Patent Application Titled “Lipid Biomarkers For Stable And Unstable Heart Disease” Published Online (USPTO 20230417777): Patent Application

2024 JAN 16 (NewsRx) -- By a News Reporter-Staff News Editor at Insurance Daily News -- According to news reporting originating from Washington, D.C., by NewsRx journalists, a patent application by the inventors Bedo, Justin (Docklands, AU); Goudey, Benjamin (Sassafras, AU); Haviv, Izhak (Caulfield, AU); Kingwell, Bronwyn Anne (Melbourne, AU); Meikle, Peter John (Lower Plenty, AU), filed on January 27, 2023, was made available online on December 28, 2023.

No assignee for this patent application has been made.

Reporters obtained the following quote from the background information supplied by the inventors: “Bibliographic details of references provided in the subject specification are listed at the end of the specification.

“Reference to any prior art is not, and should not be taken as an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.

“Atherosclerosis (AS) is the single most common cause of heart disease and is the major contributor to the development of angina, heart attacks and stroke. Despite the introduction of statin-based therapy to reduce levels of plasma low density lipoprotein (LDL) cholesterol, the epidemic of heart disease is claiming tens of thousands of lives each year, particularly in Western countries and costs the health system over billions of dollars per year (National Health Survey: Summary of Results, Australia, 2004-05, cat. no. 4364.0, ABS, Canberra, Vol: Australian Bureau of Statistics, 2006, (AIHW) AloHaW. Health system expenditure on disease and injury in Australia, 2000-01. Health and Welfare Expenditure Series No. 19, 2004; HWE 26).

“Atherosclerosis begins to develop early in life and progresses with time. However, the rate of progression is, to a large extent, unpredictable and differs markedly amongst seemingly comparable individuals. One of the early events leading to Atherosclerosis is the formation of “fatty streaks”, deposits of monocytes, macrophages, foam cells and lipids within the intima of the arterial wall. Fatty streaks exist in most adults and can remain as fatty streaks for years or decades, having little or no adverse clinical effects. Some, but not all, fatty steaks progress into fibriolipid plaques which are distinguished by the presence of smooth muscle cells and increased extracellular fibres within the intima. Cell death within the plaque leads to the formation of a necrotic core, the accumulation of extracellular material and the formation of the complex plaque. At this stage, the plaque may severely restrict blood flow leading to a range of clinical complications; however, many individuals will be unaware of the problem and show no symptoms.

“Complex plaques can become unstable (a “vulnerable” plaque) as a result of the thinning of the smooth muscle cell layer over the plaque. Unstable plaques may rupture leading to thrombosis, myocardial infarction and stroke with the associated morbidity and mortality (the “vulnerable” patient). Although plaque accumulation and development is progressive throughout life, the switch from stable to unstable plaque can occur earlier or later in the disease process. Thus a 45 year old with relatively low levels of plaque can become unstable leading to a coronary event.

“Despite our detailed knowledge of plaque pathology and progression many individuals have no clinical symptoms and so are unaware of their risk. In 30 to 50% of these individuals, the first indicator of Atherosclerosis is an acute heart attack which is often fatal (Heart Disease and Stroke Statistics-2006 Update, Dallas TX: American Heart Association, 2006. Available at http://www.americanheart.org/downloadable/heart/1198257493273HS_Stats%202008.pdf)

“A non-invasive assay is required to identify and monitor heart disease.”

In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors’ summary information for this patent application: “Each embodiments described herein is to be applied mutatis mutandis to each any every embodiment unless specifically stated otherwise.

“The present invention applies a lipidomic approach to identifying the presence, development, stage or severity of heart disease or its various manifestations.

“An association is therefore identified between the level of lipidomic analytes in a subject and heart disease. The term “analyte” includes biomarker and indicator. By “heart disease” is meant an individual condition as well as a collection of conditions within the clinical spectrum of symptomatic or asymptomatic heart disease. The lipidomic biomarkers provide a range of risk indicators of the severity of disease and rate of progression and a classification of the disease such as stable or unstable in relation to plaques. This risk ranges from minor to extreme. Knowledge of the level of risk enables intervention to mitigate further development of heart disease. The ability to monitor and identify markers of heart disease including diagnosing it in asymptomatic subjects further enables decisions on the type of medical intervention required from behavioural modification and medicaments to surgical intervention. The lipidomic biomarkers are also instructive as to the level of risk for an individual developing more severe symptomology associated with heart disease. The lipidomic profile also defines a desired state of health in subjects. Hence, monitoring changing levels of lipid analytes is a useful tool in pharmacotranslational studies and clinical management of patients.

“Reference to “heart disease” includes conditions such as coronary heart disease (including coronary artery disease, angina pectoris and myocardial infarction), atherosclerosis, cardiomyopathy (including that associated with arrhythmia), cardiovascular disease, ischaemic heart disease, heart failure (including cor pulmonale), hypertensive heart disease (including left ventricular hypertrophy and congestive heart failure), inflammatory heart disease (including endocarditis, inflammatory cardiomegaly and myocarditis) and valvular heart disease (including aortic valve stenosis and mitral valve prolapse). Heart disease spectrum also includes associated conditions such as aortic aneurysm, hypertension, thrombosis and pericarditis. Heart disease is a spectrum of clinical manifestations.

“The present invention is predicated in part on the determination that subjects with heart disease or at risk of developing heart disease exhibit altered lipid metabolism. The levels of particular lipidomic analytes correlate with the state, stage and/or classification of heart disease and its progression in symptomatic and asymptomatic subjects. By “classification” includes identifying subjects with stable and unstable plaques and hence, individuals can be classified as vulnerable or non-vulnerable subjects. Hence, the present invention enables stratification of subjects into risk categories, treatment categories and likely progression outcomes.

“Twenty-three different lipid classes and three hundred and twenty-nine lipid analytes were analysed. Ten different lipid classes comprising thirty lipid analytes were particularly useful for distinguishing between vulnerable and non-vulnerable subjects. Further, eighteen lipid classes comprising ninety-five lipid analytes were useful for distinguishing between control normal subjects and subjects with coronary artery disease. Furthermore, as summarised in Table 16, phosphatidylinositol lipids including seventeen lipid analytes in this class were on average significantly reduced in vulnerable subjects; thirteen lipid classes were reduced on average in coronary artery disease subjects and one lipid class, the diacylglycerols, was increased in coronary artery disease subjects.

“The lipidomic approach uses one or more of three groups of lipid analytes:

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“(i) modified ceramides (modCER), modified phosphatidylcholines (modPC) and modified cholesterol esters (modCE) selected from those listed in Table 1;

“(ii) two or more non-modified lipid analytes selected from the list in Table 1; and/or

“(iii) two or more lipid analytes wherein at least one is a modified lipid analyte (modCER, modPC and/or modCE) and at least one is a non-modified lipid analyte selected from the list in Table 1.

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“The levels or ratios of levels the lipidomic analytes are determined relative to a control. The assay may also be automated or semi-automated. In particular, the levels or ratios of levels may be used as input data for multivariate or univariate analysis leading to an algorithm which can be used to generate an index of probability of having or progressing with heart disease.

“The levels of the lipid biomarkers may also be used in combination with other standard indicators of heart disease, whether biochemical markers, symptoms or electrocardial techniques.

“Accordingly, one aspect of the present invention is directed to an assay to stratify a subject as a vulnerable or non-vulnerable subject with respect to plaques, the assay comprising determining the levels of a lipid analyte selected from the list consisting of:

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“(i) one or more modified lipid analytes listed in Table 1;

“(ii) two or more non-modified lipid analytes listed in Table 1, and

“(iii) two or more lipid analytes wherein at least one is a modified lipid analyte listed in Table 1 and at least one is a non-modified lipid analyte listed in Table 1;

“wherein the level or ratio of the lipid analyte or analytes relative to a control identifies the subject as being vulnerable or non-vulnerable.

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“Yet another aspect of the present invention contemplates an assay to stratify a subject with respect to heart disease, the assay comprising determining the levels of a lipid analyte selected from the list consisting of:

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“(i) one or more modified lipid analytes listed in Table 1;

“(ii) two or more non-modified lipid analytes listed in Table 1, and/or

“(iii) two or more lipid analytes wherein at least one is a modified lipid analyte listed in Table 1 and at least one is a non-modified lipid analyte listed in Table 1;

“wherein the level or ratio of the lipid analyte or analytes relative to a control provides a correlation as to the presence, state, classification or progression of heart disease.

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“In some embodiments, the assays comprise determining the levels of at least two lipid analytes.

“Still another aspect of the present invention contemplates the use of a panel of lipid analytes selected from the list consisting of:

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“(i) one or more modified lipid analytes listed in Table 1;

“(ii) two or more non-modified lipid analytes listed in Table 1, and

“(iii) two or more lipid analytes wherein at least one is a modified lipid analyte listed in Table 1 and at least one is a non-modified lipid analyte listed in Table 1;

“in the manufacture of an assay to identify the presence, state, classification or progression of heart disease in a subject. In particular embodiments, the assay is used to identify vulnerable or non-vulnerable subjects.

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“Even yet another aspect of the present invention relates to a method of treatment or prophylaxis of a subject comprising assaying the subject with respect to heart disease by determining the levels of a lipid analyte selected from the list consisting of:

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“(i) one or more modified lipid analytes listed in Table 1;

“(ii) two or more non-modified lipid analytes listed in Table 1, and

“(iii) two or more lipid analytes wherein at least one is a modified lipid analyte listed in Table 1 and at least one is a non-modified lipid analyte listed in Table 1;

“wherein the level or ratio of the lipid analyte or analytes relative to a control provides a correlation to the presence, state, classification or progression of heart disease and then providing therapeutic and/or behavioural modification to the subject.

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“The “stratification” is in effect a level of risk that a subject has heart disease or is developing heart disease or is likely to develop symptoms of heart disease.

“The determination of the levels or ratios of the lipid biomarkers may be used in combination with other indicators of heart disease and may be used to monitor efficacy of treatment. In addition, the assay may be useful in determining the most effective therapeutic or behavioural intervention to treat heart disease in symptomatic or asymptomatic subjects.

“The assay may also be used in a personalized medicine approach in the management of heart disease and/or as part of a pathology architecture platform.

“The above summary is not and should not be seen in any way as an exhaustive recitation of all embodiments of the present invention.”

There is additional summary information. Please visit full patent to read further.”

The claims supplied by the inventors are:

“1. An assay to stratify a subject as a vulnerable or non-vulnerable subject with respect to plaques, the assay comprising determining the levels of at least two lipid analytes selected from the list consisting of: (i) one or more modified lipid analytes listed in Table 1; (ii) two or more non-modified lipid analytes listed in Table 1; and/or (iii) two or more lipid analytes wherein at least one is a modified lipid analyte listed in Table 1 and at least one is a non-modified lipid analyte listed in Table 1; wherein the level of an individual lipid analyte listed in Table 1 is different between vulnerable subjects and non-vulnerable subjects and wherein the level of the lipid analytes in the subject relative to a control identifies the subject as being vulnerable or non-vulnerable.

“2. The assay of claim 1, comprising comparing the level of the at least two lipid analytes in the subject to the respective levels of the same lipid analytes in at least one control subject selected from a vulnerable subject and a non-vulnerable subject, wherein a similarity in the respective levels of the at least two lipid analytes between the subject and the non-vulnerable subject identifies the subject as being non-vulnerable, and wherein a similarity in the respective levels of the at least two lipid analytes between the subject and the vulnerable subject identifies the subject as being vulnerable.

“3. The assay of claim 2, further comprising comparing the level of the at least two lipid analytes in the subject to the respective levels of the same lipid analytes in at least one normal subject, wherein a similarity in the respective levels of the at least two lipid analytes between the subject and the normal subject identifies the subject as being normal with respect to plaques.

“4. The assay of claim 1, comprising determining or determining and comparing the levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 lipid analytes listed in Table 1 wherein the level of an individual lipid analyte listed in Table 1 is different between vulnerable subjects and non-vulnerable subjects.

“5. The assay of claim 1, further comprising determining the levels of at least two lipid analytes selected from the list consisting of: (i) one or more modified lipid analytes listed in Table 1; (ii) two or more non-modified lipid analytes listed in Table 1; and/or (iii) two or more lipid analytes wherein at least one is a modified lipid analyte listed in Table 1 and at least one is a non-modified lipid analyte listed in Table 1; wherein the level of an individual lipid analyte listed in Table 1 is different between normal subjects and heart disease subjects and wherein the level of the lipid analytes in the subject relative to a control identifies the subject as being a normal subject or a heart disease subject.

“6. The assay of claim 5, comprising comparing the level of the at least two lipid analytes in the subject to the respective levels of the same lipid analytes in at least one control subject selected from a normal subject and a heart disease subject, wherein a similarity in the respective levels of the at least two lipid analytes between the subject and the heart disease subject identifies the subject as having heart disease, and wherein a similarity in the respective levels of the at least two lipid analytes between the subject and the normal subject identifies the subject as being normal with respect to heart disease.

“7. The assay of claim 5, comprising determining or determining and comparing the levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 lipid analytes listed in Table 1 wherein the level of an individual lipid analyte listed in Table 1 is different between normal subjects and heart disease subjects.

“8. The assay of claim 1, wherein the or each modified lipid analyte in (i) is selected from a modified ceramide (modCER) and a modified phosphatidylcholine (modPC).

“9. The assay of claim 1, wherein the non-modified lipid analytes in (ii) are selected from a dihexosylceramide (DHC), a sphingomyelin (SM), a phosphatidylinositol (PI), a lysophosphatidylcholine (LPC), a phosphatidylcholine (PC), an alkylphosphatidylcholine (APC), a cholesterol ester (CE), a diacylglycerol (DG) and a triacylglycerol (TG).

“10. The assay of claim 1, wherein the or each modified lipid analyte in (iii) is selected from a modified ceramide (modCER) and a modified phosphatidylcholine (modPC) and the or each non-modified lipid in (iii) is selected from a dihexosylceramide (DHC), a sphingomyelin (SM), a phosphatidylinositol (PI), a lysophosphatidylcholine (LPC), a alkylphosphatidylcholine (APC), a cholesterol ester (CE), a diacylglycerol (DG) and a triacylglycerol (TG).

“11. The assay of claim 1, comprising determining the levels of at least two lipid analytes selected from modCer 731.6, GM3 18:0, PC34:5, DHC 18:1, APC 34:2, SM 18:0, Cer 18:1, PI 36:1, APC 36:0, DG 18:1 20:0, LPC 14:0, LPC 16:1, PC 24:0, Cer 18:0, PI 36:3, PI 38:2, modPC.622.4/40, LPC 18:2, LPC 24:0, PC 34:3, modPC 752.6/5.58, PI 34:0, modCer 703.6/5.87 and SM 22:1.

“12. The assay of claim 11, comprising determining the levels of at least four, six, eight or sixteen lipid analytes selected from the group consisting of modCer 731.6, GM3 18:0, PC34:5, DHC 18:1, APC 34:2, SM 18:0, Cer 18:1, PI 36:1, APC 36:0, DG 18:1 20:0, LPC 14:0, LPC 16:1, PC 24:0, Cer 18:0, PI 36:3, PI 38:2, modPC.622.4/40, LPC 18:2 and LPC 24:0, PC 34:3, modPC 752.6/5.58, PI 34:0, modCer 703.6/5.87 and SM 22:1.

“13. The assay of claim 1, wherein the assayed levels of lipid analytes are used in combination with one or more traditional risk factors selected from age, sex, smoker, diabetes, hypertension, CAD family history, BMI, total cholesterol, LDL, HDL, triglycerides, glucose and hsCRP to thereby identify the subject as being vulnerable or non-vulnerable.

“14. An assay to stratify a subject with respect to heart disease, the assay comprising determining the levels of at least two lipid analytes selected from the list consisting of: (i) one or more modified lipid analytes listed in Table 1; (ii) two or more non-modified lipid analytes listed in Table 1, and/or (iii) two or more lipid analytes wherein at least one is a modified lipid analyte listed in Table 1 and at least one is a non-modified lipid analyte listed in Table 1; wherein the level of an individual lipid analyte listed in Table 1 is different between normal and heart disease subjects and wherein the level of the lipid analytes in the subject relative to a control provides an indication of the presence or absence of heart disease.

“15. The assay of claim 14, comprising comparing the level of the at least two lipid analytes in the subject to the respective levels of the same lipid analytes in at least one control subject selected from a normal subject and a heart disease subject, wherein a similarity in the respective levels of the at least two lipid analytes between the subject and the heart disease subject identifies the subject having heart disease, and wherein a similarity in the respective levels of the at least two lipid analytes between the subject and the normal subject identifies the subject as a normal subject with respect to heart disease.

“16. The assay of claim 14, comprising determining or determining and comparing the levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 lipid analytes.

“17. The assay of claim 14, wherein the modified lipid analyte in (i) is one or more of a modified ceramide (modCER) and a modified phosphatidylcholine (modPC).

“18. The assay of claim 14 wherein the non-modified lipid analyte in (ii) is two or more of a ceramide (CER), monohexosylceramide (MHC), dihexosylceramide (DHC), trihexosylceramide (THC), GM3 Ganglioside (GM3), modified ceramides (modCer), sphingomyelin (SM), phosphatidylserine (PS), phosphatidylinositol (PI), lysophosphatidylcholine (LPC), lysoplatelet activating factor (LPAF), phosphatidylcholine (PC), odd-chain phosphatidylcholine (oddPC), alkylphosphatidylcholine (APC), modified phosphatidylcholine (modPC), cholesterol esters (CE), diacylglycerol (DG), and triacylglycerol (TG).

“19. The assay of claim 14, wherein the or each modified lipid analyte in (iii) is one or more of a modified ceramide (modCER) and a modified phosphatidylcholine (modPC) and the or each non-modified lipid in (iii) is selected from a ceramide (CER), a monohexosylceramide (MHC), a dihexosylceramide (DHC), trihexosylceramide (THC), GM3 Ganglioside (GM3), modified ceramides (modCer), sphingomyelin (SM), phosphatidylserine (PS), phosphatidylinositol (PI), lysophosphatidylcholine (LPC), lysoplatelet activating factor (LPAF), phosphatidylcholine (PC), odd-chain phosphatidylcholine (oddPC), alkylphosphatidylcholine (APC), modified phosphatidylcholine (modPC), cholesterol esters (CE), diacylglycerol (DG) and a triacylglycerol (TG).

“20. The assay of claim 14, wherein the lipid analyte is two or more of LPC 22:0, PS 40:6, PI 34:0, Cer 20:0, Cer 18:0, APC 34:2, PC 34:5, LPC 20:3, PC 28:0, modPC 692.4/5.8, APC 30:0, modPC 736.5/5.7, LPC 20:4, APC 38:6, modPC 720.5.4.5, PI 36:0, LPC 24:0, PS 40:5, LPC 20:0, modPC 877.6/6.0, CE 22:4, modPC 752.6/5.58, APC 32:1, oddPC 37:3, GM3 24:1, oddPC 33:0, APC 36:0, CE 24:3, SM 20:1, SM 18:0, LPC 20:0, modCE 682.7/8.76, COH, Cer 20:0, LPC 16:1, TG 16:1 16:1 16:1, modPC 564.4/4.70, modPC 720.6/4.52, modPC 608.4/5.33, PE 38:3, PE 38:1, modPC 580.4/4.84, PS 40:6, GM3 22:0, PC 37:3, PC 33:0, modPC 788.6/5.19, C24:3, C24:4, modPC 666.4/2.99, modPC 678.4/4.37, modCer 731.6/6.22, SM 18:1, APC 36:5, modPC 769.6/6.25, APC 36:3, oddPC 35:4, PG 18:1 18:1, TG 18:1 18:1 18:2, modPC 881.7/6.05, CE 17:0 and PI 38:5.”

There are additional claims. Please visit full patent to read further.

For more information, see this patent application: Bedo, Justin; Goudey, Benjamin; Haviv, Izhak; Kingwell, Bronwyn Anne; Meikle, Peter John. Lipid Biomarkers For Stable And Unstable Heart Disease. U.S. Patent Application Number 20230417777, filed January 27, 2023 and posted December 28, 2023. Patent URL (for desktop use only): https://ppubs.uspto.gov/pubwebapp/external.html?q=(20230417777)&db=US-PGPUB&type=ids

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