graph LR
Lifestyle_Modification["Lifestyle Modification"]
Pasteurized_Akkermansia_muciniphila_MucT_Supplementation["Pasteurized Akkermansia muciniphila MucT Supplementation"]
High_Calorie_Diet["High-Calorie Diet"]
LEP["LEP"]
MC4R["MC4R"]
Energy_Imbalance["Energy Imbalance"]
POMC["POMC"]
Obesogenic_Environment["Obesogenic Environment"]
Post_Weight_Loss_Weight_Regain["Post-Weight-Loss Weight Regain"]
Increased_Body_Mass_Index["Increased Body Mass Index"]
Intestinal_Barrier_Dysfunction_and_Metabolic_Endotoxemia["Intestinal Barrier Dysfunction and Metabolic Endotoxemia"]
LEPR["LEPR"]
GLP_1_GIP_Dual_Agonists["GLP-1/GIP Dual Agonists"]
Chronic_Low_Grade_Inflammation["Chronic Low-Grade Inflammation"]
Depletion_of_Mucosal_Symbiont_Akkermansia_muciniphila["Depletion of Mucosal Symbiont Akkermansia muciniphila"]
GLP_1_Receptor_Agonists["GLP-1 Receptor Agonists"]
Orlistat["Orlistat"]
Hypothalamic_Dysregulation["Hypothalamic Dysregulation"]
Bariatric_Surgery["Bariatric Surgery"]
Efficient_Intestinal_Energy_Harvest["Efficient Intestinal Energy Harvest"]
Naltrexone_Bupropion["Naltrexone-Bupropion"]
Depletion_of_Mucosal_Symbiont_Akkermansia_muciniphila --> Intestinal_Barrier_Dysfunction_and_Metabolic_Endotoxemia
Intestinal_Barrier_Dysfunction_and_Metabolic_Endotoxemia --> Chronic_Low_Grade_Inflammation
Efficient_Intestinal_Energy_Harvest --> Energy_Imbalance
Post_Weight_Loss_Weight_Regain --> Increased_Body_Mass_Index
High_Calorie_Diet --> Energy_Imbalance
Obesogenic_Environment --> Increased_Body_Mass_Index
Lifestyle_Modification --> Energy_Imbalance
GLP_1_Receptor_Agonists --> Hypothalamic_Dysregulation
GLP_1_Receptor_Agonists --> Energy_Imbalance
GLP_1_Receptor_Agonists --> Post_Weight_Loss_Weight_Regain
GLP_1_GIP_Dual_Agonists --> Energy_Imbalance
GLP_1_GIP_Dual_Agonists --> Post_Weight_Loss_Weight_Regain
Bariatric_Surgery --> Hypothalamic_Dysregulation
Bariatric_Surgery --> Energy_Imbalance
Orlistat --> Efficient_Intestinal_Energy_Harvest
Orlistat --> Post_Weight_Loss_Weight_Regain
Naltrexone_Bupropion --> Hypothalamic_Dysregulation
Pasteurized_Akkermansia_muciniphila_MucT_Supplementation --> Post_Weight_Loss_Weight_Regain
Pasteurized_Akkermansia_muciniphila_MucT_Supplementation --> Efficient_Intestinal_Energy_Harvest
Pasteurized_Akkermansia_muciniphila_MucT_Supplementation --> Intestinal_Barrier_Dysfunction_and_Metabolic_Endotoxemia
MC4R --> Hypothalamic_Dysregulation
LEP --> Hypothalamic_Dysregulation
LEPR --> Hypothalamic_Dysregulation
POMC --> Hypothalamic_Dysregulation
style Lifestyle_Modification fill:#fce7f3
style Pasteurized_Akkermansia_muciniphila_MucT_Supplementation fill:#fce7f3
style High_Calorie_Diet fill:#dcfce7
style LEP fill:#f3e8ff
style MC4R fill:#f3e8ff
style Energy_Imbalance fill:#dbeafe
style POMC fill:#f3e8ff
style Obesogenic_Environment fill:#dcfce7
style Post_Weight_Loss_Weight_Regain fill:#dbeafe
style Increased_Body_Mass_Index fill:#fef3c7
style Intestinal_Barrier_Dysfunction_and_Metabolic_Endotoxemia fill:#dbeafe
style LEPR fill:#f3e8ff
style GLP_1_GIP_Dual_Agonists fill:#fce7f3
style Chronic_Low_Grade_Inflammation fill:#dbeafe
style Depletion_of_Mucosal_Symbiont_Akkermansia_muciniphila fill:#dbeafe
style GLP_1_Receptor_Agonists fill:#fce7f3
style Orlistat fill:#fce7f3
style Hypothalamic_Dysregulation fill:#dbeafe
style Bariatric_Surgery fill:#fce7f3
style Efficient_Intestinal_Energy_Harvest fill:#dbeafe
style Naltrexone_Bupropion fill:#fce7f3
graph LR
CircAdapt_virtual_pacing_CRT_response_twin["CircAdapt virtual-pacing CRT response twin"]
Tissue_Glucocorticoid_Amplification_by_11beta_HSD1["Tissue Glucocorticoid Amplification by 11beta-HSD1"]
SGLT2_Inhibitors["SGLT2 Inhibitors"]
Orthopnea["Orthopnea"]
Peripheral_Edema["Peripheral Edema"]
Postmenopausal_Oestrogen_Withdrawal["Postmenopausal Oestrogen Withdrawal"]
ARNI_Sacubitril_Valsartan["ARNI (Sacubitril/Valsartan)"]
CircAdapt_par_75_imaging_based_left_ventricular_digital_twin["CircAdapt par-75 imaging-based left-ventricular digital twin"]
Myocardial_Contractile_Dysfunction["Myocardial Contractile Dysfunction"]
BNP_NT_proBNP["BNP/NT-proBNP"]
Coronary_Artery_Disease["Coronary Artery Disease"]
Cardiac_Resynchronization_Therapy["Cardiac Resynchronization Therapy"]
Lipoproteina_Driven_Coronary_Microvascular_Dysfunction["Lipoprotein(a)-Driven Coronary Microvascular Dysfunction"]
Alcohol_Abuse["Alcohol Abuse"]
Hypertension["Hypertension"]
Neurohormonal_Activation["Neurohormonal Activation"]
Loss_of_Myocardial_Oestrogen_Receptor_Signalling["Loss of Myocardial Oestrogen Receptor Signalling"]
Troponin["Troponin"]
Mineralocorticoid_Receptor_Antagonists["Mineralocorticoid Receptor Antagonists"]
Dyspnea["Dyspnea"]
Fatigue["Fatigue"]
Cardiomegaly["Cardiomegaly"]
Fluid_Retention["Fluid Retention"]
Endocrine_Convergence_on_Shared_Profibrotic_Effectors["Endocrine Convergence on Shared Profibrotic Effectors"]
Exercise_Intolerance["Exercise Intolerance"]
Beta_Blockers["Beta Blockers"]
ACE_Inhibitors_ARBs["ACE Inhibitors/ARBs"]
Ventricular_Remodeling["Ventricular Remodeling"]
Diuretics["Diuretics"]
Myocardial_Contractile_Dysfunction --> Neurohormonal_Activation
Myocardial_Contractile_Dysfunction --> Exercise_Intolerance
Myocardial_Contractile_Dysfunction --> Fatigue
Neurohormonal_Activation --> Endocrine_Convergence_on_Shared_Profibrotic_Effectors
Neurohormonal_Activation --> Ventricular_Remodeling
Neurohormonal_Activation --> Fluid_Retention
Ventricular_Remodeling --> Myocardial_Contractile_Dysfunction
Fluid_Retention --> Dyspnea
Fluid_Retention --> Orthopnea
Fluid_Retention --> Peripheral_Edema
Endocrine_Convergence_on_Shared_Profibrotic_Effectors --> Ventricular_Remodeling
Tissue_Glucocorticoid_Amplification_by_11beta_HSD1 --> Endocrine_Convergence_on_Shared_Profibrotic_Effectors
Postmenopausal_Oestrogen_Withdrawal --> Loss_of_Myocardial_Oestrogen_Receptor_Signalling
Postmenopausal_Oestrogen_Withdrawal --> Endocrine_Convergence_on_Shared_Profibrotic_Effectors
Loss_of_Myocardial_Oestrogen_Receptor_Signalling --> Endocrine_Convergence_on_Shared_Profibrotic_Effectors
Lipoproteina_Driven_Coronary_Microvascular_Dysfunction --> Myocardial_Contractile_Dysfunction
Hypertension --> Ventricular_Remodeling
Coronary_Artery_Disease --> Myocardial_Contractile_Dysfunction
Alcohol_Abuse --> Myocardial_Contractile_Dysfunction
ACE_Inhibitors_ARBs --> Neurohormonal_Activation
Beta_Blockers --> Neurohormonal_Activation
Beta_Blockers --> Ventricular_Remodeling
ARNI_Sacubitril_Valsartan --> Neurohormonal_Activation
SGLT2_Inhibitors --> Fluid_Retention
Mineralocorticoid_Receptor_Antagonists --> Endocrine_Convergence_on_Shared_Profibrotic_Effectors
Diuretics --> Fluid_Retention
Cardiac_Resynchronization_Therapy --> Myocardial_Contractile_Dysfunction
CircAdapt_par_75_imaging_based_left_ventricular_digital_twin --> Myocardial_Contractile_Dysfunction
CircAdapt_virtual_pacing_CRT_response_twin --> Ventricular_Remodeling
Neurohormonal_Activation -.-> BNP_NT_proBNP
Myocardial_Contractile_Dysfunction -.-> Troponin
Ventricular_Remodeling -.-> Cardiomegaly
style CircAdapt_virtual_pacing_CRT_response_twin fill:#ecfccb
style Tissue_Glucocorticoid_Amplification_by_11beta_HSD1 fill:#dbeafe
style SGLT2_Inhibitors fill:#fce7f3
style Orthopnea fill:#fef3c7
style Peripheral_Edema fill:#fef3c7
style Postmenopausal_Oestrogen_Withdrawal fill:#dbeafe
style ARNI_Sacubitril_Valsartan fill:#fce7f3
style CircAdapt_par_75_imaging_based_left_ventricular_digital_twin fill:#ecfccb
style Myocardial_Contractile_Dysfunction fill:#dbeafe
style BNP_NT_proBNP fill:#e0e7ff
style Coronary_Artery_Disease fill:#dcfce7
style Cardiac_Resynchronization_Therapy fill:#fce7f3
style Lipoproteina_Driven_Coronary_Microvascular_Dysfunction fill:#dbeafe
style Alcohol_Abuse fill:#dcfce7
style Hypertension fill:#dcfce7
style Neurohormonal_Activation fill:#dbeafe
style Loss_of_Myocardial_Oestrogen_Receptor_Signalling fill:#dbeafe
style Troponin fill:#e0e7ff
style Mineralocorticoid_Receptor_Antagonists fill:#fce7f3
style Dyspnea fill:#fef3c7
style Fatigue fill:#fef3c7
style Cardiomegaly fill:#fef3c7
style Fluid_Retention fill:#dbeafe
style Endocrine_Convergence_on_Shared_Profibrotic_Effectors fill:#dbeafe
style Exercise_Intolerance fill:#fef3c7
style Beta_Blockers fill:#fce7f3
style ACE_Inhibitors_ARBs fill:#fce7f3
style Ventricular_Remodeling fill:#dbeafe
style Diuretics fill:#fce7f3
name: com_Obesity__Heart_Failure
creation_date: "2026-08-27T00:00:00Z"
curation_status: CANDIDATE
notes: >-
Split out of `kb/disorders/Heart_Failure.yaml`'s `environmental:` block
(dismech#8296, dismech#8551). That entry listed `Obesity` as an exposure with
the note "Risk factor for HFpEF", but obesity is a first-class `Disease` entry
in its own right (`kb/disorders/Obesity.yaml`) rather than something external
to the organism acting on it, and ECTO has no term that would bind it as an
exposure. Modeling it here as a disease-disease comorbidity makes the
relationship queryable and avoids an exposure edge that could never be
grounded.
The original note pointed specifically at heart failure with preserved
ejection fraction. HFpEF is a `has_subtypes` entry on `Heart_Failure` rather
than a separate disorder file, so `disease_b` is `Heart_Failure` and the
subtype specificity is recorded here instead of being asserted by a term this
KB does not carry. The evidence supports both readings: the Framingham cohort
measured incident heart failure without ejection-fraction stratification,
while the HFpEF-specific statement comes from a trial population selected for
it.
Directionality is A_BEFORE_B: obesity is the antecedent risk state. The
reverse arm is real but different in kind -- heart failure causes cachexia
rather than obesity -- and is not modeled here.
disease_a:
slug: Obesity
preferred_term: obesity disorder
term:
id: MONDO:0011122
label: obesity disorder
disease_b:
slug: Heart_Failure
preferred_term: heart failure
term:
id: MONDO:0005252
label: heart failure
directionality: A_BEFORE_B
effect_direction: RISK
hypotheses:
- description: >-
Obesity raises heart failure risk through a combination of haemodynamic
loading, adipose-driven inflammation and the metabolic comorbidities that
accompany it, and does so across the body-mass index range rather than only
at its extreme. The association is strongest for the preserved
ejection-fraction phenotype.
evidence:
- reference: PMID:39555826
reference_title: Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Obesity increases the risk of heart failure with preserved ejection fraction."
explanation: >-
States the subtype-specific relationship the original environmental entry
asserted. This is the trial's framing of established risk rather than its
own result -- SUMMIT measured tirzepatide, not whether obesity causes
HFpEF -- so it is cited for the direction of the association only; the
measured magnitude is carried by the Framingham signal below.
association_signals:
- source: LITERATURE
method: LITERATURE_ASSOCIATION
population: >-
Framingham Heart Study community cohort, 5881 participants of mean age 55
years, 54 percent women, followed a mean of 14 years, with heart failure
incidence modeled against body-mass index by Cox proportional hazards and
adjusted for established risk factors.
directionality: A_BEFORE_B
effect_direction: RISK
statistics:
metrics:
- metric_type: HR
metric_value: 2.12
notes: >-
Adjusted hazard ratio for incident heart failure in obese versus
normal-body-mass-index women; 1.90 in men. A graded increase was seen
across body-mass-index categories rather than only at the obese
threshold, which is why the entry does not restrict the claim to extreme
obesity.
evidence:
- reference: PMID:12151467
reference_title: Obesity and the risk of heart failure.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "For women, the hazard ratio was 2.12 (95 percent confidence interval, 1.51 to 2.97); for men, the hazard ratio was 1.90 (95 percent confidence interval, 1.30 to 2.79)."
explanation: >-
Gives the adjusted hazard ratios behind this signal, measured
prospectively in a community cohort followed forward from body-mass
index to incident heart failure, which is what a directed A_BEFORE_B
risk signal requires.
- reference: PMID:12151467
reference_title: Obesity and the risk of heart failure.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "As compared with subjects with a normal body-mass index, obese subjects had a doubling of the risk of heart failure."
explanation: >-
The study's own summary of the effect size, stated without the
sex-stratified detail.