and relative positions will also all have an impact on the induced current density distribution. Thus, while one to four electrodes are preferred, five to eight electrodes also are feasible.
The cardiac harness and the associated cardiac rhythm management device can be used not only for providing a defibrillating shock, but also can be used as a pacing/sensing device for treating the synchrony of both ventricles, for resynchronization, for biventricular pacing and for left ventricular pacing or right ventricular pacing. As shown in
As shown in
Importantly, coils 72 not only perform the function of being highly flexible and provide the attachment means between the coils and the undulating strands, but they also provide structural columns or spines that assist in deploying the harness 60 over the epicardial surface of the heart. Thus, as shown for example in
Referring to the embodiments shown in
The cardiac harness embodiments 60 shown in
Similar to the embodiment shown in
Referring to
It is to be understood that several embodiments of cardiac harnesses can be constructed and that such embodiments may have varying configurations, sizes, flexibilities, etc. Such cardiac harnesses can be constructed from many suitable materials including various metals, fabrics, plastics and braided filaments. Suitable materials also include superelastic materials and materials that exhibit shape memory properties. For example, a preferred embodiment cardiac harness is constructed of Nitinol. Shape memory dielectric materials can also be employed. Such shape memory dielectric materials can include shape memory polyurethanes or other dielectric materials such as those containing oligo(e-caprolactone) dimethacrylate and/or poly(e-caprolactone), which are available from mnemoScience.
As shown in
Again referring to
As shown in
The cardiac harness, having either electrodes or coils, can be formed using injection molding techniques as shown in
As shown in
As shown in
As further shown in
As shown in
When removing portions of the silicone rubber from the electrode 120 using soda blasting or a similar technique, it may be desirable to leave portions of the electrode masked or insulated so that the masked portion is non-conductive. By masking portions of two electrodes positioned, for example, on opposite sides of the left ventricle, it is possible to vector a shock at a desirable angle through the myocardium and ventricle. The shock will travel from the bare metal (unmasked) portion of one electrode through the myocardium and the ventricle to the bare metal (unmasked) portion of the opposing electrode at a vector angle determined by the position of the masking on the electrodes.
The associated cardiac rhythm management devices are implantable devices that provide electrical stimulation to selected chambers of the heart in order to treat disorders of cardiac rhythm and can include pacemakers and implantable cardioverter/defibrillators and/or cardiac resynchronization therapy devices (CRT-D). A pacemaker is a cardiac rhythm management device which paces the heart with timed pacing pulses. As previously described, common conditions for which pacemakers are used is in the treatment of bradycardia (ventricular rate is too slow) and tachycardia (cardiac rhythms are too fast). As used herein, a pacemaker is any cardiac rhythm management device with a pacing functionality, regardless of any other functions it may perform such as the delivery of cardioversion or defibrillation shocks to terminate atrial or ventricular fibrillation. An important feature is to provide a cardiac harness having the capability of providing a pacing function in order to treat the synchrony of both ventricles. To accomplish the objective, a pacemaker with associated leads and electrodes are associated with and incorporated into the cardiac harness of the present invention. The pacing/sensing electrodes, alone or in combination with defibrillating electrodes, provide treatment to synchronize the ventricles and improve cardiac function.
A pacemaker and a pacing/sensing electrode are incorporated into the design of the cardiac harness. As shown in
Multi-site pacing (as previously shown in
As shown in
The defibrillating electrode 130, can be used with commercially available pacing/sensing electrodes and leads. For example, Oscor (Model HT 52PB) endocardial/passive fixation leads can be integrated with the defibrillator electrode 130 by molding the leads into the fibrillator electrode using the same molds previously disclosed herein.
The incorporation of cardiac rhythm management devices into the cardiac harness combines several treatment modalities that are particularly beneficial to patients suffering from congestive heart failure. The cardiac harness provides a compressive force on the heart thereby relieving wall stress, and improving cardiac function. The defibrillating and pacing/sensing electrodes associated with the cardiac harness, along with ICD's and pacemakers, provide numerous treatment options to correct for any number of maladies associated with congestive heart failure. In addition to the defibrillation function previously described, the cardiac rhythm devices can provide electrical pacing stimulation to one or more of the heart chambers to improve the coordination of atrial and/or ventricular contractions, which is referred to as resynchronization therapy. Cardiac resynchronization therapy is pacing stimulation applied to one or more heart chambers, typically the ventricles, in a manner that restores or maintains synchronized bilateral contractions of the atria and/or ventricles thereby improving pumping efficiency. Resynchronization pacing may involve pacing both ventricles in accordance with a synchronized pacing mode. For example, pacing at more than one site (multi-site pacing) at various sites on the epicardial surface of the heart to desynchronize the contraction sequence of a ventricle (or ventricles) may be therapeutic in patients with hypertrophic obstructive cardiomyopathy, where creating asynchronous contractions with multi-site pacing reduces the abnormal hyper-contractile function of the ventricle. Further, resynchronization therapy may be implemented by adding synchronized pacing to the bradycardia pacing mode where paces are delivered to one or more synchronized pacing sites in a defined time relation to one or more sensing and pacing events. An example of synchronized chamber-only pacing is left ventricle only synchronized pacing where the rate in synchronized chambers are the right and left ventricles respectively. Left-ventricle-only pacing may be advantageous where the conduction velocities within the ventricles are such that pacing only the left ventricle results in a more coordinated contraction by the ventricles than by conventional right ventricle pacing or by ventricular pacing. Further, synchronized pacing may be applied to multiple sites of a single chamber, such as the left ventricle, the right ventricle, or both ventricles. The pacemakers are typically implanted subcutaneously on a patient's chest and have leads threaded to the pacing/electrodes as previously described in order to connect the pacemaker to the electrodes for sensing and pacing. The pacemakers sense intrinsic cardiac electrical activity through the electrodes disposed on the surface of the heart. Pacemakers are well known in the art and any commercially available pacemaker or combination defibrillator/pacemaker can be used.
The cardiac harness and the associated cardiac rhythm management device system can be designed to provide left ventricular pacing. In left heart pacing, there is an initial detection of a spontaneous signal, and upon sensing the mechanical contraction of the right and left ventricles. In a heart with normal right heart function, the right mechanical atrio-ventricular delay is monitored to provide the timing between the initial sensing of right atrial activation (known as the P-wave) and right ventricular mechanical contraction. The left heart is controlled to provide pacing which results in left ventricular mechanical contraction in a desired time relation to the right mechanical contraction, e.g., either simultaneous or just preceding the right mechanical contraction. Cardiac output is monitored by impedence measurements and left ventricular pacing is timed to maximize cardiac output. The proper positioning of the pacing/sensing electrodes disclosed herein provides the necessary sensing functions and the resulting pacing therapy associated with left ventricular pacing.
An important feature is the minimally invasive delivery of the cardiac harness and the cardiac rhythm management device system which will be described immediately below.
Delivery of the cardiac harness 20, 60, and 100 and associated electrodes and leads can be accomplished through conventional cardio-thoracic surgical techniques such as through a median sternotomy. In such a procedure, an incision is made in the pericardial sac and the cardiac harness can be advanced over the apex of the heart and along the epicardial surface of the heart simply by pushing it on by hand. The intact pericardium is over the harness and helps to hold it in place. The previously described grip pads and the compressive force of the cardiac harness on the heart provide sufficient attachment means of the cardiac harness to the epicardial surface so that sutures, clips or staples are unnecessary. Other procedures to gain access to the epicardial surface of the heart include making a slit in the pericardium and leaving it open, making a slit and later closing it, or making a small incision in the pericardium.
Preferably, however, the cardiac harness and associated electrodes and leads may be delivered through minimally invasive surgical access to the thoracic cavity, as illustrated in
The delivery device 140 also includes a dilator tube 150 that has a distal end 151 and a proximal end 152. The cardiac harness 20, 60, 100 is collapsed to a low profile configuration and inserted into the distal end of the dilator tube, as shown in
As shown in
As shown in
As more clearly shown in
As shown in
As shown in the embodiments of
As shown in
Importantly, during delivery of the cardiac harness 20, 60, 100, the harness itself, the electrodes 32,120,130, as well as leads 31 and 132 have sufficient column strength in order for the physician to push from the proximal end of the harness to advance it distally through the dilator tube 150. While the entire cardiac harness assembly is flexible, there is sufficient column strength, especially in the electrodes, to easily slide the cardiac harness over the epicardial surface of the heart in the manner described.
If the cardiac harness 20, 60, 100 includes coils 72, as opposed to the electrodes and leads, the harness can be delivered in the same manner as previously described with respect to
Delivery of the cardiac harness 20, 60, 100 can be by mechanical means as opposed to the hand delivery previously described. As shown in
Suitable materials for the delivery system 140, 180 can include the class of polymers typically used and approved for biocompatible use within the body. Preferably, the tubing associated with delivery systems 140 and 180 are rigid, however, they can be formed of a more flexible material. Further, the delivery systems 140, 180 can be curved rather than straight, or can have a flexible joint in order to more appropriately maneuver the cardiac harness 20, 60, 100 over the epicardial surface of the heart during delivery. Further, the tubing associated with delivery systems 140, 180 can be coated with a lubricious material to facilitate relative movement between the tubes. Lubricious materials commonly known in the art such as Teflon™ can be used to enhance slidable movement between the tubes.
Delivery and implantation of an ICD, CRT-D, pacemaker, leads, and any other device associated with the cardiac rhythm management devices can be performed by means well known in the art. Preferably, the ICD/CRT-D/pacemaker, are delivered through the same minimally invasive access site as the cardiac harness, electrodes, and leads. The leads are then connected to the ICD/CRT-D/pacemaker in a known manner. The ICD or CRT-D or pacemaker (or combination device) may be implanted in a known manner in the abdominal area and then the leads are connected. Since the leads extend from the apical ends of the electrodes (on the cardiac harness) the leads are well positioned to attach to the power source in the abdominal area.
Systolic heart failure patients with a depressed left ventricular ejection fraction (usually less than 40%) are the primary targets for cardiac harness therapy. The patients may have either ischemic or non-ischemic etiologies. Patients will have enlarged ventricular dimensions with a reduction in the overall contractility of the heart. A number of beneficial medicaments have already proven to be effective against this disease. Among these are angiotensin-converting-enzyme (ACE) inhibitors, β-blockers, angiotensin II receptor blockers (ARBs), aldosterone antagonists, and diuretics.
One embodiment of the present invention relates to coating a HeartNet™ Implant (which provides ventricular elastic support therapy) with a drug-eluting polymer to enable localized long-term delivery of an anti-hypertrophic/anti-fibrotic therapeutic agent directly to the heart via the pericardial space. The HeartNet™ Implant is currently in clinical trials and is manufactured by Paracor Medical, Inc. (Santa Clara, Calif.). The HeartNet™ Implant is referred to herein as a cardiac harness and is shown, for example in
The cardiac harness having a pharmacologic agent coating provides a combination device which simultaneously provides therapy to the heart via: (1) mechanical support to the failing heart muscle, and (2) localized intra-pericardial delivery of a beneficial pharmacologic agent to reduce hypertrophy and fibrosis. These two features of the novel device are provided by (1) a coated cardiac harness, and by (2) controlled delivery of a suitable pharmacologic agent from a drug-eluting polymer coating applied to the harness. The device will serve to reduce the cardiac hypertrophy and fibrosis that play a role in the pathophysiology of systolic HF, diastolic HF, and HF following acute MI.
mTOR inhibitors are pharmacologic agents that inhibit the mammalian target of rapamycin (mTOR). Rapamycin (sirolimus), and its derivatives including everolimus, zotarolimus, and biolimus A9, act as mTOR inhibitors. Sirolimus has been used in a clinical setting, often in conjunction with calcineurin inhibitors (CNIs), as anti-rejection therapy for organ transplant patients. mTOR inhibitors are also commonly used as anti-proliferative agents on drug-eluting stents (DES). Pre-clinical evidence for their use as cardiac anti-hypertrophic and anti-fibrotic agents has been shown in small-animal models, such as mouse and rat. Preliminary clinical evidence for their utility as cardiac anti-hypertrophic and anti-fibrotic agents exists in transplant patients. Local delivery of mTOR inhibitors to the cardiac tissue has the potential to provide therapeutic levels of anti-hypertrophic and anti-fibrotic mTOR inhibition without the side effects associated with systemic administration.
mTOR inhibitors bind to the cytosolic immunophilin FK Binding Protein-12 (FKBP12) in cells to generate an immunosuppressive complex that, in turn, binds to and inhibits the activation of the mTOR pathway (specifically, mTORC1). mTOR is a key regulatory serine/threonine kinase (phosphotransferase) that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. mTOR exerts its effects primarily by switching on and off the cell's translational machinery to affect protein synthesis. Blockade of the mTOR prevents the activation of mTOR targets, thus regulating protein synthesis. Disorders that involve enhanced rates of protein synthesis can lead to tissue hypertrophy (increased cell growth), as in the case of cardiac hypertrophy.
mTOR controls a number of components involved in the initiation and elongation stages of protein synthesis (translation). Each step involves protein factors that are extrinsic to the ribosome, and regulation generally involves alterations in phosphorylation of the protein factors. In a number of cases, the rapid activation of protein synthesis by insulin, growth factors, or other growth-promoting agonists is at least partially inhibited by mTOR inhibitors, implying that mTOR signaling is involved in stimulating the translational machinery.
Systemic dosages of mTOR inhibitors can lead to hypertriglyceridemia, hypercholesterolemia, and vasculitis of the GI tract. Other side effects of systemic mTOR inhibitors include diarrhea, thrombocytopenia, delays in wound healing, rash, hypertension, anemia, hypokalemia, and photosensitivity. The incidence of side effects from systemic dosages of mTOR inhibitors was shown in the ORBIT (Oral Rapamune to Inhibit Restenosis) trial, where 43% of patients receiving 2 mg daily, and 66% of patients receiving 5 mg daily, experienced side effects which ranged from mild to severe in nature. Cessation of oral sirolimus treatment relieved symptoms. These side effects, particularly thrombocytopenia and delays in wound healing, make local delivery of mTOR inhibitors a preferable administration route, particularly for treating HF, where systemic administration is not required.
Drug-Eluting Stents (DES) currently utilize mTOR inhibitors to prevent the re-blockage of arteries post-intervention via local delivery of the mTOR inhibitor to the vessel. The CYPHER™ sirolimus-eluting stent (manufactured by Johnson & Johnson) was approved by the FDA for sale in the United States in April of 2003. The Endeavor DES (manufactured by Boston Scientific) uses the sirolimus analogue zotarolimus, and has been approved for sale in Europe since April 2005 and in the United States since February 2008. The XIENCE/PROMUS DES (manufactured by Abbott Labs) uses yet another mTOR inhibitor (everolimus), and has very rapidly become the leading DES in the United States since its FDA approval in July 2008. There are several other corporations that also market a DES whose pharmacologic agent is a related mTOR inhibitor. The extensive clinical history associated with DES that incorporate mTOR inhibitors into their coating reflects the safety of these devices. Indeed, millions of patients worldwide have been implanted with these permanent devices over the past decade, and it has been demonstrated that local delivery of mTOR inhibitors to the coronary arteries is efficacious in ameliorating the effects of restenosis.
As noted previously, mTOR inhibitors have been shown to have both anti-hypertrophic and anti-fibrotic effects in animal models and humans. McMullen (McMullen, J. R., et al., Inhibition of mTOR Signaling With Rapamycin Regresses Established Cardiac Hypertrophy Induced by Pressure Overload, Circulation, Vol. 109, pp. 3050-3055, 2004) demonstrated that in mice with compensated or decompensated hypertrophy induced by aortic banding, systemic administration of sirolimus regressed increases in heart size by 68% and 41%, respectively. In decompensated mice, significant decreases in left ventricular end-systolic diameter were also observed with treatment, as were improvements in fractional shortening and EF. Significant decreases in LV end diastolic diameter were observed in compensated sirolimus-treated mice. Gao (Gao, X. M., et al., Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis, Journal of Hypertension, Vol. 24, pp. 1663-1670, 2006) has demonstrated that the murine aortic banding model produces LV hypertrophy and fibrosis, that hypertrophy and fibrosis are inter-related events, and that treatment with an mTOR inhibitor reduces these effects. Aortic banding was associated with myocyte enlargement, interstitial fibrosis and enhanced expression of collagen I, collagen III, and ANP, while aortic banding caused decreased expression of α-MHC and SERCA2a. Mice with transverse aortic constriction (TAC) developed LV hypertrophy with increased wall thickness and a 20% increase in LV mass index (LVMI) measured after 5 weeks of TAC. After treatment with sirolimus for 4 weeks, LVMI was significantly decreased (35-45%), LV wall thickening index was decreased, cardiomyocyte size was reduced by 46%, and collagen deposition was suppressed by 38%, when compared to control animals with LV hypertrophy. Throughout sirolimus treatment, LV contractile function was preserved. Another effect of mTOR inhibition in these animals was the restoration of α-MHC and SERCA2a expression to normal levels and the reduction of ANP levels. Furthermore, S6 and eIF4E phosphorylation, which was up-regulated in mice with LV hypertrophy when compared to sham-operated mice, was significantly attenuated. The critical component of these findings is that sirolimus treatment can positively affect chronically established cardiac hypertrophy and fibrosis. Shioi (Shioi, T., et al., Rapamycin Attenuates Load-Induced Cardiac Hypertrophy in Mice, Circulation, Vol. 107, pp. 1664-1670, 2003) also demonstrated that sirolimus acts as an anti-hypertrophic agent in a mouse model of aortic banding. Mice with aortic banding had induced LV hypertrophy with increased S6K1 activation and S6 phosphorylation in the heart resulting from the acute pressure overload. Sirolimus completely inhibited the basal activity and the load-induced increase in S6 phosphorylation. In addition, sirolimus suppressed load-induced increases in heart weight/tibial length by 67%, without affecting body weight, lung weight, or liver weight. Increases in myocyte size were also reduced by 57% with sirolimus. These data provide further evidence for the role of mTOR inhibition in decreasing chamber size in load-induced hypertrophy without compromising systolic function.
A study of rats with MI induced by left anterior descending coronary artery ligation also illustrates the anti-hypertrophic effects of mTOR inhibitors. Animals treated with everolimus experienced a significant reduction in LV end-diastolic diameter and a significant increase in EF, compared to untreated MI rats. In the everolimus-treated animals, myocyte size was also reduced by 33%.
Sirolimus has been implicated as an anti-hypertrophic agent in a study of 58 cardiac transplant patients who were switched from a calcineurin inhibitor (CNI) to sirolimus for anti-rejection therapy. These patients were compared to a control group that remained on the CNI anti-rejection therapy. Patients in the sirolimus arm experienced a significant decrease in LV mass. Systolic and diastolic blood pressure was also decreased in sirolimus patients, while no change was observed in CNI patients. In addition, left atrial volume index (LAVI), which was used as a surrogate for ventricular function, was significantly decreased in sirolimus patients. Of note, patients treated with CNIs saw a slight increase in LV mass with concomitant increase in LAVI. Myocardial biopsies performed in both patient groups showed that a protein induced by mTOR inhibition, p27Kip1, was increased in sirolimus patients and unchanged in CNI patients. These data in combination with the aforementioned animal data suggest that the sirolimus acts directly on the myocardium and has an anti-hypertrophic effect.
Sirolimus has also been implicated as an anti-fibrotic agent in a study of 29 patients maintained on a calcineurin inhibitor (CNI) for 3.8±3.4 years before switching to sirolimus for post-cardiac transplantation anti-rejection therapy. These patients were compared to a control group that remained on the CNI. Intravascular ultrasound was used to show that both mean plaque volume and plaque index were significantly increased in the control patients on CNI therapy, but remained the same in sirolimus patients. These data suggest that in addition to having anti-hypertrophic properties, mTOR inhibitors also have anti-fibrotic effects.
The aforementioned data support the premise that a coated cardiac harness used to deliver an mTOR inhibitor directly to the myocardium via local elution into the pericardial space will lead to a reduction in cardiac hypertrophy and fibrosis, thus benefiting HF patients.
Intra-pericardial delivery of pharmacologic agents offers a promising new technique for providing pharmacologic therapy to the cardiac tissues, while avoiding side effects often associated with systemic administration of efficacious doses. The pericardium provides a natural reservoir in which pharmacologic agents can be administered and distributed to the cardiac tissue while minimizing systemic distribution. Because the cardiac harness resides inside the pericardial space, it provides a vehicle upon which the pharmacologic agent can reside for controlled intra-pericardial delivery.
The drug-eluting cardiac harness platform, once established, can be modified to deliver any of a number of pharmacologic agents for the treatment of HF.
The current basic standard of care for systolic heart failure includes ACE inhibitors and β-blockers. The primary side effect of β-blockers is a lower heart rate. Local drug delivery from the pericardium would not be expected to alter this side effect. ACE inhibitors are very well tolerated and most recent trials show the use of this therapy in around 95% of patients. Many other treatments, including endothelin-receptor antagonists, antibodies against tumor necrosis factor a, and ARBs, have not been found to reduce mortality among patients with left ventricular dysfunction and heart failure who are being treated with this standard of care therapy.
All of these therapies have dose effects and all have systemic side effects. Many of these therapies may be more advantageously delivered via the intrapericardial space. To be effective, the therapeutic agent must provide benefits incremental to this standard of care background therapy.
However, aldosterone blockade reduces total mortality and hospitilization due to progressive heart failure and the rate of sudden death from cardiac causes, as well as the rate of hospitalizations for heart failure, among patients with severe heart failure due to systolic left ventricular dysfunction who are being treated with an ACE inhibitor. Aldosterone blockade also prevents ventricular remodeling and collagen formation in patients with left ventricular dysfunction after acute myocardial infarction and affects a number of pathophysiological mechanisms that are thought to be important in the prognosis of patients with acute myocardial infarction.
Furthermore, aldosterone blockade reduces coronary vascular inflammation and the risk of subsequent development of interstitial fibrosis in animal models of myocardial disease. Aldosterone blockade also reduces oxidative stress, improves endothelial dysfunction, attenuates platelet aggregation, decreases activation of matrix metalloproteinases, and improves ventricular remodeling.
The use of aldosterone blockades is primarily limited by its side effects, the most serious being hyperkalemia. A number of patients cannot tolerate being on the drug at all and for those patients prescribed the drug the dose is limited by the systemic side effects. In recent heart failure studies with strong background medicine for the patients, typically less than 40% of the patients use an aldosterone blockade drug.
In the Randomized Aldosterone Evaluation Study (RALES) study, the aldosterone blocker spironolactone significantly reduced the risk of both morbidity and death among the high-risk heart failure patients with a low incidence of serious hyperkalemia. This safety was attributed to previous efforts determining an effective and safe dose of the drug when used in conjunction with an ACE inhibitor. Spironolactone at a dose of 12.5 to 25 mg daily was effective in blocking the aldosterone receptors and decreasing atrial natriuretic peptide concentrations. Serious hyperkalemia occurs most frequently with daily doses of 50 mg or greater.
In a long-term French study of spironolactone use, the blood pressure decrease was greater with doses of 75 to 100 mg (12.4% and 12.2%) than with doses of 25 to 50 mg (5.3 and 8.5%), but no additional decrease was found with doses above 150 mg. The side-effect of gynecomastia, the development of abnormally large mammary glands in males resulting in breast enlargement, was found to be reversible and dose-related; at doses of 50 mg or less the incidence was 8.9%, but 52.2% for doses of 150 mg or higher.
One embodiment of the present invention is directed to a cardiac harness that is combined with beneficial medicaments, particularly aldosterone blockade, and a system for delivery of the medicament wherein the aldosterone blockade is controllably released to a patient's heart at a dose range of 0.1 to 200 mg per day. The combination of the present invention provides for a novel way to extend the efficacy of a cardiac harness and beneficial medicaments for use in the site-specific treatment of cardiac and non-cardiac maladies.
In one embodiment of the invention, as shown in
An FDA-approved polymer matrix that is a durable coating technology designed for the site-specific delivery of low-molecular weight drugs, such as mTOR inhibitors, has been identified for use with the cardiac harness. The polymer matrix is currently used in a number of implantable applications, including DES and ophthalmic applications. The matrix has a significant clinical history through its application on the first-to-market coronary DES (CYPHER™). It consists of a proprietary blend of poly-butyl methacrylate (PBMA) and polyethylene vinyl acetate (PEVA) polymers. By varying the ratios of the constituent polymers within the coating, both drug delivery rates and mechanical properties can be controlled. An mTOR inhibitor (with an established Drug Master File) with the PEVA/PMBA polymer coating is applied to the cardiac harness for controlled elution into the pericardial space.
For example, one such coating is the a polymer matrix Bravo™ from Surmodics (Eden Prairie, Minn.). It is a blend of poly-butyl methacrylate (PBMA) and polyethylene vinyl acetate (PEVA) with a tunable elution rate capable of maintaining an elution rate up to two years. Other possible coatings include, but are not limited to, ethyl vinyl alcohol and PLA. These coatings can determine the rate of delivery of the selected medicament, and provide a prolonged effect from the medicament. If the agent is soluble in silicone, the therapeutic drug target may be loaded directly into the harness tubing. In one embodiment, the cardiac harness 20 is coated with a dialectric material (e.g., silicone rubber) (see
Intrapericardial delivery for local cardiac therapy has been hampered by the difficulty in accessing the pericardial space and the lack of any usable long-term platforms or structures for use in delivery. Adding medically-beneficial medicaments to the cardiac harness is a novel way to overcome these limitations of systemic beneficial medicament use and of intrapericardial delivery.
The epicardial coronaries are exposed to the pericardial space. With stents and optimal medical therapy, there is still a 12% risk of acute coronary syndrome (ACS) within two years. Intrapericardial drug delivery for local cardiac therapy and pancoronary therapy may prevent the issue. Also, intrapericardial delivery may facilitate the treatment of vulnerable plaque throughout the coronary tree without necessarily having to identify the exact vulnerable plaque to be treated.
It has been shown that intrapericardially delivered agents cause measurable effects in the coronary circulation without systemic side effects. Different concentrations of various proteins between blood and pericardial fluid of different factors may help in regulation of coronary tone or even myocardial function, such as fibroblast growth factor-2 and atrial natriuretic factor. Patients with unstable angina have higher pericardial fluid concentrations of basic fibroblast growth factor as compared with patients undergoing surgery for non-coronary causes.
Another promising pharmacologic therapy for intra-pericardial delivery is a class of proteinases that target the ECM. Collagen degradation has been implicated as a cause of LV dilation. Generally, matrix metalloproteinases (MMPs) break down specific elements of the ECM, leading to dilated cardiomyopathy. A balance of MMPs and tissue inhibitors of MMPs (TIMPs) regulates the ECM; alterations in this balance have been documented in animal models of MI and pressure-overload hypertrophy, and in humans with pressure-overload hypertrophy. A broad-spectrum MMP inhibitor improved ECM composition and LV function, and a selective MMP inhibitor reduced LV dilation and increased EF in animal models of MI. However, “frozen-joint syndrome” was observed in 30% of patients treated systemically with a broad-spectrum MMP inhibitor, and plasma concentration of a selective-spectrum MMP inhibitor was likely too low to show significant results. As such, systemic administration of MMP inhibitors has not been shown as a viable therapeutic option for HF patients. Local delivery may be the only viable option for MMP inhibition as a HF treatment.
The drug-eluting cardiac harness can be readily adopted to incorporate the pharmacologic agents described above, as well as other peptides and pharmacologic agents for future study in the HF population. Alternatively, these agents can be used in conjunction with, or as an alternative to, mTOR inhibitors. In summary, the drug-eluting cardiac harness can be safely placed in the pericardial space of a HF patient using an established surgical procedure. It can be coated with a drug-eluting polymer for controlled intra-pericardial elution of a pharmacologic agent to directly target the cardiac tissue, and may represent an effective platform for targeted intra-pericardial delivery of a broad array of pharmacologic agents.
Paclitaxel delivered intrapericardially has been shown to have the ability to inhibit neointimal proliferation in the coronaries of pigs in response to balloon injury, suggesting that intrapericardially delivered drugs may be used to modulate the inflammatory response in coronaries. Intrapericardially delivered agents thus can prevent restenosis, decrease rethrombosis, unstable angina, myocardial infarction, stabilize vulnerable plaque, and reduce risk of sudden death without the systemic side effects.
In another embodiment shown in
A durable drug delivery coating may be applied over the existing harness. For example, one such coating is the a polymer matrix Bravo™ from Surmodics. It is a blend of poly-butyl methacrylate (PBMA) and polyethylene vinyl acetate (PEVA) with a tunable elution rate capable of maintaining an elution rate up to 2 years. Other possible coatings include but are not limited to ethyl vinyl alcohol and PLA. These coatings can determine the rate of delivery of the selected medicament, and provide a prolonged effect from the medicament. If the agent is soluble in silicone, the therapeutic drug target may be loaded directly into the harness tubing. The rate and extent of release of the therapeutic agent from the delivery source are controlled via the characteristics of the matrix or coating or reservoir as well as by the characteristics of the therapeutic agent.
U.S. Pat. No. 7,056,533 (Chudzik et al.), provides for a crosslinkable coating composition for use in delivering a medicament from the surface of a medical device positioned in a patient. Specifically, once crosslinked, the coating composition provides a gel matrix that is adapted to contain the medicament to be released from the matrix in a controlled manner. The Chudzik et al. patent is incorporated herein by reference thereto.
Many factors ultimately determine the dose rate and duration from the coating material: the size and shape, the material type and molecular weight of the matrix material; solubility, biodegradability, and/or hydrophilicity of the coating; permeability factors involving the therapeutic agent and the particular matrix material; degradation of the matrix; and the concentration and kinds of other additives. Porosity in the coating can impact the ease of movement of therapeutic agents from the coating into adjacent cardiac tissue. Coating composition and chemical structure of the therapeutic agent or agents can influence the nature of interaction between these materials.
Coatings such as polymeric matrix materials and hydrogels can be applied in any suitable fashion. Known methods are dipping, coating, spraying, or impregnating the coating onto the harness. These coatings may be applied to the entire harness or selectively to the silicone jacketing, grip pads, or electrode locations. The coatings can be elastic and capable of handling the cyclic loading conditions on the heart. The coatings can be designed such that they do not affect the elastic, chronic fatigue, and performance characteristics of the harness.
Other potential coating methods include the deposition of a tether molecule, such as a peptide, to provide a site on the surface of the harness for attachment of the selected therapeutic medicament. Nano materials, virus or bacteria vectors, hydrogels, stem cells, hydroxypropylchitosan acetate, collagen, biostable and/or biodegradable polymers may also be used as carriers for drug delivery. Such carriers may sense epicardial gene expression or chemistry and tailor therapy accordingly.
Another possible method to facilitate surface delivery of selected medicaments is to provide a structure on the surface of the harness into which appropriately sized spaces are provided for the deposition and subsequent release of medicaments. Such release can be initiated by chemical reactions with elements on the myocardical surface, by dissolution of the medicaments in fluids that occur naturally inside the pericardium, or by pressure introduced through the structure of the harness externally, among others. Since the cardiac harness can be designed and delivered to provide a target therapeutic pressure “dose,” the harness can also be used for pressure mediated drug elution. Biodegradable or non-biodegradable hydrogels swell such that an aqueous therapeutic agent solution can be effectively squeezed out of the coating when pressure is applied, especially when the pericardium is left intact and covers the harness, thereby applying a slight compressive force on the harness, and hence the coating.
The beneficial medicaments applied through the methods listed above or other delivery means may be coated with a biodegradable material and/or surface that is designed to deteriorate at a pre-determined rate, such that the medicament is released to the surface of the heart, from the harness, over a pre-defined time period.
Possible biodegradable coatings are polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, parylene, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazens, polyhydroxybutyrates, polyhdyroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, and copolymers, terpolymers, or combinations or mixtures of the above materials.
The mechanical energy of the heart during each cardiac cycle may also drive delivery. The micro-protruding self-anchoring features of the cardiac harness may be used for medicament delivery. These would effectively act as “microneedles” and inject the agents below the epicardial surface. Thus, as the heart beats during the cardiac cycle, the grip pads 27 (
In yet another embodiment, the material coating 37 such as a dielectric coating in the cardiac harness 20 is itself impregnated with aldosterone blockade. In this embodiment, over time the aldosterone blockade elutes directly from the impregnated dielectric material.
In another embodiment, as shown in
In yet another embodiment, as shown in
Alternatively, the implant 190 can contain cells for providing a therapeutic response. Cell populations can be attached to the harness by various means. Cells can be cultured directly onto the harness or developed into implant 190 and then attached to the undulations 103. The silicone rubber on the harness would act as a scaffold. The implanted cells may also serve as a platform for protein delivery at the surface of the heart (myocardial repair and enhance growth of the transplanted cells). They may be delivered via injection, via grip pads, or via exposure to the epicardial surface. Neurotrophic factors and/or angiogenic factors, such as vascular endothelial growth factor or fibroblast growth factor, can be locally expressed from these cells to avoid the potentially harmful effects of systemic delivery of these proteins.
The beneficial medicament may be one or more therapeutic genes. As used herein, the term “therapeutic gene” is a segment of nucleic acid that specifies a particular protein or polypeptide chain that, when expressed, provides a therapeutic effect. Many such therapeutic genes are known to prevent restenosis, promote angiogenesis, modulate pathways of electrical conductance to control cardiac arrhythmias, enhance the wound healing process, and/or express thrombolytic agents such as tissue plasminogen activator (TPA) or urokinase. They may be oligonucleotides, naked gene plasmids, ribozymes, or viral vectors containing specific genes. Possible delivery systems for these genes include: nanospheres, liposomes, microspheres, polymer matrices (biodegradable or non-biodegradable or a blend of the two), and naked nucleic acids. Therapeutic agents can be surface-acting or can penetrate the myocardium, coronary vessels, or surrounding tissue (e.g. small molecule compounds). When carriers are required to deliver the therapeutic agent, they may be designed to further reduce any undesirable side effects of the agent.
The beneficial medicament may also be one or more agents of cellular material. Cellular material can improve the function and structure of diseased tissue. The cellular material may be delivered via injection, via grip pads, or via exposure to the epicardial surface. Potential candidates for cellular material are: differentiated cells with different phenotypes (such as smooth muscle cells, endothelial cells, and fibroblasts); differentiated cells with the same phenotype (such as myocardial cells); non-differentiated cells, such as mesenchymal and other stem cells; cells that are xenogenic, allogenic and/or isogenic to the host; and genetically engineered cells.
Cellular material may be of a single tissue type or may contain a mixed population of cells. If desired, the culture media for the cells may also be delivered. This media may be supplemented as necessary with hormone and/or other growth factors, salts, buffers, nuclosides, antibiotics and trace elements (inorganic compounds usually present at final concentrations in the micromolar range).
Transdifferentiation may also be used as part of the therapy. Transdifferentiation involves the conversion of a committed, differentiated, or specialized cell to another differentiated cell type with a distinctly different phenotype. For myocytes, the cells can be made to contract synchronously.
Localized, targeted delivery of the beneficial medicament can avoid undesirable systemic effects by eliminating circulation of the drug in areas of the body other than the target tissue. Many existing heart failure medicaments have an improved effect on the heart at higher doses, but these doses are unusable due to the severity of the side effects (e.g. aldosterone antagonists and hyperkalemia). Lower amounts but potentially higher localized concentrations of the beneficial medicament can thus potentially be delivered without significant side effects.
Therapeutic agents can be added to the cardiac harness in a number of ways. The delivery dose can be based on time, a tethering molecule, or it may be based on “smart” signaling or sensing from the immediate environment or other systemic indicators. The release of an agent may be zero order, multi-phasic, or delayed. There may be an initial bolus dose of the therapeutic agent, followed by a relatively constant release of the agent over time.
Beneficial medicament delivery can be achieved through passive or active methods. Passive methods include diffusion from the delivery source. Active delivery mechanisms use an energy source to deliver the agent to the target tissue. Energy sources may be pumps or electrical current or osmosis. Other suitable external energy sources include ultrasound, thermal energy, radiofrequency, or microwave energy. The movement of the heart through each cardiac cycle can be used as an energy source (for bladder or coating or hydrogel delivery).
Durect Corporation has a number of potential reservoir-type delivery systems: the Duros osmotic pump, the SABER Depot Injection Technology, and the Durin Biodegradable Implants. The Durin product family allows high drug loading (up to 80%), is fully biodegradable (by hydrolysis), has a history of safe human use (lactide-glycolide co-polymers), will work with peptides, and allows for first order, zero order, delayed or biphasic drug release up to 6 months or more. The material used has been approved in over 30 medical devices and drug delivery systems.
All of the aforementioned methods would provide predictable release and delivery of beneficial medicament at the time of harness implantation and afterwards at an appropriate targeted dose and duration.
It may be desired to reduce the likelihood of the development of fibrotic tissue over the cardiac harness so that the elastic properties of the harness are not compromised. As fibrotic tissue increases, the right and left ventricular thresholds may increase, commonly referred to as “exit block.” When exit block is detected, the pacing therapy may have to be adjusted. Certain drugs such as steriods, have been found to inhibit cell growth leading to scar tissue or fibrotic tissue growth. Examples of therapeutic drugs or pharmacologic compounds that may be loaded onto the cardiac harness or into a polymeric coating on the harness, on a polymeric sleeve, on individual undulating strands on the harness, or infused through the lumens in the electrodes and delivered to the epicardial surface of the heart include steroids, taxol, aspirin, prostaglandins, and the like. Various therapeutic agents such as antithrombogenic or antiproliferative drugs are used to further control scar tissue formation. Examples of therapeutic agents or drugs that are suitable for use in accordance with the present invention include 17-beta estradiol, sirolimus, everolimus, actinomycin D (ActD), taxol, paclitaxel, or derivatives and analogs thereof. Examples of agents include other antiproliferative substances as well as antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, and antioxidant substances. Examples of antineoplastics include taxol (paclitaxel and docetaxel). Further examples of therapeutic drugs or agents include antiplatelets, anticoagulants, antifibrins, anti-inflammatories, antithrombins, and antiproliferatives. Examples of antiplatelets, anticoagulants, antifibrins, and antithrombins include, but are not limited to, sodium heparin, low molecular weight heparin, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogs, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist, recombinant hirudin, thrombin inhibitor (available from Biogen located in Cambridge, Mass.), and 7E-3B® (an antiplatelet drug from Centocor located in Malvern, Pa.). Examples of antimitotic agents include methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, adriamycin, and mutamycin. Examples of cytostatic or antiproliferative agents include angiopeptin (a somatostatin analog from Ibsen located in the United Kingdom), angiotensin converting enzyme inhibitors such as Captopril® (available from Squibb located in New York, N.Y.), Cilazapril® (available from Hoffman-LaRoche located in Basel, Switzerland), or Lisinopril® (available from Merck located in Whitehouse Station, N.J.); calcium channel blockers (such as Nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, Lovastatin® (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug from Merck), methotrexate, monoclonal antibodies (such as PDGF receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitor (available from GlaxoSmithKline located in United Kingdom), Seramin (a PDGF antagonist), serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. Other therapeutic drugs or agents which may be appropriate include alpha-interferon, genetically engineered epithelial cells, and dexamethasone.
Diazeniumdiolates, more commonly referred to as NONOates, have been extremely useful in the investigation of the biological effects of nitric oxide (NO) and related nitrogen oxides. The NONOate releases nitric oxide under physiological conditions and exhibits unique cardiovascular features that may have relevance for pharmacological treatment of heart failure.
The beneficial medicament may be delivered to one or more specific target areas on or around the heart, or the entire surface of the heart can be treated. An example of a potential specific target area is an ischemic zone with poor blood flow. A combination of therapeutic agents may be used independently or overlapping in target areas (e.g. simultaneous use of aldosterone antagonists and anti-arrhythmic drugs). After delivery to the target tissue, the therapeutic agent can penetrate the tissue surface and act below the surface of the tissue. The beneficial medicaments may be released only in the direction of the heart or they may be released more universally within the pericardial space.
Although the present invention has been described in terms of certain preferred embodiments, other embodiments that are apparent to those of ordinary skill in the art are also within the scope of the invention. Further, none of the above disclosures or embodiments should be limited to treatment of the heart. The device and method can be used to treat tissues surrounding the heart or other tissues of the body, as desired. Accordingly, the scope of the invention is intended to be defined only by reference to the appended claims. While the dimensions, types of materials and coatings described herein are intended to define the parameters of the invention, they are by no means limiting and are exemplary embodiments.
This application claims priority from U.S. Provisional Application No. 61/121,800, filed Dec. 11, 2008 and U.S. Provisional Application No. 61/181,531, filed May 27, 2009, each incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 61121800 | Dec 2008 | US | |
| 61181531 | May 2009 | US |
