In vivo quantitative mapping of human mitochondrial cardiac membrane potential: a feasibility study

Abstract

Purpose: Alteration in mitochondrial membrane potential (ΔΨm) is an important feature of many pathologic processes, including heart failure, cardiotoxicity, ventricular arrhythmia, and myocardial hypertrophy. We present the first in vivo, non-invasive, assessment of regional ΔΨm in the myocardium of normal human subjects.

Methods: Thirteen healthy subjects were imaged using [18F]-triphenylphosphonium ([18F]TPP+) on a PET/MR scanner. The imaging protocol consisted of a bolus injection of 300 MBq followed by a 120-min infusion of 0.6 MBq/min. A 60 min, dynamic PET acquisition was started 1 h after bolus injection. The extracellular space fraction (fECS) was simultaneously measured using MR T1-mapping images acquired at baseline and 15 min after gadolinium injection with correction for the subject's hematocrit level. Serial venous blood samples were obtained to calculate the plasma tracer concentration. The tissue membrane potential (ΔΨT), a proxy of ΔΨm, was calculated from the myocardial tracer concentration at secular equilibrium, blood concentration, and fECS measurements using a model based on the Nernst equation.

Results: In 13 healthy subjects, average tissue membrane potential (ΔΨT), representing the sum of cellular membrane potential (ΔΨc) and ΔΨm, was - 160.7 ± 3.7 mV, in excellent agreement with previous in vitro assessment.

Conclusion: In vivo quantification of the mitochondrial function has the potential to provide new diagnostic and prognostic information for several cardiac diseases as well as allowing therapy monitoring. This feasibility study lays the foundation for further investigations to assess these potential roles. Clinical trial identifier: NCT03265431.

Keywords: Mitochondria; Mitochondrial membrane potential; Positron emission tomography; Tissue membrane potential; Triphenylphosphonium.

Conflict of interest statement

Conflict of Interest:

Matthieu Pelletier-Galarneau declares that he has no conflict of interest. Yoann Petibon declares that he has no conflict of interest. Chao Ma declares that he has no conflict of interest. Paul Han declares that he has no conflict of interest. Sally Ji Who Kim declares that she has no conflict of interest. Felicitas J Detmer declares that she has no conflict of interest. Daniel Yokell declares that he has no conflict of interest. Nicolas Guehl declares that he has no conflict of interest. Marc Normandin declares that he has no conflict of interest. Georges El Fakhri declares that he has no conflict of interest. Nathaniel M Alpert declares that he has no conflict of interest.

Figures

Figure 1:

A, Average extracellular fraction (fECS) of the 13 study subjects. B, Time activity curves (TAC) of a representative subject showing that tracer concentrations in the blood and in the myocardium are at secular equilibrium between 90 and 120 minutes post tracer injection. C, Average tissue membrane potential (ΔΨT) of the 13 study subjects. D, ΔΨT of the 17 left ventricular segments of the 13 study subjects.

Figure 2:

Parametric image of the volume of distribution (top) and tissue membrane potential (bottom). SA, short axis. HLA, horizontal long axis. VLA, vertical long axis.

Figure 3:

Extracellular fraction (fECS) and tissue membrane potential (ΔΨT) versus age (left) and according to sex (right).