NL2019106B1

NL2019106B1 - Blood pressure regulating device

Info

Publication number: NL2019106B1
Application number: NL2019106A
Authority: NL
Inventors: Frederick Benson Jacobus
Original assignee: Frederick Benson Jacobus
Priority date: 2017-06-22
Filing date: 2017-06-22
Publication date: 2019-01-07

Abstract

The invention relates to a device and a method for controlling blood pressure in a subject, the device including a power supply, pulse generating circuit and electrode; the electrode transmitting a pulsed electric signal to aortic baroreceptors; the electric stimulation of aortic arch baroreceptors by means of the electric currents transmitted through the electrode serving to lower Mean Arterial Pressure (MAP) in the subject via the baroreceptor reflex.

Description

BLOOD PRESSURE REGULATING DEVICE

FIELD OF THE INVENTION

The invention relates to a device and means for controlling the blood pressure of a subject.

BACKGROUND OF THE INVENTION

Blood pressure is determined by both the amount of blood that a subject’s heart pumps and the amount of resistance to blood flow in the subject’s arteries, wherein an increased heart pump rate and/or narrowing of the arteries causes an increase in the subject’s blood pressure. A blood pressure reading, given in millimetres of mercury (mm Hg), has two numbers. The first number corresponds to the pressure in a subject’s arteries when the subject’s heart pumps and is often referred to as the systolic pressure. The second number is a measure of the blood pressure of a subject in between sequential heart pumps and is often referred to as diastolic pressure. The ideal blood pressure for a healthy adult human subject is 120/80 mm Hg.

Blood pressure measurements in a human subject can be classified into four general categories:

Normal blood pressure: a blood pressure of less than or equal to 120/80 mm Hg; Prehypertension: a systolic pressure ranging from 120 to 139 mm Hg or a diastolic pressure ranging from 80 to 89 mm Hg;

Stage 1 hypertension: a systolic pressure ranging from 140 to 159 mm Hg or a diastolic pressure ranging from 90 to 99 mm Hg; and

Stage 2 hypertension: a systolic pressure higher than 160 mm Hg or a diastolic pressure of 100 mm Hg or higher.

Hypertension poses a major risk factor for morbidity and mortality worldwide. It is known that hypertension is a common contributor to morbidity from cardiovascular disease and has a complex multi factorial aetiology, which includes both generic and environmental influences.

The art teaches of the use of various medicaments in the treatment of hypertension, including thiazide diuretics, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers and renin inhibitors.

Thiazide diuretics, also known as water pills, are medications that act on the kidneys of a subject resulting in an increased elimination rate of sodium and water from the subject’s blood and thereby causing a decrease in the subject’s blood volume; a decrease in a subject’s blood volume will lower the blood pressure of the subject. There are significant disadvantages associated with the use of thiazide diuretics, including an increased urination rate, a possible increase in blood sugar levels and an upset in the salinity of the subject’s blood.

Beta blockers and reduces the workload of a subject’s heart by opening the subject’s blood vessels, causing the subject’s heart to pump slower and with less force and thereby lowering the subject’s blood pressure. The art acknowledges that the use of beta blockers, by itself, is often insufficient to treat hypertension and may result in fatigue, weakness and shortness of breath.

Angiotensin-converting enzyme inhibitors, ACEs, ARBs and calcium channel blockers have a similar mode of action to that of beta blockers and retain many of the disadvantages associated with beta blockers.

Renin inhibitors inhibit the production of renin enzymes in the renin-angiotensin-aldosterone hormone system. The renin-angiotensin-aldosterone hormone system is involved in regulating plasma sodium concentrations in the blood of a subject, which in turn, regulates the blood pressure of the subject. Renin inhibitors show limited tissue distribution and may react adversely with other medications, resulting in serious complications such as renal impairment, strokes and hypotension.

Stimulation, including electrical stimulation, of carotid baroreceptors is known in the art as a means to reduce hypertension. However, the surgery required for implantation of stimulatory devices and electrodes is risky due to the density of important structures within the neck.

It is apparent from the above that there is a dire need in the art for alternative treatments of hypertension which has fewer risks and side effects when compared to the treatments known in the art, and does not react adversely with other medicaments.

OBJECT OF THE INVENTION

It is accordingly an object of the present invention to provide an alternative device and means for controlling a subject’s blood pressure which, at least partially, alleviates some of the abovementioned disadvantages.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention, there is provide a device for controlling blood pressure in a subject, the device comprising: a power supply, pulse generating circuit and electrode; the electrode transmitting a pulsed electric signal to aortic arch baroreceptors; the electric stimulation of aortic arch baroreceptors by means of the electric currents transmitted through the electrode serving to lower mean arterial pressure (MAP) in the subject via the baroreceptor reflex.

In an embodiment, implantation of the electrode may be carried out via mediastinoscopy or thoracotomy. In a further embodiment, the electrode may include one or more sub-electrodes.

In a yet further embodiment, the electric stimulation may be carried out at a voltage of between 1 and 3 mV with a safety margin of 10 mV, and a frequency of 150 - 200 Hz. Here it should be understood that a range of approaches related to electrical stimulation are known in the art, with the exact waveform, frequency, safety margin, current and voltage being selected in order to provide the optimum level of baroreceptor stimulation using the lowest amount of energy.

In an alternative embodiment, the device may include a mean arterial pressure (MAP) detecting component, the device adjusting the electric stimulation based on the mean arterial pressure (MAP).

According to a second aspect of the invention, there is provided for the use of a device as discussed herein to stimulate a subject’s aortic arch baroreceptors, thereby, regulating the subject’s mean arterial pressure (MAP).

According to a third aspect of the present invention, there is provided a method of controlling blood pressure in a subject, including: implanting an electrode into the aortic arch of the subject; and electrically stimulating aortic arch baroreceptors by means of electric currents transmitted through the electrode; the electric stimulation serving to lower mean arterial pressure (MAP) in the subject via the baroreceptor reflex.

In an embodiment of the invention, the implantation of the electrode may be carried out via mediastinoscopy or thoracotomy. In a further embodiment, the electrode may include one or more sub-electrodes.

In an alternative embodiment of the invention, the electric stimulation may be carried out at a voltage of between 1 and 3 mV with a safety margin of 10 mV, and a frequency of 150 - 200 Hz. Here it should be understood that a range of approaches related to electrical stimulation are known in the art, with the exact waveform, frequency, safety margin, current and voltage being selected in order to provide the optimum level of baroreceptor stimulation using the lowest amount of energy.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in more detail, by way of example only, with reference to the accompanying figures in which:

Figure 1 is a schematic representation of experimental results obtained during the stimulation of the aortic arch baroreceptors of 38 animals; and

Figure 2 is a schematic representation of the results of a statistical analysis which was performed on the experimental results obtained during the stimulation of aortic arch baroreceptors of 21 animals.

The presently disclosed subject matter can, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the embodiments to those skilled in the art.

DETAILED DESCRIPTION OF THE DRAWINGS

The invention is not limited to the precise details as described herein and it will be appreciated by those skilled in the art that various embodiments are possible without departing from the scope of the invention.

Theory

Baroreceptors are located in the blood vessels of all vertebrate animals, wherein the sensory nerve endings of arterial baroreceptors are simple sprayed endings that lie in the adventitia of an artery. Baroreceptors are divided into two categories based on the type of arteries in which the receptor is found. High pressure arterial baroreceptors are located in the aortic arch and the carotid sinus areas, whereas low pressure arterial baroreceptors are located in the right atrium and large veins.

Changes in mean arterial pressure (MAP) and the stretching of the arteries accompanying an increase in blood pressure, results in action potentials being triggered in the said baroreceptor endings; baroreceptors provoke action potentials with each heartbeat. These receptors can therefore be said to function as a mechanoreceptor sensory system, wherein the neurons are triggered by the stretching of the blood vessel wall.

An increase in mean arterial pressure (MAP) increases the impulse generation from the baroreceptors located at the carotid and aortic areas, whereas a decrease in impulse generation from baroreceptors is observed in conditions that reduce mean arterial pressure.

The neuron stimulation which is triggered by the action potentials in the baroreceptor endings is mainly via the autonomic nervous system. This neuron stimulation modulates heart rate and inotropic activity and, thus, cardiac output and vascular tone in the form of peripheral resistance in the arteries.

Baroreceptor resetting refers to a shift in the pressure threshold required to activate a receptor in the direction of the prevailing mean arterial pressure (MAP). During chronic resetting, the baroreceptor mechanism’s sensitivity is reduced and is adjusted to a higher operating pressure, thereby maintaining, rather than suppressing the hypertension.

Carotid receptors, which responds to pressures ranging from 60 - 180 mm Hg are, quantitatively, the most important baroreceptors for regulating arterial pressure. Studies which investigated and confirmed a positive correlation between carotid receptor stimulation and a lowering of mean arterial pressure (MAP) are known. However, this method of lowering mean arterial pressure (MAP) have - due to the carotid receptors low threshold for generating an impulse - proved difficult to control.

Aortic arch baroreceptors have, in contrast to carotid receptors, a higher threshold for generating an impulse and, accordingly, the inventor has postulated that a stimulation of same would provide a more controlled regulation and, accordingly, a more predictable change in mean arterial pressure (MAP).

Experimental method A total of 38 animals of the goat species Capra aegagurs hircus was used to prove the efficacy of regulating mean arterial pressure (MAP). The study was conducted on both sexes and the animals’ ages varied between 6 months to 2 years.

The procedure for proving the efficacy of regulating mean arterial pressure (MAP) via stimulation of aortic arch baroreceptors consisted of a left lateral thoracotomy incision, where after the aortic arch was dissected down to the adventitia. A bolus of Buprenorphine was administered prior to the surgical procedure to ensure that there was no pain to influence systolic blood pressure.

The stimulation of the aortic arch baroreceptors, which followed the dissection of the aortic arch, was performed via the Octad™ probe system on the outer surface of the aortic arch and the blood pressure response thereto was measured by the arterial pressure wave of the femoral artery. Data was collected using the Vigileo™ System which was connected to the femoral artery catheter.

The end-point of the above experiments was the maximum blood pressure reduction that could be achieved with each stimulation, whereby the change in blood pressure was calculated using the average of 5 measurements taken during the stable anaesthetic phase against the maximum blood pressure drop in the stimulation phase.

Experimental results

The results of the aforementioned experiments are shown in Figure 1, where the Y-axis represents a subject’s systolic blood pressure in mm Hg and the X-axis represents the two conditions being pre-stimulation and post-stimulation of the subject’s aortic baroreceptors.

Figure 1 shows, upon stimulation of the subject’s aortic arch baroreceptors, a definite and significant reduction in all of the subjects’ systolic blood pressure. Furthermore, it is noticeable that, in general, the reducing effect of the stimulation of the aortic arch baroreceptors were more pronounced at higher systolic blood pressures. Most surprising and advantageously, Figure 1 shows a predictable trend in the reducing effect which the said stimulation has on the systolic blood pressure of a subject. A statistical analysis on the results obtained during the aforementioned experiments was performed to determine both the efficacy and predictability thereof. Per trial design assumptions, sample size was calculated to adequately power end-point results for a power of 90% at the significance level of 0.05. Sample size was determined based on 17 experimental animals, but, 21 animals were included in the final statistical data analysis.

For this research, the null hypothesis of no relationship between aortic arch baroreceptor stimulation and a reduction in blood pressure was applied. Rejecting or disproving the null hypothesis would lead one to conclude that there is a relationship between the said stimulation and a reduction in a subject’s blood pressure.

The null hypothesis would be rejected if a significant reduction in blood pressure, defined as a 20 mm Hg pressure reduction, could be achieved. A standard deviation of 23.62 mm Hg was assumed and baseline and end-point blood pressure results were compared.

Figure 2 shows the pre- and post-stimulation data, together with the p-value of the Wilcoxon signed-rank test. The Y-axis represents a subject’s systolic blood pressure in mm Hg and the X-axis represents the two conditions being the pre- and post-stimulation of the subject’s aortic arch baroreceptors.

Figure 2 shows that the mean baseline systolic blood pressure was 114.2 mm Hg with a median of 111.8 mm Hg. After stimulation, the mean blood pressure was 91.95 mm Hg with a median of 88 mm Hg. The mean drop in systolic blood pressure was 22.26 mm Hg and the Wilcoxon signed-rank test produced a p-value of less than 0.0001, thereby, rejecting the aforementioned null hypothesis.

The device

An implantable device for controlling the blood pressure of a subject in a manner corresponding to the mode applied during the experimental phase was subsequently developed.

The device includes a power supply, pulse generating circuit and an electrode which can be contacted with an aortic arch baroreceptor. After implantation of the device, a pulsed electrical signal may be transmitted to the contacted baroreceptors, serving to lower the mean arterial pressure (MAP) in a subject via the baroreceptor reflex.

Most advantageously, the device may be implanted in a subject via the much less invasive and safer - as compared to traditional open surgery methods - medical procedures known as mediatinoscopy and thoracotomy.

The number of electrodes connected to the pulse generating circuit may vary and would depend, among other factors, on the physiology of a subject which is to be treated, the quantitative and qualitative reduction of mean arterial pressure (MAP) which is to be achieved during the treatment, the morphology of a subject’s aortic valve, etc.

Whilst only certain embodiments of the instant invention have been shown in the above description, it will be readily understood by a person skilled in the art that other modifications and/or variations of the invention are possible. Such modifications and/or variations are therefore considered as following within the spirit and scope of the present invention as defined herein.

Claims

Device for controlling blood pressure in a patient, the device comprising: - a power supply, pulse generation circuit and electrode; - wherein the electrode sends a pulsed electrical signal to aortic arc baroreceptors; - the electrical stimulation of aortic-arc baroreceptors by means of the electrical currents transmitted by the electrode serves to reduce the mean arterial pressure (MAP) in the patient via the baroreceptor reflex.

The device of claim 1, wherein implantation of the electrode is performed via mediastinoscopy or thoracotomy.

The device of claim 1 or claim 2, wherein the electrode comprises one or more sub-electrodes.

The device according to any of claims 1 to 3, wherein the electrical stimulation is performed at a voltage of 1 to 3 mV with a safety margin of 10 mV and a frequency of 150-200 Hz.

The device of any one of claims 1 to 4, wherein the device further comprises an average arterial pressure (MAP) detecting component, the device adjusting electrical stimulation based on the average arterial pressure (MAP).

Use of the device according to any of the following claims to stimulate aortic arc baroreceptors of a patient, thereby controlling the average arterial pressure of the patient (MAP).

A method for controlling blood pressure in a compartment, including: - implanting an electrode in the aortic arch of the patient; and electrically stimulating the aortic-arc baroreceptors by means of electric currents transmitted by the electrode; - the electrical stimulation lowers the mean arterial pressure (MAP) in the patient via the baroreceptor reflex.

The method of claim 7, wherein the implantation of the electrode is performed via mediastinoscopy or thoracotomy.

The method of claim 7 or claim 8, wherein the electrode comprises one or more sub-electrodes.

The method according to any of claims 7 to 9, wherein the electrical stimulation is performed at a voltage of 1 to 3 mV with a safety margin of 10 mV and a frequency of 150 - 200 Hz.

The device of claim 1, substantially as described and explained and / or described herein with reference to the accompanying figures.

A method according to claim 7, substantially as described and explained and / or described herein with reference to the accompanying figures.