METHOD OF TREATING DRUG RESISTANT HYPERTENSION AND HEART FAILURE WITH PRESERVED EJECTION FRACTION BY COMBINED DRUG TREATMENT WITH BAROPACING AND BETA BLOCKERS

Abstract

The invention is directed to a method of treating a patient with DRH and/or HFpEf including the steps of: treating the patient with angiotensin converting enzyme inhibitor (ACEI) and/or an angiotensin receptor blocking [ARB] drug; and cardiac pacing the patient as controlled by a BaroPace algorithm. Performance is improved by simultaneously withholding administration of any beta-1 selective beta adrenergic blockers. A method of cardiac pacing to treat drug resistant hypertension and heart failure with preserved ejection fraction (HFpEF) includes the steps of administering to a patient a therapeutic amount of a beta blocker having intrinsic sympathomimetic activity (ISA); and pacing the heart of a patient using the BaroPace algorithm.

Claims

1-30. (canceled)

31. A method for determining a pacing rate, the method comprising: providing at least one of an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocking (ARB) treatment; providing a beta blocker intrinsic sympathomimetic activity (ISA) treatment; receiving a first blood pressure value at a first time subsequent to providing the at least one of the ACEI or the ARB treatment and subsequent to providing the ISA treatment; determining that the first blood pressure value deviates from a target blood pressure value by at least a threshold amount; in response to determining that the first blood pressure value deviates from the target blood pressure value by at least a threshold amount, determining a first pacing rate of a pacing device based on the first blood pressure value; and outputting the first pacing rate.

32. The method of claim 31, wherein determining the first pacing rate of the pacing device is performed in real-time upon receiving the first blood pressure value or determining that the first blood pressure value deviates from the target blood pressure value by at least the threshold amount.

33. The method of claim 31, wherein the first pacing rate is determined based on an artificial intelligence (AI) trend analysis.

34. The method of claim 31, wherein the first pacing rate is approximately 10% greater than a baseline atrial pacing rate.

35. The method of claim 31, further comprising: receiving a second blood pressure value at a second time subsequent to the first time; determining that the second blood pressure value deviates from the target blood pressure value by at least the threshold amount; and in response to determining that the second blood pressure value deviates from the target blood pressure value by at least the threshold amount, determining a second pacing rate of the pacing device.

36. The method of claim 31, wherein the first blood pressure value is a systolic blood pressure (SBP) value.

37. The method of claim 31, further comprising: receiving a second blood pressure value at a second time subsequent to the first time; determining that the second blood pressure value is within the threshold amount of the target blood pressure value; and in response to determining that the second blood pressure value is within the threshold amount of the target blood pressure value, maintaining the first pacing rate of the pacing device.

38. The method of claim 31, further comprising: receiving a second blood pressure value at a second time subsequent to the first time; determining that the second blood pressure value is lower than the first blood pressure value by a threshold pressure value; and in response to determining that the second blood pressure value is lower than the first blood pressure value by the threshold pressure value, maintaining the first pacing rate of the pacing device.

39. A system comprising: a first module configured to provide at least one of an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocking (ARB) treatment; a second module configured to provide a beta blocker intrinsic sympathomimetic activity (ISA) treatment; a pacing device configured to output electric pacing signals based on pacing rates; and at least one processor executing instructions to perform a process, the at least one processor configured to: receive a first blood pressure value at a first time subsequent to providing the at least one of the ACEI or the ARB treatment and subsequent to providing the ISA treatment; determine that the first blood pressure value deviates from a target blood pressure value by at least a threshold amount; in response to determining that the first blood pressure value deviates from the target blood pressure value by at least a threshold amount, determine a first pacing rate of a pacing device based on the first blood pressure value; and output the first pacing rate.

40. The system of claim 39, wherein the processor is configured to determine the first pacing rate of the pacing device in real-time upon receiving the first blood pressure value or determining that the first blood pressure value deviates from the target blood pressure value by at least the threshold amount.

41. The system of claim 39, further comprising an artificial intelligence (AI) module configured to output the first pacing rate based on trend analysis.

42. The system of claim 39, wherein the first pacing rate is approximately 10% greater than a baseline atrial pacing rate.

43. The system of claim 39, wherein the processor is further configured to: receive a second blood pressure value at a second time subsequent to the first time; determine that the second blood pressure value deviates from the target blood pressure value by at least the threshold amount; and in response to determining that the second blood pressure value deviates from the target blood pressure value by at least the threshold amount, determine a second pacing rate of the pacing device.

44. The system of claim 39, wherein the first blood pressure value is a systolic blood pressure (SBP) value.

45. The system of claim 39, wherein the processor is further configured to: receive a second blood pressure value at a second time subsequent to the first time; determine that the second blood pressure value is within the threshold amount of the target blood pressure value; and in response to determining that the second blood pressure value is within the threshold amount of the target blood pressure value, maintain the first pacing rate of the pacing device.

46. The system of claim 39, wherein the processor is further configured to: receive a second blood pressure value at a second time subsequent to the first time; determine that the second blood pressure value is lower than the first blood pressure value by a threshold pressure value; and in response to determining that the second blood pressure value is lower than the first blood pressure value by the threshold pressure value, maintain the first pacing rate of the pacing device.

47. A system comprising: a pacing device configured to output electric pacing signals based on pacing rates; and at least one processor executing instructions to perform a process, the at least one processor configured to: receive a first blood pressure value at a first time subsequent to administration of at least one of an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocking (ARB) treatment and subsequent to administration of a beta blocker intrinsic sympathomimetic activity (ISA) treatment; determine that the first blood pressure value deviates from a target blood pressure value by at least a threshold amount; in response to determining that the first blood pressure value deviates from the target blood pressure value by at least a threshold amount, determine a first pacing rate of a pacing device based on the first blood pressure value; and output the first pacing rate.

48. The system of claim 47, wherein the processor is further configured to: receive a second blood pressure value at a second time subsequent to the first time; determine that the second blood pressure value deviates from the target blood pressure value by at least the threshold amount; and in response to determining that the second blood pressure value deviates from the target blood pressure value by at least the threshold amount, determine a second pacing rate of the pacing device.

49. The system of claim 47, wherein the processor is further configured to: receive a second blood pressure value at a second time subsequent to the first time; determine that the second blood pressure value is within the threshold amount of the target blood pressure value; and in response to determining that the second blood pressure value is within the threshold amount of the target blood pressure value, maintain the first pacing rate of the pacing device.

50. The system of claim 47, wherein the processor is further configured to: receive a second blood pressure value at a second time subsequent to the first time; determine that the second blood pressure value is lower than the first blood pressure value by a threshold pressure value; and in response to determining that the second blood pressure value is lower than the first blood pressure value by the threshold pressure value, maintain the first pacing rate of the pacing device.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] It has only recently been found that the concurrent use of a beta-1 selective adrenergic blocking drug in patients with drug resistant hypertension (DRH) and/or heart failure with preserved ejection fraction (HFpEf) negates the beneficial effect of conventional pacing therapies, as predicted by the BaroPace Effect that states that any maneuver or drug that lowers heart rate has an adverse effect, likely by increasing peripheral resistance. The negative effect of a beta-1 selective beta blocker on a conventionally paced patient is seen as: 1) a failure to lower blood pressure with pacing; 2) a failure to improve New York Heart Association Functional Classification or NYHA Class with pacing; and 3) an increase in hospitalizations for HFpEF, and 4) the continued need for maximal drug therapy. Because beta-1 selective beta adrenergic blocking drugs are a primary focus of all therapeutic guidelines for treatment of both DRH and HFpEF, this finding has profound implications.

[0031] The concurrent use of an angiotensin converting enzyme inhibitor (ACEI) and/or an angiotensin receptor blocking [ARB] drug in the same subsets of pacing patients significantly improves the same categories of outcomes when combined with BaroPacing, which is defined herein as a pacing method using AI or using a pacing method without AI to identify a trend analysis using a stimulus architecture algorithm (SAA), as disclosed in An Intelligently, Continuously And Physiologically Controlled Pacemaker And Method Of Operation Of The Same, International Pat. App. PCT/US20/25447; and/or Method of Treatment of Drug Resistant Hypertension by Electrically Stimulating the Right Atrium to Create Inhibition of the Autonomic Nervous System, International Pat. Appl., PCT/US20/44784, both incorporated herein by reference, including in particular the drawings and related textual material therefrom which illustrate various ones of the claims below.

[0032] Therefore, the combination of a pacemaker regulated according to the BaroPace or PressurePace AI methods provides an improved method of treatment for DRH and HFpEF, and also likely improves exercise tolerance in both subsets of patients.

[0033] ACEIs and ARBs reduce blood pressure in normal patients by blocking the effect of the natural vasoconstrictive substance angiotensin. An ACEI blocks the conversion of the inactive form of angiotensin to its active form. An ARB blocks the receptor for angiotensin preventing it from producing an effect. Angiotensin has no effect on heart rate at useful dosages. However, ACEIs and ARBs alone have no beneficial effect in DRH and HFpEF patients. The combination of the ANI inhibitor sacubitril with the ARB valsartan was recently approved as an adjunct drug therapy for the treatment of HFpEF.

[0034] Beta blockers block the effect of the hormones epinephrine and norepinephrine by occupying their receptors. The effects epi and norepi are complex and include an increase in heart rate which is dose dependent, an increase in blood pressure by direct vasoconstriction different from angiotensin, an increase in cardiac contractility, vasoconstriction in the gut blood flow which isn't needed during fight or flight, and more. Beta-1 selective beta adrenergic blockers are bad for HFpEF and DRH patients because they lower heart rate. Beta adrenergic blocking drugs with ISA may be either less deleterious or beneficial because they do not lower heart rate to the same drug, or at all. ACEIs and ARBs are probably good because they reduce resistance without doing anything else, such as lowering heart rate.

[0035] More importantly, there is no direct evidence of any one or combination of ACEI/ARBs improve HFpEF, NYHA class or reduce hospitalizations. Surprisingly, it is only when you combine ACEI/ARBs with BaroPacing that you unlock the therapeutic potential of the drugs. This is further amplified when you withhold or remove the negative effect of beta-1 selective beta blockers.

[0036] ACEIs/ARBs have heretofore no documented beneficial effect in HFpEF or DRH patients, who were conventionally paced. This new effect with BaroPacing is seen objectively in our data. The effect is striking in the case of DRH patients. Drug resistant hypertension means by definition, that even in the presence of ACEI/ARBS, the hypertension is still resistant. By definition the drugs aren't working. Add BaroPacing and the drugs have the same beneficial effects as they do in other patients. The combination of BaroPacing plus ACEI/ARB treatment gives rise to a new method to treat DRH patients.

[0037] In the case of HFpEF, the most recent American College of Cardiology position statement on HFpEF begins by saying, in essence, that nothing is known to work, either in drugs or devices, to treat HFpEF, with the exception of sacubitril/valsartan. Add BaroPacing to one of the drug classes and subtract beta-1 selective beta blockers, and a clear beneficial effect of ACE/ARB's in HFpEF patients becomes demonstrable. No such relationship for ACE/ARB's without sacubitril is known to exist absent the BaroPacing. The combination of sacubitril with valsartan is known to be associated severe side effects, including hyperkalemia, hypotension, and increased serum creatinine. Other side effects include: acute kidney injury, and renal failure syndrome. Thus, while sacubitril/valsartan is approved for use in HFpEF, the combination of BaroPacing alone or with an ACEI or ARB alone or in combination with the conventional treatment modalities listed above offers much less risk of an adverse event.

[0038] Again the combination of BaroPacing and ACEI/ARBs and the absence of beta blockers forms a new method for the treatment of HFpEF patients that can't be demonstrated for the ACEI/ARB without BaroPacing.

[0039] We have previously published retrospective data in patients with permanent pacing and drug resistant hypertension (HTN), showing a significant decline in systolic BP (SBP) that was strongly correlated with atrial pacing. It has also been reported that cardiac pacing inhibits sympathetic autonomic nerve activity. In an office-based study, we tested the acute effects of increasing atrial pacing rate in patients with pre-existing HTN and permanent pacemakers.

[0040] A total of 12 patients with HTN and previously implanted pacemakers for routine clinical indications were included in this study. Patients with atrial fibrillation were excluded. After a one-hour rest period, atrial pacing was increased by 10% over baseline atrial pacing or sensing rate every 15 minutes. If the SBP did not decline by >10 mmHg, pacing rate was increased by additional 10% increments for a maximal total of four interventions/patient, when applicable. If SBP declined by >10 mmHg at any stage, no further pacing changes were made.

[0041] A total of 33 treatment events, i.e., changes in programmed atrial pacing rate, were performed in the 12 patients. Mean drop in SBP was 8.17.5 mmHg; diastolic BP (DBP) declined 6.13.6 mmHg (p<0.01). Patients taking beta-1 selective beta blockers (BIB) were significantly less likely to show this effect (63% interventions vs 14%, B1B vs no B1B, p=0.01). No patient on B1B therapy showed a SBP decline>10 mmHg vs 37% treatment events in patients not on BB (p=0.013).

[0042] In hypertensive patients, incremental atrial pacing results in significant acute drops in SBP and DBP. This effect is largely blocked by chronic beta-1 selective beta blocker therapy. The latter may be secondary to a pre-existing low sympathetic tone in patients treated with beta blockers. The results of this preliminary study suggest that further investigation of atrial pacing in patients with HTN is warranted. As well, the current paradigm of treating HTN with B1B may not apply to patients with permanent atrial pacing.

[0043] Many alterations and modifications may be made by those having ordinary skill in the art without departing from the spirit and scope of the embodiments. Therefore, it must be understood that the illustrated embodiment has been set forth only for the purposes of example and that it should not be taken as limiting the embodiments as defined by the following embodiments and its various embodiments.

[0044] Therefore, it must be understood that the illustrated embodiment has been set forth only for the purposes of example and that it should not be taken as limiting the embodiments as defined by the following claims. For example, notwithstanding the fact that the elements of a claim are set forth below in a certain combination, it must be expressly understood that the embodiments includes other combinations of fewer, more or different elements, which are disclosed in above even when not initially claimed in such combinations. A teaching that two elements are combined in a claimed combination is further to be understood as also allowing for a claimed combination in which the two elements are not combined with each other, but may be used alone or combined in other combinations. The excision of any disclosed element of the embodiments is explicitly contemplated as within the scope of the embodiments.

[0045] The words used in this specification to describe the various embodiments are to be understood not only in the sense of their commonly defined meanings, but to include by special definition in this specification structure, material or acts beyond the scope of the commonly defined meanings. Thus if an element can be understood in the context of this specification as including more than one meaning, then its use in a claim must be understood as being generic to all possible meanings supported by the specification and by the word itself.

[0046] The definitions of the words or elements of the following claims are, therefore, defined in this specification to include not only the combination of elements which are literally set forth, but all equivalent structure, material or acts for performing substantially the same function in substantially the same way to obtain substantially the same result. In this sense it is therefore contemplated that an equivalent substitution of two or more elements may be made for any one of the elements in the claims below or that a single element may be substituted for two or more elements in a claim. Although elements may be described above as acting in certain combinations and even initially claimed as such, it is to be expressly understood that one or more elements from a claimed combination can in some cases be excised from the combination and that the claimed combination may be directed to a subcombination or variation of a subcombination.

[0047] Insubstantial changes from the claimed subject matter as viewed by a person with ordinary skill in the art, now known or later devised, are expressly contemplated as being equivalently within the scope of the claims. Therefore, obvious substitutions now or later known to one with ordinary skill in the art are defined to be within the scope of the defined elements.

[0048] The claims are thus to be understood to include what is specifically illustrated and described above, what is conceptionally equivalent, what can be obviously substituted and also what essentially incorporates the essential idea of the embodiments.