Summary
Skeletal muscle mitochondrial oxidative capacity declines with age and negatively affects walking performance, but the mechanism for this association is not fully clear. We tested the ...hypothesis that impaired oxidative capacity affects muscle performance and, through this mechanism, has a negative effect on walking speed. Muscle mitochondrial oxidative capacity was measured by in vivo phosphorus magnetic resonance spectroscopy as the postexercise phosphocreatine resynthesis rate, kPCr, in 326 participants (154 men), aged 24–97 years (mean 71), in the Baltimore Longitudinal Study of Aging. Muscle strength and quality were determined by knee extension isokinetic strength, and the ratio of knee extension strength to thigh muscle cross‐sectional area derived from computed topography, respectively. Four walking tasks were evaluated: a usual pace over 6 m and for 150 s, and a rapid pace over 6 m and 400 m. In multivariate linear regression analyses, kPCr was associated with muscle strength (β = 0.140, P = 0.007) and muscle quality (β = 0.127, P = 0.022), independent of age, sex, height, and weight; muscle strength was also a significant independent correlate of walking speed (P < 0.02 for all tasks) and in a formal mediation analysis significantly attenuated the association between kPCr and three of four walking tasks (18–29% reduction in β for kPCr). This is the first demonstration in human adults that mitochondrial function affects muscle strength and that inefficiency in muscle bioenergetics partially accounts for differences in mobility through this mechanism.
Despite opposing insulin sensitivity and cardiometabolic risk, both athletes and patients with type 2 diabetes have increased skeletal myocyte fat storage: the so-called "athlete's paradox". In a ...parallel non-randomised, non-blinded trial (NCT03065140), we characterised and compared the skeletal myocyte lipid signature of 29 male endurance athletes and 30 patients with diabetes after undergoing deconditioning or endurance training respectively. The primary outcomes were to assess intramyocellular lipid storage of the vastus lateralis in both cohorts and the secondary outcomes were to examine saturated and unsaturated intramyocellular lipid pool turnover. We show that athletes have higher intramyocellular fat saturation with very high palmitate kinetics, which is attenuated by deconditioning. In contrast, type 2 diabetes patients have higher unsaturated intramyocellular fat and blunted palmitate and linoleate kinetics but after endurance training, all were realigned with those of deconditioned athletes. Improved basal insulin sensitivity was further associated with better serum cholesterol/triglycerides, glycaemic control, physical performance, enhanced post insulin receptor pathway signalling and metabolic sensing. We conclude that insulin-resistant, maladapted intramyocellular lipid storage and turnover in patients with type 2 diabetes show reversibility after endurance training through increased contributions of the saturated intramyocellular fatty acid pools. Clinical Trial Registration: NCT03065140: Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity (MISTY).
: The heart is the organ with the highest metabolic demand in the body, and it relies on high ATP turnover and efficient energy substrate utilisation in order to function normally. The derangement of ...myocardial energetics may lead to abnormalities in cardiac metabolism, which herald the symptoms of heart failure (HF). In addition, phosphorus magnetic resonance spectroscopy (
P MRS) is the only available non-invasive method that allows clinicians and researchers to evaluate the myocardial metabolic state in vivo. This review summarises the importance of myocardial energetics and provides a systematic review of all the available research studies utilising
P MRS to evaluate patients with a range of cardiac pathologies.
: We have performed a systematic review of all available studies that used
P MRS for the investigation of myocardial energetics in cardiovascular disease.
: A systematic search of the Medline database, the Cochrane library, and Web of Science yielded 1092 results, out of which 62 studies were included in the systematic review. The
P MRS has been used in numerous studies and has demonstrated that impaired myocardial energetics is often the beginning of pathological processes in several cardiac pathologies.
: The
P MRS has become a valuable tool in the understanding of myocardial metabolic changes and their impact on the diagnosis, risk stratification, and prognosis of patients with cardiovascular diseases.
Maximum oxidative capacity of skeletal muscle measured by
phosphorus magnetic resonance spectroscopy (
P-MRS) declines with age, and negatively affects whole-body aerobic capacity. However, it ...remains unclear whether the loss of oxidative capacity is caused by reduced volume and function of mitochondria or limited substrate availability secondary to impaired muscle perfusion. Therefore, we sought to elucidate the role of muscle perfusion on the age-related decline of muscle oxidative capacity and ultimately whole-body aerobic capacity. Muscle oxidative capacity was assessed by
P-MRS post-exercise phosphocreatine recovery time (τ
), with higher τ
reflecting lower oxidative capacity, in 75 healthy participants (48 men, 22-89 years) of the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing study. Muscle perfusion was characterized as an index of blood volume at rest using a customized diffusion-weighted MRI technique and analysis method developed in our laboratory. Aerobic capacity (peak-VO
) was also measured during a graded treadmill exercise test in the same visit. Muscle oxidative capacity, peak-VO
, and resting muscle perfusion were significantly lower at older ages independent of sex, race, and body mass index (BMI). τ
was significantly associated with resting muscle perfusion independent of age, sex, race, and BMI (
-value = 0.004, β = -0.34). τ
was also a significant independent predictor of peak-VO
and, in a mediation analysis, significantly attenuated the association between muscle perfusion and peak-VO
(34% reduction for β in perfusion). These findings suggest that the age-associated decline in muscle oxidative capacity is partly due to impaired muscle perfusion and not mitochondrial dysfunction alone. Furthermore, our findings show that part of the decline in whole-body aerobic capacity observed with aging is also due to reduced microvascular blood volume at rest, representing a basal capacity of the microvascular system, which is mediated by muscle oxidative capacity. This finding suggests potential benefit of interventions that target an overall increase in muscle perfusion for the restoration of energetic capacity and mitochondrial function with aging.
Myocardial inflammation has been hypothesised to be the common underlying mechanism through which several cardiovascular diseases develop and progress. Cardiac magnetic resonance (CMR) has become a ...powerful non-invasive tool that enables the direct visualisation of the myocardium. The emerging use of ultrasmall superparamagnetic particles of iron oxide (USPIO) and their magnetic properties is gaining a lot of research interest. USPIO-enhanced CMR can provide valuable information, as it allows for the identification of active inflammation in the myocardium, a process that has been hypothesised to be the substrate for adverse remodelling and, eventually, heart failure. In this review, we summarise the properties of USPIO and their role in cardiac magnetic resonance imaging as well as their clinical applications.
Purpose
This study aims to investigate the role of diffusion-weighted imaging (DWI) and T
2
-weighted imaging (T
2
WI) in combination for the detection of prostate cancer, specifically assessing the ...role of high
b
-values (> 1000 s/mm
2
), with a systematic review and meta-analysis of the existing published data.
Methods
The electronic databases MEDLINE, EMBASE, and OpenSIGLE were searched between inception and September 1, 2017. Eligible studies were those that reported the sensitivity and specificity of DWI and T
2
WI for the diagnosis of prostate cancer by visual assessment using a histopathologic reference standard. The QUADAS-2 critical appraisal tool was used to assess the quality of included studies. A meta-analysis with pooling of sensitivity, specificity, likelihood, and diagnostic odds ratios was undertaken, and a summary receiver-operating characteristics (sROC) curve was constructed. Predetermined subgroup analysis was also performed.
Results
Thirty-three studies were included in the final analysis, evaluating 2949 patients. The pooled sensitivity and specificity were 0.69 (95% CI 0.68–0.69) and 0.84 (95% CI 0.83–0.85), respectively, and the sROC AUC was 0.84 (95% CI 0.81–0.87). Subgroup analysis showed significantly better sensitivity with high
b
-values (> 1000 s/mm
2
). There was high statistical heterogeneity between studies.
Conclusion
The diagnostic accuracy of combined DWI and T
2
WI is good with high
b
-values (> 1000 s/mm
2
) seeming to improve overall sensitivity while maintaining specificity. However, further large-scale studies specifically looking at
b
-value choice are required before a categorical recommendation can be made.
We sought to systematically review and meta-analy the role of cerebral blood flow (CBF) in the medial temporal lobe (MTL) using arterial spin labeling magnetic resonance imaging (ASL-MRI) and compare ...this in patients with Alzheimer's disease (AD), individuals with mild cognitive impairment (MCI), and cognitively normal adults (CN). The prevalence of AD is increasing and leading to high healthcare costs. A potential biomarker that can identify people at risk of developing AD, whilst cognition is normal or only mildly affected, will enable risk-stratification and potential therapeutic interventions in the future. All studies investigated the role of CBF in the MTL and compared this among AD, MCI, and CN participants. A total of 26 studies were included in the systematic review and 11 in the meta-analysis. Three separate meta-analyses were conducted. Four studies compared CBF in the hippocampus of AD compared with the CN group and showed that AD participants had 2.8 mL/min/100 g lower perfusion compared with the CN group. Eight studies compared perfusion in the hippocampus of MCI vs. CN group, which showed no difference. Three studies compared perfusion in the MTL of MCI vs. CN participants and showed no statistically significant differences. CBF measured via ASL-MRI showed impairment in AD compared with the CN group in subregions of the MTL. CBF difference was significant in hippocampus between the AD and CN groups. However, MCI and CN group showed no significant difference in subregions of MTL.
Background Exercise-induced pulmonary hypertension is common in heart failure with preserved ejection fraction ( HF p EF ). We hypothesized that this could result in pericardial constraint and ...diastolic ventricular interaction in some patients during exercise. Methods and Results Contrast stress echocardiography was performed in 30 HF p EF patients, 17 hypertensive controls, and 17 normotensive controls (healthy). Cardiac volumes, and normalized radius of curvature ( NRC ) of the interventricular septum at end-diastole and end-systole, were measured at rest and peak-exercise, and compared between the groups. The septum was circular at rest in all 3 groups at end-diastole. At peak-exercise, end-systolic NRC increased to 1.47±0.05 ( P<0.001) in HF p EF patients, confirming development of pulmonary hypertension. End-diastolic NRC also increased to 1.54±0.07 ( P<0.001) in HF p EF patients, indicating septal flattening, and this correlated significantly with end-systolic NRC (ρ=0.51, P=0.007). In hypertensive controls and healthy controls, peak-exercise end-systolic NRC increased, but this was significantly less than observed in HF p EF patients ( HF p EF , P=0.02 versus hypertensive controls; P<0.001 versus healthy). There were also small, non-significant increases in end-diastolic NRC in both groups (hypertensive controls, +0.17±0.05, P=0.38; healthy, +0.06±0.03, P=0.93). In HF p EF patients, peak-exercise end-diastolic NRC also negatively correlated ( r=-0.40, P<0.05) with the change in left ventricular end-diastolic volume with exercise (ie, the Frank-Starling mechanism), and a trend was noted towards a negative correlation with change in stroke volume ( r=-0.36, P=0.08). Conclusions Exercise pulmonary hypertension causes substantial diastolic ventricular interaction on exercise in some patients with HF p EF , and this restriction to left ventricular filling by the right ventricle exacerbates the pre-existing impaired Frank-Starling response in these patients.
In this acute intervention study, we investigated the potential benefit of ketone supplementation in humans by studying cardiac phosphocreatine to adenosine-triphosphate ratios (PCr/ATP) and skeletal ...muscle PCr recovery using phosphorus magnetic resonance spectroscopy (
31
P-MRS) before and after ingestion of a ketone ester drink. We recruited 28 healthy individuals: 12 aged 23–70 years for cardiac
31
P-MRS, and 16 aged 60–75 years for skeletal muscle
31
P-MRS. Baseline and post-intervention resting cardiac and dynamic skeletal muscle
31
P-MRS scans were performed in one visit, where 25 g of the ketone monoester, deltaG
®
, was administered after the baseline scan. Administration was timed so that post-intervention
31
P-MRS would take place 30 min after deltaG
®
ingestion. The deltaG
®
ketone drink was well-tolerated by all participants. In participants who provided blood samples, post-intervention blood glucose, lactate and non-esterified fatty acid concentrations decreased significantly (−28.8%,
p
≪ 0.001; −28.2%,
p
= 0.02; and −49.1%,
p
≪ 0.001, respectively), while levels of the ketone body
D
-beta-hydroxybutyrate significantly increased from mean (standard deviation) 0.7 (0.3) to 4.0 (1.1) mmol/L after 30 min (
p
≪ 0.001). There were no significant changes in cardiac PCr/ATP or skeletal muscle metabolic parameters between baseline and post-intervention. Acute ketone supplementation caused mild ketosis in blood, with drops in glucose, lactate, and free fatty acids; however, such changes were not associated with changes in
31
P-MRS measures in the heart or in skeletal muscle. Future work may focus on the effect of longer-term ketone supplementation on tissue energetics in groups with compromised mitochondrial function.
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