phosphorus-31-magnetic-resonance-spectroscopy-for-serial-measurements

Phosphorus-31 Magnetic Resonance Spectroscopy for Serial Measurements of Cardiac Energetics During Temperature-Controlled Heart Preservation

Reliable organ preservation is critical to increasing donor availability and improving transplant outcomes. While static storage remains the standard for ...

Johns Hopkins University School of Medicine

BACKGROUNDPhysical frailty in older individuals is characterized by subjective symptoms of fatigue and exercise intolerance (EI). Objective abnormalities in skeletal muscle (SM) mitochondrial high-energy phosphate (HEP) metabolism contribute to EI in inherited myopathies; however, their presence or link to EI in the frail older adult is unknown.METHODSHere, we studied 3 groups of ambulatory, community-dwelling adults with no history of significant coronary disease: frail older (FO) individuals (81 ± 2.7 years, mean ± SEM), nonfrail older (NFO) individuals (79 ± 2.0 years), and healthy middle-aged individuals, who served as controls (CONT, 51 ± 2.1 years). Lower extremity SM HEP levels and mitochondrial function were measured with 31P magnetic resonance (MR) techniques during graded multistage plantar flexion exercise (PFE). EI was quantified by a 6-minute walk (6MW) and peak oxygen consumption during cardiopulmonary testing (peak VO2).RESULTSDuring graded exercise, FO, NFO, and CONT individuals all fatigued at similar SM HEP levels, as measured by 31P-MR. However, FO individuals fatigued fastest, with several-fold higher rates of PFE-induced HEP decline that correlated closely with shorter exercise duration in the MR scanner and with 6MW distance and lower peak oxygen consumption on cardiopulmonary testing (P < 0.001 for all). SM mitochondrial oxidative capacity was lower in older individuals and correlated with rapid HEP decline but less closely with EI.CONCLUSIONSeveral-fold faster SM energetic decline during exercise occurs in FO individuals and correlates closely with multiple measures of EI. Rapid energetic decline represents an objective, functional measure of SM metabolic changes and a potential new target for mitigating frailty-associated physical limitations.FUNDINGThis work was supported by NIH R21 AG045634, R01 AG063661, R01 HL61912, the Johns Hopkins University Claude D. Pepper Older Americans Independence Center P30AG021334, and the Clarence Doodeman Endowment in Cardiology at Johns Hopkins.

Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty.

The spatial distribution, innervation, and functional role of the bone-associated skeletal nerves have been previously reported in detail. However, studies examining exercise-induced associations between skeletal nerves and bone metabolism are limited. This review introduces a potential relationship between exercise and the skeletal nerves and discusses how it can contribute to exercise-induced bone anabolism. First, the background and current understanding of nerve fiber types and their functions in the skeleton are provided. Next, the influence of exercise and mechanical loading on the skeletal nervous system is elaborated. Effective synthesis of recent studies could serve as an established baseline for the novel discovery of the effects of exercise on skeletal nerve density and bone anabolic activity in the future. Therefore, this review overviews the existing evidence for the neural control of bone metabolism and the potential positive effects of exercise on the peripheral skeletal nervous system. The influence of exercise training models on the relationships of sensory nerve signals with osteoblast-mediated bone formation and the increased bone volume provides the first insight on the potential importance of exercise training in stimulating positive adaptations in the skeletal nerve-bone interaction and its downstream effect on bone metabolism, thereby highlighting its therapeutic potential in a variety of clinical populations.

The Potential Role of Exercise Training and Mechanical Loading on Bone-Associated Skeletal Nerves.

BACKGROUNDSudden cardiac death (SCD) remains a worldwide public health problem in need of better noninvasive predictive tools. Current guidelines for primary preventive SCD therapies, such as implantable cardioverter defibrillators (ICDs), are based on left ventricular ejection fraction (LVEF), but these guidelines are imprecise: fewer than 5% of ICDs deliver lifesaving therapy per year. Impaired cardiac metabolism and ATP depletion cause arrhythmias in experimental models, but to our knowledge a link between arrhythmias and cardiac energetic abnormalities in people has not been explored, nor has the potential for metabolically predicting clinical SCD risk.METHODSWe prospectively measured myocardial energy metabolism noninvasively with phosphorus magnetic resonance spectroscopy in patients with no history of significant arrhythmias prior to scheduled ICD implantation for primary prevention in the setting of reduced LVEF (≤35%).RESULTSBy 2 different analyses, low myocardial ATP significantly predicted the composite of subsequent appropriate ICD firings for life-threatening arrhythmias and cardiac death over approximately 10 years. Life-threatening arrhythmia risk was approximately 3-fold higher in patients with low ATP and independent of established risk factors, including LVEF. In patients with normal ATP, rates of appropriate ICD firings were several-fold lower than reported rates of ICD complications and inappropriate firings.CONCLUSIONTo the best of our knowledge, these are the first data linking in vivo myocardial ATP depletion and subsequent significant arrhythmic events in people, suggesting an energetic component to clinical life-threatening ventricular arrhythmogenesis. The findings support investigation of metabolic strategies that limit ATP loss to treat or prevent life-threatening cardiac arrhythmias and herald noninvasive metabolic imaging as a complementary SCD risk stratification tool.TRIAL REGISTRATIONClinicalTrials.gov NCT00181233.FUNDINGThis work was supported by the DW Reynolds Foundation, the NIH (grants HL61912, HL056882, HL103812, HL132181, HL140034), and Russell H. Morgan and Clarence Doodeman endowments at Johns Hopkins.

Myocardial ATP depletion detected noninvasively predicts sudden cardiac death risk in patients with heart failure.

Left ventricular (LV) circumferential and longitudinal strain provide important insight into LV mechanics and function, each contributing to volumetric changes throughout the cardiac cycle. We sought to explore this strain-volume relationship in more detail, by mathematically integrating circumferential and longitudinal strain and strain rate to predict LV volume and volumetric rates of change.

Integration of longitudinal and circumferential strain predicts volumetric change across the cardiac cycle and differentiates patients along the heart failure continuum.

Energetic Basis of Recovered Ejection Fraction in Human Heart Failure.

To investigate the feasibility of rapid CEST MRI acquisition for evaluating oxidative phosphorylation (OXPHOS) in human skeletal muscle at 3T, utilizing ultrafast Z-spectroscopy (UFZ) combined with MRI and the Polynomial and Lorentzian line-shape Fitting (PLOF) technique.

Mitochondrial oxidative phosphorylation capacity in skeletal muscle measured by ultrafast Z-spectroscopy (UFZ) MRI at 3T.

Heart failure with preserved ejection fraction (HFpEF) is a systemic process with contributions from peripheral factors, including skeletal muscle (SM). Age-associated SM loss and impaired energy metabolism occur without heart failure, but the relative importance of changes in SM quantity versus metabolic quality in patients with HFpEF for exercise intolerance (EI) or outcomes has not been studied. We hypothesized that EI and subsequent clinical outcomes across the adult lifespan in patients with HFpEF are related to impaired SM energy metabolism rather than age-associated SM loss.

Skeletal Muscle Quantity Versus Quality in Heart Failure: Exercise Intolerance and Outcomes in Older Patients With HFpEF Are Related to Abnormal Skeletal Muscle Metabolism Rather Than Age-Related Skeletal Muscle Loss.

Article	Year
Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty. JCI insight\| PubMed ID: 32941181	2020
The Potential Role of Exercise Training and Mechanical Loading on Bone-Associated Skeletal Nerves. Journal of bone metabolism\| PubMed ID: 34905674	2021
Myocardial ATP depletion detected noninvasively predicts sudden cardiac death risk in patients with heart failure. JCI insight\| PubMed ID: 35579938	2022
Integration of longitudinal and circumferential strain predicts volumetric change across the cardiac cycle and differentiates patients along the heart failure continuum. Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance\| PubMed ID: 37779191	2023
Energetic Basis of Recovered Ejection Fraction in Human Heart Failure. Circulation\| PubMed ID: 38079486	2023
Mitochondrial oxidative phosphorylation capacity in skeletal muscle measured by ultrafast Z-spectroscopy (UFZ) MRI at 3T. Magnetic resonance in medicine\| PubMed ID: 39428676	2025
Skeletal Muscle Quantity Versus Quality in Heart Failure: Exercise Intolerance and Outcomes in Older Patients With HFpEF Are Related to Abnormal Skeletal Muscle Metabolism Rather Than Age-Re... Circulation. Heart failure\| PubMed ID: 40534551	2025

T. Jake Samuel

Biography

JoVE Journal Publications

Other Publications