Altered systemic bioenergetic reserve in chronic kidney disease predisposes hearts to worse functional outcomes DOI Creative Commons

Megan Young,

Malene Aastrup, Nikayla Patel

et al.

Published: Oct. 29, 2024

Abstract Chronic kidney disease (CKD) is the tenth biggest killer worldwide and projected to be fifth leading cause of mortality by 2040. CKD an inherently systemic with progressive deterioration kidney, muscle, liver function creating a vicious cycle comorbidity. However, whether energetic deficiency in contributes cardiac dysfunction uraemic cardiomyopathy remains unknown. Using two pre-clinical renal failure models different aetiology rats (4-week 0.75% adenine diet 12-week post-partial nephrectomy) we investigated both metabolic remodelling CKD. In addition significant uraemia, anaemia alterations exogenous plasma substrate homeostasis, non-targeted 1 H NMR spectroscopy metabolomic profiling peripheral tissues (skeletal liver, kidneys) revealed extensive changes bioenergetic reserve experimental models. Similarly, 31 P magnetic resonance assessment exercising lower leg muscle human patients identified deficiency. During exercise were unable utilise capacity same extent as healthy controls. Both developed mild dysfunction, however was less severe than that organs. Upon challenge 25-minute total global ischemia, hearts from had poorer functional outcome. Thus, perturbation metabolism precedes exceeds severity changes. Prevention derangement may new therapeutic approach improve outcomes One Sentence Summary Perturbations precede exceed chronic disease.

Language: Английский

Metabolic rewiring and inter-organ crosstalk in diabetic HFpEF DOI Creative Commons

Lingyun Luo,

Yuyue Zuo, Lei Dai

et al.

Cardiovascular Diabetology, Journal Year: 2025, Volume and Issue: 24(1)

Published: April 4, 2025

Heart failure with preserved ejection fraction (HFpEF) represents a significant and growing clinical challenge. Initially, for an extended period, HFpEF was simply considered as subset of heart failure, manifesting haemodynamic disorders such hypertension, myocardial hypertrophy, diastolic dysfunction. However, the rising prevalence obesity diabetes has reshaped phenotype, nearly 45% cases coexisting diabetes. Currently, it is recognized multi-system disorder that involves heart, liver, kidneys, skeletal muscle, adipose tissue, along immune inflammatory signaling pathways. In this review, we summarize landscape metabolic rewiring crosstalk between other organs/systems (e.g., adipose, gut, liver hematopoiesis system) in diabetic first instance. A diverse array metabolites cytokines play pivotal roles intricate process, rewiring, chronic responses, dysregulation, endothelial dysfunction, fibrosis identified central mechanisms at complex interplay. The liver-heart axis links nonalcoholic steatohepatitis through shared lipid accumulation, inflammation, pathways, while gut-heart dysbiosis-driven trimethylamine N-oxide, indole-3-propionic acid short-chain fatty acids) impacting cardiac function inflammation. Adipose-heart highlights epicardial tissue source local inflammation mechanical stress, whereas hematopoietic system contributes via cell activation cytokine release. We contend that, based on viewpoints expounded breaking inter-organ/system vicious cycle linchpin treating HFpEF.

Language: Английский

Citations

1
Cardiac-specific deletion of GCN5L1 promotes fatty liver disease in HFpEF DOI Creative Commons
Paramesha Bugga, Bellina A.S. Mushala, Michael W. Stoner

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

ABSTRACT The prevalence of cardiometabolic heart failure with preserved ejection fraction (HFpEF) continues to grow, representing over half cases in the United States. As no specific medication for HFpEF exists, treatment guidelines focus on management comorbidities related metabolic syndrome (e.g. obesity, diabetes, hypertension) that promote disease. These same also drive pathology non-cardiac tissues, and links between disease presentations different organs are increasingly being recognized. Preclinical studies potential crosstalk liver metabolic-associated fatty disease; MAFLD) have focused how dysfunction may affect heart, particularly through release secreted proteins. This reflect situation clinic, where incident MAFLD is a risk factor future development. Here, contrast this developing paradigm liver-initiated cardiac disease, we report first time defect metabolism mitochondrial protein GCN5L1 drives hepatic steatosis HFpEF.

Language: Английский

Citations

0
Impact of Metabolic Dysfunction-Associated Steatotic Liver Disease on Cardiovascular Structure, Function, and the Risk of Heart Failure DOI
Bhavik Bansal,

Fanny Lajeunesse-Trempe,

Neil Keshvani

et al.

Canadian Journal of Cardiology, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
Integrated systems biology identifies disruptions in mitochondrial function and metabolism as key contributors to heart failure with preserved ejection fraction (HFpEF) DOI Creative Commons
Andrew Gibb, Kyle B. LaPenna, Ryan B. Gaspar

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 25, 2024

ABSTRACT Background Heart failure with preserved ejection fraction (HFpEF) accounts for ∼50% of HF cases, no effective treatments. The ZSF1-obese rat model recapitulates numerous clinical features HFpEF including hypertension, obesity, metabolic syndrome, exercise intolerance, and LV diastolic dysfunction. Here, we utilized a systems-biology approach to define the early transcriptional signatures gain mechanistic insight into pathways contributing development. Methods Male ZSF1-obese, ZSF1-lean hypertensive controls, WKY (wild-type) controls were compared at 14w age extensive physiological phenotyping tissue harvesting unbiased metabolomics, RNA-sequencing, assessment mitochondrial morphology function. Utilizing enabled distinction between hypertension-driven molecular changes pathology, versus hypertension + syndrome. Results rats displayed HFpEF. Comparison vs (i.e., hypertension-exclusive effects) revealed remodeling suggestive increased aerobic glycolysis, decreased β-oxidation, dysregulated purine pyrimidine metabolism few changes. worsened robust highlighted by upregulation inflammatory genes downregulation structure/function cellular processes. Integrated network analysis metabolomic RNAseq datasets nearly all catabolic energy production, manifesting in marked decrease energetic state reduced ATP/ADP, PCr/ATP). Cardiomyocyte ultrastructure area, size, cristae density, as well lipid droplet content hearts. Mitochondrial function was also impaired demonstrated substrate-mediated respiration calcium handling. Conclusions Collectively, integrated omics applied here provides framework uncover novel genes, metabolites, underlying HFpEF, an emphasis on potential target intervention.

Language: Английский

Citations

1
Altered systemic bioenergetic reserve in chronic kidney disease predisposes hearts to worse functional outcomes DOI Creative Commons

Megan Young,

Malene Aastrup, Nikayla Patel

et al.

Published: Oct. 29, 2024

Abstract Chronic kidney disease (CKD) is the tenth biggest killer worldwide and projected to be fifth leading cause of mortality by 2040. CKD an inherently systemic with progressive deterioration kidney, muscle, liver function creating a vicious cycle comorbidity. However, whether energetic deficiency in contributes cardiac dysfunction uraemic cardiomyopathy remains unknown. Using two pre-clinical renal failure models different aetiology rats (4-week 0.75% adenine diet 12-week post-partial nephrectomy) we investigated both metabolic remodelling CKD. In addition significant uraemia, anaemia alterations exogenous plasma substrate homeostasis, non-targeted 1 H NMR spectroscopy metabolomic profiling peripheral tissues (skeletal liver, kidneys) revealed extensive changes bioenergetic reserve experimental models. Similarly, 31 P magnetic resonance assessment exercising lower leg muscle human patients identified deficiency. During exercise were unable utilise capacity same extent as healthy controls. Both developed mild dysfunction, however was less severe than that organs. Upon challenge 25-minute total global ischemia, hearts from had poorer functional outcome. Thus, perturbation metabolism precedes exceeds severity changes. Prevention derangement may new therapeutic approach improve outcomes One Sentence Summary Perturbations precede exceed chronic disease.

Language: Английский

Citations

0