Mitochondrial-targeted antioxidant ingestion acutely blunts VO2max in physically inactive females.

PURPOSE: To determine the acute effects of a mitochondrial targeting antioxidant (MitoQ) on the metabolic response during exercise. METHODS: Nine (n = 9) physically inactive females (age 47 ± 22 years) performed two trials (Placebo and MitoQ) in a double-blind randomized cross-over design. In both trials, participants performed an exercise protocol consisting of 3-min stages at submaximal workloads followed by a ramp protocol to volitional exhaustion. Participants received either Placebo or MitoQ (80 mg) 1 h prior to exercise. Indirect calorimetry and cardiovascular measurements were collected throughout the duration of the exercise bout. RESULTS: Submaximal metabolic and cardiovascular variables were not different between trials (p > 0.05). VO2max was higher (p = 0.03) during Placebo (23.5 ± 5.7 mL kg min-1 ) compared to MitoQ (21.0 ± 6.6 mL kg min-1 ). Maximal ventilation was also higher (p = 0.02) in Placebo (82.4 ± 17.7 L/min) compared to MitoQ (75.0 ± 16.8 L/min). Maximal cardiovascular variables and blood lactate were not different between trials (p > 0.05). CONCLUSION: An acute dose of MitoQ blunted VO2max , which was primarily mediated by impairment of ventilatory function. These data suggest that the acute accumulation of exercise-induced mitochondrial reactive oxygen species (mtROS) are necessary for maximal aerobic capacity. Further research is warranted on mtROS-antioxidant cell signaling cascades, and how they relate to mitochondrial function during exercise.

The right ventricular transcriptome signature in Ossabaw swine with cardiometabolic heart failure: implications for the coronary vasculature.

Heart failure (HF) patients with deteriorating right ventricular (RV) structure and function have a nearly twofold increased risk of death compared with those without. Despite the well-established clinical risk, few studies have examined the molecular signature associated with this HF condition. The purpose of this study was to integrate morphological, molecular, and functional data with the transcriptome data set in the RV of a preclinical model of cardiometabolic HF. Ossabaw swine were fed either normal diet without surgery (lean control, n = 5) or Western diet and aortic-banding (WD-AB; n = 4). Postmortem RV weight was increased and positively correlated with lung weight in the WD-AB group compared with CON. Total RNA-seq was performed and gene expression profiles were compared and analyzed using principal component analysis, weighted gene co-expression network analysis, module enrichment analysis, and ingenuity pathway analysis. Gene networks specifically associated with RV hypertrophic remodeling identified a hub gene in MAPK8 (or JNK1) that was associated with the selective induction of the extracellular matrix (ECM) component fibronectin. JNK1 and fibronectin protein were increased in the right coronary artery (RCA) of WD-AB animals and associated with a decrease in matrix metalloproteinase 14 protein, which specifically degrades fibronectin. RCA fibronectin content was correlated with increased vascular stiffness evident as a decreased elastin elastic modulus in WD-AB animals. In conclusion, this study establishes a molecular and transcriptome signature in the RV using Ossabaw swine with cardiometabolic HF. This signature was associated with altered ECM regulation and increased vascular stiffness in the RCA, with selective dysregulation of fibronectin.

Trends in cardiorespiratory fitness among apparently healthy adults from the Ball State Adult Fitness Longitudinal Lifestyle STudy (BALL ST) cohort from 1970-2019.

INTRODUCTION: Cardiorespiratory fitness (CRF) is a strong independent predictor of cardiovascular disease (CVD) and CVD mortality. However, little is known in regards to how CRF has trended in apparently healthy adults over the past several decades. PURPOSE: To analyze trends in CRF and CVD risk factors over the last 50 years in a population of apparently healthy adult men and women. METHODS: Participants were 4,214 apparently healthy adults (2,390 men and 1,824 women) from the Ball State Adult Fitness Longitudinal Lifestyle STudy (BALL ST) that performed maximal cardiopulmonary exercise testing between 1970-2019 for the assessment of CRF defined as VO2max (ml/kg/min). Participants were self-referred either to a community-based exercise program, fitness testing, or were research subjects in exercise related studies and were placed into groups by decade based on testing date. RESULTS: CRF showed a general trend to decline (P<0.05) from the 1970s to the 2000s with an increase (P<0.05) from the 2000s to the 2010s for both men and women. This pattern persisted for age and sex-adjusted CRF level, determined by Fitness Registry and the Importance of Exercise: A National Data Base (FRIEND). For both women and men, CRF across the decades was associated (P<0.05) with the prevalence of physical inactivity, smoking, obesity, dyslipidemia and hypertension, and with diabetes in men only. CONCLUSION: CRF declined from 1970 through the 2000s in a cohort of apparently healthy men and women which was associated with worsening CVD risk profiles. However, the decline in CRF was attenuated over the past decade which may have a positive impact on future CVD in the population. Promoting physical activity to increase CRF should be a primary aspect of CVD prevention programs.

Cardiorespiratory Fitness Normalized to Fat-Free Mass and Mortality Risk.

PURPOSE: Cardiorespiratory fitness (CRF) is known to be directly related to fat-free mass (FFM), therefore, it has been suggested that normalizing CRF to FFM (V˙O2peakFFM) may be the most accurate expression of CRF as related to exercise performance and cardiorespiratory function. However, the influence of V˙O2peakFFM (mL·kg FFM·min) on predicting mortality has been largely unexplored. This study aimed to primarily assess the relationship between V˙O2peakFFM and all-cause and disease-specific mortality risk in apparently healthy adults. Further, this study sought to compare the predictive ability of V˙O2peakFFM to V˙O2peak normalized to total body weight (V˙O2peakTBW) for mortality outcomes. METHODS: Participants included 2905 adults (1555 men, 1350 women) who completed a cardiopulmonary exercise test between 1970 and 2016 to determine CRF. Body composition was assessed using the skinfold method to estimate FFM. Cardiorespiratory fitness was expressed as V˙O2peakTBW and V˙O2peakFFM. Participants were followed for 19.0 ± 11.7 yr after their cardiopulmonary exercise test for mortality outcomes. Cox-proportional hazard models were performed to determine the relationship of V˙O2peakFFM with mortality outcomes. Parameter estimates were assessed to compare the predictive ability of CRF expressed as V˙O2peakTBW and V˙O2peakFFM. RESULTS: Overall, V˙O2peakFFM was inversely related to all-cause, cardiovascular disease, and cancer mortality, with a 16.2%, 8.4%, and 8.0% lower risk per 1 mL·kg FFM·min improvement, respectively (P < 0.01). Further, assessment of the parameter estimates showed V˙O2peakFFM to be a significantly stronger predictor of all-cause mortality than V˙O2peakTBW (parameter estimates, -0.49 vs -0.16). CONCLUSIONS: Body composition is an important factor when considering the relationship between CRF and mortality risk. Clinicians should consider normalizing CRF to FFM when feasible, because it will strengthen the predictive power of the measure.

Curcumin and arterial function in health and disease: impact on oxidative stress and inflammation.

PURPOSE OF REVIEW: The purpose of this review is to provide a concise overview of the polyphenol curcumin for improving arterial health, specifically endothelial function and arterial stiffness, to reduce cardiovascular disease (CVD) risk and to highlight potential mechanisms of action by which curcumin may improve artery function. RECENT FINDINGS: The primary findings of this review support the notion for curcumin to improve arterial health both with aging and obesity. There are few clinical trials on curcumin, and those that currently exist are small in scale but provide evidence for curcumin to improve endothelial function in older adults and reduce arterial stiffness in young, obese men. The antioxidant and anti-inflammatory properties of curcumin appear to be important targets of curcumin that are related to improved arterial health. Mechanistic studies have revealed superoxide dismutase, heme oxygenase-1 and nuclear factor erythroid 2-related factor 2 as emerging targets for the beneficial effects of curcumin on the vasculature. SUMMARY: In summary, the efficacy of curcumin for improving arterial function is promising in the limited number of clinical studies performed to date. Still, much investigation is needed to elucidate the effectiveness of curcumin for improving arterial health to lower CVD risk.

The Association between the Change in Directly Measured Cardiorespiratory Fitness across Time and Mortality Risk.

BACKGROUND: The relationship between cardiorespiratory fitness (CRF) and mortality risk has typically been assessed using a single measurement, though some evidence suggests the change in CRF over time influences risk. This evidence is predominantly based on studies using estimated CRF (CRFe). The strength of this relationship using change in directly measured CRF over time in apparently healthy men and women is not well understood. PURPOSE: To examine the association of change in CRF over time, measured using cardiopulmonary exercise testing (CPX), with all-cause and disease-specific mortality and to compare baseline and subsequent CRF measurements as predictors of all-cause mortality. METHODS: Participants included 833 apparently healthy men and women (42.9 ±â€¯10.8 years) who underwent two maximal CPXs, the second CPX being ≥1 year following the baseline assessment (mean 8.6 years, range 1.0 to 40.3 years). Participants were followed for up to 17.7 (SD 11.8) years for all-cause-, cardiovascular disease- (CVD), and cancer mortality. Cox-proportional hazard models were performed to determine the association between the change in CRF, computed as visit 1 (CPX1) peak oxygen consumption (VO2peak [mL·kg-1·min-1]) - visit 2 (CPX2) VO2peak, and mortality outcomes. A Wald-Chi square test of equality was used to compare the strength of CPX1 to CPX2 VO2peak in predicting mortality. RESULTS: During follow-up, 172 participants died. Overall, the change in CPX-CRF was inversely related to all-cause, CVD, and cancer mortality (p < 0.05). Each 1 mL·kg-1·min-1 increase was associated with a ~11, 15, and 16% (all p < 0.001) reduction in all-cause, CVD, and cancer mortality, respectively. The inverse relationship between CRF and all-cause mortality was significant (p < 0.05) when men and women were examined independently, after adjusting for years since first CPX, baseline VO2peak, and age. Further, the Wald Chi-square test of equality found CPX2 VO2peak to be a significantly stronger predictor of all-cause mortality than CPX1 VO2peak (p < 0.05). CONCLUSION: The change in CRF over time was inversely related to mortality outcomes, and mortality was better predicted by CRF measured at subsequent test than CPX1 CRF. These findings emphasize the importance of adopting lifestyle behaviors that promote CRF, as well as support the need for routine assessment of CRF in clinical practice to better assess risk.

Aortic perivascular adipose-derived interleukin-6 contributes to arterial stiffness in low-density lipoprotein receptor deficient mice.

We tested the hypothesis that aortic perivascular adipose tissue (PVAT) from young low-density lipoprotein receptor-deficient (LDLr(-/-)) mice promotes aortic stiffness and remodeling, which would be mediated by greater PVAT-derived IL-6 secretion. Arterial stiffness was assessed by aortic pulse wave velocity and with ex vivo intrinsic mechanical properties testing in young (4-6 mo old) wild-type (WT) and LDLr(-/-) chow-fed mice. Compared with WT mice, LDLr(-/-) mice had increased aortic pulse wave velocity (407 ± 18 vs. 353 ± 13 cm/s) and intrinsic mechanical stiffness (5,308 ± 623 vs. 3,355 ± 330 kPa) that was associated with greater aortic protein expression of collagen type I and advanced glycation end products (all P < 0.05 vs. WT mice). Aortic segments from LDLr(-/-) compared with WT mice cultured in the presence of PVAT had greater intrinsic mechanical stiffness (6,092 ± 480 vs. 3,710 ± 316 kPa), and this was reversed in LDLr(-/-) mouse arteries cultured without PVAT (3,473 ± 577 kPa, both P < 0.05). Collagen type I and advanced glycation end products were increased in LDLr(-/-) mouse arteries cultured with PVAT (P < 0.05 vs. WT mouse arteries), which was attenuated when arteries were cultured in the absence of PVAT (P < 0.05). PVAT from LDLr(-/-) mice secreted larger amounts of IL-6 (3.4 ± 0.1 vs. 2.3 ± 0.7 ng/ml, P < 0.05), and IL-6 neutralizing antibody decreased intrinsic mechanical stiffness in LDLr(-/-) aortic segments cultured with PVAT (P < 0.05). Collectively, these data provide evidence for a role of PVAT-derived IL-6 in the pathogenesis of aortic stiffness and remodeling in chow-fed LDLr(-/-) mice.

Replicative aging induces endothelial to mesenchymal transition in human aortic endothelial cells: potential role of inflammation.

Thickening of the intimal layer of arteries characterized by expression of smooth muscle α-actin (SMαA), collagen deposition, and inflammation is an important pathophysiological change with aging assumed to be mediated by smooth muscle cells migrating from the medial layer. We tested the novel hypothesis that these characteristics could also reflect an endothelial-mesenchymal (smooth muscle-like) transition (EnMT). Late ('old') compared with early ('young') passage (45.0 ± 1.2 vs. 27.1 ± 0.5 population doublings) human aortic endothelial cells demonstrated greater smooth muscle (spindle) morphological changes, expression of SMαA and collagen I, nuclear factor-κB activation, and transforming growth factor-ß (TGF-ß) (all p < 0.05). Based on increases in SMαA, stimulation with the proinflammatory cytokine tumor necrosis factor-α, but not with TGF-ß, induced EnMT in early passage cells similar to that observed in late passage cells. Here, we present the first evidence for EnMT induced in a model of endothelial cell aging and provide support for proinflammatory signaling in mediating this phenotypic change.