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Principal Investigator: Ahmed Abdel Latif
Organization: VETERANS HEALTH ADMINISTRATION
Fiscal Year: 2024
Funding agency: Veterans Affairs
PROJECT SUMMARY/ABSTRACT
Obesity is approaching an epidemic state in the United States and is strongly associated with a higher risk of
heart failure with preserved ejection fraction (HFpEF), a major cause of morbidity and mortality in obese
individuals. In the VA population, HFpEF accounts for approximately 7% of all mortalities, and its prevalence in
the VA Healthcare system is expected to increase exponentially over the coming decade with the aging Veterans
population. Despite significant advances in the management of heart failure with reduced ejection fraction, few
advances have been made in the management of HFpEF which carries a dismal survival rate of 50% in two
years after diagnosis. Therefore, HFpEF represents an unmet need in modern clinical practice. Obesity induces
systemic inflammation contributing to HFpEF, however, the mechanisms responsible for this phenomenon are
not fully understood. In fact, therapeutics that nonspecifically target inflammation failed in multiple HF trials,
highlighting the knowledge gap in the field. We identified a critical role for the bioactive lipid lysophosphatidic
acid (LPA) in cardiac-BM signaling, cardiac inflammation, and adverse cardiac remodeling. Our preliminary data
and published reports demonstrate increased plasma levels of autotaxin (ATX) and LPA in obese patients and
animal models of diet-induced obesity (DIO), related to the increased mRNA expression of ATX in adipocytes,
which hydrolyzes lysophosphatidylcholine (LPC) into LPA. However, the role of ATX/LPA signaling in obesity-
induced cardiac inflammation and HFpEF, as well as related therapeutic targets, have not been explored. This
project is clinically relevant as targeting this pathway, using clinically available therapeutics, can improve the
outcomes of millions of patients with HFpEF who have limited therapeutic options. Our long-term goal is to
identify the immune mechanisms regulating pathological heart remodeling in obesity. Our central hypothesis
is that LPA plays an important role in obesity-related cardiac inflammation and fibrosis and that inhibiting
ATX/LPA signaling is therapeutically beneficial. We collected extensive pilot data using unbiased
approaches, including mass cytometry (CyTOF) and RNA sequencing (RNAseq), to characterize the immune
landscape during DIO-related pathological cardiac remodeling. This data highlights the critical role of ATX/LPA
signaling and macrophages in obesity-induced HFpEF and support the following specific aims: 1) Aim 1.
Identify the mechanistic role of ATX/LPA nexus in macrophage signaling during obesity-induced HFpEF,
2) Determine how adipose-derived ATX signaling mediates obesity-induced HFpEF, and 3) Investigate
the association between LPA levels, heritable genetic variability in LPA metabolism, and the
development of HFpEF in humans. These aims will be conducted by a team with extensive clinical, basic and
translational research experience in studying heart/BM signaling, immunomodulation of cardiac inflammation,
and ATX/LPA signaling; and utilize state-of-the-art approaches to untangle the role of ATX/LPA signaling in
obesity-induced cardiac remodeling and the development of HFpEF. The impact of these studies derives from
our innovative focus on the targetable ATX/LPA signaling nexus to reduce the pathological inflammation and
subsequent development of heart failure in millions of overweight/obese patients.
Terms: <Adipocytes><Adipose Cell><Adipose tissue><Affect><Aging><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Area><Basic Research><Basic Science><Biological><Biological Markers><Blood Plasma><Body Tissues><Cardiac><Cell Communication and Signaling><Cell Signaling><Clinical><Clinical Research><Clinical Study><Complex><Cytometry><Data><Development><Diagnosis><Disease><Disease Management><Disease Progression><Disorder><Disorder Management><Dysfunction><EFRAC><Early Diagnosis><Early Intervention><Ejection Fraction><Epidemic><Fat Cells><Fatty Tissue><Fibrosis><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><Foundations><Functional disorder><Future><Gene variant><Genetic><Genomics><Goals><Health><Health Care Systems><Healthcare><Healthcare Systems><Heart><Heart failure><Heritability><Human><Immune><Immune signaling><Immunes><Immunomodulation><Individual><Infiltration><Inflammation><Inflammatory><Intermediary Metabolism><Intracellular Communication and Signaling><Ischemia><Knowledge><Leanness><Lipids><Lipocytes><Lysolecithins><Lysophosphatidylcholines><MOPA><Macrophage><Mature Lipocyte><Mature fat cell><Mediating><Metabolic Processes><Metabolism><Michigan><Mission><Modeling><Modern Man><Modernization><Morbidity><Morbidity - disease rate><Myeloid Cells><Myocarditis><Myocardium><Mφ><Obesity><Over weight><Overweight><Pathologic><Pathway interactions><Patients><Physiopathology><Plasma><Plasma Serum><Play><Population><Prevalence><Process><Prognosis><Publishing><RNA Seq><RNA sequencing><RNAseq><Reporting><Research><Research Specimen><Reticuloendothelial System, Serum, Plasma><Risk><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Source><Specimen><Survival Rate><System><Techniques><Therapeutic><Therapeutic Studies><Therapy Research><Thinness><Tissues><Translational Research><Translational Science><United States><United States Department of Veterans Affairs><United States Veterans Administration><Veterans><Veterans Administration><Veterans Affairs><adipose><adiposity><allele variant><allelic variant><bio-markers><biologic><biologic marker><biological signal transduction><biomarker><cardiac failure><cardiac fibrosis><cardiac inflammation><cardiac muscle><clinical practice><clinical prognosis><clinical relevance><clinically relevant><cohort><coronary fibrosis><corpulence><design><designing><developmental><diet-associated obesity><diet-induced obesity><diet-related obesity><early detection><experience><fibrotic heart><genetic variant><genomic variant><health care><heart failure and reduced ejection fraction><heart failure with reduced ejection fraction><heart fibrosis><heart muscle><high risk><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><improved><improved outcome><innovate><innovation><innovative><insight><lysophosphatidic acid><mRNA Expression><military veteran><model of animal><monooleylphosphatidate><monooleylphosphatidic acid><mortality><mouse model><murine model><myocardial fibrosis><novel><obese individuals><obese patients><obese people><obese person><obese population><obese subjects><pathophysiology><pathway><patients with obesity><preservation><prevent><preventing><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><systemic inflammation><systemic inflammatory response><therapeutic target><therapeutically effective><transcriptome sequencing><transcriptomic sequencing><translation research><translational investigation><veteran population><white adipose tissue><yellow adipose tissue>