The state of the science on the health benefits of blueberries: a perspective.

Mounting evidence indicates that blueberry consumption is associated with a variety of health benefits. It has been suggested that regular consumption of blueberries can support and/or protect against cardiovascular disease and function, pre-diabetes and type 2 diabetes, and brain and cognitive function in individuals with health conditions and age-related decline. Further, mechanistic investigations highlight the role of blueberry anthocyanins in mediating these health benefits, in part through interactions with gut microbiota. Also, nutritional interventions with blueberries have demonstrated the ability to improve recovery following exercise-induced muscle damage, attributable to anti-inflammatory effects. Despite these advancements in blueberry health research, research gaps persist which affects the generalizability of findings from clinical trials. To evaluate the current state of knowledge and research gaps, a blueberry health roundtable with scientific experts convened in Washington, DC (December 6-7, 2022). Discussions centered around five research domains: cardiovascular health, pre-diabetes and diabetes, brain health and cognitive function, gut health, and exercise recovery. This article synthesizes the outcomes of a blueberry research roundtable discussion among researchers in these domains, offering insights into the health benefits of blueberries and delineating research gaps and future research directions.

Perivascular Adipose Tissue and Uterine Artery Adaptations to Pregnancy.

Pregnancy is characterized by longitudinal maternal, physiological adaptations to support the development of a fetus. One of the cardinal maternal adaptations during a healthy pregnancy is a progressive increase in uterine artery blood flow. This facilitates sufficient blood supply for the development of the placenta and the growing fetus. Regional hemodynamic changes in the uterine circulation, such as a vast reduction in uterine artery resistance, are mainly facilitated by changes in uterine artery reactivity and myogenic tone along with remodeling of the uterine arteries. These regional changes in vascular reactivity have been attributed to pregnancy-induced adaptations of cell-to-cell communication mechanisms, with an emphasis on the interaction between endothelial and vascular smooth muscle cells. Perivascular adipose tissue (PVAT) is considered the fourth layer of the vascular wall and contributes to the regulation of vascular reactivity in most vascular beds and most species. This review focuses on mechanisms of uterine artery reactivity and the role of PVAT in pregnancy-induced maternal vascular adaptations, with an emphasis on the uterine circulation.

Vascular health of fathers with history of intracytoplasmic sperm injection.

OBJECTIVE: Studies suggest that men who undergo assisted reproductive technologies (ART) may have a higher risk of cardiovascular disease; however, limited data on this matter is available. This observational pilot study aimed to investigate the overall vascular health of fathers with history of intracytoplasmic sperm injection (ICSI) compared to fathers whose partners conceived spontaneously. METHODS: Diet quality, physical activity, sedentary behavior as well as overall vascular function including the assessment of pulse wave analysis, intima-media thickness (cIMT), arterial stiffness of the common carotid artery (CCA) and blood lipids, were evaluated. RESULTS: A total of 34 fathers with history of ICSI and 29 controls (48.49 [46.32 - 57.09] years vs. 47.19 [40.62 - 55.18] years, p = 0.061) were included. After adjusting for age, no significantly increased cardiovascular risk was detected regarding vascular function. CONCLUSIONS: The results suggest an unaltered cardiovascular risk profile in fathers with history of ICSI. In the future, prospective multicenter studies are required to validate these preliminary results.

Chronic Administration of Red Yeast Rice Mitigates Endothelial Dysfunction in Spontaneously Hypertensive Rats by Inhibiting Oxidative Stress and Endothelial Nitric Oxide Synthase Uncoupling.

BACKGROUND: Hypertension is associated with endothelial dysfunction. An imbalance in the production of Nitric Oxide (NO) and Reactive Oxygen Species (ROS), leading to impaired NO-cyclic Guanosine Monophosphate (cGMP) pathway, contributes to this disorder. Red Yeast Rice (RYR), produced from the fermentation of rice with Monascus purpureus, is a traditional functional food originating from China. Although recognized for its anti-dyslipidemia properties, there has been growing evidence regarding the anti-hypertensive effects of RYR. However, these studies only focused on its direct and short-term effects. AIM: This study aims to investigate the vasoprotective effects of chronic oral RYR administration using Spontaneously Hypertensive Rats (SHR). MATERIALS AND METHODS: SHR were randomly divided into 3 groups: SHR - Control; SHR - RYR extract (100 mg/kg/day); SHR - lovastatin (10 mg/kg/day). Wistar-Kyoto Rats (WKY) were used as normotensive controls. All animals were treated for 12 weeks by oral gavage. Systolic Blood Pressure (SBP) was measured weekly (tail-cuff method). Vascular reactivity was determined using isolated rat aortic rings in an organ bath. Aortic ROS, NO, tetrahydrobiopterin (BH4 ), and cGMP levels were evaluated. RESULTS: Administration of RYR attenuated SBP elevation and enhanced endothelium-dependent vasodilation in aortic rings. In addition, RYR decreased ROS production and significantly improved the level of vascular NO, BH4, and cGMP. CONCLUSION: In an SHR model, treatment with RYR for 12 weeks exerts an SBP lowering effect that can be attributed to improved vascular function via reduction of oxidative stress, decreased endothelial NO Synthase (eNOS) uncoupling and enhanced NO-cGMP pathway.

Carotid Arterial Compliance during Different Intensities of Submaximal Endurance Exercise.

Background: The purpose of this investigation was to determine the elastic characteristics of the common carotid artery (CCA) during endurance exercise at 3 different intensities. Methods: Twenty young healthy participants (10 males and 10 females) participated in this quasi-experimental cross-sectional study. Participants were tested in two sessions: (1) we took resting measurements of the elastic characteristics of the CCA and performed a cardiopulmonary exercise test (CPET) on a cycle ergometer to determine submaximal exercise intensities, and we conducted (2) measurements of the elastic characteristics of the CCA while exercising in a cycle ergometer at 3 intensities based on blood lactate levels of low (<2 mmol/L), moderate (2-4 mmol/L), and high (>4 mmol/L). Beta stiffness was calculated using CCA diameters during systole and diastole, measured with high-definition ultrasound imaging, and CCA systolic and diastolic pressures were measured via applanation tonometry. Results: Overall, there were no differences between males and females in terms of any of the studied variables (p > 0.05). In addition, no significant changes were found in the CCA beta stiffness and vessel diameter (p > 0.05) between exercise intensities. There was a significant exercise intensity effect on CCA systolic pressure (p < 0.05), but not on CCA diastolic pressure (p > 0.05). Conclusions: The biomechanical characteristics of the CCA, determined via compliance and beta-stiffness, do not change during cyclical aerobic exercise, regardless of exercise intensity.

Advanced Cardiovascular Physiology in an Individual with Type 1 Diabetes After 10-Year Ketogenic Diet.

Adults with type 1 diabetes (T1D) have an elevated risk for cardiovascular disease (CVD) compared with the general population. HbA1c is the primary modifiable risk factor for CVD in T1D. Fewer than 1% of patients achieve euglycemia (<5.7%HbA1c). Ketogenic diets (KD; ≤50g carbohydrate/day) may improve glycemia and downstream vascular dysfunction in T1D by reducing HbA1c and insulin load. However, there are concerns regarding the long-term CVD risk from a KD. Therefore, we compared data collected in a 60-day window in an adult with T1D on exogenous insulin who consumed a KD for 10 years versus normative values in those with T1D (T1D norms). The participant achieved euglycemia with an HbA1c of 5.5%, mean glucose of 98[5]mg/dL(median[IQR]), and 90[11]%time-in-range 70-180mg/dL (T1D norms: 1st percentile for all); and low insulin requirements of 0.38±0.03IU/kg/day (T1D norms: 8th percentile). Seated systolic blood pressure (SBP) was 113mmHg (T1D norms: 18th percentile) while ambulatory awake SBP was 132±15mmHg (T1D target: <130mmHg), blood triglycerides were 69mg/dL (T1D norms: 34th percentile), low-density lipoprotein was 129mg/dL (T1D norms: 60th percentile), heart rate was 56bpm (T1D norms: >1SD below the mean), carotid-femoral pulse wave velocity was 7.17m/s (T1D norms: lowest quartile of risk), flow-mediated dilation was 12.8% (T1D norms: >1SD above mean), and cardiac vagal baroreflex gain was 23.5ms/mmHg (T1D norms: >1SD above mean). Finally, there was no indication of left ventricular diastolic dysfunction from echocardiography. Overall, these data demonstrate below-average CVD risk relative to T1D norms despite concerns regarding the long-term impact of a KD on CVD risk.

Acute sympathetic activation blunts the hyperemic and vasodilatory response to passive leg movement.

Heightened muscle sympathetic nerve activity (MSNA) contributes to impaired vasodilatory capacity and vascular dysfunction associated with aging and cardiovascular disease. The contribution of elevated MSNA to the vasodilatory response during passive leg movement (PLM) has not been adequately addressed. This study sought to test the hypothesis that elevated MSNA diminishes the vasodilatory response to PLM in healthy young males (n = 11, 25 ± 2 year). Post exercise circulatory occlusion (PECO) following 2 min of isometric handgrip (HG) exercise performed at 25% (ExPECO 25%) and 40% (ExPECO 40%) of maximum voluntary contraction was used to incrementally engage the metaboreceptors and augment MSNA. Control trials were performed without PECO (ExCON 25% and ExCON 40%) to account for changes due to HG exercise. PLM was performed 2 min after the cessation of exercise and central and peripheral hemodynamics were assessed. MSNA was directly recorded by microneurography in the peroneal nerve (n = 8). Measures of MSNA (i.e., burst incidences) increased during ExPECO 25% (+ 15 ± 5 burst/100 bpm) and ExPECO 40% (+ 22 ± 4 burst/100 bpm) and returned to pre-HG levels during ExCON trials. Vasodilation, assessed by the change in leg vascular conductance during PLM, was reduced by 16% and 44% during ExPECO 25% and ExPECO 40%, respectively. These findings indicate that elevated MSNA attenuates the vasodilatory response to PLM and that the magnitude of reduction in vasodilation during PLM is graded in relation to the degree of sympathoexcitation.

Shexiang Baoxin Pill enriches Lactobacillus to regulate purine metabolism in patients with stable coronary artery disease.

BACKGROUND: It has been clinically confirmed that the Shexiang Baoxin Pill (SBP) dramatically reduces the frequency of angina in patients with stable coronary artery disease (SCAD). However, potential therapeutic mechanism of SBP has not been fully explored. PURPOSE: The study explored the therapeutic mechanism of SBP in the treatment of SCAD patients. METHODS: We examined the serum metabolic profiles of patients with SCAD following SBP treatment. A rat model of acute myocardial infarction (AMI) was established, and the potential therapeutic mechanism of SBP was explored using metabolomics, transcriptomics, and 16S rRNA sequencing. RESULTS: SBP decreased inosine production and improved purine metabolic disorders in patients with SCAD and in animal models of AMI. Inosine was implicated as a potential biomarker for SBP efficacy. Furthermore, SBP inhibited the expression of genes involved in purine metabolism, which are closely associated with thrombosis, inflammation, and platelet function. The regulation of purine metabolism by SBP was associated with the enrichment of Lactobacillus. Finally, the effects of SBP on inosine production and vascular function could be transmitted through the transplantation of fecal microbiota. CONCLUSION: Our study reveals a novel mechanism by which SBP regulates purine metabolism by enriching Lactobacillus to exert cardioprotective effects in patients with SCAD. The data also provide previously undocumented evidence indicating that inosine is a potential biomarker for evaluating the efficacy of SBP in the treatment of SCAD.

Deletion of Sigmar1 leads to increased arterial stiffness and altered mitochondrial respiration resulting in vascular dysfunction.

Sigmar1 is a ubiquitously expressed, multifunctional protein known for its cardioprotective roles in cardiovascular diseases. While accumulating evidence indicate a critical role of Sigmar1 in cardiac biology, its physiological function in the vasculature remains unknown. In this study, we characterized the expression of Sigmar1 in the vascular wall and assessed its physiological function in the vascular system using global Sigmar1 knockout (Sigmar1-/-) mice. We determined the expression of Sigmar1 in the vascular tissue using immunostaining and biochemical experiments in both human and mouse blood vessels. Deletion of Sigmar1 globally in mice (Sigmar1-/-) led to blood vessel wall reorganizations characterized by nuclei disarray of vascular smooth muscle cells, altered organizations of elastic lamina, and higher collagen fibers deposition in and around the arteries compared to wildtype littermate controls (Wt). Vascular function was assessed in mice using non-invasive time-transit method of aortic stiffness measurement and flow-mediated dilation (FMD) of the left femoral artery. Sigmar1-/- mice showed a notable increase in arterial stiffness in the abdominal aorta and failed to increase the vessel diameter in response to reactive-hyperemia compared to Wt. This was consistent with reduced plasma and tissue nitric-oxide bioavailability (NOx) and decreased phosphorylation of endothelial nitric oxide synthase (eNOS) in the aorta of Sigmar1-/- mice. Ultrastructural analysis by transmission electron microscopy (TEM) of aorta sections showed accumulation of elongated shaped mitochondria in both vascular smooth muscle and endothelial cells of Sigmar1-/- mice. In accordance, decreased mitochondrial respirometry parameters were found in ex-vivo aortic rings from Sigmar1 deficient mice compared to Wt controls. These data indicate a potential role of Sigmar1 in maintaining vascular homeostasis.

Lower vascular conductance responses to handgrip exercise are improved following acute antioxidant supplementation in young individuals with post-traumatic stress disorder.

Young individuals with post-traumatic stress disorder (PTSD) display peripheral vascular and autonomic nervous system dysfunction, two factors potentially stemming from a redox imbalance. It is currently unclear if these aforementioned factors, observed at rest, alter peripheral haemodynamic responses to exercise in this population. This study examined haemodynamic responses to handgrip exercise in young individuals with PTSD following acute antioxidant (AO) supplementation. Thirteen young individuals with PTSD (age 23 ± 3 years), and 13 age- and sex-matched controls (CTRL) participated in the study. Exercise-induced changes to arm blood flow (BF), mean arterial pressure (MAP) and vascular conductance (VC) were evaluated across two workloads of rhythmic handgrip exercise (3 and 6 kg). The PTSD group participated in two visits, consuming either a placebo (PL) or AO prior to their visits. The PTSD group demonstrated significantly lower VC (P = 0.04) across all exercise workloads (vs. CTRL), which was significantly improved following AO supplementation. In the PTSD group, AO supplementation improved VC in participants possessing the lowest VC responses to handgrip exercise, with AO supplementation significantly improving VC responses (3 and 6 kg: P < 0.01) by blunting elevated exercise-induced MAP responses (3 kg: P = 0.01; 6 kg: P < 0.01). Lower VC responses during handgrip exercise were improved following AO supplementation in young individuals with PTSD. AO supplementation was associated with a blunting of exercise-induced MAP responses in individuals with PTSD displaying elevated MAP responses. This study revealed that young individuals with PTSD exhibit abnormal, peripherally mediated exercise responses that may be linked to a redox imbalance.

The Positive Impact of Bariatric Surgery on Vascular Health.

BACKGROUND: Obesity is one of the most prevalent medical conditions in the Western world. There are many risk factors associated with obesity, including cardiovascular and pulmonary risk. Vascular health is not studied in obese patients, and whether obesity has an adverse effect on vascular health in these patients remains unknown. OBJECTIVE: The first objective is to find a correlation between vascular health and obesity and whether obesity can be classified as a risk factor for vascular health. The second objective is to see if weight loss leads to an improvement in vascular health in patients. METHODS: The study was conducted with pre- and post-surgical methods at Baylor Scott & White (BSWH) Medical Center, Temple, Texas, USA. Ten patients were approached, consented, and prepared to obtain baseline values through WatchPAT and EndoPAT devices prior to their bariatric surgery. Values obtained include their initial weight, respiratory disturbance index, apnea-hypopnea index, oxygen desaturation index, and degree of endothelial dysfunction via the EndoPAT device. Post-surgery, these values were obtained again and compared using Wilcoxon non-parametric analyses with a level of significance at p < 0.05. RESULTS: Our study results demonstrate a correlation between obesity and vascular health as endothelial dysfunction is widely seen. In our patients, after bariatric surgery, we saw a significant weight change (31.2% +11.2, p < 0.0001). There was a significant degree of endothelial function improvement after the weight loss (31.2% +34.7, p < 0.04). CONCLUSION: Our results indicate that there is a correlation between obesity and vascular health, which also correlates with cardiovascular risk. There is a significant reduction in endothelial dysfunction after weight loss. We believe that obesity is a risk factor for vascular health outcomes.

Vascular function and skeletal fragility: A study of tonometry, brachial hemodynamics, and bone microarchitecture.

Osteoporosis and cardiovascular disease frequently occur together in older adults; however, a causal relationship between these two common conditions has not been established. By the time clinical cardiovascular disease develops, it is often too late to test whether vascular dysfunction developed before or after the onset of osteoporosis. Therefore, we assessed the association of vascular function, measured by tonometry and brachial hemodynamic testing, with bone density, microarchitecture, and strength, measured by high-resolution peripheral quantitative computed tomography (HR-pQCT), in 1391 individuals in the Framingham Heart Study. We hypothesized that decreased vascular function (pulse wave velocity, primary pressure wave, brachial pulse pressure, baseline flow amplitude and brachial flow velocity) contributes to deficits in bone density, microarchitecture and strength, particularly in cortical bone, which is less protected from excessive blood flow pulsatility than the trabecular compartment. We found that individuals with increased carotid-femoral pulse wave velocity had lower cortical volumetric bone mineral density (tibia: -0.21 [-0.26,-0.15] standardized beta [95% confidence interval], radius: -0.20 [-0.26,-0.15]), lower cortical thickness (tibia: -0.09 [-0.15,-0.04], radius: -0.07 [-0.12,-0.01]) and increased cortical porosity (tibia: 0.20 [0.15,0.25], radius: 0.21 [0.15,0.27]). However, these associations did not persist after adjustment for age, sex, height, and weight. These results suggest that vascular dysfunction with aging may not be an etiologic mechanism that contributes to the co-occurrence of osteoporosis and cardiovascular disease in older adults. Further study employing longitudinal measures of HR-pQCT parameters is needed to fully elucidate the link between vascular function and bone health.

Osteoporosis and heart disease are both medical conditions that commonly develop in older age. It is not known whether abnormal functioning of blood vessels contributes to the development of bone fragility with aging. In this study, we investigated the relationship between impaired blood vessel function and bone density and micro-structure in a group of 1391 people enrolled in the Framingham Heart Study. Blood vessel function was measured using specialized tools to assess blood flow and pressure. Bone density and micro-structure were measured using advanced imaging called high-resolution peripheral quantitative computed tomography (HR-pQCT). We found that people with impaired blood vessel function tended to have lower bone density and worse deterioration in bone micro-structure. However, once we statistically controlled for age and sex and other confounders, we did not find any association between blood vessel function and bone measures. Overall, our results showed that older adults with impaired blood vessel function do not exhibit greater deterioration in the skeleton.

Socioeconomic Status as a Potential Mediator of Arterial Aging in Marginalized Ethnic and Racial Groups: Current Understandings and Future Directions.

Cardiovascular diseases (CVD) are the leading cause of death in the United States. However, disparities in CVD-related morbidity and mortality exist as marginalized racial and ethnic groups are generally at higher risk for CVD (Black Americans, Indigenous People, South and Southeast Asians, Native Hawaiians and Pacific Islanders) and/or development of traditional CVD risk factors (groups above plus Hispanics/Latinos) relative to non-Hispanic Whites. In this comprehensive review, we outline emerging evidence suggesting these groups experience accelerated arterial dysfunction, including vascular endothelial dysfunction and large-elastic artery stiffening, a non-traditional CVD risk factor that may predict risk of CVD in these groups with advancing age. Adverse exposures to social determinants of health (SDOH), specifically lower socioeconomic status (SES), are exacerbated in most of these groups (except South Asians - higher SES) and may be a potential mediator of accelerated arterial aging. SES negatively influences the ability of marginalized racial and ethnic groups to meet aerobic exercise guidelines, the first-line strategy to improve arterial function, due to increased barriers, such as time and financial constraints, lack of motivation, facility access and health education, to performing conventional aerobic exercise. Thus, identifying alternative interventions to conventional aerobic exercise that: 1) overcome these common barriers and 2) target the biological mechanisms of aging to improve arterial function may be an effective, alternative method to aerobic exercise to ameliorate accelerated arterial aging and reduce CVD risk. Importantly, dedicated efforts are needed to assess these strategies in randomized-controlled clinical trials in these marginalized racial and ethnic groups.

Long-term effects of an egg-protein hydrolysate on cognitive performance and brain vascular function: a double-blind randomized controlled trial in adults with elevated subjective cognitive failures.

PURPOSE: Short-term intake of the egg-protein hydrolysate Newtricious (NWT)-03 improved executive function, but underlying mechanisms and long-term effects, including other cognitive domains, are unknown. METHODS: A 36-week randomized controlled trial involving 44 overweight/obese individuals experiencing elevated Subjective Cognitive Failures (SCF; aged 60-75 years) assessed the impact of daily consumption of 5.7 g of NWT-03 or placebo powders on cognitive performance (psychomotor speed, executive function, memory) and Cerebral Blood Flow (CBF), a marker of brain vascular function. Cognitive performance was evaluated using a neurophysiological test battery (CANTAB) and CBF was measured using magnetic resonance imaging perfusion method Arterial Spin Labeling (ASL). Serum samples were collected to determine brain-derived neurotrophic factor (BDNF) concentrations. RESULTS: Anthropometrics, and energy and nutrient intakes remained stable throughout the trial. NWT-03 was well tolerated, and compliance was excellent (median: 99%; range: 87-103%). No overall intervention effects were observed on cognitive performance or CBF, but post-hoc analyses revealed significant improvements on executive function in women, but not men. Specifically, a reduction of 74 ms in reaction latency on the multitasking task (95% CI: -134 to -15; p = 0.02), a reduction of 9 between errors (95%CI: -14 to -3; p < 0.001), and a reduction of 9 total errors (95%CI: -15 to -3; p < 0.001) on the spatial working memory task were found in women. No intervention effects were observed on serum BDNF concentrations (p = 0.31). CONCLUSION: Long-term consumption of NWT-03 improved multitasking abilities and working memory in women with elevated SCF. Brain vascular function remained unaffected. Sex differences in executive function require additional clarification.

Guidelines for assessing maternal cardiovascular physiology during pregnancy and postpartum.

Maternal mortality rates are at an all-time high across the world and are set to increase in subsequent years. Cardiovascular disease is the leading cause of death during pregnancy and postpartum, especially in the United States. Therefore, understanding the physiological changes in the cardiovascular system during normal pregnancy is necessary to understand disease-related pathology. Significant systemic and cardiovascular physiological changes occur during pregnancy that are essential for supporting the maternal-fetal dyad. The physiological impact of pregnancy on the cardiovascular system has been examined in both experimental animal models and in humans. However, there is a continued need in this field of study to provide increased rigor and reproducibility. Therefore, these guidelines aim to provide information regarding best practices and recommendations to accurately and rigorously measure cardiovascular physiology during normal and cardiovascular disease-complicated pregnancies in human and animal models.

Effects of Empagliflozin in Type 2 Diabetes With and Without Chronic Kidney Disease and Nondiabetic Chronic Kidney Disease: Protocol for 3 Crossover Randomized Controlled Trials (SiRENA Project).

BACKGROUND: Sodium-glucose-cotransporter 2 inhibitors (SGLT2is) have revolutionized the treatment of type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD), reducing the risk of cardiovascular and renal end points by up to 40%. The underlying mechanisms are not fully understood. OBJECTIVE: The study aims to examine the effects of empagliflozin versus placebo on renal hemodynamics, sodium balance, vascular function, and markers of the innate immune system in patients with DM2, DM2 and CKD, and nondiabetic CKD. METHODS: We conducted 3 double-blind, crossover, randomized controlled trials, each with identical study protocols but different study populations. We included patients with DM2 and preserved kidney function (estimated glomerular filtration rate >60 mL/min/1.73 m2), DM2 and CKD, and nondiabetic CKD (both with estimated glomerular filtration rate 20-60 mL/min/1.73 m2). Each participant was randomly assigned to 4 weeks of treatment with either 10 mg of empagliflozin once daily or a matching placebo. After a wash-out period of at least 2 weeks, participants were crossed over to the opposite treatment. End points were measured at the end of each treatment period. The primary end point was renal blood flow measured with 82Rubidium positron emission tomography-computed tomography (82Rb-PET/CT). Secondary end points include glomerular filtration rate measured with 99mTechnetium-diethylene-triamine-pentaacetate (99mTc-DTPA) clearance, vascular function assessed by forearm venous occlusion strain gauge plethysmography, measurements of the nitric oxide (NO) system, water and sodium excretion, body composition measurements, and markers of the complement immune system. RESULTS: Recruitment began in April 2021 and was completed in September 2022. Examinations were completed by December 2022. In total, 49 participants completed the project: 16 participants in the DM2 and preserved kidney function study, 17 participants in the DM2 and CKD study, and 16 participants in the nondiabetic CKD study. Data analysis is ongoing. Results are yet to be published. CONCLUSIONS: This paper describes the rationale, design, and methods used in a project consisting of 3 double-blind, crossover, randomized controlled trials examining the effects of empagliflozin versus placebo in patients with DM2 with and without CKD and patients with nondiabetic CKD, respectively. TRIAL REGISTRATION: EU Clinical Trials Register 2019-004303-12; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004303-12, EU Clinical Trials Register 2019-004447-80; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004447-80, EU Clinical Trials Register 2019-004467-50; https://www.clinicaltrialsregister.eu/ctr-search/search?query=and+2019-004467-50. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/56067.

Acute effects of MitoQ on vascular endothelial function are influenced by cardiorespiratory fitness and baseline FMD in middle-aged and older adults.

A key mechanism promoting vascular endothelial dysfunction is mitochondrial-derived reactive oxygen species (mtROS). Aerobic exercise preserves endothelial function in preclinical models by lowering mtROS. However, the effects of mtROS on endothelial function in exercising and non-exercising adults is limited. In a double-blind, randomized, placebo-controlled crossover study design 23 (10 M/13 F, age 62.1 ± 11.5 years) middle-aged and older (MA/O, ≥45 years) adults were divided into two groups: exercisers (EX, n = 11) and non-exercisers (NEX, n = 12). All participants had endothelial function (brachial artery flow-mediated dilatation, FMDBA) measured before and ∼1 h after mitoquinone mesylate (MitoQ) (single dose, 80 mg) and placebo supplementation. A two-way repeated measures ANOVA was used to determine the effects of MitoQ and placebo on FMDBA. Pearson correlations assessed the association between the change in FMDBA with MitoQ and baseline FMDBA and cardiorespiratory fitness (CRF). Compared with placebo, MitoQ increased FMDBA in NEX by + 2.1% (MitoQ pre: 4.9 ± 0.4 vs. post: 7.0 ± 0.4 %, P = 0.004, interaction) but not in EX (P = 0.695, interaction). MitoQ also increased endothelial function in adults with a FMDBA <6% (P < 0.0001, interaction) but not >6% (P = 0.855, interaction). Baseline FMDBA and CRF were correlated (r = 0.44, P = 0.037), whereas the change in FMDBA with MitoQ was inversely correlated with CRF (r = -0.66, P < 0.001) and baseline FMDBA (r = -0.73, P < 0.0001). The relationship between the change in FMDBA and baseline FMDBA remained correlated after adjusting for CRF (r = -0.55, P = 0.007). These data demonstrate that MitoQ acutely improves FMDBA in NEX and EX adults who have a baseline FMDBA <6%. KEY POINTS: A key age-related change contributing to increased cardiovascular disease (CVD) risk is vascular endothelial dysfunction due to increased mitochondrial-derived reactive oxygen species (mtROS). Aerobic exercise preserves endothelial function via suppression of mtROS in preclinical models but the evidence in humans is limited. In the present study, a single dose of the mitochondria-targeted antioxidant, mitoquinone mesylate (MitoQ), increases endothelial function in non-exercisers with lower cardiorespiratory fitness (CRF) but not in exercisers with higher CRF. The acute effects of MitoQ on endothelial function in middle-aged and older adults (MA/O) are influenced by baseline endothelial function independent of CRF. These data provide initial evidence that the acute MitoQ-enhancing effects on endothelial function in MA/O adults are influenced, in part, via CRF and baseline endothelial function.

Short-term Aronia melanocarpa extract supplementation improves cognitive performance: a randomized, double-blind, placebo-controlled cross-over study in healthy young adults.

PURPOSE: Evidence on the potential beneficial effects of anthocyanin-rich foods and supplements on cognitive performance is mainly based on acute or long-term studies in older adults. However, short-term studies focusing on a younger population are lacking. Therefore, short-term effects of Aronia melanocarpa extract (AME) supplementation on cognitive performance were investigated in healthy young adults. Potential underlying mechanisms were also addressed. METHODS: A randomized, double-blind, placebo-controlled cross-over study was performed involving 35 apparently healthy young adults. Participants consumed AME (180 mg anthocyanins/day) or a placebo for 1 week, separated by at least 2 weeks of wash-out. Cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Furthermore, arterial stiffness (carotid-to-femoral pulse wave velocity), retinal microvascular calibers (fundus photography), and serum brain-derived neurotrophic factor (BDNF) concentrations were measured at baseline and after 1 week. RESULTS: Participants had a mean age of 25 ± 4 years and an average BMI of 23.4 ± 2.7 kg/m2. Compliance was excellent and the study product was well-tolerated. As compared to placebo, movement time was significantly reduced by 4.8% within the five-choice reaction time test after 1 week of AME supplementation (intervention effect: - 12 ms; p < 0.05). Memory and executive function did however not change. Serum BDNF concentrations were significantly higher after AME supplementation as compared to placebo (+ 5.7%; intervention effect: 1.8 ng/mL; p < 0.05). However, arterial stiffness and retinal microvascular calibers were not affected. CONCLUSION: Short-term AME supplementation beneficially affected cognitive performance as attention and psychomotor speed improved. Serum BDNF concentrations were increased, but vascular function markers were not affected. CLINICAL TRIAL REGISTRATION: The study was registered on Clinical Trials under NCT03793777 on January 4th, 2019.

Microvascular Function and Exercise Training: Functional Implication of Nitric Oxide Signaling and Ion Channels.

Background: Exercise training elicits indubitable positive adaptation in microcirculation in health and disease populations. An inclusive overview of the current knowledge regarding the effects of exercise on microvascular function consolidates an in-depth understanding of microvasculature. Summary: The main physiological function of microvasculature is to maintain optimal blood flow regulation to supply oxygen and nutrition during elevated physical demands in the cardiovascular system. There are several cellular and molecular alterations in resistance vessels in response to exercise intervention, an increase in nitric oxide-mediated vasodilation through the regulation of oxidative stress, inflammatory response, and ion channels in endothelial cells, thus increasing myogenic tone via voltage-gated Ca2+ channels in smooth muscle cells. Key Messages: In the review, we postulate that exercise should be considered a medicine for people with diverse diseases through a comprehensive understanding of the cellular and molecular underlying mechanisms in microcirculation through exercise training.

Biological effects of diesel exhaust inhalation. III cardiovascular function.

OBJECTIVE: Inhalation of diesel exhaust (DE) has been shown to be an occupational hazard in the transportation, mining, and gas and oil industries. DE also contributes to air pollution, and therefore, is a health hazard to the general public. Because of its effects on human health, changes have been made to diesel engines to reduce both the amounts of particulate matter and volatile fumes they generate. The goal of the current study was to examine the effects of inhalation of diesel exhaust. MATERIALS AND METHODS: The study presented here specifically examines the effects of exposure to 0.2 and 1.0 mg/m3 DE or filtered air (6h/d for 4 d) on measures of peripheral and cardio-vascular function, and biomarkers of heart and kidney dysfunction in male rats. A Tier 2 engine used in oil and gas fracking operations was used to generate the diesel exhaust. RESULTS: Exposure to 0.2 mg/m3 DE resulted in an increase in blood pressure 1d following the last exposure, and increases in dobutamine-induced cardiac output and stroke volume 1 and 27d after exposure. Changes in peripheral vascular responses to norepinephrine and acetylcholine were minimal as were changes in transcript expression in the heart and kidney. Exposure to 1.0 mg/m3 DE did not result in major changes in blood pressure, measures of cardiac function, peripheral vascular function or transcript expression. DISCUSSION AND CONCLUSIONS: Based on the results of this study, we suggest that exposure to DE generated by a Tier 2 compliant diesel engine generates acute effects on biomarkers indicative of cardiovascular dysfunction. Recovery occurs quickly with most measures of vascular/cardiovascular function returning to baseline levels by 7d following exposure.