Endothelial Dysfunction Clinical Trials

High blood pressure (BP) is the major modifiable risk factor for cardiovascular diseases (CVD) and related health conditions, particularly among postmenopausal (PM) women. In adults age ≥50 years this risk is primarily driven by above-normal systolic BP (SBP ≥120 mmHg), as diastolic BP plateaus, then decreases in older adulthood. Although SBP is lower in premenopausal women vs. age-matched men, SBP reaches, then surpasses men after age 60. As such, >75% of PM women in the U.S. have above-normal SBP, which, in turn, is responsible for a 2-fold increase in risk of hypertension and corresponding increases in risk of CVD, chronic kidney disease and many other disorders. A key process linking high SBP to CVD and related conditions is vascular endothelial dysfunction, mediated by excessive reactive oxygen species (ROS)-induced oxidative stress and reductions in nitric oxide (NO) bioavailability. As the number of PM women is rapidly growing, further increases in SBP-related CV disorders are projected without effective intervention. Aerobic exercise (AE) is a first-line, standard-of-care therapy for lowering BP. In PM women with baseline SBP ≥120 mmHg, AE reduces casual (resting) SBP by ~3 mmHg (back to baseline ≤4 weeks post-training), whereas 24-hour SBP is typically unchanged. However, only 25-30% of PM women meet guidelines for 150 min/week of moderate-intensity AE, citing the extensive time requirement, facility access and travel disruptions as major barriers. Another, far less recognized, limitation is that AE training consistently improves endothelial function in midlife/older men, but not in estrogen-deficient PM (PMe-) women, i.e., in >95% of the 60+million PM women in the U.S. Thus, establishing new lifestyle therapies that induce and sustain reductions in SBP and increases in endothelial function in PMe- women with above-normal SBP is an important public health goal. High-resistance inspiratory muscle strength training (IMST) is a time-efficient (5 minutes per session) lifestyle intervention consisting of 30 inspiratory maneuvers performed against a high resistance. Preliminary data suggest 6-weeks of IMST performed 6 days/week reduces SBP by 9 mmHg in adults with above-normal SBP (i.e., greater than 120 mmHg) at baseline. Importantly, this reduction in SBP is equal to or greater than the reduction in blood pressure typically achieved with time- and effort-intensive healthy lifestyle strategies like conventional aerobic exercise. In addition, IMST improved endothelial function in the PMe- women in a small pilot study. To translate these promising preliminary results towards clinical practice, this randomized clinical trial is being conducted to directly compare the efficacy of a longer, clinically relevant treatment duration of IMST (3 months) against home-based, moderate-intensity (standard-of-care) AE in PMe-women. The primary outcome will be the change in casual SBP (IMST vs. AE). Changes in 24-hour SBP and endothelial function will serve as secondary outcomes. Effects on NO bioavailability, ROS/oxidative stress, and the role of "circulating factors" will provide insight into mechanisms of action. The sustained effects on SBP and endothelial function also will be assessed. Accordingly, a randomized, blinded, sham-controlled, parallel group design clinical trial will be conducted to assess the efficacy of 3-months of IMST (75 percent maximal inspiratory pressure) vs. brisk walking (40-60% heart rate reserve; an established healthy lifestyle strategy) for lowering SBP and improving endothelial function in PMe- women age 50 years and older with above-normal SBP. It is hypothesized that IMST will lower SBP and improve endothelial function by decreasing oxidative stress and increasing nitric oxide bioavailability. It is also expect that adherence to the intervention will be excellent (over 80 percent of all training sessions completed at the appropriate intensity). To test this hypothesis, 90 PMe- women age 50 years and older who have SBP >/= 120 mmHg will be recruited. Participants will undergo baseline testing for casual (resting) SBP, 24-hour ambulatory SBP and endothelial function. Innovative mechanistic probes including pharmaco-dissection with vitamin C, analysis of biopsied endothelial cells, and high-throughput metabolomics, will be performed to assess oxidative stress and nitric oxide bioavailability at baseline. After baseline testing, subjects will be randomized to perform either 3-months of high-resistance IMST or brisk walking. Subjects will train 6 days/week. Following 3 months of training, subjects will redo all the tests that were done during baseline testing to assess training-induced changes in SBP, physiological functions, and underlying mechanisms. Subjects will then cease training for 6 weeks before returning to the lab for follow-up testing to determine the persistent effects of IMST. Read Less

This study will test whether endothelial dysfunction could be the early subclinical mechanism by which posttraumatic stress disorder (PTSD) increases cardiovascular disease (CVD) risk, and whether posttraumatic fear-a key component of PTSD-or another PTSD dimension could be the target to offset that risk. The results of this study may help trauma-exposed individuals who are at risk of having CVD events. Read Less

The proposed mechanistic trial will test the effect of dietary sodium reduction on cardiac and vascular structure and function in those with elevated blood pressure or hypertension. Findings from this study will fill the knowledge gap on the underlying mechanisms of dietary sodium intake on cardiovascular disease risk in addition to blood pressure and could provide further evidence on sodium reduction for the prevention of cardiovascular disease. Read Less

This is a pilot clinical trial to test the efficacy of intermittent treatment with the flavonoid compound fisetin for improving vascular endothelial function and reducing aortic stiffness in older adults. This trial will also determine the potential mechanisms by which fisetin may improve vascular function, including by decreasing mitochondrial oxidative stress, cellular senescence and senescence-associated secretory phenotype (SASP) factors in circulation. Lastly, safety, tolerability and adherence of fisetin treatment will be assessed. Read Less

The investigators will test the hypothesis that, in adults with type 1 diabetes (T1D), glucagon-like peptide-1 receptor agonism (GLP-1RA, i.e. dulaglutide) and exercise training each enhance insulin-mediated skeletal muscle microvascular perfusion via attenuating endothelial oxidative stress and thereby improving endothelial function. Read Less

Above-normal systolic blood pressure (SBP), defined as SBP >/= 120 mmHg, is the major modifiable risk factor for cardiovascular disease, stroke, cognitive decline/dementia, and other chronic health problems. Despite the availability of treatments to lower SBP, over 75 percent of adults with above-normal SBP fail to control BP, which has led to a nearly 50 percent increase in the number of deaths attributable to BP over the past decade. Therefore, above-normal SBP is a major public health burden. Greater than 65 percent of adults 50 years of age and older have above-normal SBP. The number of adults age 50 years and older is rapidly increasing, predicting a continued increase in above-normal SBP driven morbidity and mortality in the absence of effective treatment strategies. This makes developing novel SBP-lowering therapies an urgent biomedical research priority. Increasing SBP is closely linked to vascular dysfunction, observable as impaired endothelial function, increased large-elastic artery stiffness, and impaired cerebrovascular function. Declines in these functions play a large role in the increased risk of chronic disease associated with above-normal SBP. The primary mechanism responsible for SBP-induced vascular dysfunction is thought to be oxidative stress-associated inhibition of nitric oxide bioavailability. Therefore, to have the largest biomedical impact, new SBP-lowering therapies should also improve vascular function by decreasing oxidative stress. Healthy lifestyle practices, such as conventional aerobic exercise, maintaining a healthy diet, or reducing sodium intake, are all first-line strategies to lower SBP. Importantly, these lifestyle practices also improve vascular function, in large part by reducing oxidative stress. However, adherence to healthy lifestyle practices is poor, with adherence to guidelines generally between 20 to 40 percent in adult Americans. The greatest reported barrier to meeting healthy lifestyle guidelines is lack of time. Therefore, time-efficient interventions have great promise for promoting adherence, reducing SBP, and improving other physiological functions. High-resistance inspiratory muscle strength training (IMST) is a time-efficient (5 minutes per session) lifestyle intervention consisting of 30 inspiratory maneuvers performed against a high resistance. Preliminary data suggest 6-weeks of IMST performed 6 days/week reduces SBP by 9 mmHg in adults with above-normal SBP (i.e., greater than 120 mmHg) at baseline. Importantly, this reduction in SBP is equal to or greater than the reduction in blood pressure typically achieved with time- and effort-intensive healthy lifestyle strategies like conventional aerobic exercise. However, these results need to be confirmed in an appropriately powered clinical trial with a longer, guideline-based treatment duration. Furthermore, the influence of IMST on functions impaired by above-normal SBP (endothelial, cerebrovascular, cognitive) needs to be determined, as do the mechanisms through which IMST exerts beneficial effects. Accordingly, we will conduct a randomized, blinded, sham-controlled, parallel group design clinical trial to assess the efficacy of 3-months of IMST (75 percent maximal inspiratory pressure) vs. brisk walking (40-60% heart rate reserve; an established healthy lifestyle strategy) for lowering SBP and improving endothelial, cerebrovascular, and cognitive function in adults age 50 years and older with above-normal SBP. I hypothesize IMST will lower SBP and improve endothelial function by decreasing oxidative stress and increasing nitric oxide bioavailability. I also hypothesize IMST will improve cerebrovascular and cognitive function, and that these improvements will be related to reductions in SBP and improvements in endothelial function. I also expect adherence to the intervention to be excellent (over 80 percent of all training sessions completed at the appropriate intensity). To test my hypothesis, I will recruit 102 adults age 50 years and older who have SBP >/= 120 mmHg. Subjects will undergo baseline testing for casual (resting) SBP, 24-hour ambulatory SBP, endothelial function, arterial stiffness, cognitive function, and cerebrovascular function. Innovative mechanistic probes including pharmaco-dissection with vitamin C, analysis of biopsied endothelial cells, and high-throughput metabolomics, will be performed to assess oxidative stress and nitric oxide bioavailability at baseline. After baseline testing, subjects will be randomized to perform either 3-months of high-resistance IMST or brisk walking. Subjects will train 6 days/week with one training session supervised in the laboratory and the other 5 performed unsupervised at home. Following 3 months of training, subjects will redo all the tests that were done during baseline testing to assess training-induced changes in SBP, physiological functions, and underlying mechanisms. Read Less

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Aging is the primary risk factor for CVD, in large part due to adverse modifications to the arteries. These modifications include vascular endothelial dysfunction and arterial stiffness. Vascular endothelial dysfunction is an initiating step in atherosclerosis, and is primarily caused by reduced nitric oxide (NO) bioavailability secondary to excessive superoxide-driven oxidative stress and inflammation. Endothelial dysfunction leads to arterial stiffness and the development of hypertension (HTN) which further increases CVD. Greater than 2/3 of the US population has elevated blood pressure or stage 1-HTN. As such, interventions that improve vascular endothelial dysfunction by increasing NO bioavailability and mitigating excessive oxidative stress and inflammation are needed. Blueberries are rich in bioactive compounds including flavonoids, phenolic acids, and pterostilbene. These compounds and their metabolites have been shown to attenuate oxidative stress and inflammation. The primary goal of this study is to assess the efficacy of blueberries to improve reduce blood pressure and improve vascular endothelial dysfunction and arterial stiffness in middle-aged/older men with elevated blood pressure or stage 1-HTN. Read Less

The goal of this clinical trial is to see how small blood vessels respond to the stress of high intensity exercise, and if a safe and simple intervention called ischemic conditioning can protect blood vessels from the stress of exercise. Participants will come in for 3 study visits and get home-based ischemic conditioning. At Study Visit 1, participants will be assessed for their frailty and physical function. Afterwards, they will perform an exercise test. At Study Visit 2, patients will undergo 2 microvascular assessments, perform a high-intensity exercise, then undergo the same 2 microvascular assessments again. Participants will be given a handheld sphygmomanometer and a blood pressure cuff to take home. Depending on which group the participants get randomized into, participants will place the blood pressure cuff around their non-dominant upper arm and inflate to either a low or high pressure for 2 weeks at home. Participants will repeat the same steps in Study Visit 2 for Study Visit 3. In addition, participants will also be assessed for their frailty and physical function. Read Less

Impaired endothelial function is observed in disease states related to obesity, such as atherosclerosis, coronary artery disease, and diabetes. Reactive oxygen species (ROS) production and resultant oxidative stress contribute to the development of these obesity-related diseases. The enzyme NADPH-oxidase is a major source of oxidative stress within the vasculature, and has been linked with the Metabolic Syndrome. In the investigator's previously funded studies, the investigators demonstrated for the first time that: 1) in vivo ROS were elevated in skeletal muscle of obese as compared to lean or overweight human subjects, 2) perfusion of the NADPH-oxidase inhibitor apocynin locally into muscle normalized ROS levels and reversed local microvascular endothelial dysfunction in the obese individuals, and 3) aerobic exercise training was effective at attenuating in vivo hydrogen peroxide production and reversing microvascular endothelial dysfunction in the obese individuals. The investigators will investigate in this R15 renewal application the mechanism of exercise training-induced alterations in ROS production and action on endothelial dysfunction in obesity using our newly developed microdialysis methodology of monitoring ROS production, in combination with analysis of muscle biopsy samples obtained before and after our previously tested 8-week intervention of aerobic interval exercise training. The objectives of this study are to determine the impact of in vivo NADPH oxidase activity on endothelial function in obese individuals, and to determine the mechanism of training-induced improvements in endothelial function. The investigator's unique microdialysis methodology will allow monitoring of microvascular/endothelial function and ROS generation, as well as the administration of pharmacological agents directly into muscle. The central hypothesis is that it is upregulation of both mitochondrial ROS and NADPH oxidase-derived ROS that results in endothelial dysfunction in obesity, and that exercise training down-regulates mitochondrial-derived ROS, and NADPH oxidase 4, thereby improving endothelial function. The aims of this proposal are to: 1) determine the contributions of mitochondrial ROS and specific NADPH oxidase isoforms to the NADPH oxidase dependent endothelial dysfunction in skeletal muscle of obese individuals; 2) determine the mechanism of ROS reduction and improved endothelial function resulting from an 8-week aerobic interval training program. Read Less

The goal of this mechanistic clinical trial is to learn about the effects of medications called soluble guanylyl cyclase stimulators on vascular function and markers of kidney and brain injury in patients having heart surgery. The main questions it aims to answer are: Does soluble guanylyl cyclase stimulation improve blood vessel function compared to placebo? Does soluble guanylyl cyclase stimulation decrease markers of kidney injury and brain injury compared to placebo? Participants will be randomized to a soluble guanylyl cyclase stimulator called vericiguat or placebo, and researchers will compare vascular function and markers of brain and kidney injury to see if vericiguat improves vascular function and reduces markers of injury. This will provide important information to determine the underlying reasons that patients have some kidney and brain function problems after having heart surgery. Read Less

In a young and healthy person, the production of nitric oxide (NO) by the endothelium, the inner lining of the blood vessel, is responsible for a) the ability of the blood vessel to dilate so it can increase its blood flow and b) act as an anti-clotting product to prevent blood clotting in those vessels. Under physiological stress either due to the development of a disease such as diabetes or simply from aging, the endothelial cells can be impacted and become dysfunctional thereby impairing their ability to make NO and even promote the development of blood clots. When such endothelial dysfunction occurs, it may be a precursor for the future development of cardiovascular (CV) disease like hypertension or even coronary artery disease later on in life in these patients. Therefore, the ability to somehow enhance the local production or availability of NO within such affected blood vessels in patients identified as prone to endothelial dysfunction could play a positive role in either preventing or delaying the onset of endothelial dysfunction and subsequent CV disease in such patients. COMP-4 is a safe, clinically available, well tolerated oral supplement that has been shown in the lab to increase NO production in a number of differing tissues including human vascular endothelial cells. In this proposed human study, the investigators plan on recruiting healthy, young participants willing to take COMP-4 for a 14 day period in whom the investigators will measure in a non-invasive way - by the use of ultrasound - the effect of COMP-4 on its ability to improve blood flow in one of the major blood vessels of the upper arm. In addition, the investigators will also determine whether COMP-4 will be capable of lowering in the blood the levels of two of the most studied inflammatory markers associated with endothelial dysfunction, IL-8 and PAI-1. Read Less

The goal of this clinical trial is to determine the effect of elevated plasma ceramides on peripheral vascular function. Subjects will consume a high fat meal consisting of long chain fatty acids (to increase plasma ceramides) or medium chain fatty acids (control). Subjects' vascular function will be assessed with laser Doppler flowmetry to measure their artery function and with the CytoCam device to assess their peripheral microvascular endothelial function. Read Less