Disease Information

General Information of the Disease (ID: DIS00123)

• Name: Heart failure
• ICD: ICD-11: BD10

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Aspirin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Prostaglandin-endoperoxide synthase 1 (PTGS1) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs10306114
• Resistant Drug: Aspirin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Key Molecule: Prostaglandin G/H synthase 2 (PTGS2) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs20417
• Resistant Drug: Aspirin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs1045642
• Resistant Drug: Aspirin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Thromboxane A2 receptor (TBXA2R) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs4523+rs1131882+rs768963+rs2238634+rs4806942
• Resistant Drug: Aspirin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Clopidogrel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: P2Y purinoceptor 1 (P2RY1) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs701265+rs1439010+rs1371097+rs1065776+rs12497578
• Resistant Drug: Clopidogrel
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Key Molecule: Purinergic receptor P2Y12 (P2RY12) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs2046934+rs12637988+rs16863336+rs6798347+rs16863323+rs9859538+rs16846673+rs6809699+rs6785930+rs5853517+rs10935838
• Resistant Drug: Clopidogrel
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Liver carboxylesterase 1 (CES1) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs8192950
• Resistant Drug: Clopidogrel
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Key Molecule: Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs4244285+rs4986893+rs28399504+rs56337013+rs72552267+rs72558186+rs12248560
• Resistant Drug: Clopidogrel
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Key Molecule: Cytochrome P450 family 2 subfamily C member 9 (CYP2C9) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs1799853+rs1057910
• Resistant Drug: Clopidogrel
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Key Molecule: Cytochrome P450 family 3 subfamily A member1 (CYP3A4) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs2740574+rs55785340+rs4986910
• Resistant Drug: Clopidogrel
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Key Molecule: Cytochrome P450 family 3 subfamily A member 5 (CYP3A5) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs776746
• Resistant Drug: Clopidogrel
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Key Molecule: Paraoxonase 1 (PON1) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs662
• Resistant Drug: Clopidogrel
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs1045642+rs2032562
• Resistant Drug: Clopidogrel
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Integrin subunit beta 3 (ITGB3) [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Molecule Alteration: SNP; rs5918
• Resistant Drug: Clopidogrel
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Digoxin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [2]

• Resistant Disease: Heart failure [ICD-11: BD10.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Digoxin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: LS-180 cells; Colon; Homo sapiens (Human); CVCL_0397
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Rhodamine 123 fluorometric assay
• Mechanism Description: Chronic use of Saint John's wort (SJW) has been shown to lower the bioavailability for a variety of co-administered drugs including indinavir, cyclosporin, and digoxin. Decreases in intestinal absorption through induction of the multidrug resistance transporter, P-glycoprotein (P-gp), may explain decreased bioavaila.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [3]

• Sensitive Disease: Heart failure [ICD-11: BD10.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Digoxin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• Experiment for Molecule Alteration: Bi-directional transport assay
• Mechanism Description: In addition to expression in tumor cells, the ATP-dependent P-gp efflux transporter is localized in a variety of normal tissues including the apical membranes of the epithelial cells lining the luminal surface of the enterocytes in the small intestine/gastrointestinal tract, the biliary canalicular membranes of hepatocytes, the apical luminal membranes of the proximal tubular epithelial cells in the kidney, and the plasma membranes of brain capillary endothelial cells forming the blood-brain barrier (BBB). P-gp in these tissues functions as a drug efflux pump greatly affecting substrate absorption, distribution, and excretion. Loxapine (as the succinate salt) was evaluated as a P-gp substrate, and inhibitor of P-gp mediated transport of digoxin in vitro in Caco-2 cells. Loxapine was not a substrate for P-gp but did exhibit weak-to-moderate inhibition (IC50 = 9.1 uM).

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [4], [5], [6]

• Sensitive Disease: Heart failure [ICD-11: BD10.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Digoxin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: MDCk-MDR1(Canis lupus familiaris (Dog)); Kidney; Homo sapiens (Human); CVCL_S586
• In Vitro Model: IPS cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Ussing chamber system assay
• Mechanism Description: Digoxin and fexofenadine (each 5 uM) were selected as P-gp substrates, and sulfasalazine and rosuvastatin (each 5 uM) were selected as BCRP substrates to evaluate the efflux transport mediated by P-gp and BCRP. PSC833 (15 uM) and ko143 (15 uM) were used as typical inhibitors of P-gp and BCRP, respectively. Serosal-to-mucosal transport of all the tested P-gp and BCRP substrate drugs was significantly decreased or tended to decrease in the presence of P-gp/BCRP inhibitor cocktail.

Hydrogen peroxide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: myosin heavy chain associated RNA transcript (MHRT) [7]

• Resistant Disease: Chronic heart failure [ICD-11: BD10.2]
• Molecule Alteration: Down-regulation; Expression
• Resistant Drug: Hydrogen peroxide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: AC16 cells; Heart; Homo sapiens (Human); CVCL_4U18
• Experiment for Molecule Alteration: qRT-PCR; Overexpression assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Chronic heart failure patients with lower expression levels of LncRNA MHRT had worse survival conditions compared to patients with higher expression levels of LncRNA MHRT.

Key Molecule: Growth arrest associated LncRNA 1 (GASAL1) [8]

• Resistant Disease: Chronic heart failure [ICD-11: BD10.2]
• Molecule Alteration: Down-regulation; Expression
• Resistant Drug: Hydrogen peroxide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AC16 cells; Heart; Homo sapiens (Human); CVCL_4U18
• Experiment for Molecule Alteration: ELISA assay; qRT-PCR; Western bloting analysis; Overexpression assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: LncRNA GASL1 is downregulated in chronic heart failure and regulates cardiomyocyte apoptosis.

Triamterene

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epithelial sodium channel (ENAC) [9]

• Resistant Disease: Hypertension [ICD-11: BA00.Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triamterene
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: In addition to pharmacokinetic effects, compensatory upregulation of sodium transporters not blocked by the diuretic also contributes to diuretic resistance. In patients with CKD, plasma aldosterone levels may be elevated even in the presence of normal plasma renin activity and normal serum potassium concentrations. Elevated plasma levels of both angiotensin II and aldosterone can activate sodium transporters in the distal nephron, including the Na+/Cl cotransporter and ENaC.

References

• Ref 1: Gene polymorphisms in dual antiplatelet therapy and the presence of hypo-attenuated leaflet thickening after transcatheter aortic valve replacement .J Thromb Thrombolysis. 2018 Apr;45(3):463-465. doi: 10.1007/s11239-018-1636-z. 10.1007/s11239-018-1636-z
• Ref 2: Saint John's wort: an in vitro analysis of P-glycoprotein induction due to extended exposure. Br J Pharmacol. 2001 Dec;134(8):1601-8. doi: 10.1038/sj.bjp.0704399.
• Ref 3: Loxapine P-glycoprotein interactions in vitro. Drug Metab Lett. 2012 Mar;6(1):26-32. doi: 10.2174/187231212800229255.
• Ref 4: Application of Intestinal Epithelial Cells Differentiated from Human Induced Pluripotent Stem Cells for Studies of Prodrug Hydrolysis and Drug Absorption in the Small Intestine. Drug Metab Dispos. 2018 Nov;46(11):1497-1506. doi: 10.1124/dmd.118.083246. Epub 2018 Aug 22.
• Ref 5: Inhibitory Effects of Commonly Used Excipients on P-Glycoprotein in Vitro. Mol Pharm. 2018 Nov 5;15(11):4835-4842. doi: 10.1021/acs.molpharmaceut.8b00482. Epub 2018 Oct 23.
• Ref 6: Characterization of the Human Intestinal Drug Transport with Ussing Chamber System Incorporating Freshly Isolated Human Jejunum. Drug Metab Dispos. 2021 Jan;49(1):84-93. doi: 10.1124/dmd.120.000138. Epub 2020 Oct 21.
• Ref 7: Circulating lncRNA MHRT predicts survival of patients with chronic heart failureJ Geriatr Cardiol. 2019 Nov;16(11):818-821. doi: 10.11909/j.issn.1671-5411.2019.11.006.
• Ref 8: LncRNA GASL1 is downregulated in chronic heart failure and regulates cardiomyocyte apoptosisCell Mol Biol Lett. 2019 Jun 13;24:41. doi: 10.1186/s11658-019-0165-x. eCollection 2019.
• Ref 9: Diuretic Resistance .Am J Kidney Dis. 2017 Jan;69(1):136-142. doi: 10.1053/j.ajkd.2016.08.027. Epub 2016 Nov 1. 10.1053/j.ajkd.2016.08.027