Patent Description:
Hypertension is the angle largest contributor to cardiovascular death. It dramatically increases risk of heart attack, stroke, heart failure, and kidney failure. The annual direct costs of hypertension are estimated at $<NUM> billion worldwide. Almost <NUM> percent of patients are completely non-adherent to oral medications while nearly half are partially non-adherent, highlighting the need for alternative treatment options.

Hypertension causes increased systemic vascular resistance (SVR) and vice versa. SVR is calculated by subtracting the right atrial pressure (RAP) or central venous pressure (CVP) from the mean arterial pressure (MAP), divided by the cardiac output and multiplied by <NUM>. Normal SVR is <NUM> to <NUM>. RAP can be measured by a pacemaker with the appropriate sensor. Non-invasive and invasive measurements of cardiac output exist.

The end result of long-standing drug resistant hypertension (DRH) is diastolic congestive heart failure (DCHF) or heart failure with preserved ejection traction (HFpEF), which is defined as the amount of Blood pumped put with each heart beat expressed as a percentage. DCHF most commonly results from left ventricular thickening (hypertrophy) and stiffness (diastolic dysfunction) caused by sub-optimally treated or drug resistant hypertension. Six million patients in the US, and twenty-three million patients, worldwide suffer from congestive heart failure. Forty percent of those patients have DCHF which is the eighth most common reason for hospital admission and represents <NUM>% of total healthcare costs in the US and Europe. The total cost of such care in the US in <NUM> was $<NUM> billion, and it is projected to exceed $<NUM> billion by <NUM>. Resistant hypertension is defined as blood pressure (hat remains above goal (American Heart Association Guidelines or other accepted criteria appropriate by virtue of demographics and geography) despite concurrent use of three antihypertensive agents of different classes, one of which should be a diuretic. Patients whose blood pressure is controlled with four or more medications are also considered to have resistant hypertension. Patients with resistant hypertension are at high risk for adverse cardiovascular events (the development of heart failure, myocardial infarction, arrhythmia, stroke, death or renal failure) and are more likely than those with controlled hypertension to have a secondary cause, which is usually at least in part reversible.

Two prior attempts to treat drug resistant hypentension (DRH) using devices have failed. Medtronics Inc. announced the results of its SPYRAL HTN trial in <NUM>, a head-to-head evaluation of invasive Renal Denervation in <NUM> patients. Renal denervation was not effective in the treatment of DRH and the technology is no longer in use. Carotid sinus electrical stimulation sponsored by the US pharmaceutical company CVRx (BAROS TIM NEO), another invasive method targeting the sympathetic nervous system, was also ineffective (<NUM>) and is no longer in use. Moreover, neither technology showed any promise for the treatment of DCHF.

Bradycardia is defined as a condition wherein an individual has a slow heart rate. typically defined as a heart rate of under <NUM> beats per minute (BPM) in adults. Bradycardia typically does not cause symptoms until the rate drops below <NUM> BPM. When symptomatic, it may cause fatigue, weakness, dizziness, swcating, and at very low rates, fainting. During sleep, a slow heartbeat with rates between <NUM>-<NUM> BPM is common, and is considered normal. Highly trained athletes may also have athletic hean syndrome, a very slow resting heart rate that occurs as a sport adaptation and helps prevent tachycardia during training. The term relative bradycardia is used in explaining a heart rate that, although not actually below <NUM> BPM, is still considered too slow for the individual's current medical condition or causes symptoms such as weakness, dizziness, or fainting.

Sinus node dysfunction refers to the condition in which a patient experiences an abnormality in the heartbeat or experiences arrhythmias (irregular heart beats) due to a malfunction of the sino atrial node or the sinus node. The sinus node is where the electrical pulse, which initiates the pumping action of the heart, originates. The earliest known version of the condition was known as "sick sinus syndrome" and today it refers to the abnormalities arising in the formation of the pulse in the sinus node and its propagation, namely conditions like sinus bradycardia, sinus pause, chronotropic incompetence and sinoatrial exit block. Sinus node dysfunction is a disease primarily associated with the elderly. It is mainly caused by the organic process of aging of the sinus node, but can also be the result of heart attack, inflammation, other forms of tissue loss or drugs.

Chronotropic incomperance (CI). which is one of the forms of sinus node dysfunction. is broadly defined as the inability of the heart to increase its rate commensurate with increased activity or demand, is common in patients with cardiovascular disease, produces exercise intolerance which impairs quality-of-life, and is an independent predictor of major adverse cardiovascular events and overall mortality. Chronotropic incompetence (CI) is most commonly diagnosed when the heart rate (HR) fails to reach an arbitrary percentage, typically <NUM>%, <NUM>%, or less commonly, <NUM>% depending upon the guidelines in use, of the age-predicted maximum heart rate (APMHR), which is usually based on the simple equation. <NUM> - age in years, obtained during an incremental dynamic exercise test. Cl is usually diagnosed during maximal exercise, most commonly assessed during a graded treadmill exercise test. CI can also be determined by the HR reserve, which is the change in HR from rest to peak exercise during an exercise test.

Relative bradycardia is herein defined as a persistent heart rate less than <NUM> beats per minute and greater than <NUM> beats per minute.

An atrial pacemaker (AP) is an apparatus that sends electrical impulses to the right or left atrium of the heart when intact atrio-ventriuclar (AV) node conduction is present in order to set the heart rhythm.

A dual chamber pacemaker (DCP) is an apparatus that sends electrical impulses to either the right or left atrium, or to the right ventricle of the heart in the presence of intact or abnormally reduced AV nodal conduction in order to set the rhythm of the heart.

An automatic implanted cardiac defibrillator (AICD) is an apparatus which is capable of shocking the heart after the detection of certain arrhythmias that is not designed to pace the cardiac atrium producing normally activated cardiac contraction.

A combined-pacemaker/AICD is an implantable cardiac device that combines the features of an AICD with a dual chamber pacemaker. This permits both standard atrio-ventricular synchronized pacing for sinus node dysfunction and the detection and reversion by defibrillation of serious cardiac arrhythmias.

A CRT bi-ventricular pacemaker is a traditional pacemaker used to treat slow heart rhythms. Pacemakers regulate the right atrium and right ventricle to maintain a good heart rate and keep the atrium and ventricle working together. This is called AV synchrony. Biventricular pacemakers add a third lead to help the left ventricle contract. RV pacing alters the normal synchrony of the heart which begins in the LV, not the RV, thus reversing normal or physiologic heart function. LV pacing can restore normal synchrony. If a patient with SHF has very slow intraventricular conduction, RV pacing further aggravates this and can worsen or precipitate heart failure. (Pacing via an LV lead restores normal activation. Ventricular sequence pacing is programmable in most modem devices. Heart failure with reduced ejection fraction (HFrEF), also called systolic failure (SHF) is where the left ventricle loses its ability to contract normally. The heart can't pump with enough force to push enough blood into circulation. The heart can't properly fill with blood during the resting period between each heat.

A CRT-D bi-ventricular pacemaker with AICD is a bi-ventricular pacemaker combined with an AICD.

Conventional guidelines for a pacemaker implant are generally based on symptoms, the presence of heart disease and the presence of symptomatic bradyarrhythmias. Pacemakers for tachyarrhythmias, cardioversion and defibrillation are also available. For example, the American Heart Association Guidelines used in the U. S divide indications for permanent pacing in sinus node dysfunction into two classes. Class <NUM> is defined as:.

Systolic heart failure heart failure is defind as severely reduced LV function, usually left ventricular ejection fraction (LVEF) < <NUM>%. This is the so-called forward heart failure, or severely impaired LV contraction.

Diastolic heart failure or clinical heart failure in the presence of a normal LVEF or HFpEF associated with impaired LV relaxation is also called reverse heart failure, or heart failure with a normal ejection fraction.

Combined heart failure is defined as the presence of both systolic and diastolic heart failure in the same patient.

In a <NUM>-country study conducted by the World Society of Arrhythmias, there were a total of <NUM>,<NUM>,<NUM> pacemakers counted. The United States has the largest number of patients with internal cardiac pacemakers, totaling <NUM>,<NUM>. In <NUM>, the National High Blood Pressure Education Program (NHBPEP) estimated <NUM> million adults had hypertension in United States. [<NUM>] Hypertension was defined as systolic blood pressure (SBP) equal to or greater than <NUM> Hg and diastolic BP (DBP) as equal or more than <NUM> Hg or defined as those taking medication for hypertension. The number of patients estimated to have severe hypenension defined as a systolic blood pressure equal to or greater than <NUM> and a diastolic BP equal to or greater than <NUM> is estimated at <NUM> million adults. The incidence of sino-atrial node dysfunction in the US severe enough to warrant a pacemaker in adults age <NUM> or older is <NUM> per <NUM>.

The Providence cohort had <NUM>,<NUM> patients, and <NUM> had pacemakers or <NUM> %. By extrapolation of the data, if patients in the Providence cohort with DRH and Sick Sinus Syndrome, the latter not necessarily severe enough to warrant a pacemaker had received a pacemaker implant to treat DRH as the primary indication, the number of pacemakers would have increased to <NUM>%. This would significantly increase the market for pacemakers worldwide. <CIT> discloses a method that electrically stimulates a heart muscle to alter the ejection profile of the heart, to control the mechanical function of the heart and reduce the observed blood pressure of the patient. The therapy may be invoked by an implantable blood pressure sensor associated with a pacemaker like device. In some cases, where a measured pretreatment blood pressure exceeds a treatment threshold, a patient's heart may be stimulated with an electrical stimulus timed relative to the patients cardiac ejection cycle. This is done to cause dyssynchrony between at least two cardiac chambers or within a cardiac chamber, which alters the patients cardiac ejection profile from a pretreatment cardiac ejection profile. This has the effect of reducing the patients blood pressure from the measured pretreatment blood pressure. <CIT> discloses a method for sensing a pulmonary artery pressure (PAP) and providing a sensed PAP signal, detecting an abnormal blood pressure (BP) condition using information from the sensed PAP signal, delivering a pacing energy to a heart, and automatically altering at least one pacing characteristic in response to the detected abnormal BP condition. The detecting an abnormal BP condition can include detecting various forms of hypertension or hypotension. The automatically altering the at least one pacing characteristic can include automatically altering at least one of a pacing rate, a pacing waveform, an atrioventricular (AV) delay, an interventricular (VV) delay, a pacing mode, or a pacing site. The method can also include delivering vagal nerve stimulation and automatically altering the vagal nerve stimulation in response to the detected abnormal BP condition. The detecting the abnormal BP condition can also include using a sensed auxiliary physiological parameter.

The combination of bradycardia and impaired left ventricular (LV) stroke volume may be seen in patients with drug resistant hypertension that can be corrected by the implantation of a permanent cardiac pacing device, which is utilized as disclosed below. This represents a new indication for pacemaker implantation and also justifies modifying existing guidelines for pacemaker and/or cardio-defibrillator implants.

Moreover, because impaired LV function results in heart failure (systolic and diastolic), it follows that optimization of peripheral resistance by pacemaker therapy in the presence of bradycardia, and possibly in those without bradycardia but with severe LV dysfunction, will enhance the non-pharmacologic treatment of both systolic and diastolic heart failure.

Current generation pacemakers provide only heart rate-based modulation. Sensors inside the pacemaker, such as accelerometers and respiratory movement detectors, regulate pacemaker-mediated heart rate according to preprogrammed heart rate profiles. NO existing pacemaker type in clinical use is also regulated by blood pressure.

Further embodiments are disclosed in dependent claims <NUM>-<NUM>. References to methods below are not part of the claimed invention as such, but are useful for the general understanding of the invention.

Based upon the clinical observations presented, regulation of pacemaker function by blood pressure promises to better treat DRH and DCHF. This can be accomplished by integrating a real-time blood pressure measurement device, such as a wristband sensor now generally available, linked via encrypted blue-tooth connectivity to a standard dual chamber pacemaker containing the software described herein. The software program is tailored to the patient's needs by the supervising physician via external programmability with access to real-time blood pressure data received from the patients blood pressure sensor. The software calculates optimal pacemaker function to better treat DRH and DCHF. The software of the illustrated embodiments could be resident in the blood pressure cuff, a smart phone or other separate peripheral device such as the standard doctor's office programmers currently in use, or the pacemaker. A different data loop integrates a blood pressure cuff sending data over the internet or phone to a distant processing site, and then the new pacemaker instructions arriving again via the internet or the phone. Below is a disclosure of various permutations and three embodiments.

No method previously or currently exists to interface a cardiac pacing device with an external blood pressure measuring device for the purpose of regulating pacemaker function for any purpose. Similarly, no automatic software-driven feedback loops are available linking an implanted cardiac pacemaker to a blood pressure measuring device, where the loop also integrates a software program to interact with the pacemaker in a manner that regulates cardiac pacing to control blood pressure and/or treat diastolic congestive heart failure.

We have shown using the data from two retrospective clinical trials that implantation of a dual chamber pacemaker for standard indications in patients with drug resistant hypertension
(DRH) and DRH with diastolic congestive heart failure (DCHF) reduces blood pressure, the magnitude of drug therapy needed for optimal blood pressure regulation, and further occurrences of DCHF. This data also showed a correlation between the drop in SBP and the percentage of right atrial (RA) pacing between RA pacing percentages of <NUM> to <NUM>% or such other percentage range consistent with the teachings of this invention and as may later be determined by clinical experience. Therefore, whenever the pacing percentage of <NUM>% is indicated in this specification, if should be understood that this parameter may be changed without departing from the scope of the invention, as defined by the appended claims. The systolic blood pressure reduction data between <NUM> and <NUM>% changes in right atrial pacing rate follows a polynomial distribution typical of physiologic data. For the clinical cohort analyzed, no further drop in SBP reliably occurred above an increase in RA pacing of <NUM>% although this drop is expected to change in different clinical cohorts. Moreover, the data approaches linearity between <NUM> and <NUM>% increases in RA pacing rates providing an equation that relates the expected drop in SBP for each incremental increase in RA Pacing. These clinical findings and the described mathematical relationship form the basis of a new method to treat both DRH and DRH with DCHF.

A software program can be written that links the pacemaker and an external or internal measurement of blood pressure. One embodiment utilizes a wristwatch-type BP monitor now generally available with blue tooth connectivity worn by the patient. The software allows either clinician-directed programming of the pacemaker's blood pressure algorithm through the use of an external programmer with access to any real-time blood pressure measurements, or direct (blue tooth connectivity) to the blood pressure algorithm resident in the pacemaker's internal processor. Together, these two types of pacemaker regulation by an algorithm linked to the measurement of blood pressure represent new treatment options for drug resistant hypertension and diastolic congestive heart failure.

What has been developed is an upgraded or modified method of operation of virtually all types of pacemakers that allows the pacing device to automatically, or by the physician to remotely tailor HR to blood pressure. This type of operation is defined in this application as "Blood Pressure Adaptive Pacing" (BPAP), which optimizes not only blood pressure but peripheral resistance in patients with DRH, heart failure (systolic and diastolic) or the combination of both. Blood Pressure Adaptive Pacing is realized in multiple embodiments.

One approach is to externally program the pacing device in the cardiologist's office using available blood pressure data through an external interface. The components of such a system is envisioned as including the pacing device, an onboard computer control and memory for storing the algorithm in the pacing device, a computer interface in the physican's office to connect the pacemaker either wirelessly or by hardwired sensor placed over the chest similar to that employed for pacemaker evaluation in the physician's office or clinic.

Another approach envisions remotely inputting the patient's electronic blood pressure measurements obtained outside the physician's office as sent wirelessly to the patient's pacemaker via an external wireless interface present in the patient's home.

Yet another approach envisions direct in vivo sensing carried out by the patient's implanted cardiac device using appropriate software on an independent dynamic basis. An in vivo blood pressure is included in or with the pacemaker. The pacemaker is programmed, monitored, and adjusted in the physician's office or clinic to operate according the disclosed methodologies,.

It can now be appreciated that the illustrated embodiments of the invention include an apparatus employing a new algorithm for pacing in the right atrium for the purpose of reducing blood pressure in patients having drug resistant hypertension and to patients with diastolic congestive heart failure using real time feedback by monitoring blood pressure, biological markers or other vital signs in which the normal synchronicity of the heart is maintained.

The apparatus and a non-claimed method employs a Bluetooth enabled wristwatch for monitoring the blood pressure, biological markers or other vital signs and generating a control signal to a right atrial implanted pacemaker. It is a cardiac pacing device that permits RA pacing via an implanted lead in the RA.

The apparatus and non-claimed method further include means for releasing atrial naturetic peptides.

Thus, it can be appreciated that the illustrated embodiments include an apparatus which has a programmable, implantable pacemaker with a controllable pacing rate; and a blood pressure monitoring device having an output communicated to the pacemaker. The pacemaker selectively and automatically modulates pacing rate in response to monitored blood pressure to reduce hypertensive blood pressure in a patient.

In one embodiment the pacemaker is a RA pacemaker or more properly a cardiac pacing device that can pace the RA via an implanted lead, and where the blood pressure monitoring device measures peripheral blood pressure.

The blood pressure monitoring device includes any known type of blood pressure sensor or cuff, such as: a pneumatic cuff relying on mechanical compression of a peripheral artery, most commonly the brachial artery in the arm but can also be used on the ankle or the wrist; a non-pneumatic cuff which analyzes the arterial waveform and function anywhere on the body where the arterial pulse contour can be sensed, most commonly at the wrist: and an implantable sensor within blood vessels or the heart chambers. The cuffless BP monitors now being FDA approved function by processing the arterial waveform which can be obtained at multiple sites on the body, including the earlobe, any digit. The implanted sensor is implanted at a vascular site or a cardiac site.

The blood pressure monitoring device communicates wirelessly with the pacemaker, such as through Bluetooth technology.

The blood pressure monitoring device may further include a pulse oximeter, and/or a chemical sensor for sensing glucose, electrolytes or other blood parameters.

The blood pressure monitoring device monitors systolic blood pressure or may be configured to monitor diastolic or systolic blood pressure or mean arterial pressure. The device may also be connected to a separate apparatus that measures cardiac stroke volume (such as ultrasound) and therefore calculates systemic vascular resistance.

The illustrated embodiments also extend to a non-claimed method for operating a pacing device including the steps of:.

While the illustrated embodiment has been disclosed in terms of systolic BP and RA pacing rtes between <NUM> and <NUM>%, it is within the scope of the invention to also use diastolic or mean BP and other RA pacing rates.

The illustrated embodiments also extend to blue tooth regulation of the pacemaker pacing function generated by a smart phone in which the software of the illustrated embodiments has been installed.

In the illustrated method the pacing rate of the pacemaker is a RA pacing rate.

Again monitoring blood pressure includes monitoring peripheral blood pressure, intravascular blood pressure or intracardiac blood pressure.

The step of monitoring peripheral blood pressure includes the step of monitoring peripheral blood pressure with a wrist mounted device or ann cuff.

The non-claimed method may further include monitoring blood oxygen levels, glucose levels, blood electrolytes levels or other blood parameters and controlling the pacing rate in response to the monitored blood oxygen levels, glucose levels, blood electrolytes levels or other blood parameters.

In one embodiment the pacing device is a RA pacemaker, and selecting the following parameters for use in a pacemaker for blood pressure regulation includes selecting a target RA pacing rate change per treatment interval where the RA pacing rate change ranges from <NUM> - <NUM>%. If systolic blood pressure exceeds the target SBP. use of a pacemaker having a RA pacing rate to treat the patient is made. Treating the patient increases the RA pacing rate of the pacemaker by either a default level of <NUM>% per treatment, or by a different predetermined value. Increasing the pacing rate of the pacemaker by a predetermined incremental amount increases the RA pacing rate. Repeating the steps compares SBP and increases the RA pacing rate of the pacemaker until either the SBP falls to the target SBP, or the RA pacing rate of the pacemaker exceeds a predetermined maximal value. Another possible pacing parameter could be the duration of RA pacing. For example, sense the SBP, raise the RA pacing <NUM>% for ten minutes where the ten minutes could be preprogrammed overriding the sample and treat every five minutes idea.

The disclosure also include non-claimed method for operating a pacing device to treat drug resistant hypertension including the steps of: monitoring blood pressure; and controlling heart rate in the pacing device in response to the monitored blood pressure to selectively prevent excessive pacing to reduce mean arterial blood pressure by either inhibiting heart rate in the pacing device or by changing heart rate parameters.

The step of changing rate modulation parameters includes changing acceleration of pacing rate including magnitude of acceleration, and/or duration of acceleration, and changing deceleration of pacing rate including magnitude of deceleration, and/or duration of deceleration.

The scope of the invention includes using the disclosed algorithm and measured BP to better regulate standard rate modulation. Current rate modulation software, particularly in the elderly, is often detrimental or high activity levels, such as treadmill exercise testing. There is reason to believe that exercise performance in the elderly, in patients with DRH, and patients with DCHF will be enhanced when rate modulation software is further regulated by the addition of the disclosed software.

The step of monitoring blood pressure in one embodiment includes the step of monitoring systolic blood pressure, and the step of controlling rate modulation in the pacing device in response to the monitored blood pressure includes the step of controlling rate modulation in the pacing device in response to the monitored systolic blood pressure to selectively prevent excessive pacing to reduce mean systolic arterial blood pressure by either inhibiting rate modulation in the pacing device or by changing rate modulation parameters.

The step of monitoring blood pressure monitors diastolic blood pressure; and the step of controlling rate modulation in the pacing device in response to the monitored blood pressure controls rate modulation in the pacing device in response to the monitored diastolic blood pressure to selectively prevent excessive pacing to reduce mean diastolic arterial blood pressure by either inhibiting rate modulation in the pacing device or by changing rate modulation parameters.

The non-claimed further includes the step of monitoring blood oxygen levels, noninvasive measurement of pulse oximetry, glucose levels, blood electrolytes levels or other blood parameters and controlling the pacing rate in response to the monitored blood oxygen levels, glucose levels, blood electrolytes levels or other blood parameters.

The step of monitoring blood pressure includes monitoring peripheral blood pressure, intravascular blood pressure or intracardiac blood pressure.

The disclosure can be better visualized by turning now to the following drawings wherein like elements are referenced by like numerals.

The disclosure and its various embodiments can now be better understood by turning to the following detailed description of the preferred embodiments which are presented as illustrated examples of the embodiments defined in the claims. It is expressly understood that the embodiments as defined by the claims may be broader than the illustrated embodiments described below.

Hypertension increases incrementally with aging. Heart Rate incrementally decreases with aging. While multiple factors combine to cause hypertension to develop and progress with aging, including but not limited to atherosclerosis, decreased elasticity of arteries, i.e.. increased "stiffness"
and progressive renal insufficiency, an argtunent can be made that bradycardia is another heretofore unrecognized important factor, one for which a new treatment option is available that will slow or prevent the progression of simple hypertension to the drug resistant variety and ultimately diastolic heart failure. Aging causes a drop in the heart rate. which is called sino atrial node dysfunction (SAND). SAND activates the sympathetic nervous system to increase peripheral vascular resistance according to the fluidic law below. The basic tenet of mammalian hemodynamics is that total blood flow is equal to driving pressure divided by resistance. This can be expressed in the same manner as Ohm's Law of electricity. <MAT>
where R is resistance to flow, AP is the change in pressure across the circulation loop (systemic / pulmonary) from its beginning (immediately after exiting the left ventricle / right ventricle) to its end (entering the right atrium / left atrium), and Q is the flow through the vasculature (when discussing systemic vascular resistance (SVR) this is equal to cardiac output). This is the hydraulic version of Ohm's law, V=IR (which can be restated as R=V/I), in which the pressure differential is analogous to the electrical voltage drop, flow is analogous to electric current, and vascular resistance is analogous to electrical resistance. In some embodiments the algorithm processes SVR instead of SBP, DBP, or mean AP. The math is different, but the logic and functionality is essentially the same.

Consider first the nature of pathophysiology. If heart rate falls, mean arterial blood pressure can be maintained by increasing stroke volume (SV), which is a known compensatory mechanism of the healthy heart. However, when the left ventricle is impaired for a variety of reasons, such as prior heart attacks, hypertensive enlargement, primary muscle disease, or in the presence of significant valvar heart disease, and for other reasons, and HR also falls, R must increase to maintain blood pressure.

It follows, therefore, that the combination of both bradycardia (HR too low) and impaired SV would lead to increased R which would then lead to clinical hypertension and ultimately hypertensive heart failure when cardiac output is inadequate to overcome excess peripheral resistance.

It also follows that, in a patient with elevated R (significant hypertension) due to both reduced HR and SV, increasing HR, such as through the action of a pacemaker, would reduce R and thereby reduce the need for medication. Lowering R by this means should also result in a lower incidence of hypertension-induced heart failure.

If the heart fails, blood flow to the body's tissues must be maintained by a combination of increased left ventricular stroke volume (LVSV) and pulse rate (PR). A combination of aging, left ventricular hypertrophy due to hypertension, and other factors such as atherosclerosis progressively impair left ventricular performance which further demands an increase in PR. This negative feedback loop is worsened by increasing LV hypertrophy stimulated by increased LV work against high PR. Diastolic heart failure occurs when the higher filling pressure required by the stiff and hypertrophied left ventricular causes back up of blood into the lungs. This results in the classic clinical presentation of DCHF, which includes shortness of breath. fatigue, and peripheral edema. As the right and left atria stretch due to the effect of higher ventricular filling pressures, a compensatory mechanism is triggered within the atrial tissues to reduce PR and intravascular volume. Although it is not currently clearly understood, we believe that this compensatory mechanism includes the release of atrial naturetic peptides.

Turn now to clinical data supporting relevant to the illustrated embodiments of the invention. We studied retrospectively thirty patients satisfying the standard criteria for permanent pacemaker implant based upon bradycardia (sinus node dysfunction) who also had drug resistant hypertension. We hypothesized that if the above argument is true, the patient's hypertension post pacemaker implant should be lessened as manifested by lower blood pressure readings compared to pre-implant levels, and the need for hypertension medication lessened.

Thirty elderly patients (n = <NUM>) with impaired SV bradycardia (sinoatrial node dysfunction,) who also had drug resistant hypertension (HTN) defined as the chronic use of at least four HTN agents from different drug classes not including a beta adrenergic blocking agent and who satisfied Class 1A criteria for permanent pacemaker implantation were studied before and after pacemaker implantation. A significant change in HTN management was defined as a drop of <NUM> mmHg systolic, or <NUM> mmHg diastolic on multiple readings over at least three months after pacemaker implant. and/or the deletion at least one anti-HTN agent without concomitant increase in the dosage of any other agent during the same period of time.

Six months after pacemaker implant <NUM> of <NUM> patients ( <NUM>%, p<, <NUM> ) showed a significant improvement in HTN. <NUM> patients had a significant decrease in systolic pressure. <NUM> patients a significant decrease in both in both systolic and diastolic blood pressure, and <NUM> patients a change in drug usage: <NUM> patients dropped at least one antihypertensive drug, <NUM> patients dropped two drugs, and <NUM> patients dropped three drugs. The average onset of this effect was observed <NUM> +/- <NUM> months after pacemaker implant.

The data proves that, in elderly patients with the combination of impaired stroke, sinus node dysfunction satisfying AHA criteria for pacemaker implant, and drug resistant HTN, pacemaker implant may significantly improve HTN, and hypertension management. The impaired stroke volume of these patients was presumed volume based upon left ventricular hypertrophy and diastolic dysfunction which is impaired LV relaxation. Pacemaker implant should also improve the long-term outcomes of patients with significant drug resistant HTN and concomitant sinus node dysfunction by reducing not only the need for complex drug regimens, but also the development of the complications of drug resistant hypertension. including diastolic heart failure, kidney disease, and stroke.

The disclosed software should be added to AICD's which are not primary pacing devices and lack an RA lead when the patient has heart failure but not enough bradycardia to qualify for a pacemaker. This would result in single chamber ICDs being dropped in favor of dual chamber ICDs exclusively in patients with DRH and DRH with DCHF. While this is an attractive hypothesis, we currently have no clinical data on this group of patients (with systolic heart failure) and permanent pacing. The primary goal of pharmacological therapy in heart failure is to reduce R. Because such patients have a high incidence of the later development of sinus node dysfunction (<NPL>. ) and are often administered drugs that suppress heart rate as a side effect of therapy, such as beta adrenergic blocking drugs, an argument can be made to implant a device that combines both an AICD and dual chamber function (with a third lead or CRT-D as appropriate) as the first device.

For the purpose of this application. bradycardia is defined as a mean heart rate sustained less than <NUM> beats per minute; chronotropic incompetence is defined as when HR fails to reach an arbitrary percentage (either <NUM>%, <NUM>%, or less commonly, <NUM>%) of the age predicted maximal HR (usually based on the "<NUM>-age" equation) obtained during an incremental dynamic exercise test. We focused on patients with DRH and DRH with DCHF and found an improvement in DRH in terms of the number of drugs needed, actual lowering of SBP in both studies and DBP too in the other, and a reduction in hospitalizations for heart failure.

It can now be appreciated that the embodiments of the invention include various kinds of blood pressure sensing devices, such as non-invasive devices like cuffless wrist-type (non-pneumatic wave form analysis), cuff type arm or leg devices, cuffless waveform devices for BP analysis on any region of the body where arterial pulse can be sensed, e.g. using optical, plethysmographic, thermographic, electrical impedance, or electromagnetic means. Also included are invasive devices implanted in blood vessel outside the heart or implanted inside the heart.

The controlling software may be located in the blood pressure sensing device which then sends signal to pacemaker. in a peripheral device, but not the blood pressure sensor or the pacemaker, namely in a smart phone or computer, a conventional medical office e-programmer, an iPad (near the patient or a remote site), or in the pacemaker. The software is based on either manual input or is automatic. Control signals are generated based on measured systolic or diastolic BP, or mean blood pressure. The control signals are used to adjust right atrial pacing. up or down although the scope of the invention also extends to RV and LV pacing.

The pacemakers which are employed to implement the pacing control include atrial pacemakers (atrioventricular conduction intact, lead in RA), dual chamber pacemakers (atrioventricular conduction not intact, leads in RA and RV), bi-ventricular pacemakers (used in systolic heart failure where intraventricular conduction is prolonged), also known as a CRT, dual chamber AICD, (essentially a dual chamber pacemaker with a shocking lead in RV), and CRT-D, (a bi-ventricular pacemaker with a shocking lead in RV).

Consider three embodiments. The simplest or most primitive example is an open loop, manually controlled system. It is employed as a medical office procedure, uses a standard pneumatic blood pressure cuff, a doctor's office pacemaker programmer near the patient, and a conventional normally programmable dual chamber pacemaker. The patient sits near doctor. Blood pressure is taken with standard pneumatic cuff. The physician looks for systolic blood pressure on a printed table displaying the disclosed algorithm in a tabular format and determines an optimum RA pacing rate. The physician places a pacemaker programmer wand (RF source) over the patient's pacemaker and uses the programmer to reprogram the pacemaker to desired RA pacing rate according to the teachings of the disclosed embodiments.

The next preferred embodiment is configured as a closed loop, automatic system. A cuffless wrist-type blood pressure sensor with wireless connectivity is used and a smart phone app with disclosed algorithm receives blood pressure readings. The BP reading is encrypted and sent to the pacemaker wirelessly. The pacemaker receives the encrypted blood pressure reading, authenticates, and alters RA pacing rate.

The third embodiment is a home monitoring and remote processing system. All front-line pacemakers offer home monitoring. The patient is given a device that is commonly left at the bedside. When the patient moves near it, such as going to bed, the device wirelessly interrogates the pacemaker, monitoring such things as battery voltage and recent arrhythmia activity, and sends it via the phone lines in encrypted form to a remote central station operated by the pacemaker company. Inbound instructions are sent by the same system to alter the pacemaker's programming and/or alert the treating physician that adverse events have occurred, such as arrhythmias or device dysfunction.

In additional ones of the illustrated embodiments all different types of pacemakers, e.g. AP, DCP, D-C/AICD. CRT, or CRT-D, were operated or used for a wide permutation of cardiac symptoms or abnormalities, for example for the indicated combinations:
<MAT>
<MAT>
<MAT>
<MAT>
<MAT>
<MAT>
<MAT>
<MAT>
<MAT>
<MAT>
<MAT>.

Where: DRH = Drug Resistant Hypertension; B = Bradycardia defined as a persistent HR < <NUM> (higher than the Guidelines); CI = chronotropic incompetence as defined above; ISV-S = Impaired Stroke Volume due to failure of systolic function; ISV-D = Impaired Stroke Volume due to failure of diastolic function; DHF = diastolic heart failure or heart failure with a preserved LV function (LVEF > <NUM>%). This is another form of ISV where the Left Ventricle contracts normally, but relaxes in an impaired manner: SHF = systolic heart failure or heart failure with reduced LV function (LVEF < <NUM>%);
The illustrated embodiments of the invention were also directed to methods of operating or using a pacemaker t to treat heart failure (systolic and diastolic) by reducing peripheral resistance (R) with or without the presence of sinus node dysfunction. The current guidelines for the implantation of a permanent pacemaker in the presence of sinus node dysfunction are too strict in patients who also have heart failure. Many heart failure patients have lower than effective heart rates (relative bradycardia) and both with and without high resistance, but do not satisfy the very strict current AHA Guidelines for pacemaker implant. The presence of relative bradycardia sufficient to increase peripheral resistance (the primary therapeutic point of attack for non-surgical heart failure therapy) and heart failure should be sufficient to warrant pacemaker implant. This would include patients with relative bradycardia and lesser chronotropic incompetance not currently meeting the AHA Guidelines for pacemaker implant.

The magnitude of the diminished capacity to respond to Bradycardia is proportional to LV function. The lower the LV function, the more profound is the effect of bradycardia on peripheral resistance. which is manifest as elevated blood pressure, and peripheral resistance is the major determinant of morbidity and mortality in heart failure. Therefore, the criteria for pacemaker implant in patients who have DRH and DRH with DCHF, and all forms of CHF and relative bradycardin should not be limited by the current AHA Guidelines. This increases the cohort of patients who should have atrioventricular pacing to include all patients with heart failure and relative bradycardia. While relative bradycardia is defined the purposes of this embodiment as either the presence of chronotropic incompetence or a HR less than <NUM> and greater than <NUM>, it is to be expressly understood that this definition can be modified as determined by later clinical trials of the pacing methodology without departing from the scope of the invention.

Thus, the illustrated embodiments of the invention are directed to a method of operating or using an implantable pacemaker (AP, DCP, CRT, CRT-D) to treat diastolic heart failure in patients with concomitant bradycardia relative or meeting the AHA guidelines, concomitant chronotropic incompetence and/or chronotropic incompetence with drug resistant hypertension to optimize peripheral resistance by the restoration of a normal heart rate. These methods of operation and use of implanted pacemakers are based upon utilizing a pacing therapy to reduce peripheral resistance as means of treatment of at least some types of heart failure. Reducing peripheral resistance is the primary goal of nonsurgical heart failure treatment, surgical treatment includes bypass surgery, heart transplantation, and implantation of heart assist devices.

Therefore, it can be appreciated that the operation and use of implanted pacemakers to treat heart failure is the primary end point of the pacing operation or use. The endpoints of treatment are both heart failure and concomitant drug resistant hypertension. In each permutation of systems what is indicated is the use and operation of all types of pacemakers, for example including in such diagnostic permutations as: DHF + CI; DHF + B; SHF + B; and SHF + Cl as well as in the treatment of heart failure with concomitant drug resistant hypertension including in such diagnostic permutations as: SHF + B +DRH; SHF + CI + DRH; DHF + B + DRH; and DHF + Cl + DRH.

Consider an embodiment of the invention wherein it is realized in a scenario as shown in <FIG> with an external programming device <NUM> and a wristwatch type blood pressure monitor <NUM>. The patient is fitted with a pacemaker <NUM> connected to the patient's heart <NUM> with the blood pressure modulation software resident in the pacemaker's processor. The patient is also fitted the blood pressure monitor <NUM> mounted in a wristwatch band with encrypted blue tooth connectivity linking it uniquely to the patient's pacemaker <NUM>. The patient or clinician activates wristwatch blood pressure monitor <NUM> and selects the number of blood pressure readings to store, and how far apart in minutes the measurements are separated. This data set comprises the baseline blood pressure readings of the illustrated embodiment of the invention. The BP measurements are carried out according to the predetermined schedule and the data set, the baseline blood pressure readings, is created and stored in the pacemaker <NUM>. Using the external programming device <NUM>, the clinician pairs the patient's wristwatch blood pressure monitor <NUM> to the pacemaker <NUM> by entering the unique serial numbers of the pacemaker <NUM> and the blood pressure monitor <NUM> allowing blue tooth encrypted interconnectivity of both devices. If the blood pressure monitor <NUM> is inactivated for any reason, the blood pressure algorithm in the pacemaker <NUM> becomes dormant and the pacemaker <NUM> returns to regular function unmodulated by the external blood pressure readings or the internal blood pressure modulation algorithm.

The clinician inputs the following parameters through the external programming device <NUM>, which parameters are transmitted to the pacemaker <NUM> and integrated into the blood pressure regulating algorithm. The clinician inputs a desired SBP (systolic blood pressure) and inputs a lower limit of acceptable SBP. For example, the desired treatment interval in minutes and a desired RA pacing change per treatment interval from <NUM> - <NUM>% is input. After the clinician directed software functions are programmed, the external programming device <NUM> is inactivated and the patient's pacemaker <NUM> paired with the wearable blood pressure monitor <NUM> begins automatic functioning. The flow diagram of <FIG> summarizes this initial programming session. At step <NUM> the clinician logs onto the external programming device <NUM> to gain access to the pacemaker <NUM> and BP monitor <NUM>. He or she enters the serial number of patient's wearable blood pressure monitor <NUM> at step <NUM>. The pacemaker <NUM> will now only accept data from the designated BP monitor <NUM>. The clinician downloads into the external programming device <NUM> the baseline BP data set from the patient's BP monitor <NUM> at step <NUM>. The clinician uses that data set to program the treatment algorithm by setting at step <NUM>: the target SBP; maximal SBP; minimum SBP; selected time between monitor intervals, which may be preset at ten minutes; selected time between RA pacing adjustments, which may be preset at ten minutes; and percentage RA pacing change per treatment interval, which may be preset at <NUM>%. The instructions are encrypted and sent to the pacemaker <NUM> at step <NUM>.

As shown in the flow diagram of <FIG> the blood pressure monitor <NUM> and the patient's pacemaker <NUM> are paired using encrypted blue tooth technology. The patient activates the wearable BP monitor's <NUM> encrypted blue tooth link to the pacemaker <NUM> at step <NUM>. BP monitor <NUM> sends a test signal to pacemaker <NUM> as step <NUM> to validate pairing and integrity of the signal. The monitor <NUM> notifies the patient that encrypted pairing is complete at step <NUM>. BP monitor <NUM> measures the BP. The BP data is encrypted and communicated to the external programming device <NUM> and to the pacemaker <NUM> at step <NUM>. The external programming device <NUM> decrypts the data and displays it at step <NUM>. Selective treatment by pacemaker <NUM> is then activated through the external programming device <NUM> at step <NUM>.

While the patient carries on ordinary activities, the software in the pacemaker <NUM> processes the blood pressure data transmitted by the blood pressure monitor <NUM> and establishes: <NUM>) the steady state BP, namely the average blood pressure based upon recent blood pressure readings; and <NUM>) the steady state RA pacing, namely the average right atrial pacing rate during the same time intervals.

If the average systolic blood pressure, namely most recent steady-state readings, exceeds the preprogrammed limits set by the clinician, treatment is automatically initiated. If the most recent steady state readings are below the treatment plateau programmed by the clinician, the software does not alter the right atrial pacing rate and no blood pressure treatment is delivered. If a decision to treat has been made by the software, the RA pacing rate is increased by either the default level of <NUM>% per treatment, or by a different value pre-programmed by the clinician using the external programming device <NUM>. For example one possible treatment option would be to increase RA pacing <NUM>%.

The SBP is monitored for twenty minutes, or for a different time interval preprogrammed by the clinician, to establish the new blood pressure baseline. If the SBP is still above the clinician's pre-selected optimal SBP, the treatment is repeated by increasing the RA pacing rate another <NUM>% or by a different amount as pre-programmed by the clinician. This cycle of monitoring and selective treatment is repeated until either the SBP falls to the pre-programmed optimal level, or the RA pacing rate exceeds <NUM>% or a different maximal value pre-programmed by the clinician.

<FIG> illustrates the selective treatment in a rate modulation mode. The blood pressure monitor <NUM>, the blood pressure modulating software <NUM>, and the pacemaker <NUM> form an automatic feedback loop to regulate pacemaker function, which in this embodiment is RA pacing but need not be so limited, to lower blood pressure. The algorithm utilizes the following parameters to determine or modulate the optimal RA pacing percentage to optimize BP:.

The treatment algorithm in the rate modulation mode relates the instantaneous change in SBP with the change in RA pacing percentage, such that the drop in SBP is mapped to an increase in RA pacing times a constant A + constant B.

In the present embodiment based upon currently available clinical data, which may be later refined by subsequent data gathered, A = -<NUM>, and B = <NUM>. In the currently preferred embodiment of the treatment algorithm the change in SBP and RA pacing are expressed as a percentage.

<FIG> is a flow diagram which illustrates further processing undertaken in pacemaker <NUM>. At step <NUM> steady state BP is input, either baseline BP if it is the first use, the BP during the last ten minutes, or such time as otherwise programmed by clinician. At step <NUM> access steady state RA pacing, either baseline if it is a first use, the rate during the last ten minutes, or at such time otherwise as programmed by clinician. If the software is in monitor-only mode as determined at step <NUM>, either because it has been disabled or the desired blood pressure has been detected in steady state, the RA pacing rate is set at step <NUM> by the clinician at a selected lower rate limit. Otherwise pacemaker <NUM> is or will continue to operate in the rate modulation mode.

When the patient exercises, or the pacemaker's rate modulation software is activated for any reason, BP will be affected and RA pacing will rise. The algorithm will default to monitor-only mode so long as the increase in RA pacing does not drop the blood pressure below the preset minimum SBP. If the SBP drops below the preset minimum, the rate modulation mode will be inhibited. This is a new pacemaker safeguard for all devices across all brands that offer rate modulation software as feature of their pacemakers. It will protect the patient from an excessive drop in SBP caused by excessive RA pacing, or dual chamber pacing such as RAIRV or RAIL V.

The apparatus and a method operate a pacing device <NUM> as depicted diagrammatically in the flow diagram of <FIG> by including the steps of:.

Claim 1:
A system suitable for operating a pacemaker (<NUM>) comprising:
a blood pressure monitor (<NUM>) couplable to a patient;
a memory communicated to the monitor for storing a number of blood pressure readings;
a processor communicated to the memory for determining a baseline blood pressure reading;
the system being characterized in that the processor determines the following parameters to use to control the pacemaker (<NUM>) for blood pressure regulation: a target BP, blood pressure, a lower limit of acceptable BP; a target treatment interval in minutes and/or target pacing rate change per treatment interval at a predetermined pacing rate change percentage;
wherein the processor determines, while monitoring blood pressure, if blood pressure exceeds the target BP,
wherein the pacemaker (<NUM>) has a controllable pacing rate to treat the patient by: increasing the pacing rate of the pacemaker by either a default level of <NUM>% per treatment, or by a different predetermined value;
wherein the processor monitors the BP for a predetermined time period to establish the new blood pressure baseline; compares BP to a preselected optimal BP; increasing the pacing rate of the pacemaker (<NUM>) by a predetermined incremental amount; and repeats the steps of comparing BP and increasing the pacing rate of the pacemaker (<NUM>) until either the BP falls to the target BP, or the pacing rate of the pacemaker (<NUM>) exceeds a predetermined maximal value.