Elevated plasma β-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic...

Area of Science:

• Biochemistry
• Cardiology
• Genetics

Background:

• Arrhythmogenic cardiomyopathy (AC) is a genetic heart disease with a high risk of sudden death.
• Current clinical indicators for predicting AC progression are limited.
• Metabolic dysregulation is increasingly recognized in AC pathogenesis.

Purpose of the Study:

• To identify predictive metabolic biomarkers for major adverse cardiac events (MACE) in AC patients and their relatives.
• To investigate metabolic pathway alterations in AC using quantitative proteomics and metabolomics.
• To validate plasma β-hydroxybutyrate (β-OHB) as a predictive marker for AC progression.

Main Methods:

• Quantitative proteomics on explanted hearts from AC patients and healthy donors.
• Analysis of coronary artery and sinus plasma for metabolic differences.
• In vitro validation using patient-derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
• Targeted metabolomics on right ventricles (RVs) from end-stage AC patients.
• Independent validation cohort analysis of plasma β-OHB in AC probands and relatives.

Main Results:

• AC RVs showed elevated ketone metabolic enzymes (OXCT1, HMGCS2), suggesting increased ketone metabolism.
• Early-stage AC plasma indicated potential ketone body synthesis.
• End-stage AC RVs exhibited a "burned-out" metabolic state with fatty acid utilization.
• Higher plasma β-OHB levels were observed in AC probands compared to healthy controls.
• Elevated plasma β-OHB was associated with MACE in AC probands and identified suspected AC in relatives.

Conclusions:

• Plasma β-hydroxybutyrate (β-OHB) is a potential biomarker for predicting MACE in arrhythmogenic cardiomyopathy (AC).
• Elevated β-OHB levels can predict disease progression in AC patients and identify at-risk, asymptomatic relatives.
• Metabolic dysregulation, particularly involving ketone bodies, plays a significant role in AC progression.