Associations between 3D-based Left Atrial Volumetric and Blood Flow Parameters in a Single-Site Cohort of the Multi-Ethnic Study of Atherosclerosis.

Purpose To investigate associations between left atrial volume (LAV) and function with impaired three-dimensional hemodynamics from four-dimensional flow MRI. Materials and Methods A subcohort of participants from the Multi-Ethnic Study of Atherosclerosis from Northwestern University underwent prospective 1.5-T cardiac MRI including whole-heart four-dimensional flow and short-axis cine imaging between 2019 and 2020. Four-dimensional flow MRI analysis included manual three-dimensional segmentations of the LA and LA appendage (LAA), which were used to quantify LA and LAA peak velocity and blood stasis (% voxels < 0.1 m/sec). Short-axis cine data were used to delineate LA contours on all cardiac time points, and the resulting three-dimensional-based LAVs were extracted for calculation of LA emptying fractions (LAEFtotal, LAEFactive, LAEFpassive). Stepwise multivariable linear models were calculated for each flow parameter (LA stasis, LA peak velocity, LAA stasis, LAA peak velocity) to determine associations with LAV and LAEF. Results This study included 158 participants (mean age, 73 years ± 7 [SD]; 83 [52.5%] female and 75 [47.4%] male participants). In multivariable models, a 1-unit increase of LAEFtotal was associated with decreased LA stasis (ß coefficient, -0.47%; P < .001), while increased LAEFactive was associated with increased LA peak velocity (ß coefficient, 0.21 cm/sec; P < .001). Furthermore, increased minimum LAV indexed was most associated with impaired LAA flow (higher LAA stasis [ß coefficient, 0.65%; P < .001] and lower LAA peak velocity [ß coefficient, -0.35 cm/sec; P < .001]). Conclusion Higher minimum LAV and reduced LA function were associated with impaired flow characteristics in the LA and LAA. LAV assessment might therefore be a surrogate measure for LA and LAA flow abnormalities. Keywords: Atherosclerosis, Left Atrial Volume, Left Atrial Blood Flow, 4D Flow MRI Supplemental material is available for this article. © RSNA, 2024.

Mitochondrial Targeted Interventions for Aging.

Changes in mitochondrial function play a critical role in the basic biology of aging and age-related disease. Mitochondria are typically thought of in the context of ATP production and oxidant production. However, it is clear that the mitochondria sit at a nexus of cell signaling where they affect metabolite, redox, and energy status, which influence many factors that contribute to the biology of aging, including stress responses, proteostasis, epigenetics, and inflammation. This has led to growing interest in identifying mitochondrial targeted interventions to delay or reverse age-related decline in function and promote healthy aging. In this review, we discuss the diverse roles of mitochondria in the cell. We then highlight some of the most promising strategies and compounds to target aging mitochondria in preclinical testing. Finally, we review the strategies and compounds that have advanced to clinical trials to test their ability to improve health in older adults.

Comparison of Biplane Area-Length Method and 3D Volume Quantification by Using Cardiac MRI for Assessment of Left Atrial Volume in Atrial Fibrillation.

Purpose: To compare maximum left atrial (LA) volume (LAV) from the routinely used biplane area-length (BAL) method with three-dimensional (3D)-based volumetry from late gadolinium-enhanced MRI (3D LGE MRI) and contrast-enhanced MR angiography (3D CE-MRA) in patients with atrial fibrillation (AF). Materials and Methods: Sixty-four patients with AF (mean age, 63 years ± 9 [SD]; 40 male patients) were retrospectively included from a prospective cohort acquired between October 2018 and February 2021. All patients underwent a research MRI examination that included standard two- and four-chamber cine acquisitions, 3D CE-MRA, and 3D LGE MRI performed prior to the atrial kick. Contour delineation on cine imaging and LA 3D segmentations were performed by a radiologist. Maximum LAV (BALmax) was extracted from the BAL volume-time curve and compared with LAV from 3D CE-MRA and 3D LGE MRI. The Kruskal-Wallis test was performed, followed by the Dunn post hoc test and Bland-Altman analyses. Interobserver variability was assessed in 10 patients. Results: BALmax underestimated LAV compared with 3D CE-MRA (bias: -23.5 mL ± 46.2, P < .001) and 3D LGE MRI (bias: -31.3 mL ± 58.3, P < .001), whereas 3D LGE MRI volumes showed no evidence of a difference from 3D CE-MRA (bias: 7.8 mL ± 45.7, P = .38). Interobserver variability yielded excellent agreement for each method (intraclass correlation coefficient, 0.96-0.98). Conclusion: BALmax underestimated LAV in patients with AF compared with 3D LGE MRI and 3D CE-MRA, suggesting that the geometric assumption of an ellipsoidal LA shape in BAL does not reflect LA geometry in patients with AF.Keywords: Left Atrial Volume, Biplane Area-Length, Late Gadolinium-enhanced 3D MRI, Contrast-enhanced 3D MR Angiography, Atrial Fibrillation Supplemental material is available for this article. © RSNA, 2023.

ATP and NAD+ Deficiency in Parkinson's Disease.

The goal of this study is to identify a signature of bioenergetic and functional markers in the muscles of individuals with Parkinson's disease (PD). Quantitative physiological properties of in vivo hand muscle (FDI, first dorsal interosseus) and leg muscle (TA, Tibialis Anterior) of older individuals with PD were compared to historical age/gender-matched controls (N = 30). Magnetic resonance spectroscopy and imaging (MRS) were used to assess in vivo mitochondrial and cell energetic dysfunction, including maximum mitochondrial ATP production (ATPmax), NAD concentrations linked to energy/stress pathways, and muscle size. Muscle function was measured via a single muscle fatigue test. TA ATPmax and NAD levels were significantly lower in the PD cohort compared to controls (ATPmax: 0.66 mM/s ± 0.03 vs. 0.76 ± 0.02; NAD: 0.75 mM ± 0.05 vs. 0.91 ± 0.04). Muscle endurance and specific force were also lower in both hand and leg muscles in the PD subjects. Exploratory analyses of mitochondrial markers and individual symptoms suggested that higher ATPmax was associated with a greater sense of motivation and engagement and less REM sleep behavior disorder (RBD). ATPmax was not associated with clinical severity or individual symptom(s), years since diagnosis, or quality of life. Results from this pilot study contribute to a growing body of evidence that PD is not a brain disease, but a systemic metabolic syndrome with disrupted cellular energetics and function in peripheral tissues. The significant impairment of both mitochondrial ATP production and resting metabolite levels in the TA muscles of the PD patients suggests that skeletal muscle mitochondrial function may be an important tool for mechanistic understanding and clinical application in PD patients. This study looked at individuals with mid-stage PD; future research should evaluate whether the observed metabolic perturbations in muscle dysfunction occur in the early stages of the disease and whether they have value as theragnostic biomarkers.

Entry tear hemodynamics using 4D flow MRI in a patient with acute type B aortic dissection.

Stanford type B aortic dissection (TBAD) is a potentially fatal condition involving a tear in the descending aorta. As TBAD can be managed with medical therapy or surgical repair, identifying predictors of adverse outcomes is important to risk-stratify patients for preemptive surgical procedures. 4D flow magnetic resonance imaging (MRI) has shown to be useful in characterizing the complex hemodynamics seen in TBAD patients and correlating flow patterns with adverse outcomes. We report a case of a 58-year-old man who presented to the hospital with acute TBAD and a large primary entry tear. He was initially managed with medical therapy due to his stable clinical status and computed tomographic angiography showing a stable dissection. However, 4D flow MRI showed high velocity flow through the entry tear, which foreshadowed the later clinical decompensation of the patient. Our case demonstrates that performing 4D flow MRI on TBAD patients is feasible and can provide valuable information in the decision to pursue medical or surgical management.

Sex difference in the associations of socioeconomic status, cognitive function and brain volume with dementia in old adults: Findings from the OASIS study.

Background: Sex differences in the association of cognitive function and imaging measures with dementia have not been fully investigated while sex-based investigation of dementia has been discussed. Understanding sex differences in the dementia-related socioeconomic, cognitive, and imaging measurements is important for uncovering sex-related pathways to dementia and facilitating early diagnosis, family planning, and cost control. Methods: We selected data from the Open Access Series of Imaging Studies with longitudinal measurements of brain volumes on 150 individuals aged 60 to 96 years. Dementia status was determined using the Clinical Dementia Rating (CDR) scale, and Alzheimer's disease was diagnosed as a CDR of ≥ 0.5. Generalized estimating equation models were used to estimate the associations of socioeconomic, cognitive and imaging factors with dementia in men and women. Results: Lower education affected dementia more in women than in men. Age, education, Mini-Mental State Examination (MMSE), and normalized whole-brain volume (nWBV) were associated with dementia in women whereas only MMSE and nWBV were associated with dementia in men. Lower socioeconomic status was associated with a reduced estimated total intracranial volume in men, but not in women. Ageing and lower MMSE scores were associated with reduced nWBV in both men and women. Conclusions: The association between education and prevalence of dementia differs in men and women. Women may have more risk factors for dementia than men.

Quantification of left atrial function by the area-length method overestimates left atrial emptying fraction.

PURPOSE: The biplane area-length method is commonly used in cardiac magnetic resonance (CMR) to assess left atrial (LA) volume (LAV) and function. Associations between left atrial emptying fraction (LAEF) and clinical outcomes have been reported. However, only limited data are available on the calculation of LAEF using the biplane method compared to 3D assessment. This study aimed to compare volumetric and functional LA parameters obtained from the biplane method with 3D assessment in a large, multiethnic cohort. METHOD: 158 participants of MESA (Multi-Ethnic Study of Atherosclerosis) underwent CMR that included standard two- and four-chamber steady-state free precession (SSFP) cine imaging for the biplane method. For 3D-based assessment, short-axis SSFP cine series covering the entire LA were obtained, followed by manual delineation of LA contours to create a time-resolved 3D LAV dataset. Paired t-tests and Bland-Altman plots were used to analyze the data. RESULTS: Standard volumetric assessment showed that LAVmin (bias: -8.35 mL, p < 0.001), LAVmax (bias: -9.38 mL, p < 0.001) and LAVpreA (bias: -10.27 mL, p < 0.001) were significantly smaller using the biplane method compared to 3D assessment. Additionally, the biplane method reported significantly higher LAEFtotal (bias: 7.22 %, p < 0.001), LAEFactive (bias: 6.08 %, p < 0.001), and LAEFpassive (bias: 4.51 %, p < 0.001) with wide limits of agreement. CONCLUSIONS: LA volumes were underestimated using the biplane method compared to 3D assessment, while LAEF parameters were overestimated. These findings demonstrate a lack of precision using the biplane method for LAEF assessment. Our results support the usage of 3D assessment in specific settings when LA volumetric and functional parameters are in focus.

In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial.

BACKGROUND: Loss of mitochondrial function contributes to fatigue, exercise intolerance and muscle weakness, and is a key factor in the disability that develops with age and a wide variety of chronic disorders. Here, we describe the impact of a first-in-class cardiolipin-binding compound that is targeted to mitochondria and improves oxidative phosphorylation capacity (Elamipretide, ELAM) in a randomized, double-blind, placebo-controlled clinical trial. METHODS: Non-invasive magnetic resonance and optical spectroscopy provided measures of mitochondrial capacity (ATPmax) with exercise and mitochondrial coupling (ATP supply per O2 uptake; P/O) at rest. The first dorsal interosseous (FDI) muscle was studied in 39 healthy older adult subjects (60 to 85 yrs of age; 46% female) who were enrolled based on the presence of poorly functioning mitochondria. We measured volitional fatigue resistance by force-time integral over repetitive muscle contractions. RESULTS: A single ELAM dose elevated mitochondrial energetic capacity in vivo relative to placebo (ΔATPmax; P = 0.055, %ΔATPmax; P = 0.045) immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATPmax there was no significant effect of treatment on fatigue resistance in the FDI. CONCLUSIONS: These results highlight that ELAM rapidly and reversibly elevates mitochondrial capacity after a single dose. This response represents the first demonstration of a pharmacological intervention that can reverse mitochondrial dysfunction in vivo immediately after treatment in aging human muscle.

Astaxanthin supplementation enhances metabolic adaptation with aerobic training in the elderly.

Endurance training (ET) is recommended for the elderly to improve metabolic health and aerobic capacity. However, ET-induced adaptations may be suboptimal due to oxidative stress and exaggerated inflammatory response to ET. The natural antioxidant and anti-inflammatory dietary supplement astaxanthin (AX) has been found to increase endurance performance among young athletes, but limited investigations have focused on the elderly. We tested a formulation of AX in combination with ET in healthy older adults (65-82 years) to determine if AX improves metabolic adaptations with ET, and if AX effects are sex-dependent. Forty-two subjects were randomized to either placebo (PL) or AX during 3 months of ET. Specific muscle endurance was measured in ankle dorsiflexors. Whole body exercise endurance and fat oxidation (FATox) was assessed with a graded exercise test (GXT) in conjunction with indirect calorimetry. Results: ET led to improved specific muscle endurance only in the AX group (Pre 353 ± 26 vs. Post 472 ± 41 contractions), and submaximal GXT duration improved in both groups (PL 40.8 ± 9.1% and AX 41.1 ± 6.3%). The increase in FATox at lower intensity after ET was greater in AX (PL 0.23 ± 0.15 g vs. AX 0.76 ± 0.18 g) and was associated with reduced carbohydrate oxidation and increased exercise efficiency in males but not in females.

Sagittal abdominal diameter and its socioeconomic correlates: perspective of sex differences.

BACKGROUND: Sagittal abdominal diameter (SAD) is an anthropometric index associated with visceral adiposity. It remains unclear whether SAD and its socio-economic correlates differ in women and men, which limits the epidemiological and clinical applications of the SAD measurement. The aims of this study are to examine the sex differences in SAD and its socio-economic correlates. METHODS: A complex stratified multistage clustered sampling design was used to select 6975 men and 7079 women aged 18 years or more from the National Health Nutrition and Examination Survey 2011-2016, representative of the US civilian non-institutionalized population. SAD was measured in accordance to the standard protocols using a two-arm abdominal caliper. The sex differences in SAD and its socio-economic correlates were evaluated by performing weighted independent t tests and weighted multiple regression. RESULTS: SAD was lower in women than in men in the entire sample, as well as in all the subgroups characterized by age, race, birth place, household income, and body mass index except for non-Hispanic blacks and those with household income < $20,000. Adjusted for other characteristics, age, birth place, household income, and body mass index were associated with SAD in both women and men. Black women were associated with higher SAD then white women (p < .0001), and Hispanic and Asian men were associated with lower SAD than white men (both p < .01). Women born in other countries were more likely to have lower SAD than women born in the US (p < .0001), and so were men (p = .0118). Both women and men with a household income of <$75,000 had higher SAD than those with an income of over $75,000. The associations of age, race, and household income with SAD differed in women and men. CONCLUSION: SAD is lower in women than in men, in the general population as well as in the most socio-economic subgroups. While socio-economic correlates of SAD are similar in women and men, the associations of age, race, and household income with SAD vary across sex.

Building strength, endurance, and mobility using an astaxanthin formulation with functional training in elderly.

BACKGROUND: Building both strength and endurance has been a challenge in exercise training in the elderly, but dietary supplements hold promise as agents for improving muscle adaptation. Here, we test a formulation of natural products (AX: astaxanthin, 12 mg and tocotrienol, 10 mg and zinc, 6 mg) with both anti-inflammatory and antioxidant properties in combination with exercise. We conducted a randomized, double-blind, placebo-controlled study of elderly subjects (65-82 years) on a daily oral dose with interval walking exercise on an incline treadmill. METHODS: Forty-two subjects were fed AX or placebo for 4 months and trained 3 months (3×/week for 40-60 min) with increasing intervals of incline walking. Strength was measured as maximal voluntary force (MVC) in ankle dorsiflexion exercise, and tibialis anterior muscle size (cross-sectional area, CSA) was determined from magnetic resonance imaging. RESULTS: Greater endurance (exercise time in incline walking, >50%) and distance in 6 min walk (>8%) accompanied training in both treatments. Increases in MVC by 14.4% (±6.2%, mean ± SEM, P < 0.02, paired t-test), CSA by 2.7% (±1.0%, P < 0.01), and specific force by 11.6% (MVC/CSA, ±6.0%, P = 0.05) were found with AX treatment, but no change was evident in these properties with placebo treatment (MVC, 2.9% ± 5.6%; CSA, 0.6% ± 1.2%; MVC/CSA, 2.4 ± 5.7%; P > 0.6 for all). CONCLUSIONS: The AX formulation improved muscle strength and CSA in healthy elderly in addition to the elevation in endurance and walking distance found with exercise training alone. Thus, the AX formulation in combination with a functional training programme uniquely improved muscle strength, endurance, and mobility in the elderly.

Skeletal muscle bioenergetics in aging and heart failure.

Changes in mitochondrial capacity and quality play a critical role in skeletal and cardiac muscle dysfunction. In vivo measurements of mitochondrial capacity provide a clear link between physical activity and mitochondrial function in aging and heart failure, although the cause and effect relationship remains unclear. Age-related decline in mitochondrial quality leads to mitochondrial defects that affect redox, calcium, and energy-sensitive signaling by altering the cellular environment that can result in skeletal muscle dysfunction independent of reduced mitochondrial capacity. This reduced mitochondrial quality with age is also likely to sensitize skeletal muscle mitochondria to elevated angiotensin or beta-adrenergic signaling associated with heart failure. This synergy between aging and heart failure could further disrupt cell energy and redox homeostasis and contribute to exercise intolerance in this patient population. Therefore, the interaction between aging and heart failure, particularly with respect to mitochondrial dysfunction, should be a consideration when developing strategies to improve quality of life in heart failure patients. Given the central role of the mitochondria in skeletal and cardiac muscle dysfunction, mitochondrial quality may provide a common link for targeted interventions in these populations.

COX Inhibitor Influence on Skeletal Muscle Fiber Size and Metabolic Adaptations to Resistance Exercise in Older Adults.

Common cyclooxygenase (COX)-inhibiting drugs enhance resistance exercise induced muscle mass and strength gains in older individuals. The purpose of this investigation was to determine whether the underlying mechanism regulating this effect was specific to Type I or Type II muscle fibers, which have different contractile and metabolic profiles. Muscle biopsies (vastus lateralis) were obtained before and after 12 weeks of knee-extensor resistance exercise (3 days/week) from healthy older men who consumed either a placebo (n = 8; 64±2 years) or COX inhibitor (acetaminophen, 4 gram/day; n = 7; 64±1 years) in double-blind fashion. Muscle samples were examined for Type I and II fiber cross-sectional area, capillarization, and metabolic enzyme activities (glycogen phosphorylase, citrate synthase, ß-hydroxyacyl-CoA-dehydrogenase). Type I fiber size did not change with training in the placebo group (304±590 µm(2)) but increased 28% in the COX inhibitor group (1,388±760 µm(2), p < .1). Type II fiber size increased 26% in the placebo group (1,432±499 µm(2), p < .05) and 37% in the COX inhibitor group (1,825±400 µm(2), p < .05). Muscle capillarization and enzyme activity were generally maintained in the placebo group. However, capillary to fiber ratio increased 24% (p < .1) and citrate synthase activity increased 18% (p < .05) in the COX inhibitor group. COX inhibitor consumption during resistance exercise in older individuals enhances myocellular growth, and this effect is more pronounced in Type I muscle fibers.

Prostaglandin E2/cyclooxygenase pathway in human skeletal muscle: influence of muscle fiber type and age.

Prostaglandin E2 (PGE2) produced by the cyclooxygenase (COX) pathway regulates skeletal muscle protein turnover and exercise training adaptations. The purpose of this study was twofold: 1) define the PGE2/COX pathway enzymes and receptors in human skeletal muscle, with a focus on type I and II muscle fibers; and 2) examine the influence of aging on this pathway. Muscle biopsies were obtained from the soleus (primarily type I fibers) and vastus lateralis (proportionally more type II fibers than soleus) of young men and women (n = 8; 26 ± 2 yr), and from the vastus lateralis of young (n = 8; 25 ± 1 yr) and old (n = 12; 79 ± 2 yr) men and women. PGE2/COX pathway proteins [COX enzymes (COX-1 and COX-2), PGE2 synthases (cPGES, mPGES-1, and mPGES-2), and PGE2 receptors (EP1, EP2, EP3, and EP4)] were quantified via Western blot. COX-1, cPGES, mPGES-2, and all four PGE2 receptors were detected in all skeletal muscle samples examined. COX-1 (P < 0.1) and mPGES-2 were ∼20% higher, while EP3 was 99% higher and EP4 57% lower in soleus compared with vastus lateralis (P < 0.05). Aging did not change the level of skeletal muscle COX-1, while cPGES increased 45% and EP1 (P < 0.1), EP3, and EP4 decreased ∼33% (P < 0.05). In summary, PGE2 production capacity and receptor levels are different in human skeletal muscles with markedly different type I and II muscle fiber composition. In aging skeletal muscle, PGE2 production capacity is elevated and receptor levels are downregulated. These findings have implications for understanding the regulation of skeletal muscle adaptations to exercise and aging by the PGE2/COX pathway and related inhibitors.

Local anesthetic effects on gene transcription in human skeletal muscle biopsies.

INTRODUCTION: We examined if epinephrine in the local anesthetic to help control incision-related bleeding interferes with molecular measurements obtained with the Duchenne-Bergström percutaneous needle biopsy technique for sampling human skeletal muscle. METHODS: Three groups received 2.5-3.0 ml of 1% lidocaine in 2 injections: (1) 0.5-1.0 ml superficially, which varied among the groups according to (i) -Epi; intra- and subcutaneous without epinephrine, (ii) +Epi -Fascia; intra- and subcutaneous with epinephrine, avoiding the fascia, and (iii) +Epi +Fascia; intra- and subcutaneous with epinephrine, directing a small amount (∽0.2 ml) into the fascia area; and (2) ∽2.0 ml without epinephrine into the fascia area for all subjects. A muscle biopsy was obtained 5-10 min later for IL-6 and MuRF-1 mRNA levels. RESULTS: IL-6 mRNA levels were low in -Epi and +Epi -Fascia, but ∽300-fold higher in +Epi +Fascia. MuRF-1 mRNA levels were similar among the groups. CONCLUSIONS: Lidocaine with epinephrine can confound intramuscular measurements from needle biopsies, but this can be avoided with a careful injection approach.

Effects of prostaglandins and COX-inhibiting drugs on skeletal muscle adaptations to exercise.

It has been ∼40 yr since the discovery that PGs are produced by exercising skeletal muscle and since the discovery that inhibition of PG synthesis is the mechanism of action of what are now known as cyclooxygenase (COX)-inhibiting drugs. Since that time, it has been established that PGs are made during and after aerobic and resistance exercise and have a potent paracrine and autocrine effect on muscle metabolism. Consequently, it has also been determined that orally consumed doses of COX inhibitors can profoundly influence muscle PG synthesis, muscle protein metabolism, and numerous other cellular processes that regulate muscle adaptations to exercise loading. Although data from acute human exercise studies, as well as animal and cell-culture data, would predict that regular consumption of a COX inhibitor during exercise training would dampen the typical muscle adaptations, the chronic data do not support this conjecture. From the studies in young and older individuals, lasting from 1.5 to 4 mo, no interfering effects of COX inhibitors on muscle adaptations to resistance-exercise training have been noted. In fact, in older individuals, a substantial enhancement of muscle mass and strength has been observed. The collective findings of the PG/COX-pathway regulation of skeletal muscle responses and adaptations to exercise are compelling. Considering the discoveries in other areas of COX regulation of health and disease, there is certainly an interesting future of investigation in this re-emerging area, especially as it pertains to older individuals and the condition of sarcopenia, as well as exercise training and performance of individuals of all ages.