Exercise MR of Skeletal Muscles, the Heart, and the Brain.

Magnetic resonance (MR) imaging (MRI) is routinely used to evaluate organ morphology and pathology in the human body at rest or in combination with pharmacological stress as an exercise surrogate. With MR during actual physical exercise, we can assess functional characteristics of tissues and organs under real-life stress conditions. This is particularly relevant in patients with limited exercise capacity or exercise intolerance, and where complaints typically present only during physical activity, such as in neuromuscular disorders, inherited metabolic diseases, and heart failure. This review describes practical and physiological aspects of exercise MR of skeletal muscles, the heart, and the brain. The acute effects of physical exercise on these organs are addressed in the light of various dynamic quantitative MR readouts, including phosphorus-31 MR spectroscopy (31P-MRS) of tissue energy metabolism, phase-contrast MRI of blood flow and muscle contraction, real-time cine MRI of cardiac performance, and arterial spin labeling MRI of muscle and brain perfusion. Exercise MR will help advancing our understanding of underlying mechanisms that contribute to exercise intolerance, which often proceed structural and anatomical changes in disease. Its potential to detect disease-driven alterations in organ function, perfusion, and metabolism under physiological stress renders exercise MR stress testing a powerful noninvasive imaging modality to aid in disease diagnosis and risk stratification. Although not yet integrated in most clinical workflows, and while some applications still require thorough validation, exercise MR has established itself as a comprehensive and versatile modality for characterizing physiology in health and disease in a noninvasive and quantitative way. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 1.

Pre-Participation Screenings Frequently Miss Occult Cardiovascular Conditions in Apparently Healthy Male Middle-Aged First-Time Marathon Runners.

INTRODUCTION: The optimal pre-participation screening strategy to identify athletes at risk for exercise-induced cardiovascular events is unknown. We therefore aimed to compare the American College of Sports Medicine (ACSM) and European Society of Cardiology (ESC) pre-participation screening strategies against extensive cardiovascular evaluations in identifying high-risk individuals among 35-50-year-old apparently healthy men. METHODS: We applied ACSM and ESC pre-participation screenings to 25 men participating in a study on first-time marathon running. We compared screening outcomes against medical history, physical examination, electrocardiography, blood tests, echocardiography, cardiopulmonary exercise testing, and magnetic resonance imaging. RESULTS: ACSM screening classified all participants as "medical clearance not necessary." ESC screening classified two participants as "high-risk." Extensive cardiovascular evaluations revealed ≥1 minor abnormality and/or cardiovascular condition in 17 participants, including three subjects with mitral regurgitation and one with a small atrial septal defect. Eleven participants had dyslipidaemia, six had hypertension, and two had premature atherosclerosis. Ultimately, three (12%) subjects had a serious cardiovascular condition warranting sports restrictions: aortic aneurysm, hypertrophic cardiomyopathy (HCM), and myocardial fibrosis post-myocarditis. Of these three participants, only one had been identified as "high-risk" by the ESC screening (for dyslipidaemia, not HCM) and none by the ACSM screening. CONCLUSION: Numerous occult cardiovascular conditions are missed when applying current ACSM/ESC screening strategies to apparently healthy middle-aged men engaging in their first high-intensity endurance sports event.

A comparison of myocardial magnetic resonance extracellular volume mapping at 3 T against histology of tissue collagen in severe aortic valve stenosis and obstructive hypertrophic cardiomyopathy.

OBJECTIVE: Quantitative extracellular volume fraction (ECV) mapping with MRI is commonly used to investigate in vivo diffuse myocardial fibrosis. This study aimed to validate ECV measurements against ex vivo histology of myocardial tissue samples from patients with aortic valve stenosis or hypertrophic cardiomyopathy. MATERIALS AND METHODS: Sixteen patients underwent MRI examination at 3 T to acquire native T1 maps and post-contrast T1 maps after gadobutrol administration, from which hematocrit-corrected ECV maps were estimated. Intra-operatively obtained myocardial tissue samples from the same patients were stained with picrosirius red for quantitative histology of myocardial interstitial fibrosis. Correlations between in vivo ECV and ex vivo myocardial collagen content were evaluated with regression analyses. RESULTS: Septal ECV was 30.3% ± 4.6% and correlated strongly (n = 16, r = 0.70; p = 0.003) with myocardial collagen content. Myocardial native T1 values (1206 ± 36 ms) did not correlate with septal ECV (r = 0.41; p = 0.111) or with myocardial collagen content (r = 0.32; p = 0.227). DISCUSSION: We compared myocardial ECV mapping at 3 T against ex vivo histology of myocardial collagen content, adding evidence to the notion that ECV mapping is a surrogate marker for in vivo diffuse myocardial fibrosis.

Dynamic MR imaging of cerebral perfusion during bicycling exercise.

Habitual physical activity is beneficial for cerebrovascular health and cognitive function. Physical exercise therefore constitutes a clinically relevant cerebrovascular stimulus. This study demonstrates the feasibility of quantitative cerebral blood flow (CBF) measurements during supine bicycling exercise with pseudo-continuous arterial spin labeling (pCASL) magnetic resonance imaging (MRI) at 3 Tesla. Twelve healthy volunteers performed a steady-state exercise-recovery protocol on an MR-compatible bicycle ergometer, while dynamic pCASL data were acquired at rest, during moderate (60% of the age-predicted supine maximal heart rate (HRmax)) and vigorous (80% of supine HRmax) exercise, and subsequent recovery. These CBF measurements were compared with 2D phase-contrast MRI measurements of blood flow through the carotid arteries. Procedures were repeated on a separate day for an assessment of measurement repeatability. Whole-brain (WB) CBF was 41.2 ± 6.9 mL/100 g/min at rest (heart rate 63 [57-71] beats/min), remained similar at moderate exercise (102 [97-107] beats/min), decreased by 10% to 37.1 ± 5.7 mL/100 g/min (p = 0.001) during vigorous exercise (139 [136-142] beats/min) and decreased further to 34.2 ± 6.0 mL/100 g/min (p < 0.001) during recovery. Hippocampus CBF decreased by 12% (p = 0.001) during moderate exercise, decreased further during vigorous exercise (-21%; p < 0.001) and was even lower during recovery (-31%; p < 0.001). In contrast, motor cortex CBF increased by 12% (p = 0.027) during moderate exercise, returned to resting-state values during vigorous exercise, and decreased by 17% (p = 0.006) during recovery. The inter-session repeatability coefficients for WB CBF were approximately 20% for all stages of the exercise-recovery protocol. Phase-contrast blood flow measurements through the common carotid arteries overestimated the WB CBF because of flow directed to the face and scalp. This bias increased with exercise. We have demonstrated the feasibility of dynamic pCASL-MRI of the human brain for a quantitative evaluation of cerebral perfusion during bicycling exercise. Our spatially resolved measurements revealed a differential response of CBF in the motor cortex as well as the hippocampus compared with the brain as a whole. Caution is warranted when using flow through the common carotid arteries as a surrogate measure for cerebral perfusion.

Quantification of Myocardial Creatine and Triglyceride Content in the Human Heart: Precision and Accuracy of in vivo Proton Magnetic Resonance Spectroscopy.

BACKGROUND: Proton magnetic resonance spectroscopy (1 H-MRS) of the human heart is deemed to be a quantitative method to investigate myocardial metabolite content, but thorough validations of in vivo measurements against invasive techniques are lacking. PURPOSE: To determine measurement precision and accuracy for quantifications of myocardial total creatine and triglyceride content with localized 1 H-MRS. STUDY TYPE: Test-retest repeatability and measurement validation study. SUBJECTS: Sixteen volunteers and 22 patients scheduled for open-heart aortic valve replacement or septal myectomy. FIELD STRENGTH/SEQUENCE: Prospectively ECG-triggered respiratory-gated free-breathing single-voxel point-resolved spectroscopy (PRESS) sequence at 3 T. ASSESSMENT: Myocardial total creatine and triglyceride content were quantified relative to the total water content by fitting the 1 H-MR spectra. Precision was assessed with measurement repeatability. Accuracy was assessed by validating in vivo 1 H-MRS measurements against biochemical assays in myocardial tissue from the same subjects. STATISTICAL TESTS: Intrasession and intersession repeatability was assessed using Bland-Altman analyses. Agreement between 1 H-MRS measurements and biochemical assay was tested with regression analyses. RESULTS: The intersession repeatability coefficient for myocardial total creatine content was 41.8% with a mean value of 0.083% ± 0.020% of the total water signal, and 36.7% for myocardial triglyceride content with a mean value of 0.35% ± 0.13% of the total water signal. Ex vivo myocardial total creatine concentrations in tissue samples correlated with the in vivo myocardial total creatine content measured with 1 H-MRS: n = 22, r = 0.44; P < 0.05. Likewise, ex vivo myocardial triglyceride concentrations correlated with the in vivo myocardial triglyceride content: n = 20, r = 0.50; P < 0.05. DATA CONCLUSION: We validated the use of localized 1 H-MRS of the human heart at 3 T for quantitative assessments of in vivo myocardial tissue metabolite content by estimating the measurement precision and accuracy. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Dynamic magnetic resonance measurements of calf muscle oxygenation and energy metabolism in peripheral artery disease.

BACKGROUND: Clinical assessments of peripheral artery disease (PAD) severity are insensitive to pathophysiological changes in muscle tissue oxygenation and energy metabolism distal to the affected artery. PURPOSE: To quantify the blood oxygenation level-dependent (BOLD) response and phosphocreatine (PCr) recovery kinetics on a clinical MR system during a single exercise-recovery session in PAD patients. STUDY TYPE: Case-control study. SUBJECTS: Fifteen Fontaine stage II patients, and 18 healthy control subjects FIELD STRENGTH/SEQUENCE: Interleaved dynamic multiecho gradient-echo 1 H T2 * mapping and adiabatic pulse-acquire 31 P-MR spectroscopy at 3T. ASSESSMENT: Blood pressure in the arms and ankles were measured to determine the ankle-brachial index (ABI). Subjects performed a plantar flexion exercise-recovery protocol. The gastrocnemius and soleus muscle BOLD responses were characterized using the T2 * maps. High-energy phosphate metabolite concentrations were quantified by fitting the series of 31 P-MR spectra. The PCr recovery time constant (τPCr ) was derived as a measure of in vivo mitochondrial oxidative capacity. STATISTICAL TESTS: Comparisons between groups were performed using two-sided Mann-Whitney U-tests. Relations between variables were assessed by Pearson's r correlation coefficients. RESULTS: The amplitude of the functional hyperemic BOLD response in the gastrocnemius muscle was higher in PAD patients compared with healthy subjects (-3.8 ± 1.4% vs. -1.4 ± 0.3%; P < 0.001), and correlated with the ABI (r = 0.79; P < 0.001). PCr recovery was slower in PAD patients (τPCr = 52.0 ± 13.5 vs. 30.3 ± 9.7 sec; P < 0.0001), and correlated with the ABI (r = -0.64; P < 0.001). Moreover, τPCr correlated with the hyperemic BOLD response in the gastrocnemius muscle (r = -0.66; P < 0.01). DATA CONCLUSION: MR readouts of calf muscle tissue oxygenation and high-energy phosphate metabolism were acquired essentially simultaneously during a single exercise-recovery session. A pronounced hypoxia-triggered vasodilation in PAD is associated with a reduced mitochondrial oxidative capacity. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:98-107.

Quantitative MRI Reveals Microstructural Changes in the Upper Leg Muscles After Running a Marathon.

BACKGROUND: The majority of sports-related injuries involve skeletal muscle. Unlike acute trauma, which is often caused by a single traumatic event leading to acute symptoms, exercise-induced microtrauma may remain subclinical and difficult to detect. Therefore, novel methods to detect and localize subclinical exercise-induced muscle microtrauma are desirable. PURPOSE: To assess acute and delayed microstructural changes in upper leg muscles with multiparametric quantitative MRI after running a marathon. STUDY TYPE: Longitudinal; 1-week prior, 24-48 hours postmarathon and 2-week follow-up POPULATION: Eleven men participants (age: 47-68 years). FIELD STRENGTH/SEQUENCE: Spin-echo echo planar imaging (SE-EPI) with diffusion weighting, multispin echo, Dixon, and fat-suppressed turbo spin-echo (TSE) sequences at 3T. MR datasets and creatine kinase (CK) concentrations were obtained at three timepoints. ASSESSMENT: Diffusion parameters, perfusion fractions, and quantitative (q)T2 values were determined for hamstring and quadriceps muscles, TSE images were scored for acute injury. The vastus medialis and biceps femoris long head muscles were divided and analyzed in five segments to assess local damage. STATISTICAL TESTS: Differences between timepoints in MR parameters were assessed with a multilevel linear mixed model and in CK concentrations with a Friedman test. Mean diffusivity (MD) and qT2 for whole muscle and muscle segments were compared using a multivariate analysis of covariance (MANCOVA). RESULTS: CK concentrations were elevated (1194 U/L [166-3906], P < 0.001) at 24-48 hours postmarathon and returned to premarathon values (323 U/L [56-2216]) at 2-week follow-up. Most of the MRI diffusion indices in muscles without acute injury changed at 24-48 hours postmarathon and returned to premarathon values at follow-up (MD, RD, and λ3; P < 0.006). qT2 values (P = 0.003) and perfusion fractions (P = 0.003) were higher at baseline compared to follow-up. Local assessments of MD and qT2 revealed more pronounced changes than whole muscle assessment (2-3-fold; P < 0.01). DATA CONCLUSION: Marathon running-induced microtrauma was detected with MRI in individual whole upper leg muscles and even more pronounced on local segments. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3 J. Magn. Reson. Imaging 2020;52:407-417.

Subclinical effects of long-chain fatty acid ß-oxidation deficiency on the adult heart: A case-control magnetic resonance study.

Cardiomyopathy can be a severe complication in patients with long-chain fatty acid ß-oxidation disorders (LCFAOD), particularly during episodes of metabolic derangement. It is unknown whether latent cardiac abnormalities exist in adult patients. To investigate cardiac involvement in LCFAOD, we used proton magnetic resonance imaging (MRI) and spectroscopy (1 H-MRS) to quantify heart function, myocardial tissue characteristics, and myocardial lipid content in 14 adult patients (two with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD); four with carnitine palmitoyltransferase II deficiency (CPT2D); and eight with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD)) and 14 gender-, age-, and BMI-matched control subjects. Examinations included cine MRI, MR tagging, native myocardial T1 and T2 mapping, and localized 1 H-MRS at 3 Tesla. Left ventricular (LV) myocardial mass (P = .011) and the LV myocardial mass-to-volume ratio (P = .008) were higher in patients, while ejection fraction (EF) was normal (P = .397). LV torsion was higher in patients (P = .026), whereas circumferential shortening was similar compared with controls (P = .875). LV hypertrophy was accompanied by high myocardial T1 values (indicative of diffuse fibrosis) in two patients, and additionally a low EF in one case. Myocardial lipid content was similar in patients and controls. We identified subclinical morphological and functional differences between the hearts of LCFAOD patients and matched control subjects using state-of-the-art MR methods. Our results suggest a chronic cardiac disease phenotype and hypertrophic LV remodeling of the heart in LCFAOD, potentially triggered by a mild, but chronic, energy deficiency, rather than by lipotoxic effects of accumulating lipid metabolites.

In vivo proton T1 relaxation times of mouse myocardial metabolites at 9.4 T.

PURPOSE: Proton magnetic resonance spectroscopy ((1) H-MRS) for quantitative in vivo assessment of mouse myocardial metabolism requires accurate acquisition timing to minimize motion artifacts and corrections for T1 -dependent partial saturation effects. In this study, mouse myocardial water and metabolite T1 relaxation time constants were quantified. METHODS: Cardiac-triggered and respiratory-gated PRESS-localized (1) H-MRS was employed at 9.4 T to acquire signal from a 4-µL voxel in the septum of healthy mice (n = 10) while maintaining a steady state of magnetization using dummy scans during respiratory gates. Signal stability was assessed via standard deviations (SD) of zero-order phases and amplitudes of water spectra. Saturation-recovery experiments were performed to determine T1 values. RESULTS: Phase SD did not vary for different repetition times (TR), and was 13.1° ± 4.5°. Maximal amplitude SD was 14.2% ± 5.1% at TR = 500 ms. Myocardial T1 values (mean ± SD) were quantified for water (1.71 ± 0.25 s), taurine (2.18 ± 0.62 s), trimethylamine from choline-containing compounds and carnitine (1.67 ± 0.25 s), creatine-methyl (1.34 ± 0.19 s), triglyceride-methylene (0.60 ± 0.15 s), and triglyceride-methyl (0.90 ± 0.17 s) protons. CONCLUSION: This work provides in vivo quantifications of proton T1 values for mouse myocardial water and metabolites at 9.4 T.

In vivo mouse myocardial (31)P MRS using three-dimensional image-selected in vivo spectroscopy (3D ISIS): technical considerations and biochemical validations.

(31)P MRS provides a unique non-invasive window into myocardial energy homeostasis. Mouse models of cardiac disease are widely used in preclinical studies, but the application of (31)P MRS in the in vivo mouse heart has been limited. The small-sized, fast-beating mouse heart imposes challenges regarding localized signal acquisition devoid of contamination with signal originating from surrounding tissues. Here, we report the implementation and validation of three-dimensional image-selected in vivo spectroscopy (3D ISIS) for localized (31)P MRS of the in vivo mouse heart at 9.4 T. Cardiac (31)P MR spectra were acquired in vivo in healthy mice (n = 9) and in transverse aortic constricted (TAC) mice (n = 8) using respiratory-gated, cardiac-triggered 3D ISIS. Localization and potential signal contamination were assessed with (31)P MRS experiments in the anterior myocardial wall, liver, skeletal muscle and blood. For healthy hearts, results were validated against ex vivo biochemical assays. Effects of isoflurane anesthesia were assessed by measuring in vivo hemodynamics and blood gases. The myocardial energy status, assessed via the phosphocreatine (PCr) to adenosine 5'-triphosphate (ATP) ratio, was approximately 25% lower in TAC mice compared with controls (0.76 ± 0.13 versus 1.00 ± 0.15; P < 0.01). Localization with one-dimensional (1D) ISIS resulted in two-fold higher PCr/ATP ratios than measured with 3D ISIS, because of the high PCr levels of chest skeletal muscle that contaminate the 1D ISIS measurements. Ex vivo determinations of the myocardial PCr/ATP ratio (0.94 ± 0.24; n = 8) confirmed the in vivo observations in control mice. Heart rate (497 ± 76 beats/min), mean arterial pressure (90 ± 3.3 mmHg) and blood oxygen saturation (96.2 ± 0.6%) during the experimental conditions of in vivo (31)P MRS were within the normal physiological range. Our results show that respiratory-gated, cardiac-triggered 3D ISIS allows for non-invasive assessments of in vivo mouse myocardial energy homeostasis with (31)P MRS under physiological conditions.