Tissue-specific mitochondrial toxicity of cigarette smoke concentrate: consequence to oxidative phosphorylation.

Cigarette smoke exposure is a well-known risk factor for developing numerous chronic health conditions, including pulmonary disease and cardiometabolic disorders. However, the cellular mechanisms mediating the toxicity of cigarette smoke in extrapulmonary tissues are still poorly understood. Therefore, the purpose of this study was to characterize the acute dose-dependent toxicity of cigarette smoke on mitochondrial metabolism by determining the susceptibility and sensitivity of mitochondrial respiration from murine skeletal (gastrocnemius and soleus) and cardiac muscles, as well as the aorta to cigarette smoke concentrate (CSC). In all tissues, exposure to CSC inhibited tissue-specific respiration capacity, measured by high-resolution respirometry, according to a biphasic pattern. With a break point of 451 ± 235 µg/mL, the aorta was the least susceptible to CSC-induced mitochondrial respiration inhibition compared with the gastrocnemius (151 ± 109 µg/mL; P = 0.008, d = 2.3), soleus (211 ± 107 µg/mL; P = 0.112; d = 1.7), and heart (94 ± 51 µg/mL; P < 0.001; d = 2.6) suggesting an intrinsic resistance of the vascular smooth muscle mitochondria to cigarette smoke toxicity. In contrast, the cardiac muscle was the most susceptible and sensitive to the effects of CSC, demonstrating the greatest decline in tissue-specific respiration with increasing CSC concentration (P < 0.001, except the soleus). However, when normalized to citrate synthase activity to account for differences in mitochondrial content, cardiac fibers' sensitivity to cigarette smoke inhibition was no longer significantly different from both fast-twitch gastrocnemius and slow-twitch soleus muscle fibers, thus suggesting similar mitochondrial phenotypes. Collectively, these findings established the acute dose-dependent toxicity of cigarette smoke on oxidative phosphorylation in permeabilized tissues involved in the development of smoke-related cardiometabolic diseases.NEW & NOTEWORTHY Despite numerous investigations into the mechanisms underlying cigarette smoke-induced mitochondrial dysfunction, no studies have investigated the tissue-specific mitochondrial toxicity to cigarette smoke. We demonstrate that, while aorta is least sensitive and susceptible to cigarette smoke-induced toxicity, the degree of cigarette smoke-induced toxicity in striated muscle depends on the tissue-specific mitochondrial content. We conclude that while the mitochondrial content influences cigarette smoke-induced toxicity in striated muscles, aorta is intrinsically protected against cigarette smoke-induced mitochondrial toxicity.

Capturing Measures That Matter: The Potential Value of Digital Measures of Physical Behavior for Alzheimer's Disease Drug Development.

Alzheimer's disease (AD) is a devastating neurodegenerative disease and the primary cause of dementia worldwide. Despite the magnitude of AD's impact on patients, caregivers, and society, nearly all AD clinical trials fail. A potential contributor to this high rate of failure is that established clinical outcome assessments fail to capture subtle clinical changes, entail high burden for patients and their caregivers, and ineffectively address the aspects of health deemed important by patients and their caregivers. AD progression is associated with widespread changes in physical behavior that have impacts on the ability to function independently, which is a meaningful aspect of health for patients with AD and important for diagnosis. However, established assessments of functional independence remain underutilized in AD clinical trials and are limited by subjective biases and ceiling effects. Digital measures of real-world physical behavior assessed passively, continuously, and remotely using digital health technologies have the potential to address some of these limitations and to capture aspects of functional independence in patients with AD. In particular, measures of real-world gait, physical activity, and life-space mobility captured with wearable sensors may offer value. Additional research is needed to understand the validity, feasibility, and acceptability of these measures in AD clinical research.

Seven days of statin treatment improves nitric-oxide mediated endothelial-dependent cutaneous microvascular function in women with endometriosis.

INTRODUCTION: Endometriosis is associated with systemic inflammation and increased risk of cardiovascular disease (CVD). Endothelial dysfunction is one of the first manifestations of CVD but is unexplored in women with endometriosis. HMG-CoA-reductase inhibitors (statins) exert potent anti-inflammatory effects, and have been proposed as an adjunctive therapy in women with endometriosis. We hypothesized that microvascular endothelial function would be impaired in otherwise healthy women with endometriosis mediated by reduced nitric oxide (NO)-dependent dilation and that short term statin administration would improve endothelial function. METHODS: In 8 healthy control (HC: 33 ± 9 yr) and 8 women with endometriosis (EN: 34 ± 9 yr), laser-Doppler flux (LDF) was measured continuously during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (Ach: 10-10-10-1 M) alone and in combination with the NO synthase inhibitor (L-NAME: 0.015 M). 6 EN repeated the microdialysis experiment following 7 days of oral atorvastatin treatment (10 mg). Cutaneous vascular conductance was calculated (CVC = LDF*mmHg-1) and normalized to site-specific maximum (28 mM sodium nitroprusside, 43 °C). The NO-dependent dilation was calculated as the difference between the areas under the dose response curves. RESULTS: Ach-induced vasodilation was blunted in women with endometriosis (main effect p < 0.01), indicating impaired endothelial function. NO-dependent vasodilation was also reduced in women with endometriosis (HC: 217 ± 120.3 AUC vs. EN: 88 ± 97 AUC, p = 0.03). Oral atorvastatin improved Ach-induced (main effect p < 0.01) and NO-dependent (295 ± 153 AUC; p = 0.05) vasodilation in women with endometriosis. CONCLUSION: Microcirculatory endothelium-dependent vasodilation is impaired in women with endometriosis, mediated in part by reductions in NO. Short-term oral atorvastatin improved endothelium-dependent vasodilation, suggesting that statin therapy may be a viable intervention strategy to mitigate accelerated CVD risk in women with endometriosis.

From heart to muscle: pathophysiological mechanisms underlying long-term physical sequelae from SARS-CoV-2 infection.

The long-term sequelae of the coronavirus disease 2019 (COVID-19) are multifaceted and, besides the lungs, impact other organs and tissues, even in cases of mild infection. Along with commonly reported symptoms such as fatigue and dyspnea, a significant proportion of those with prior COVID-19 infection also exhibit signs of cardiac damage, muscle weakness, and ultimately, poor exercise tolerance. This review provides an overview of evidence indicating cardiac impairments and persistent endothelial dysfunction in the peripheral vasculature of those previously infected with COVID-19, irrespective of the severity of the acute phase of illness. In addition, V̇o2peak appears to be lower in convalescent patients, which may stem, in part, from alterations in O2 transport such as impaired diffusional O2 conductance. Together, the persistent multi-organ dysfunction induced by COVID-19 may set previously healthy individuals on a trajectory towards frailty and disease. Given the large proportion of individuals recovering from COVID-19, it is critically important to better understand the physical sequelae of COVID-19, the underlying biological mechanisms contributing to these outcomes, and the long-term effects on future disease risk. This review highlights relevant literature on the pathophysiology post-COVID-19 infection, gaps in the literature, and emphasizes the need for the development of evidence-based rehabilitation guidelines.

Acute systemic inhibition of inflammation augments endothelium-dependent dilation in women with a history of preeclamptic pregnancy.

Women who have had preeclampsia demonstrate microvascular endothelial-dysfunction, mediated in part by reduced nitric oxide (NO)-dependent dilation. Preeclamptic pregnancies are associated with elevated inflammation, and inhibition of inflammation attenuates endothelial damage in animal models of preeclampsia. However, it is unclear if inhibition of vascular inflammation improves endothelial function in women after a preeclamptic pregnancy. Using the cutaneous microcirculation as a model, we hypothesized that acute systemic inhibition of vascular inflammation (oral salsalate; 1500 mg/twice daily, 4 days) would improve endothelium- and NO-dependent vasodilation in women with a history of preeclampsia (PE) but not in women with a history of uncomplicated pregnancy (HC). Twelve HC (30 ± 1yrs, 10 ± 2 months postpartum) and 10 PE (30 ± 2yrs, 8 ± 2 months postpartum) participated in a double-blind placebo-controlled study. Following each treatment, 2 intradermal microdialysis fibers were placed in the skin of the ventral forearm for graded infusion of acetylcholine (Ach, 10-7-102mM) or Ach + 15 mM L-NAME (NO synthase antagonist). Red blood cell flux was measured over each site by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated (CVC = LDF/mean arterial pressure) and normalized to maximum (%CVCmax; 28 mM SNP + local heat 43 °C). ACh-induced (77 ± 3 vs. 92 ± 3%CVCmax; p = 0.01) and NO-dependent (20 ± 6 vs. 33 ± 4%; p = 0.02) vasodilation were attenuated in PE compared to HC. Salsalate augmented ACh-induced (95 ± 2%CVCmax; p = 0.002) and NO-dependent (39 ± 3%; p = 0.009) dilation in PE compared to placebo but had no effect in HC (all p > 0.05). Salsalate treatment augmented endothelium-dependent vasodilation via NO-mediated pathways in women who have had preeclampsia, suggesting that inflammatory signaling mediates persistent endothelial dysfunction following preeclampsia.

The influence of menopause and cardiorespiratory fitness on lipoprotein particles in midlife women.

Lipoprotein particles may provide better information about cardiovascular risk than standard cholesterol measures for women. Whether lipoprotein subclasses change with menopausal stage is unclear. Given the high prevalence of low cardiorespiratory fitness in midlife women and benefit of cardiovascular disease risk, it is also important to understand the effect of fitness on lipoprotein profiles. This study evaluated the influence of menopausal status and fitness on lipoprotein particles in healthy midlife women. Lipoprotein particles were measured in high- (n = 25) and low- (n = 13) fit perimenopausal and late postmenopausal women, and in high-fit premenopausal (n = 10), perimenopausal (n = 12), and late postmenopausal women (n = 13). There were larger low-density lipoprotein particles (LDL-P; 21.7 ± 0.06 vs. 21.3 ± 0.1 nm, p = 0.002), more large LDL-P (623.1 ± 32.8 vs. 500.2 ± 52.6 nmol/L, p = 0.045), and fewer small LDL-P (145.5 ± 31.4 vs. 311.5 ± 44.7 nmol/L, p = 0.001) in the high-fit group vs. the low-fit group. High-density lipoprotein particles (HDL-P) were larger (10.1 ± 0.1 vs. 9.7 ± 0.1 nm, p = 0.002) in the high-fit group, with more large (14.8 ± 0.7 vs. 11.0 ± 0.9 µmol/L, p = 0.002), medium (12.9 ± 0.8 vs. 8.4 ± 0.9 µmol/L, p = 0.002) HDL-P, and fewer small HDL-P (10.2 ± 1.1 vs. 15.4 ± 1.6 µmol/L, p = 0.009) compared with the low-fit group. High-fit postmenopausal women had more large LDL-P (662.9 ± 47.5 nmol/L) compared with premenopausal women (479.1 ± 52.6 nmol/L, p = 0.035), and more HDL-P (40.2 ± 1.1 µmol/L) compared with premenopausal (34.9 ± 1.5 µmol/L, p = 0.023) and perimenopausal women (35.4 ± 1.3 µmol/L, p = 0.033). High fitness positively influences lipoprotein particles in healthy perimenopausal and late postmenopausal women. In healthy fit women, menopause may not have a large influence on lipoprotein particles. Novelty: In highly fit women, menopause may not have a negative influence on lipoprotein particle subclasses. High fitness is associated with a less atherogenic lipoprotein profile in perimenopausal and late postmenopausal women.

Hydrogen sulfide-dependent microvascular vasodilation is improved following chronic sulfhydryl-donating antihypertensive pharmacotherapy in adults with hypertension.

Hypertension is characterized by systemic microvascular endothelial dysfunction, in part due to a functional absence of hydrogen sulfide (H2S)-mediated endothelium-dependent dilation. Treatment with a sulfhydryl-donating ACE inhibitor (SH-ACE inhibitor) improves endothelial function in preclinical models of hypertension. To date, no studies have directly assessed the effects of SH-ACE-inhibitor treatment on H2S-dependent vasodilation in humans with hypertension. We hypothesized that SH-ACE-inhibitor treatment would improve H2S-mediated endothelium-dependent vasodilation. Ten adults with hypertension [1 woman and 9 men; 56 ± 9 yr; systolic blood pressure (SBP): 141 ± 8.5 mmHg; diastolic blood pressure (DBP): 90.3 ± 6 mmHg] were treated (16 wk) with the SH-ACE-inhibitor captopril. Red blood cell flux (laser-Doppler flowmetry) was measured continuously during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh; 10-10 to 10-1 M) alone (control) and in combination with an inhibitor of enzymatic H2S production [10-3 M aminooxyacetate (AOAA)] preintervention and postintervention. Cutaneous vascular conductance (CVC; flux/mmHg) was calculated and normalized to the site-specific maximal CVC (0.028 M sodium nitroprusside and local heat to 43°C). Area under the curve was calculated using the trapezoid method. The 16-wk SH-ACE-inhibitor treatment resulted in a reduction of blood pressure (systolic BP: 129 ± 10 mmHg; diastolic BP: 81 ± 9 mmHg, both P < 0.05). Preintervention, inhibition of H2S production had no effect on ACh-induced vasodilation (316 ± 40 control vs. 322 ± 35 AU AOAA; P = 0.82). Captopril treatment improved ACh-induced vasodilation (316 ± 40 pre vs. 399 ± 55 AU post; P = 0.04) and increased the H2S-dependent component of ACh-induced vasodilation (pre: -6.6 ± 65.1 vs. post: 90.2 ± 148.3 AU, P = 0.04). These data suggest that SH-ACE-inhibitor antihypertensive treatment improves cutaneous microvascular endothelium-dependent vasodilation in adults with hypertension, in part via H2S-dependent mechanisms.NEW & NOTEWORTHY This is the first study to prospectively assess the effects of sulfhydryl antihypertensive treatment on microvascular endothelial function in adults with hypertension. Our data suggest that 16 wk of SH-ACE-inhibitor antihypertensive treatment improves cutaneous microvascular endothelium-dependent vasodilation in middle-aged adults with hypertension, in part via H2S-dependent mechanisms.

The role of cardiorespiratory fitness on quality of life in midlife women.

OBJECTIVE: We aimed to characterize the relationship between cardiorespiratory fitness and quality of life in a sample of healthy midlife women aged 40 to 65 years. METHODS: Cardiorespiratory fitness was measured with a VO2max test. Quality of life was assessed with the menopause-specific Utian Quality of Life scale (UQOL). The UQOL measures overall quality of life, which comprises health, emotional, occupational, and sexual domains. Simple and multiple linear regression models were built to analyze relationships between cardiorespiratory fitness and overall quality of life as well as the separate UQOL domains. RESULTS: Forty-nine women with an average age of 52.5 years were included in the analysis. In simple linear models, cardiorespiratory fitness was related to overall (R2 = 0.34, P < 0.001), health (R2 = 0.55, P < 0.001), emotional (R2 = 0.08, P = 0.05), and occupational (R2 = 0.09, P = 0.03) quality of life. In multiple regression models, cardiorespiratory fitness was associated with overall (P < 0.01) and health (P < 0.001) quality of life, after controlling for physical activity, age, body mass index, and time sedentary. CONCLUSIONS: Higher cardiorespiratory fitness is associated with better quality of life during midlife, particularly in the health domain. Increasing cardiorespiratory fitness may be a useful means to promote quality of life in this population.

Healthy active older adults have enhanced K+ channel-dependent endothelial vasodilatory mechanisms.

Microvascular endothelial dysfunction, a precursor to atherosclerotic cardiovascular disease, increases with aging. Endothelium-derived hyperpolarizing factors (EDHFs), which act through K+ channels, regulate blood flow and are important to vascular health. It is unclear how EDHFs change with healthy aging. To evaluate microvascular endothelial reliance on K+ channel-mediated dilation as a function of age in healthy humans. Microvascular function was assessed using intradermal microdialysis in healthy younger (Y; n = 7; 3 M/4 W; 26 ± 1 yr) and older adults (O; n = 12; 5 M/7 W; 64 ± 2 yr) matched for V̇o2peak (Y: 39.0 ± 3.8, O: 37.6 ± 3.1 mL·kg-1·min-1). Participants underwent graded local infusions of: the K+ channel activator Na2S (10-6 to 10-1 M), acetylcholine (ACh, 10-10 to 10-1 M), ACh + the K+ channel inhibitor tetraethylammonium (TEA; 25 or 50 mM), and ACh + the nitric oxide synthase-inhibitor l-NAME (15 mM). Red blood cell flux was measured with laser-Doppler flowmetry and used to calculate cutaneous vascular conductance (CVC; flux/mean arterial pressure) as a percentage of each site-specific maximum (%CVCmax, 43°C+28 mM sodium nitroprusside). The %CVCmax response to Na2S was higher in older adults (mean, O: 51.7 ± 3.9% vs. Y: 36.1 ± 5.3%; P = 0.03). %CVCmax was lower in the ACh+TEA vs. the ACh site starting at 10-5 M (ACh: 34.0 ± 5.7% vs. ACh+TEA: 19.4 ± 4.5%; P = 0.002) in older and at 10-4 M (ACh: 54.5 ± 9.4% vs. ACh+TEA: 31.2 ± 6.7%; P = 0.0002) in younger adults. %CVCmax was lower in the ACh+l-NAME vs. the ACh site in both groups starting at 10-4 M ACh (Y: P < 0.001; O: P = 0.02). Healthy active older adults have enhanced K+ channel-dependent endothelial vasodilatory mechanisms, suggesting increased responsiveness to EDHFs with age.

Moderate-intensity exercise reduces activated and apoptotic endothelial microparticles in healthy midlife women.

Endothelial microparticles (EMPs) are related to cardiovascular disease (CVD) risk. Risk factors for CVD increase with menopause, and greater cardiorespiratory fitness is generally expected to reduce CVD risk. The effects of habitual physical activity on endothelial health may be due in part to the effect of acute exercise on circulating EMPs. This study was performed to evaluate the effect of an acute bout of exercise on CD62E+ and CD31+/42b- EMPs in healthy fit midlife women at different menopausal stages. Healthy, active premenopausal (PRE), perimenopausal (PERI), and postmenopausal (POST) women completed a single bout of moderate-intensity treadmill exercise. Activated (CD62E+) and apoptotic (CD31+/42b-) EMPs were evaluated before and 30 min after exercise by using fluorescent activated cell sorting. In an exploratory analysis, these results were compared with data from low-fit peri- and postmenopausal women. Differences by group and time point were evaluated with repeated-measure ANOVAs. There was a reduction in the number of total microparticles ( P < 0.001), CD62E+ ( P = 0.003), and CD31+/42b- ( P < 0.001) EMPs/µl plasma following acute exercise. The percentage of CD62E+ EMPs increased with acute exercise ( P < 0.001), whereas the percentage of CD31+/42b- EMPs did not change ( P = 0.40). There was no effect of menopausal status on CD62E+or CD31+/42b- EMPs, or on total microparticles (all P > 0.05). The exploratory analysis revealed that low-fit women had similar changes in EMPs with acute exercise. We concluded that acute moderate-intensity exercise reduces CD62E+and CD31+/42b- EMPs, as well as total microparticles, in healthy midlife women. These effects occurred despite differences in menopausal status and fitness. NEW & NOTEWORTHY This study demonstrates that acute moderate-intensity exercise reduces activated and apoptotic endothelial microparticles in healthy midlife women.

Follicle-stimulating hormone, but not cardiorespiratory fitness, is associated with flow-mediated dilation with advancing menopausal stage.

OBJECTIVE: The aim of the study was to evaluate if there are differences in endothelial function before and after acute exercise in women at different menopausal stages with high and low cardiorespiratory fitness. METHODS: Participants were healthy high-fit premenopausal (n = 11), perimenopausal (n = 12), and postmenopausal women (n = 13) and low-fit perimenopausal (n = 7) and postmenopausal women (n = 8). Brachial artery flow-mediated dilation (FMD) was measured before and after acute moderate intensity exercise. FMD was calculated as (Diameterpeak-Diameterbaseline)/ Diameterbaseline) × 100. Differences between high-fit women and between high- and low-fit perimenopausal and postmenopausal women were assessed with repeated-measure ANOVAs. Relations with FMD were assessed with Pearson correlations. RESULTS: FMD was reduced with progressive menopausal stage in high-fit women (P = 0.005) and was lower in perimenopausal compared to postmenopausal women (P = 0.047). FMD was lower in high-fit compared to low-fit women (P = 0.006) and there was no relation between FMD and VO2peak (P > 0.05). There was an inverse relation between FMD and follicle-stimulating hormone (P < 0.05), but not estradiol (P > 0.05). CONCLUSIONS: These data suggest that endothelial function is lower with progressive menopausal stage in women with high cardiorespiratory fitness; that FMD is lower in women with higher cardiorespiratory fitness; and that FSH, but not estradiol, is associated with FMD.

Follicle-stimulating hormone is associated with lipids in postmenopausal women.

OBJECTIVE: The purpose of this study was to evaluate the relation between FSH and lipid levels in postmenopausal women from the Kuopio Ischaemic Heart Disease Risk Factor Study. METHODS: Postmenopausal women (n = 588) aged 53 to 73 years and not using hormone therapy were included. The relation between FSH and total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs) was evaluated using linear regression, adjusting for estradiol, body mass, smoking, and other hormonal and lifestyle factors. The relation between FSH, dyslipidemia, and abnormal lipid levels were also evaluated. RESULTS: FSH was positively and linearly associated with TC (P = 0.001) and LDL-C (P = 0.01) in all participants, with stronger relations seen in younger compared with older postmenopausal women. FSH was less strongly associated with HDL-C and TG. FSH was not associated with dyslipidemia; however, higher FSH was associated with increased risk of high TC (P = 0.02) and high LDL-C (P = 0.03). CONCLUSIONS: These data suggest that higher FSH in postmenopausal women is related to higher levels of both TC and LDL-C.

Endothelial and inflammatory responses to acute exercise in perimenopausal and late postmenopausal women.

Endothelial dysfunction and inflammation are characteristics of subclinical atherosclerosis and may increase through progressive menopausal stages. Evaluating endothelial responses to acute exercise can reveal underlying dysfunction not apparent in resting conditions. The purpose of this study was to investigate markers of endothelial function and inflammation before and after acute exercise in healthy low-active perimenopausal (PERI) and late postmenopausal (POST) women. Flow-mediated dilation (FMD), CD31+/CD42b- and CD62E+ endothelial microparticles (EMPs), and the circulating inflammatory factors monocyte chemoattractant protein 1 (MCP-1), interleukin 8 (IL-8), and tumor necrosis factor-α (TNF-α) were measured before and 30 min after acute exercise. Before exercise, FMD was not different between groups (PERI: 6.4 ± 0.9% vs. POST: 6.5 ± 0.8%, P = 0.97); however, after acute exercise PERI tended to improve FMD (8.5 ± 0.9%, P = 0.09), whereas POST did not (6.2 ± 0.8%, P = 0.77). Independent of exercise, we observed transient endothelial dysfunction in POST with repeated FMD measures. There was a group × exercise interaction for CD31+/CD42b- EMPs (P = 0.04), where CD31+/CD42b- EMPs were similar before exercise (PERI: 57.0 ± 6.7 EMPs/µl vs. POST: 58.5 ± 5.3 EMPs/µl, P = 0.86) but were higher in POST following exercise (PERI: 48.2 ± 6.7 EMPs/µl vs. POST: 69.4 ± 5.3 EMPs/µl, P = 0.023). CD62E+ EMPs were lower in PERI compared with POST before exercise (P < 0.001) and increased in PERI (P = 0.04) but did not change in POST (P = 0.68) in response to acute exercise. After acute exercise, MCP-1 (P = 0.055), TNF-α (P = 0.02), and IL-8 (P < 0.001) were lower in PERI but only IL-8 decreased in POST (P < 0.001). Overall, these data suggest that perimenopausal and late postmenopausal women display different endothelial and inflammatory responses to acute exercise.