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Dynamic [18F]Fluoroleucine PET Detects Impaired Cardiac Leucine Uptake Before Hypertensive Left Ventricular
William Terrell1,2, Jie Li3, Damodara N Kommi4
1Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA.
Insights
Dynamic cardiac PET imaging reveals reduced leucine uptake in hypertensive rats before left ventricular hypertrophy develops. This impaired uptake may serve as an early biomarker for cardiovascular risk in hypertension.
Area of Science:
- Cardiovascular Medicine
- Nuclear Medicine
- Biochemistry
Background:
- Left ventricular hypertrophy (LVH) is a significant cardiovascular risk factor in hypertension.
- Current methods lack validated biomarkers to predict LVH development in hypertensive individuals.
- Previous studies identified altered branched-chain amino acid (BCAA) metabolism preceding LVH in rat hearts.
Purpose of the Study:
- To investigate if impaired cardiac leucine uptake, measured by dynamic 5-[18F]fluoroleucine ([18F]FLE) PET imaging, can serve as an in vivo marker for hypertension-induced LVH.
- To assess [18F]FLE PET as an early diagnostic tool for identifying hypertensive individuals at risk of LVH progression.
Main Methods:
- Dynamic [18F]FLE-PET/CT imaging was performed on spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats.
- Cardiac MR (CMR) imaging was used for structural co-registration.
- A two-tissue compartment model quantified leucine uptake kinetics (K1, Vt). L-type amino acid transporter 1 (LAT1) expression and BCKDH phosphorylation were assessed via immunoblotting.
Main Results:
- SHR exhibited significantly lower cardiac leucine uptake (K1 and Vt) compared to WKY rats.
- Reduced LAT1 protein expression was observed in SHR hearts.
- Elevated BCKDH phosphorylation at Ser293 indicated impaired BCAA catabolism in SHR.
Conclusions:
- Dynamic cardiac [18F]FLE-PET successfully detected reduced leucine uptake in hypertensive rat hearts at 3 months, preceding established LVH at 5 months.
- Impaired cardiac leucine uptake shows potential as an early cardiometabolic biomarker for predicting LVH progression in hypertension.
Purpose:
Left ventricular hypertrophy (LVH) is a major complication of chronic hypertension and an independent cardiovascular risk factor. No clinically validated markers exist to identify hypertensive individuals at risk for developing LVH. We previously described metabolic changes preceding LVH in hypertensive rat hearts, including alterations in branched-chain amino acid (BCAA) metabolism. This study investigated whether impaired cardiac leucine uptake, measured with dynamic 5-[18F]fluoroleucine ([18F]FLE) PET imaging, could serve as in vivo marker for hypertension-induced LVH development.
Procedures:
[18F]FLE was synthesized following established radiochemistry protocols and dynamic [18F]FLE-PET/CT imaging was performed in 3-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) control rats (n = 4/group). Cardiac MR (CMR) imaging enabled structural co-registration. A dual-output reversible two-tissue compartment model with spill-over and partial volume corrections quantified the first-pass rate constant (K1) and total distribution volume (Vt). L-type amino acid transporter 1 (LAT1/SLC7A5) protein expression and branched-chain keto acid dehydrogenase (BCKDH) phosphorylation status were assessed by immunoblotting of heart tissue.
Results:
SHR demonstrated markedly lower K1 and Vt compared with WKY rats, consistent with reduced cardiac leucine uptake. Simultaneously, LAT1 expression was significantly reduced in SHR hearts. Elevated BCKDH phosphorylation at Ser293 suggested impaired BCAA catabolism.
Conclusions:
Dynamic cardiac [18F]FLE-PET detects decreased leucine uptake in hypertensive rat hearts at 3 months of age, before LVH is established at 5 months. Impaired cardiac leucine uptake may thus serve as an early cardiometabolic biomarker to identify hypertensive patients at risk for LVH progression.
