Diastolic coronary perfusion detection for timed delivery of therapeutic and/or diagnostic agents

During diastolic coronary perfusion, blood perfuses through the heart via the coronary arteries. Delivery of a therapeutic and/or diagnostic agent to the heart during diastolic coronary perfusion allows the therapeutic and/or diagnostic agent to efficiently perfuse through the heart. A medical device according to the invention detects closure of the aortic valve of a heart, and initiates delivery of a therapeutic and/or diagnostic agent upon detection of aortic valve closure. The medical device detects aortic valve closure by processing a signal. Exemplary signals used by the medical device to detect aortic valve closure include left or right ventricular accelerometer signals, left or right ventricular flow signals, left or right ventricular pressure signals, aortic pressure signals, pulse pressure signals, systemic arterial pressure signals, electrogram signals, and phonocardiogram signals

TECHNICAL FIELD

The invention relates to medical devices, and more particularly, to medical devices that deliver therapeutic and/or diagnostic agents to a heart.

BACKGROUND OF THE INVENTION

Various conditions that afflict the heart are treated through delivery of one or more therapeutic and/or diagnostic agents. A variety of techniques involving delivery of biological, genetic, and/or pharmacological therapeutic and/or diagnostic agents to the heart are known for treating conditions such as myocardial infarction (MI), blood clots within the coronary arteries, cardiac arrhythmias, coronary artery disease (CAD), heart failure (HF), or the like. For example, myoblasts, myocytes or stem cells may be delivered to the heart as a therapeutic and/or diagnostic agent to treat an Ml (i.e., the death of muscle cells within the heart). As another example, anticoagulants such as warfarin or heparin, or enzymes such as Tissue type plasminogen activator (t-PA), Streptokinase or Urokinase are delivered to the heart to deter or dissolve blood clots within the coronary arteries.

Therapeutic and/or diagnostic agents are delivered into, for example, a chamber of the heart, blood vessels near the heart, such as the aorta, or the pericardial sac of the heart. Typically, therapeutic and/or diagnostic agents are delivered to the heart in the form of a bolus using an infusion apparatus, such as a pump or syringe, coupled to a catheter, and/or a hollow needle. However, it is generally understood that a small percentage (<10%) of a therapeutic and/or diagnostic agent delivered as a bolus actually “perfuses” (e.g., enters the coronary vasculature) of the heart, with the remaining therapeutic and/or diagnostic agent escaping to the systemic circulation.

Consequently, a bolus must include substantially more than a therapeutically effective amount of the therapeutic and/or diagnostic agent, increasing the cost of the treatment, among other disadvantages. Where an implantable drug pump is used to deliver a therapeutic and/or diagnostic agent to the heart, the requirement of excess therapeutic and/or diagnostic agent impacts the size and/or the refilling schedule of a reservoir of a drug pump. Further, the portion of the delivered therapeutic and/or diagnostic agent lost to the systemic circulation may have unintended and potentially undesirable effects on systemic and peripheral tissues of the patient to whose heart the therapeutic and/or diagnostic agent is intended to be delivered.

SUMMARY OF THE INVENTION

In general, the invention is directed to techniques for delivering a therapeutic and/or diagnostic agent to a heart during diastolic coronary perfusion. A medical device detects closure of an aortic valve of the heart, and initiates delivery of the therapeutic and/or diagnostic agent upon detection of the closure of the aortic valve. Because the therapeutic and/or diagnostic agent is delivered timed to the incidence of coronary perfusion, a controlled relative amount of the therapeutic and/or diagnostic agent is allowed to enter the coronary vasculature of the heart, versus being lost to the systemic circulation, such as when delivered using conventional therapeutic and/or diagnostic agent delivery techniques.

Diastolic coronary perfusion occurs upon and for a period of time after the closing of the aortic valve. The aortic valve closes when the pressure in the aorta exceeds the pressure in the left ventricle. After the aortic valve closes the pressure in the aorta increases slightly in response to the closing of the valve. This small increase in pressure forces blood from the aorta into the coronary arteries through the coronary sinus of the heart.

A medical device to deliver a therapeutic and/or diagnostic agent during coronary perfusion includes a sensor to monitor activity within the heart and a processor. The sensor generates a signal that reflects the events of left cardiac or ventricular activity, and the processor processes the signal to detect closure of the aortic valve. The processor controls a pump, which in exemplary embodiments forms a part of the medical device, to deliver the therapeutic and/or diagnostic agent to the heart via a catheter, or the like, at a duration or interval, including simultaneously, timed to aortic valve closure. In exemplary embodiments, the medical device and drug pump are implanted within the patient, and a distal end of the catheter is fluidly coupled to the aorta to deliver the therapeutic and/or diagnostic agent into the aorta and thus, the heart.

In one embodiment, the invention is directed to a method comprising receiving a signal that reflects activity of a heart, processing the signal to detect closure of an aortic valve of the heart, and initiating delivery of a therapeutic and/or diagnostic agent to the heart upon detection of closure of the aortic valve.

In another embodiment, the invention is directed to a medical device comprising a pump to deliver a therapeutic and/or diagnostic agent to a heart via a catheter and a processor. The processor receives a signal that reflects activity of the heart, processes the signal to detect closure of an aortic valve of the heart, and controls the drug pump to deliver the therapeutic and/or diagnostic agent to the heart upon detection of closure of the aortic valve.

In another embodiment, the invention is directed to a system comprising of a catheter, a pump to deliver a therapeutic and/or diagnostic agent to a heart via the catheter, a sensor to generate a signal that reflects activity of the heart, and a processor to receive the signal. The processor processes the signal to detect closure of an aortic valve of the heart, and controls the pump to deliver the therapeutic and/or diagnostic agent to the heart upon detection of closure of the aortic valve.

In another embodiment, the invention is directed to a computer-readable medium containing instructions. The instructions cause a programmable processor to receive a signal that reflects activity of a heart, process the signal to detect closure of an aortic valve of the heart, and control a pump to deliver a therapeutic and/or diagnostic agent to the heart upon detection of closure of the aortic valve.

In another embodiment, the invention is directed to a system comprising means for detecting activity within a heart and generating a signal as a function of the activity, means for delivering a therapeutic and/or diagnostic agent to the heart, and means for processing the signal to detect closure of an aortic valve of the heart and controlling the delivery means to deliver the therapeutic and/or diagnostic agent upon detection of closure of the aortic valve.

By example, and without limitation, a diagnostic agent may include a bolus, droplet(s) or stream of a contrast media used in conjunction with a machine vision system such as a fluoroscope and the like, or a dye or other fluid that adheres to or is metabolized to a perceptible state in the presence of one or more tissue, metabolic or fluid flow irregularities. In the event that a contrast media is dispensed a delivery catheter may be utilized that having manually-timed contrast media delivery or an external contrast media pump synchronized to the cardiac cycle via telemetry, wired connection, or the like.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1is a conceptual diagram illustrating an exemplary therapeutic and/or diagnostic agent delivery device10that delivers a therapeutic and/or diagnostic agent to a heart12according to the invention. In exemplary embodiments, as shown inFIG. 1, device10is implanted within a patient (not shown). However, in some embodiments, therapeutic and/or diagnostic agent delivery device10, or components thereof, reside(s) outside of the body of the patient.

Therapy delivery device10includes an infusion apparatus14, e.g., a catheter that provides a conduit for delivery of a therapeutic and/or diagnostic agent, e.g., one or more biological therapeutic and/or diagnostic agents, genetic therapeutic and/or diagnostic agents, and/or pharmaceutical therapeutic and/or diagnostic agents, to a heart12. In the illustrated embodiment, a distal end16of infusion apparatus14is positioned within, and/or fluidly coupled to a vessel, or port formed in a vessel, such as a portion of the aorta24of heart12, and device10dispenses a precisely timed bolus or dose of at least one therapeutic or diagnostic agent to aorta24. In such embodiments, a physician manipulates infusion apparatus14into fluid communication with an artery, such as the jugular or femoral arteries, and guides distal end16to the aorta. In other embodiments, distal end16is implanted into the coronary sinus18of heart12via the great vein or branches thereof. In some embodiments, distal end16includes a needle, which can be retractable, to facilitate pericardial therapeutic and/or diagnostic agent delivery.

Therapeutic and/or diagnostic agent delivery device10includes a sensor22to detect closure of an aortic valve26of heart12, and delivers one or more therapeutic and/or diagnostic agents via infusion apparatus14upon detection of the closure. Sensor22generates a signal as a function of the activity of heart16, e.g., the mechanical contractions and/or electrical depolarizations of heart16. In various embodiments, sensor22takes the form of a microphone, a flow sensor, an accelerometer, a pressure sensor, an oximeter, or the like. Device10processes the signal generated by sensor22to detect closure of aortic valve26.

In the illustrated embodiment, sensor22is carried on a lead20and positioned within coronary sinus18along a left ventricular free wall of heart12. In exemplary embodiments where sensor22is positioned as illustrated, sensor takes the form of an accelerometer that senses motion of and vibration within the free wall of the left ventricle. In this regard, co-pending non-provisional U.S. patent application Ser. No. 10/377,207 filed on 28 Feb. 2003, invented by Edward Chinchoy and entitled, “METHOD AND APPARATUS FOR OPTIMIZING CARDIAC RESYNCHRONIZATION THERAPY BASED ON LEFT VENTRICULAR ACCELERATION” is hereby incorporated by reference herein. In some embodiments, sensor22takes the form of an accelerometer positioned within a right ventricle, atria or is mechanically coupled to a portion of septal wall tissue of a heart. In this regard, co-pending non-provisional U.S. patent application Ser. No. 10/xxx,xxx filed on 30 Jul. 2003, invented by Robert Nehls and Todd Sheldon and entitled, “METHOD OF OPTIMIZING CARDIAC RESYNCHRONIZATION THERAPY USING SENSOR SIGNALS OF SEPTAL WALL MOTION” is hereby also incorporated by reference herein. Suitable accelerometers for the practice of the invention include piezoceramic accelerometers, among many others known and/or used in the cardiac pacing arts.

The invention is not however limited to embodiments where sensor22takes the form of an accelerometer. For example, in some embodiments, sensor22comprises a pressure sensor implanted in the aortic arch to measure the aortic pressure, the left ventricle to measure left ventricular pressure, pulse pressure, the right ventricle to measure right ventricular pressure, or the systemic arteries to measure arterial pressure. In other embodiments, sensor22takes the form of a similarly positioned flow sensor or oximeter. In some embodiments, a pressure, flow, or oximetery sensor22is implanted in the left ventricle by accessing the right ventricle and puncturing the intraventricular septum of heart12.

In some embodiments, sensor22takes the form of a vibration sensor, e.g. a microphone, that generates a signal that includes vibration associated with the closure of aortic valve26. Such a sensor22can be implanted anywhere within a body of a patient, or positioned on the surface of the patient. In exemplary embodiments, such a sensor22is not carried on a lead, but is included within a housing of device10.

The invention is not limited to the above-identified sensors. Further, the invention is not limited to embodiments where device10includes a single sensor22. Rather, in some embodiments, IMD10uses two or more sensors22or types of sensors22to detect closure of aortic valve26.

FIG. 2is a block diagram further illustrating device10ofFIG. 1. As illustrated inFIG. 2, therapeutic and/or diagnostic agent delivery device10includes processor40that communicates with pump42and monitor module44. Processor40takes the form of one or more of a microprocessor, digital signal processor, application specific integrated circuit, field-programmable gate array, and other logic circuitry programmed to provide the functionality ascribed to processor40herein. In some embodiments, device10includes a memory that stores program instructions. The program instructions control processor40to provide the functions ascribed to it herein.

Pump42typically includes fill port46to facilitate filling and re-filling of reservoir48. Reservoir48holds a therapeutic and/or diagnostic agent or a mixture of therapeutic and/or diagnostic agents. In some embodiments, a therapeutic and/or diagnostic agent delivery device10includes one or more pumps42to deliver a therapy agent or a mixture of therapy agents stored in one or more reservoirs48to a heart via one or more infusion apparatuses14. However, for ease of illustration, therapy agent delivery device10, as shown inFIG. 2, includes one of each.

Processor40controls pump42to create. a pressure gradient, thereby forcing the therapeutic and/or diagnostic agent stored in reservoir48along infusion apparatus14. In some embodiments, a distal end of infusion apparatus14is implanted near heart12(FIG. 1). In exemplary embodiments, infusion apparatus14is implanted in the aortic arch, as shown inFIG. 1. Another exemplary implant location, as described above, includes any location fluidly coupled to coronary sinus18.

As discussed above, in exemplary embodiments the signal generated by sensor22includes one of a left or right ventricular accelerometer signal, a left or right ventricular flow signal, an aortic pressure signal, a left or right ventricular pressure signal, a systemic arterial pressure signal, an electrogram signal and a phonocardiogram signal. Upon receiving such a signal, monitor module44analyzes the signal to detect closure of the aortic valve. In some embodiments, monitor module44applies analog analysis, such as envelope detection, and monitor module44includes analog filters, sense threshold circuits and the like to identify the closure of aortic valve26. In some embodiments monitor module44applies digital signal analysis techniques, such as wavelet analysis and/or Fourier transforms, to the signal to identify the closure of aortic valve26.

In digital signal analysis embodiments of device10, monitor module44converts the signal from an analog signal into a digital signal. In some embodiments, monitor module44does not process the digital signal, but instead provides the digital signal to processor40for digital signal analysis and detection of closure of aortic valve26.

FIG. 3is a timing diagram illustrating exemplary signals62and64processed by device10ofFIG. 1to detect closure of aortic valve26of heart16.FIG. 3depicts signals62and64over a single cardiac cycle. Region66indicates a period of time during which aortic valve26closes when onset of diastolic coronary perfusion occurs. A therapeutic and/or diagnostic agent delivery device10detects the aortic valve closure by identifying one or more morphological characteristics of signals62,64.

Monitor module44receives signals62and64from sensors22. In the illustrated example, signal62is an aortic pressure signal generated by a pressure sensor22as a function of the aortic pressure. Further, signal64is an accelerometer signal generated by an accelerometer sensor22as a function of the motion of the left ventricular wall. In some embodiments, the monitor module converts signals62,64from analog signals to digital signals and delivers the digital signals to processor40for monitoring. In other embodiments, monitor module processes the signal to detect aortic valve closure using analog or digital signal processing techniques as discussed above.

As illustrated inFIG. 3, aortic pressure signal62comprises fairly constant amplitude for the first half of the cardiac cycle. During this time the heart is in diastole and the aortic valve is closed. Once the heart enters systole the aortic valve opens and blood from the left ventricle is pumped into the aorta increasing the amplitude of aortic pressure signal62. When the aortic valve closes again and a local minimum occurs within region66. This local minimum is known as the dicrotic notch and further indicates diastolic coronary perfusion. Processor40or monitor module44detects this local minimum to detect closure of the aortic value using digital, e.g., Fourier or wavelet, analysis.

Left ventricular accelerometer signal64measures the motion of the outer wall of the left ventricle. In some embodiments, a left ventricular accelerometer sensor22is implanted via the coronary sinus, as illustrated inFIG. 1, near the left ventricular free wall to facilitate measuring this motion. As the cardiac cycle begins small disturbances are noted that correspond to ventricular filling. As ventricles contract the absolute amplitude of signal64increases. At region66, where closure of aortic valve26occurs, the absolute amplitude of signal64again increases. Processor40or monitor module44detects this second amplitude increase using, for example, Fourier or wavelet analysis, or analog envelope detection circuitry, and the like.

In some embodiments where monitor module44or processor40applies digital signal analysis to identify morphological characteristics of signals62and/or64associated with aortic valve closure, module44or processor40compares the signal to a template that includes, for example, local minimums, maximum slopes, minimum slopes, local maximums, or some other fiducial point. Device10can further tailor templates using learning algorithms to fit specific patient data, thereby improving accuracy.

In some embodiments, the pump42delivers the therapeutic and/or diagnostic agent for a set period of time. The set period of time pertains to heartbeats and various embodiments deliver the therapeutic and/or diagnostic agent in various modes. Exemplary modes include continuous delivery, i.e., delivery every heartbeat and delivery every nth beat. For example, n can equal 5 and thus delivery occurs every 5thheart beat. Other exemplary modes enable delivery of the drug based on physiological parameters. For example, a patient with a weak heart requires epinephrine to strengthen cardiac performance. Thus, pump42delivers epinephrine based on measures of the strength of the heart. Further embodiments can incorporate modes of delivery where the therapeutic and/or diagnostic agent is delivered according to a schedule stored in a memory.

FIG. 4is a flowchart illustrating an exemplary method employed by medical device10ofFIG. 1to deliver a therapeutic and/or diagnostic agent to the heart. Monitor module44receives a left ventricular accelerometer signal from sensor22(80), which resembles signal64ofFIG. 3. Monitor module44analyzes the signal to detect closure of aortic valve26(82).

In exemplary embodiments described above, monitor module44applies analog analysis to detect the closure of aortic valve26. For example, monitor module44can apply envelope detection to the signal to detect closure of aortic valve26. If monitor module44does not detect closure of the aortic valve then monitor module44continues to receive and analyze the signal (44).

In the event that monitor module44detects the closure of aortic valve26, module44provides an indication to processor40, which controls pump42to initiate delivery of a therapeutic and/or diagnostic agent from reservoir48to the heart (86). Delivery of the therapeutic and/or diagnostic agent during diastolic coronary perfusion post aortic valve closure can allow for a controlled relative amount of therapeutic and/or diagnostic agent to perfuse the heart.

Device10delivers one or more therapeutic and/or diagnostic agents or mixtures of therapeutic and/or diagnostic agents in accordance with the inventions. In particular, device10delivers any one or combination of genetic agents, biological agents and pharmaceutical agents to provide specific therapies to a patient. For example, in some embodiments, device10delivers pharmaceutical agents, such as epinephrine and digitalis, to enhance cardiac performance. Other pharmaceutical agents such as t-PC can be delivered to dissolve blood clots in heart12. Device10can further deliver genetic agents to provide therapy for ischemia. For example, device10can deliver stem cells to replace dying heart cells.

FIG. 5is a conceptual diagram illustrating another exemplary medical device90that delivers a therapeutic and/or diagnostic agent to a heart according to the invention. Therapeutic and/or diagnostic agent delivery device90, as shown inFIG. 5, delivers a therapeutic and/or diagnostic agent to heart92via infusion apparatus94, e.g. a catheter. Furthermore, therapeutic and/or diagnostic agent delivery device90receives a signal from sensor96via filaments included within lead98. Based on this signal, therapeutic and/or diagnostic agent delivery device90delivers the therapeutic and/or diagnostic agent.

In particular,FIG. 5illustrates alternative locations for a sensor96and distal end100of infusion apparatus94that are employed according to some embodiments of the invention. Infusion apparatus94, as shown inFIG. 5, is implanted into the coronary sinus of heart92. Sensor96is inserted into the right ventricle of heart92. These exemplary implant locations can be selected due to the ease of positioning lead98and infusion apparatus94in these positions relative to the positions of lead20and infusion apparatus14illustrated inFIG. 1.

Infusion apparatus94delivers a therapeutic and/or diagnostic agent to the coronary arteries, similar to infusion apparatus14. However, apparatus94access the coronary arteries via the right atrium of heart92. Nonetheless, therapeutic and/or diagnostic agents delivered by device90via infusion apparatus94perfuse heart92.

Sensor96generates a signal as a function of the acoustics or mechanical motion within the right ventricle of heart92. Other acoustic locations where sensor96can monitor heart92include the housing of device90, the skin surface of patient proximate to heart92, and the like. Placement of sensor96, e.g., a microphone, pressure transducer, or accelerometer in either the right or left ventricle provides sensor96proximity to heart92to facilitate sensing of the noise and/or motion associated with the closure of the aortic valve. Thus this position is viable to monitor heart activity and more particularly the closure of the aortic valve (not shown) of the heart92.

FIG. 6is a diagram illustrating another exemplary medical device110that delivers a therapeutic and/or diagnostic agent to a heart112according to the invention. Therapeutic and/or diagnostic agent delivery device110, as shown inFIG. 6, delivers a therapeutic and/or diagnostic agent to heart112via infusion apparatus114, which is shown as a catheter. Furthermore, therapeutic and/or diagnostic agent delivery device110receives a signal from sensor116via filaments included within lead118. Similar to therapy agent delivery device90, therapy agent delivery device110delivers the therapeutic and/or diagnostic agent based on the signal.

In particular,FIG. 6illustrates a further alternative location for distal end120of infusion apparatus114that is employed according to some embodiments of the invention. Infusion apparatus114, as shown inFIG. 6, is implanted into left ventricle122by puncturing a portion of ventricular septal wall tissue or a portion of the apex124of heart112. Other exemplary implant procedures exist to implant distal end120into left ventricle122. For example, distal end120can be implanted into right ventricle126via the right atrium of heart112. Once in the right ventricle, distal end120of infusion apparatus114is inserted into left ventricle122via a puncture in the septum between right ventricle126and left ventricle122. A further example of implanting distal end120into left ventricle122includes inserting distal end120into the right atrium of heart112. Distal end120is then inserted into the left atrium of heart112via a puncture in the septum between the right and left atrium. From the left atrium, distal end120of infusion apparatus114is implanted in left ventricle122.

In some embodiments, distal end120of infusion apparatus114, after being inserted into left ventricle122, is fed through the aortic valve into the aorta of heart112. In these embodiments, wherein distal end120is implanted into the aorta via left ventricle122, infusion apparatus114delivers a therapeutic and/or diagnostic agent similar to infusion apparatus14. However, the implant locations differ in that infusion apparatus14is implanted via the femoral or jugular arteries, as described above. Nevertheless, therapeutic and/or diagnostic agents delivered by device110via infusion apparatus114perfuse heart112. In embodiments where a therapeutic and/or diagnostic agent is delivered to left ventricle122, a smaller percentage of the delivered therapeutic and/or diagnostic agent may perfuse heart112than is possible with direct aortic delivery.

Sensor116generates a signal similar to that of sensor96. The signal represents acoustics or mechanical motion, or both acoustics and mechanical motion of heart112. Similar to sensor96, locations of sensor116include the housing of device110, on the skin of the patient proximal to heart112, within heart112, as shown byFIG. 6, and the like. Placement of sensor116, which includes similar sensor types as sensor96listed above, in either the right or left ventricle provides sensor116proximity to heart112to facilitate detection of the closure of the aortic valve.

The invention as described above provides for the efficient delivery of a therapeutic and/or diagnostic agent to a heart. In particular, a therapeutic and/or diagnostic agent delivery device in accordance with the invention may delivery a therapeutic and/or diagnostic agent such that a majority of the therapeutic and/or diagnostic agent perfuses the heart. Moreover, the therapeutic and/or diagnostic agent delivery device may ensure this by detecting the closure of the aortic valve and delivering the therapeutic and/or diagnostic agent during diastolic coronary perfusion. A number of embodiments are described above that illustrate therapeutic and/or diagnostic agent delivery devices in accordance with these techniques.

Various embodiments of the invention have been described. However, one skilled in the art will appreciate that various medications can be made to these embodiments without departing from the scope of the invention. For example, although described herein in the context of a single device, a device according to the invention can include components, e.g., a pump, a processor, and/or a sensor; one or more of which may be disposed external to the body. In some embodiments, a catheter and/or lead percutaneously access a position within a patient. For example, in some embodiments and external device according to the invention could be used to perfuse the heart with a therapeutic and/or diagnostic agent during a stay in a hospital. Finally, all forms of therapeutic and/or diagnostic agents are intended to benefit from the teaching of the present invention, including without limitation such agents when rendered at an appropriate viscosity or when diluted in a fluid medium, and the like. These and other embodiments are within the scope of the following claims.