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Top Tips When Talking to a Healthcare Provider

daughter explaining elderly mother how using smartphone

Because of lockdowns prompted by the global health crisis, many people still fear visiting hospitals and even private clinics in person. Talking to a healthcare provider is a great way to avoid pandemic-related risk without sacrificing your access to proper healthcare.

Written exclusively for doxyva.com by Aria Covers

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By getting in touch with a healthcare provider, you can get essential medical prescriptions, specific instructions on treating particular conditions, and even practical information on new treatments for COVID-19 patients. Today, the field of telehealth has expanded to include not just home health monitoring devices, but also efficient online communication platforms that make remote diagnosis possible. What can you do to streamline your communication with your healthcare provider when contacting them online?

Get in touch with and get to know the right specialists

Make sure you’re contacting the right people for the job. This will allow you to arrive at a safe and correct medical solution faster. Rather than getting transferred from call-to-call or email-to-email, actively finding the best specialist who can answer your specific inquiries makes the entire process quicker and more convenient for everyone involved. This is particularly crucial in the modern pandemic era, in which there is a massive shortage of health workers, particularly nurses.

Nurses are not only the backbone of the front-line efforts against COVID, they’re also likely to be the first qualified specialists you will be put in touch with by healthcare providers. This demand is why the nursing profession is expected to grow by 7% until 2029. Unfortunately, the bachelor’s and graduate degree programs from brick-and-mortar nursing schools and universities are currently unable to accommodate new students to respond to the demand. But the good news is that the digital migration of education is allowing both traditional and online universities to pick up the slack. In fact, current online RN to BSN degree programs which allow registered nurses to train for in-demand specializations can now be taken and completed 100% through remote work. So if you are looking for specialist advice and get through to a nurse know that they will be fully qualified to answer your concerns and questions. Just note that when you do manage to contact the right specialist, it’s important to remember that their time may be limited, as the shortage has stretched practically all nurses and other health providers thin. This brings us to our next point.

Ask informed questions

You can always turn to Google to find fundamental and objective information on practically any medical or health-related concern or inquiry. Doing this is a good way to further streamline the online consultation process. By coming to an online discussion with your healthcare provider from an informed perspective, they can more efficiently provide you with the right solutions, treatments, prescriptions, or plans. While speaking directly with a healthcare provider is still much safer than scrounging the web for info, a little online research definitely helps. There’s also a variety of legitimate sources of medical information that can be found on the web today. The Centers for Disease Control and Prevention for instance has been quite active at updating its online portal for any questions that people might have about the COVID-19 vaccine. The better you can ask informed questions, the faster you can get useful answers.

Be honest, straightforward, and upfront

If there’s anyone that you should be honest and straightforward with, it’s your healthcare provider. For instance, the more you can tell us about your condition and any related concerns, the better we at D’oxyva can develop your online personalized recovery-oriented program or plan. Having a full and upfront purview of your medical history gives healthcare providers everything they need to provide adequate solutions.

In the era of telehealth, it’s easier than ever to talk to healthcare providers. And by following these aforementioned tips, you can maximize your limited time online with these nurses, doctors, therapists, and other specialists.

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Why Use D'OXYVA?

Experts say D’OXYVA® can help patients find relief. Overwhelming  medical data shows people with preexisting conditions, including diabetes may experience serious complications with COVID-19.

D’OXYVA significantly helps people and their pets by gently and quickly spraying a patented and patent-pending ultra-purified, supersaturated solution on the skin surface to achieve major health benefits for well over 90% of users.

Experts call D’OXYVA a game-changer biotech. “Studies with D’OXYVA have shown unmatched results in noninvasive wound care,” Dr. Michael McGlamry. Anyone with an underlying condition should know this option is available.

Reduce unwanted doctor visits, recommended and ranked top by experts!

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Circularity Healthcare Announces Expansion with Global CRO of Series of Successful Pivotal Human Clinical Trials to Study Use of D’OXYVA® for Rapid, Economical and Noninvasive Home Treatment of Diabetic Foot Ulcers (DFU)

D'OXYVA | Blood Flow, Cardiovascular, Diabetes Care, Pain Relief in CA

Addressing urgent and increased health issues related to pandemic lockdowns and beyond.

PASADENA, Calif., Feb. 01, 2021 – Circularity Healthcare announced it had successfully executed a contract with the Professional Educational Research Institute (PERI) in 2020 to immediately begin a new clinical trial to study the use of D’OXYVA® to help prevent amputations and treat human diabetic foot ulcers at one-tenth the time and cost, and at least five times the efficacy of competing modalities.

A widely recognized global clinical research organization (CRO), PERI will specifically study at multiple sites at prestigious U.S. universities the use of D’OXYVA® to help address the recent epidemic of DFUs occurring in diabetic patients due to long-term pandemic quarantines and stay-at-home orders.

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Manufactured by Circularity, D’OXYVA® is a painless, noninvasive transdermal delivery system used in minutes to significantly improve blood perfusion, tissue oxygenation, and wound healing even where standard treatments have failed.

“D’OXYVA®‘s pivotal human clinical trial for complete healing of diabetic foot ulcers has been approved by the Western Institutional Review Board (WIRB), the largest in the world, and will include over a dozen high profile research sites at top U.S. universities and clinics,” said Senior Sales and Marketing Manager for Circularity, Jennifer Boadilla-Pelaez, RN. “Thousands of competing products in the past nearly twenty-five years have failed in achieving what D’OXYVA® has obtained in terms of regulatory approvals, clinical safety and efficacy in the past seven years. This is truly a game-changing milestone, not just for the company itself, but the entire medical community and the world and a preliminary report with meaningful results is expected within 6 months from starting the pivotal trial,” said Dr. Charles M. Zelen, PERI’s CEO.

DFUs are a major wound complication arising out of diabetes mellitus and occur in 3–13% of global diabetes patients, affecting millions of people. DFUs are caused by a variety of factors including decreased activity, diminished blood circulation, and people with underlying health conditions like diabetes are at higher risk for complications from COVID-19. Healthcare workers can expect to see far more instances of this persistent problem, especially with quarantine lockdowns, and it represents a significant health and economic risk to both patients and the overall healthcare system. Effective treatments that can reduce DFU recovery time, like D’OXYVA®, are absolutely crucial to combatting this newest wound epidemic.

About Circularity Healthcare LLC

Circularity Healthcare is an emerging world leader in proprietary circulatory health and noninvasive delivery technologies, committed to helping improve quality of life by developing, manufacturing, and marketing medical, pharmaceutical, and consumer health products. Circularity specializes in groundbreaking noninvasive technologies for affordable and portable transdermal delivery systems, and is currently pursuing regulatory approval worldwide as a way of treating cardiovascular and microcirculatory blood flow issues, as well as immune and autonomic nervous system disorders. Learn more at: https://doxyva.com/about-the-company/

About Professional Education and Research Institute, Inc.

PERI was established in 2005 as a premier CRO to manage Phase I – IV clinical trials around the world. PERI conducts clinical trials in both pharmaceutical and orthopedic research and performs specialty research in diabetic wound care, venous leg disease, neuropathy, peripheral vascular disease and gene therapy. One of the most unique advantages of choosing PERI as a partner in clinical trial management is a feature few CRO’s can match, which is our contracted sites throughout the United States, including IBC-certified sites. Learn more at: www.periedu.com

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Why Use D'OXYVA?

Experts say D’OXYVA® can help patients find relief. Preliminary medical data shows people with preexisting conditions, including diabetes may experience serious complications with COVID-19. D’OXYVA significantly helps people and their pets by gently and quickly spraying a patented and patent-pending ultra-purified, supersaturated solution on the skin surface to achieve major health benefits for well over 90% of users. Experts call D’OXYVA a game-changer biotech.

“Studies with D’OXYVA have shown unmatched results in noninvasive wound care,” Dr. Michael McGlamry. Anyone with an underlying condition should know this option is available.

Reduce unwanted doctor visits, recommended and ranked top by experts!

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This One Thing Makes You Twice as Likely to Die from Coronavirus

D'OXYVA Nurse
One pre-existing condition doubles your chances of death. Since the first cases of COVID-19 were identified in Wuhan, China, in December 2019, health experts have been attempting to determine why exactly, becoming infected with the virus proves deadly for some, while others show mild or even no symptoms. Over the last several months, they have pinpointed a variety of risk factors, ranging from age to heart health.
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Now, according to researchers from the NHS and Imperial College London, there is another preexisting condition that can heavily influence your death risk if infected with the coronavirus. Read on, and to ensure your health and the health of others, don’t miss these Sure Signs You’ve Already Had Coronavirus.

Obese People Are Twice as Likely to Die From COVID-19

One study claims that people who suffer from the coronavirus who have Type 2 diabetes—the most common form of diabetes—are twice as likely to die than those who do not suffer from diabetes. Those with Type 1 diabetes—the autoimmune form of diabetes—fare worse if infected. According to the study they are more than three-and-a-half times more likely to die. In total, researchers found that one-third of all COVID-19 deaths have one thing in common—diabetes.

Furthermore, those who are also severely obese, with a body mass index (BMI) above 40, are twice as likely to die than those who were obese or normal weight.

“This research shows the extent of the risk of coronavirus for people with diabetes and the different risks for those with type 1 and type 2 diabetes,” Prof Jonathan Valabhji, NHS England’s national clinical director for diabetes and obesity and the study’s lead author, said. “Importantly, it also shows that higher blood glucose levels and obesity further increase the risk in both types of diabetes.”

In other words, lifestyle choices can strongly influence your death risk when it comes to the highly infectious virus.

“This can be worrying news but we would like to reassure people that the NHS is here for anyone with concerns about diabetes—and has put extra measures in place to help people and keep them safe, including online sites to support people to care for themselves, digital consultations, and a dedicated new helpline for advice and support for people treated with insulin.

But You Can “Prevent or Delay” It

A previous study conducted by researchers at Wuhan Union Hospital published in the journal Diabetes Metabolism Research and Reviews, established a link between people with diabetes who contract COVID-19, and severe illness. Researchers found that patients who had diabetes but no other serious health problems were “more susceptible to an inflammatory storm eventually leading to rapid deterioration of COVID‐19.” This being at a “higher risk of severe pneumonia, release of tissue injury-related enzymes, excessive uncontrolled inflammation responses, and dysregulation of glucose metabolism” compared to patients without diabetes.

According to the Centers for Disease Control and Prevention, 34.2 million people of all ages—or 10.5% of the US population—have diabetes. The percentage of adults with diabetes increases with age, reaching 26.8% among those aged 65 years or older. The government health agency also points out that you can “prevent or delay” Type 2 diabetes even if you are genetically predisposed and at high risk via “proven, achievable lifestyle changes.” As for yourself: to get through this pandemic at your healthiest, don’t miss these 35 Places You’re Most Likely to Catch COVID.

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Why Use D'OXYVA?

Experts say D’OXYVA® can help patients find relief. Preliminary medical data shows people with preexisting conditions, including diabetes may experience serious complications with COVID-19. D’OXYVA significantly helps people and their pets by gently and quickly spraying a patented and patent-pending ultra-purified, supersaturated solution on the skin surface to achieve major health benefits for well over 90% of users. Experts call D’OXYVA a game-changer biotech.

“Studies with D’OXYVA have shown unmatched results in noninvasive wound care,” Dr. Michael McGlamry. Anyone with an underlying condition should know this option is available.

Reduce unwanted doctor visits, recommended and ranked top by experts!

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Dr. Kayte Susse on the importance of blood flow for tissue survival and optimal organ function

Adequate blood flow in the capillary bed is essential for tissue survival and optimal organ function. If blood passes too quickly or does not pass at all, the tissue cannot extract O2 efficiently and will degenerate. This is known as capillary dysfunction, and it is related to chronic pain, poor wound healing, diabetic neuropathy and Alzheimer’s disease, among other conditions.
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“I am pleased with the result, and it seems well received. I am grateful to have D’OXYVA. I have added your product and the discount code to my website as well. I hope that as I grow, our affiliate relationship will strengthen. Thank you for your guidance and product education.”

Dr. Kayte Susse

What do we usually remember about CO2 ?

    • It is a key player in regulating extracellular hydrogen concentrations and pH through various systems, such as the respiratory system, kidneys and various buffers.
    • Biochemistry: An increase or decrease of 1 mmHg pCO2 will cause a decrease or increase in pH of 0.08 units in acute patients. In chronic patients, a pCO2 change of 1 mmHg will cause a pH change of 0.03 units.
    • The Bohr and Haldane effects determine the interaction of O2 and CO2 . At the cellular level, pCO2 concentration causes Hb-O2 dissociation.

    • Our bodies attain it through inhalation.

What do we usually forget about pCO2?

  • Increased pCO2 promotes arteriolar dilatation in various tissues, while a modest effect has been shown in skeletal muscle tissues.

  • Transdermal delivery of CO2 has been proven to improve local microcirculation (capillary bed blood flow) and tissue perfusion, but it also positively improves systemic blood pressure and TcpO2 (most likely due to the Bohr effect).

Local CO2 therapy has shown great success rates for:

✓ Treatment for diabetic foot
✓ Increased microcirculation and dissociated O2 in healthy and diabetic individuals
✓ Treatment for arterial stenosis obliterans
✓ Chronic wound healing
✓ Adipose tissue treatment


Systemically, CO2 therapy has shown great success in improving:

✓ The health of patients with high blood pressure
✓ General vital organ function, such as that of the pancreas, liver, brain and kidneys

dr. kayte susse

About Dr. Kayte

Dr. Kayte Susse, D.C., is a functional and preventative health expert who works with patients to optimize their health and help them feel their absolute best. She has extensive backgrounds in allopathic and natural health, having completed 1000+ hours of training in functional medicine, nutrition, immunology and epigenetics. Dr. Susse’s primary focus centers on supporting hormonal imbalance, anti-aging medicine, autoimmune disease, vitamin and mineral imbalances, thyroid health, fertility and detoxification, as well as pre- and post-operative wellness.

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Why Use D'OXYVA?

Increasing demand for painless drug delivery, coupled with rising demand for self-administration of drugs, is anticipated to fuel market growth. D’OXYVA® (deoxyhemoglobin vasodilator) is the only fully non-invasive, non-irritating, non-opioid, and completely painless, over-the-skin delivery nerve stimulant and microcirculatory solution with over seven years of industry-leading research results.D’OXYVA® has been demonstrating for years that it does not break the skin’s barrier, while it provides exceptional quality of life and health benefits quickly and affordably. In short, based on current leading neurology, immunology, microvascular, and cellular oxygenation science, D’OXYVA® is leading the field by:Significantly lowering the risk of diabetes and cardiovascular complications.Providing complete significant improvement of difficult wounds together with major pain relief and improved quality of life.

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6 Effective Ways to Reduce Back Pain by Increasing Blood Flow

D'OXYVA Quickly Eliminates Chronic Pain

Back pain is consistently one of the top reasons why a person may need to visit their doctor. Because there are so many different causes for back pain, there are a number of different methods for treating it. One method in particular that has shown to be beneficial is increasing blood flow. By increasing blood flow, you are effectively reducing stiffness, relaxing the muscles and promoting more flexibility and overall comfort for the aching area.

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Ways to increase blood flow to the back to reduce pain

There are many different ways you can increase the blood flow to your back to alleviate the pain you’re feeling. Some methods, like exercise, may already be a part of your daily routine, and may just need some fine tuning to cater to your injury. Other examples may need to be introduced to your routines altogether in order to reduce your back pain and get you back to living well.

The following exercises are great options for relieving common back pain like general soreness, achiness, and pulled muscles. By exercising consistently, you are boosting your circulation, or the flow of blood throughout your body. If you don’t have a specific, more serious diagnosis than just that general soreness, these two exercises will be able to help with your blood flow and in turn alleviate your back pain.

LOW IMPACT EXERCISE

Any exercise that will get you up and moving and increasing your heart rate is sure to increase your blood flow. In particular though, low impact exercises such as walking, riding a stationary bike, and water therapy will benefit those experiencing back pain. These get you up and moving more so than the routine movements you experience throughout your day, such as walking to and from your desk at work. At the same time, it provides you with aerobic conditioning needed to promote the increase in blood flow throughout your body.

STRENGTHENING EXERCISES

A big part of relieving the pain in your back is strengthening the muscles in the general area. By strengthening these muscles, you reduce the stress placed on your back and relieve any excess pressure to the area. Focusing on building up the strength in your legs, abdomen, lower back and hips will go a long way in relieving that stress and alleviate the pain that you’re feeling.

Blood Flow Restriction training is a technique that you can use while working to strengthen these muscle groups. With this type of training, you use an elastic band or wrap around the upper portion of the area you are exercising (arm or leg). The use of the band allows for the arterial blood inflow but restricts the venous blood return flow. This creates the same effect that is present during heavy weight training. It’s particularly useful for those who have suffered injuries due to the fact that you can use lighter weights while getting the same systematic response you’d get from lifting heavy weights. This technique should be practiced only under the supervision of a trained professional.

A common reason for back pain is stiffness and lack of stabilization, which will progressively get worse with lack of physical activity and neglecting your body’s range of motion. Consistent stretching is necessary for increasing the flexibility of your muscles, tendons, and ligaments. You should focus not only on your back when stretching, but also the parts of your body indirectly involved with your back, like your hamstrings for instance. By increasing and strengthening these parts of your body, you will start to notice a reduction in your back pain.

When back pain persists over the course of 2 to 6 weeks, it’s often recommended that you seek options for physical therapy to treat the ailment. Physical therapy serves to increase the function of the target area, provide you with the knowledge to continue maintaining that function, and reduce the overall pain you’re experiencing in the area. Typically, therapy includes the use of both passive physical therapy (methods a therapist does to you) and active physical therapy (methods you take action with such as stretching or strengthening exercises)

HEAT AND COLD THERAPY

One form of passive physical therapy that is commonly used for back injuries caused by strain or over-exertion is the use of heat therapy. The benefit of heat therapy is the ability to manipulate blood flow to the area based on the time frame of the injury and the type of injury itself. For back pain, sticking to heat therapy is advised and you should avoid using cold therapy such as ice packs or cold chemical packs. This is because cold therapy serves to decrease the blood flow which can result in stiffness to the area. Because back pain is commonly caused by muscle tension, using cold therapy can aggravate these injuries further.

Applying heat to the injury promotes an increase of blood flow to the area, helping to relax the muscle tension in that area. Different methods of heating your back include using a safe heating device such as heating pads or hot water bottles and soaking in a hot bath (between 92 and 100 degrees Fahrenheit). Typically heat should be applied for 20 minutes up to 3 times a day.

Massage therapy is a great way to increase the blood flow throughout target areas. The squeezing and pulling involved in massage techniques actually assist the circulation process. The pressure that’s added to the area during the massage moves blood through the inflamed area while the release of that pressure allows for new blood to flow. By increasing and improving this circulation, any damaged or stiff muscles are receiving the oxygen filled blood needed to begin that healing process.

While exercising is a great way of increasing your blood flow and reducing the inflammation in your back, too much can further aggravate the injury. This is where activity modification comes in. If you’re used to strenuous physical activity or intense exercise, changing these routines would be recommended. You want to have the mindset of working around your back pain symptoms rather than trying to work through them, especially during the early stages of the injury.

Some daily physical exertions you will want to avoid when nursing a back injury include, carrying heavy bags or backpacks, over bending at the waist or twisting at the hips and if you include yoga as part of your daily routine you may also need to refrain from performing any exercises that put added pressure to your head, neck or back.

It has been validated that poor circulation can cause pain. Also, when the blood does not circulate correctly, oxygen and nutrients cannot reach tissues effectively, which can result in stiffness and cramping.

D’OXYVA® (deoxyhemoglobin vasodilator) is an over-the-counter (OTC) device, which is the first biotech solution of its kind backed by widely-established groundbreaking Nobel Prize-winning science validated to significantly improve macro-, and micro-circulation of blood flow and certain nerve activities in the body such as the autonomic nervous system, which together are widely reported to form an effective solution option for many of the most severe and widespread health conditions.

D’OXYVA® delivers remarkable pain management results without the use of opioids. It has proven itself noticeably effective in the reduction and elimination of chronic pain — achieving over 90%* elimination of all varieties of chronic pain in 100% of subjects either the same day or in a few days.

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Microcirculation: Exploring and understanding the unknown

cancer

Everything is in the microcirculation. According to Dr. Ricardo Quintos II, most medical problems, particularly serious ones like stroke, kidney failure or heart attack, can trace its roots to circulation.

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Medical practitioners need to focus on, and have a better understanding of, the blood flow through the smallest vessels in the circulatory system, or microcirculation, he said. Just like vascular surgery, of which Dr Quintos is a pioneer of in the Philippines, he is now setting his sights on looking at the unseen.

“One of the reasons that made me go into vascular is the realization that all these organs are served by the vascular tree,” Quintos told MIMS in an interview.

The vascular tree is made up of arteries, arterioles, capillaries, venules and veins. All together, these constitute the complex system that is at the heart of circulation – capillary exchange.

To illustrate the importance of microcirculation, Quintos used cancer as an example.

One reason there is cancer is because of a disordered growth in the vascular tree supplying cancer cells with too much blood and nutrients, he explained.

Using chemotherapy agents is not the answer to treat the cancer because not only will it kill the cancerous cells, but also the normal ones. The better treatment course is to address the vascular problem. – Dr. Ricardo Quintos

“What you do is just starve the cancer cells. You give antiandrogenic substances so that vascular tree will just shrink. And once that happens, they will have no more blood and will just die.”

A second example is how to treat vascular problems when a patient has a heart attack. Instead of doing a bypass to allow more blood to go to the heart, Quintos recommended making the heart “grow its own arteries.” More specifically, to give androgenic factors to make the arteries grow its own bypasses, which is not only less risky but also more natural.

“And that is what we mean by looking into the microcirculation,” Quintos stressed.

The vascular surgeon said they have put up their own microcirculatory laboratory and undertaken research on microcirculation.

“All of these vascular procedures will not work if your microcirculation is not working,” he explained.

He said a heart attack is not the result of blockage in the arteries of the heart, but rather the microcirculation of the heart is not working very well, because the cells there are poor. The brain, Quintos pointed out, stops working not due to poor circulation but because microcirculation to the brain breaks down.

Having made great inroads in the field of vascular surgery, Quintos now sees microcirculation as the future in medical treatment.

“We have to look into what we cannot see before. And the thing we cannot see in the vascular world is microcirculation,” he said, adding, “Ultimately, it’s all for the patient.”

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Why Use D'OXYVA?

The link between oxygen and cancer is clear. In fact, an underlying cause of cancer is usually low cellular oxygenation levels.

In 1931 Dr. Warburg won his first Nobel Prize for proving cancer is caused by a lack of oxygen respiration in cells. He stated in an article titled “The Prime Cause and Prevention of Cancer… the cause of cancer is no longer a mystery, we know it occurs whenever any cell is denied 60% of its oxygen requirements…”

D’OXYVA® (deoxyhemoglobin vasodilator) is an over-the-counter (OTC) device, which is the first biotech solution of its kind backed by widely-established groundbreaking Nobel Prize-winning science validated to significantly improve macro-, and micro-circulation of blood flow and certain nerve activities in the body such as the autonomic nervous system, which together are widely reported to form an effective solution option for many of the most severe and widespread health conditions.

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The microcirculation: a key player in obesity-associated cardiovascular disease

D'OXYVA Inspiring Diabetes Story

It is increasingly recognized that obesity is a risk factor for microvascular disease, involving both structural and functional changes in the microvasculature. This review aims to describe how obesity impacts the microvasculature of a variety of tissues, including visceral adipose tissue, skeletal muscle, heart, brain, kidneys, and lungs.

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These changes involve endothelial dysfunction, which in turn (i) impacts control of vascular tone, (ii) contributes to development of microvascular insulin resistance, (iii) alters secretion of paracrine factors like nitric oxide and endothelin, but (iv) also influences vascular structure and perivascular inflammation. In concert, these changes impair organ perfusion and organ function thereby contributing to altered release and clearance of neurohumoral factors, such as adipokines and inflammatory cytokines. Global microvascular dysfunction in obese subjects is therefore a common pathway that not only explains exercise-intolerance but also predisposes to development of chronic kidney disease, microvascular dementia, coronary microvascular angina, heart failure with preserved ejection fraction, chronic obstructive pulmonary disease, and pulmonary hypertension.

Introduction

A large body of evidence has accumulated over the years, from both clinical and experimental studies, indicating that obesity is associated with endothelial dysfunction and development of atherosclerosis, and that obesity has become one of the most important risk factors for cardiovascular disease including coronary artery disease, heart failure, and stroke. In addition to atherosclerosis in the larger arteries, obesity is also a risk factor for microvascular disease. Interestingly, a single high fat meal already perturbs endothelial function in the brachial artery, and reduces flow reserve in the coronary vasculature, illustrating how a single exposure to a high circulating lipid load has an impact, albeit transient, on the microvasculature. Regular exposure to high circulating lipid loads, even prior to the onset of overt obesity, leads to an inflammatory response that is accompanied by microvascular dysfunction, the severity of which correlates with the amount of visceral adipose tissue present in the body. Eventually, obesity and the associated inflammation not only impact function, but also structure of the microvasculature (Figure 1).

Figure 1

Proposed mechanisms of obesity-related microvascular dysfunction predisposing to multi-organ disease. High fat diet on a regular basis changes the composition of visceral adipose tissue, and induces a low grade local inflammatory response, which together modify the secretion of adipokines. Simultaneously, high fat diet results in endothelial dysfunction throughout the body, which not only alters vascular tone, and contributes to development of microvascular insulin resistance, but also influences vascular structure and perivascular inflammation. In concert, these microvascular changes impair organ perfusion and organ function thereby further contributing to altered release and clearance of metabolites and neurohumoral factors, like adipokines, inflammatory cytokines as well as (cardio)myokines. Global microvascular dysfunction in obese subjects therefore is a common pathway that contributes to exercise-intolerance and predisposes to development of chronic kidney disease, microvascular dementia, coronary microvascular angina, COPD and pulmonary hypertension. CKD, chronic kidney disease; HFpEF, heart failure with preserved ejection fraction; COPD, chronic obstructive pulmonary disease.

Two main types of adipose tissue can be distinguished in the body, which have distinctly different functions both in healthy and obese subjects being white and brown adipose tissue (WAT and BAT respectively). WAT is the primary site of fat accumulation, and not only allows efficient fat storage, but also quick mobilization of fat stores to meet energy demands of the body. WAT comprises both subcutaneous and visceral adipose tissue (VAT). The main role of BAT is thermogenesis. Thermogenesis in BAT is activated by the sympathetic nervous system. High expression of uncoupling protein-1 on the inner membrane of BAT mitochondria results in uncoupling of mitochondrial respiration so that heat is generated instead of ATP. In adult humans, BAT is mainly located in cervical, supraclavicular, mediastinal, paravertebral, suprarenal, and peri-renal areas. In addition, epicardial and perivascular adipose tissue have a phenotype that more closely resembles BAT than WAT. Both WAT and BAT contain dense microvascular networks, but microvascular density is higher in BAT as compared to WAT, with 3 vs. 1 capillary per adipocyte, respectively. The microvasculature in WAT serves as the exchange site for fat deposition and mobilization, while in BAT it is required for both delivery of fuel for and dissipation of heat produced during thermogenesis. Metabolism, perfusion and function of both WAT and BAT are affected by obesity.

Obesity, by definition an excessive accumulation of fat mass, results in expansion of particularly WAT. Ingestion of a single high fat meal induces upregulation of P-selectin on the venular side of the visceral adipose microvasculature, thereby forming an anchoring point for leucocytes. The leucocytes infiltrate the VAT and initiate an inflammatory response. Hence, low grade inflammation particularly in visceral adipose tissue may precede excessive fat accumulation, increase oxidative stress, and cause chronic microvascular dysfunction. Interestingly, blood flow to VAT increases following meal ingestion in lean but not obese subjects. Moreover, diet-induced obesity is accompanied by decreased eNOS-expression and activity, while eNOS overexpression protects against diet-induced obesity . These observations suggest a key role for microvascular function in adipose tissue homeostasis. Besides this paracrine interaction between adipocytes and the microvasculature, it should be noted that fat accumulation in VAT results in an increase in adipocyte-size from 50 μm up to 150–200 μm, which is beyond the diffusion distance for oxygen, while the accompanying reduction in capillary density will further decrease adipose tissue oxygenation. Indeed, chronic hypoxia has been shown to be present in expanded VAT. Similar to WAT, brown adipocytes hypertrophy in obesity. Intriguingly, it has recently been shown that capillary rarefaction, leading to focal hypoxia in BAT, is sufficient to induce ‘whitening’ of BAT, which is associated with reduced beta-adrenergic signaling, mitochondrial dysfunction, loss of thermogenic capacity and further accumulation of lipid droplets.

Hypoxia per se induces a reduction in adiponectin and an increase in leptin release from isolated adipocytes. Moreover, chronic hypoxia results in sustained inflammation thereby further modulating the secretion of adipokines from both WAT and BAT and contributing to metabolic derangement in obesity. In healthy subjects, the secretion of the anti-inflammatory adipokine adiponectin predominates, whereas in obese subjects, there is a shift toward pro-inflammatory adipokines such as leptin, resistin, TNFα, IL-6, and IL-18 (Table 1).  Thus, adipose tissue hypoxia and inflammation are centrally involved in the pathophysiology of obesity, and can, through release of vasoactive and/or inflammatory adipokines, modulate microvascular function throughout the body (Figure 1).

Although some studies in young adult humans suggest that skeletal muscle blood flow is relatively well-maintained in obesity  even during exercise,  others show a reduction in flow normalized for muscle mass both at rest and during exercise. These findings seem to be independent of age and vascular bed, as the reduction in flow is present in children,  and adults,  both in the forearm and upper leg. Similarly, the exercise-induced increase in systemic vascular conductance is blunted in obese swine as compared to lean swine, consistent with a decrease in flow to exercising muscle. This decrease in flow is compensated by an increase in oxygen extraction to fulfill the oxygen-requirement of skeletal muscle. 

In skeletal muscle, close coupling of blood flow to metabolic activity is required and besides substances released from nerve terminals, the endothelium and the contracting muscle, also involves mechanical interaction between the contracting muscle and the vasculature. The nervous system contributes to exercise hyperemia in skeletal muscle via activation of sympathetic vasodilator fibers, vasodilation elicited by acetylcholine spillover from active motor nerves as well as functional sympatholysis in active muscle. Resting muscle sympathetic nerve activity (MSNA) is significantly higher in obese patients with metabolic syndrome, but it does not further increase during exercise. Interestingly, in the presence of β-blockade, exercise resulted in larger increase in forearm blood flow and conductance in obese as compared to lean men. Together with the observation that the exercise-induced increase in skeletal muscle blood flow is reduced or at best preserved in obesity, these data suggest that β-adrenergic vasodilation is reduced in obesity. Furthermore, in the presence of β-blockade, α2– but not α1-stimulation resulted in a larger decrease in forearm vascular conductance in obese vs. lean subjects at rest and during exercise. Similarly, there was a tendency towards a larger increase in conductance with α-blockade with phentolamine at rest in obese vs. lean subjects, but a reduced increase in conductance upon α-blockade during exercise. These data suggest that obesity results in a shift in the balance of neurogenic control of skeletal muscle blood flow, with increased α-adrenergic constriction at rest, that is withdrawn during exercise, thereby compensating for a loss of β-adrenergic vasodilation .

In humans, endothelium-dependent skeletal muscle microvascular vasodilation in response to acetylcholine is either preserved or reduced in obesity, while eNOS expression is unaltered. However, the contribution of both NOS- and cyclooxygenase (COX)- dependent vasodilator mechanisms to acetylcholine-induced vasodilation is reduced, which is compensated by NOS- and COX-independent vasodilator mechanisms, potentially an increase in endothelium-derived hyperpolarizing factors such as EETs and/or H2O2.  An increase in H2O2 may result from superoxide dismutase (SOD)-mediated conversion of superoxide, particularly in more active obese individuals. In addition, a reduction in NO-bioavailability has been shown to be counterbalanced by reduced phosphodiesterase 5 (PDE5) activity, as well as by a reduced vasoconstrictor influence of ET. The latter is mediated through a reduction in ET-sensitivity of the skeletal muscle arterioles together with a decrease in circulating ET, reflecting a decrease in local ET production. Interestingly, a study in rodents suggests that basal differences exist in endothelial cell phenotype between arteries perfusing slow-twitch and those perfusing fast-twitch muscle fibers, with the former being less susceptible to endothelial dysfunction.

Alterations in endothelial function may also play a role in insulin-dependent modulation of microvascular tone. In healthy individuals, insulin-induced vasodilation serves to facilitate glucose delivery and uptake in skeletal muscle. As outlined in the introduction, insulin resistance is associated with a shift from insulin-induced vasodilation to vasoconstriction. Indeed, the change in femoral vascular conductance upon glucose ingestion is smaller in obese as compared to lean women, which is associated with impaired body glucose uptake. Moreover, flow to the quadriceps muscle of obese men is lower in the presence of insulin both at rest and during exercise, and insulin-induced vasodilation is converted into vasoconstriction in skeletal muscle arterioles isolated from obese women. The latter is mediated, at least in part, by alterations in perivascular adipose tissue (PVAT), that displays a pro- inflammatory phenotype in obesity. 

Although low grade inflammation may lead to an increase in oxidative stress, TBARS (as index of systemic oxidative stress) do not appear to be different between normal and obese young adults. Conversely, ROS production by NADPH-oxidase and Xanthine oxidase in skeletal muscle is increased in overtly obese, but not mildly obese individuals. In accordance with this observation, infusion of the NADPH-oxidase inhibitor and antioxidant apocynin augmented the acetylcholine-induced increase in flow to skeletal muscle in obese but not lean subjects. However, despite a significant inverse correlation between TBARS and vasodilator responses, the antioxidant ascorbic acid augmented acetylcholine-induced vasodilation to a similar extent in normal and obese subjects under resting conditions. Nevertheless, the significant correlation between waist-to-height ratio and TBARS post-exercise, together with a negative correlation between catalase and BMI, suggests that anti-oxidant capacity may fall short during stress in obese subjects.

The obesity-induced decrease in exercise capacity (VO2max) closely correlates with capillary density in skeletal muscle, indicating that besides functional, also structural changes in the skeletal muscle microvasculature are present. A study in rodents suggests that capillary rarefaction in obesity occurs in two phases, of which the first one is mediated by an increase in oxidative stress, and the second one by a decrease in NO-bioavailability. 

Taken together, obesity moderately reduces skeletal muscle blood flow at rest. The mechanisms of this reduction are incompletely understood but may involve factors released from perivascular fat that modulate insulin sensitivity and endothelial function as well as an increased vasoconstrictor influence caused by an increase in MSNA. In addition, structural changes in the skeletal muscle microvasculature may contribute to the decreased resting blood flow. Because exercise hyperemia involves many redundant regulatory mechanisms, it is relatively well-maintained. However, the impairments in blood flow and its distribution are likely to become more severe when the metabolic disturbance persists for a longer time or when other co-morbidities such as hypertension, hyperlipidemia, and hyperinsulinemia co-exist in the same patient, which may contribute to exercise intolerance in obese people.

Similar to skeletal muscle, coronary microvascular function plays an important role in coupling of myocardial perfusion to cardiac metabolism.54 Clinical studies have shown that in conditions such as obesity and hypercholesterolemia the coupling of coronary blood flow to the myocardial metabolic demand is altered.2 Thus, coronary flow velocity of obese patients during dobutamine stress-echo is impaired, with the impairment becoming even more evident when obesity is associated with other risk factors.55 Also, myocardial blood flow measurements with PET indicate that increases in myocardial blood flow in response to cold-pressor testing are diminished in obese patients.56 Interestingly, female sex and the volume of visceral fat are associated with a reduction in myocardial perfusion at peak dose of dobutamine, as measured by MRI.57 These clinical observations are supported by studies in obese Ossabaw swine with metabolic syndrome and swine with severe familial hypercholesterolemia (FH), demonstrating that coronary blood flow regulation and myocardial oxygen balance are altered in particular during treadmill exercise.58,59

Several studies have reported reduced coronary flow reserve and increased minimal vascular resistance in patients with obesity and hypercholesterolemia as assessed by either PET, Doppler echocardiography or MRI.60–64 Such abnormalities can be the result of either changes in microvascular function, i.e. the regulation of vascular tone, or structural changes within the coronary microcirculation, such as vascular rarefaction or inward remodeling.54,65 Alterations in control of coronary microvascular tone are generally characterized by a loss of endothelial vasodilator influence (such as NO) as well as by increased neurohumoral (angiotensin II) and endothelium-derived vasoconstrictor (ROS, ET, prostanoids) influences resulting in a shift in the vasomotor balance towards increased vasoconstriction (Table 1).2,3,66 Indeed, several studies in humans and animal models have demonstrated that obesity is associated with alterations in the vasodilator-vasoconstrictor balance controlling coronary microvascular tone.2–4,67 Thus, hyperoxia-induced vasoconstriction in the coronary microvasculature is enhanced in obese adolescents,68 while bradykinin-induced vasodilation is impaired in isolated coronary arterioles from obese patients due to increased tissue angiotensin-converting enzyme activity.69 Similarly, in swine with hypercholesterolemia, endothelial dysfunction of isolated small coronary arteries due to impaired NO biovailability is noted early in the disease process (2.5 months after start of the high fat diet).70 In contrast, at 15 months of diet, NO signaling is restored but the constriction to ET-1 is exacerbated, this response being mediated by ETB-mediated vasoconstriction, indicating that disturbances in the balance between vasodilators and vasoconstrictors are modulated during progression of the disease (Table 1).71 The observations that eNOS activity is impaired by adipokines secreted by perivascular fat72 and that coronary microvascular dysfunction correlates with increased inflammation62 suggest that inflammation and fat-derived cytokines in obesity are also important determinants of coronary microvascular dysfunction. This is consistent with the correlation of fat deposits with the decline in coronary microvascular function.57,63

In addition to the functional changes in the control of vascular tone, obesity can also result in structural remodeling of the coronary microcirculation. Histological analysis of left ventricular tissue biopsies obtained during coronary bypass surgery show significantly lower capillary densities in obese patients (Table 1).73 Importantly, both arteriolar remodeling and capillary rarefaction likely contribute to the reduced coronary flow reserve in obese patients as reported in several,60–62 though not all studies.66 Similarly, hypertrophic inward remodeling of coronary arterioles, increased stiffness as well as capillary rarefaction are reported in animal models of obesity and hypercholesterolemia.58,71,74

It is increasingly recognized that the factors released by the coronary endothelium also impact the function of the surrounding cardiomyocytes in a paracrine fashion. Loss of NO, increased oxidative stress and the ensuing tissue inflammatory response are thought to play a key role in development of left ventricular diastolic dysfunction through altering relaxation of the cardiac myocytes and increasing collagen fraction in the extracellular matrix.75,100

In conclusion, both clinical and experimental evidence indicate that obesity is an independent risk factor for coronary microvascular dysfunction, with both functional and structural alterations in the coronary microcirculation contributing to the impairments in coronary flow regulation and having a negative impact on the coronary flow reserve in these patients. Some, but not all, of these changes can be alleviated by weight loss and physical exercise.68,76 However, in order to be able to specifically address the different aspects the obesity-associated coronary microvascular dysfunction, future studies should focus on revealing the underlying mechanisms that drive the obesity-associated coronary microvascular abnormalities.

Similar to the heart, the brain relies on a continuous supply of blood flow, with regional alterations in brain activity requiring corresponding changes in brain flow distribution via metabolic vasodilation, which is referred to in the brain as neurovascular coupling. Obesity-induced changes in brain microvascular structure and function have been proposed to result in disruptions in neurovascular coupling, thereby leading to vascular cognitive impairment.20,77 Importantly, the brain microvasculature is only surrounded by neurons and glia as there is no perivascular adipose tissue. Therefore, the effects of obesity likely manifest as the result of changes in neural/glia-vascular (metabolic) interactions, and hemodynamic (i.e. blood pressure) or circulating factors (hyperglycemia and dyslipidemia) that have a direct vasoactive effect or act indirectly via influencing neurons and glia.

Both pre-clinical78,79 and clinical80,81 obese human populations exhibit reduced brain blood flow and impaired vasodilation during hypercapnia. The mechanisms responsible likely relate to microvascular rarefaction,19,20,82 decreased contribution of NO to basal cerebral microvascular tone control, altered release of vasodilator prostanoids, and/or a direct effect of H+ on vascular smooth muscle ion channels.83 Impaired cerebral vasoreactivity in obesity occurs independently of clinical insulin resistance,78,84 but may also worsen with accompanying hypertension and poor glycemic control.80,81 Obese Zucker rats display impaired endothelium-dependent NO-mediated middle cerebral artery (MCA) vasodilation as well as depressed insulin-stimulated vasodilation, potentially due to increased PKC- and MAPK-activation, combined with eNOS uncoupling resulting in augmented superoxide production.82,85 Indeed, depressed vasodilator responses to hypoxia and NOS-dependent dilators, as well as enhanced constrictor responses to 5-hydroxytryptophan1 reflect potential pathological adaptations that impair neurovascular coupling. Decreased insulin-mediated vasodilation potentially contributes to impaired microvascular insulin delivery in the brain (Table 1).86 The physiological significance of this remains incompletely understood, but similar to skeletal muscle, altered insulin signaling in the brain (i.e. brain insulin resistance) can link microvascular and metabolic dysfunction, thereby leading to cognitive impairment. Collectively, the data from humans81 and rodents82,85 suggest that obesity induces endothelial dysfunction with impaired NO production/bioavailability, resulting in altered cerebral vasoreactivity.

Obesity also affects the structure of small arteries, arterioles and capillaries in the brain, with many of these changes reflecting the development of cerebral microvascular disease.20,77 Indices of cerebral microvascular disease, including cerebral microbleeds, lacunas and microlacunas, increase the vulnerability to neurodegeneration,20,77 and occur more commonly in obese individuals with insulin resistance,87 dyslipidemia,87 and central adiposity.88 In addition, genetic predispositions may also contribute to this relationship.77 Beyond these preliminary observations, the underlying mechanisms responsible for obesity-induced cerebrovascular remodeling in humans remain elusive. However, cortical microvascular density decreases,89 and the MCA undergoes eutrophic inward remodeling and progressive arterial stiffening during the progression of metabolic syndrome in obese Zucker rats.82 In diet-induced obesity in Sprague–Dawley rats, similar MCA adaptations are observed in conjunction with increased MMP-2 activity, collagen I expression, and reduced MMP-13 expression, suggesting that increases in collagen deposition contribute to vascular stiffening (Table 1).90 In the aforementioned studies,82,89,90 inward MCA remodeling coincided with the development of hypertension, while pharmacological treatment of hypertension ameliorated the remodeling.82 This suggests that obesity-induced hypertension, and not metabolic dysfunction,91 serves as the primary stimulus responsible for inducing inward remodeling of the MCA.

Although pharmacological treatment of hypertension ameliorates MCA remodeling, it does not improve cortical microvascular rarefaction in obese Zucker rats.89 Also in Rhesus monkeys, diet-induced obesity causes cortical capillary rarefaction, but without concurrent changes in blood pressure.92 In the latter study, cortical capillary rarefaction occurred alongside decreased VEGF, increased von Hippel-Lindau protein (which degrades HIF-1α) and (paradoxically) increased expression of FOXO3, eNOS, and eNOS uncoupling. In contrast to inward remodeling in the MCA, it appears that obesity-induced metabolic dysfunction and oxidative stress, and not hypertension, is responsible for the observed microvascular/capillary rarefaction (Table 1). Therefore, while inward remodeling may prevent hypertension-induced cerebral hyperperfusion, inward remodeling and microvascular rarefaction may limit cerebrovascular reserve and impair brain blood flow control.

Functional and structural microvascular deficits resulting in impaired neurovascular coupling likely reflect an acquired, and not programmed feature of obesity, suggesting that these abnormalities can be environmentally induced, prevented or even reversed.93–95 Indeed, short-term diet-induced obesity reduces prefrontal cortex blood flow in mini-pigs,94 and impairs metabolic vasodilation and precedes neuronal loss in rodents.95 Furthermore, individuals with an elevated BMI exhibit reduced basal flow79 and post-prandial vasodilation93 in the prefrontal cortex, but formerly obese individuals do not display this defect.93 Reversal of such adaptations is of growing importance as the early signs of cerebral microvascular disease can manifest very early in life, as seen in an obese 2-year-old child.96

In conclusion, the cumulative effect of cerebral inward remodeling, microvascular rarefaction, and impaired vasodilator capacity, likely contribute to obesity-related impairments in brain flow control and neurovascular coupling. Such obesity-induced changes can occur rapidly and in young individuals, but it appears these pathological adaptations are modifiable. Gathering more knowledge about mechanisms of obesity-related changes in brain microvascular structure and function along the (micro)vascular tree is essential in understanding the pathology of disease progression and developing effective prevention and treatment strategies.

Obesity is associated with an increased risk for chronic renal failure. In a Swedish case-control study, particularly diabetic nephropathy, nephrosclerosis, and glomerulonephritis were associated with obesity,97 suggesting that obesity negatively impacts the renal microvascular bed. Indeed, clinical studies show that in obesity, afferent arteriolar vasodilation results in an increased renal blood flow (RBF), that causes a state of hyperfiltration.98 Results in experimental animals are equivocal with some laboratories showing that RBF and glomerular filtration rate (GFR) are increased 3–4 months99,100 of high fat diet, whereas others show no change in RBF and GFR.101–105 The reported increase in RBF is mostly due to an increase in renal cortical volume, vascular volume fraction and cortical perfusion, whereas filtration fraction, medullary size, and medullary perfusion showed no difference.99,100,106

Obesity is linked to increased peri-renal fat deposition,100,107 which in turn leads to low grade inflammation and renovascular endothelial dysfunction. Indeed, endothelium-dependent vasodilation to acetylcholine was impaired both in vivo98,102,103,108 and in vitro in renal arteries of obese swine,100 while endothelium-independent vasodilation to the NO donor sodium nitroprusside (SNP) was unaltered in vitro (Table 1).100 Although renal eNOS-expression may initially increase,99 prolonged exposure to high fat diet reduces expression of eNOS and promotes eNOS-uncoupling and activation of xanthine oxidase resulting in impaired bioavailability of NO in obese swine.102 Antioxidant capacity in obesity is further reduced by a decrease in SOD activity.103,108 Moreover, increased NAD(P)H-oxidase and LOX-1 expression further contribute to increased oxidative stress, which together with upregulation of iNOS, may have led to increased nitrotyrosine levels.99,102,104,105,108,109 ROS in turn, induce upregulation of renal pre-pro ET-1 and ETA receptors thereby promoting vasoconstriction (Table 1).102–104

Interestingly, incubating renal arteries of lean swine with peri-renal fat of obese animals transferred the impaired endothelial function to those arteries.100 This response appears to be the result of fat derived inflammatory molecules, and not of oxidative stress, as the endothelial dysfunction could only be reversed by neutralizing TNF-α, but not by the free radical scavenger Tempol, in vitro.100 Furthermore, anti-inflammatory treatment with thalidomide in vivo, abolished the renal increase in TNF-α, and improved endothelial function without altering oxidative stress, suggesting that increased levels of TNF-α play a vital role in impaired function of the endothelium.102

In addition to renovascular dysfunction, structural alterations in the kidney produced by obesity have also been reported (Table 1). Interestingly, obesity is associated with a change in the balance of angiogenic and anti-angiogenic factors in the kidney that favors angiogenesis. Thus, VEGF and its receptor Flk-1108 as well as Angpt2110 are increased. Moreover, protein expression of the angiogenesis inhibitor TSP-1 is decreased as a result of increased oxidative stress,99 although this is not a unanimous finding.104 Indeed, both arteriolar and capillary density in the outer cortex of the kidney are increased in animals with obesity.99,108 However, these newly formed vessels are more tortuous and erythrocyte exudation has been shown, suggesting that the newly formed vessels are leaky and immature.99,102,103,108,109 Furthermore, glomerular density is decreased in animals with metabolic derangement,109 while glomerular hypertrophy due to matrix hyperplasia and glomerular swelling are also observed in obese swine.99,109–111 Taken together, these data suggest that the newly-formed microvasculature does enhance glomerular filtration, but is rather damaged and dysfunctional. Vascular remodeling in obesity is facilitated by dynamic processes in the extracellular matrix, as an increased MMP expression, which promotes extracellular matrix (ECM) degradation was noted at 10 weeks,99 but not at 16 weeks104 of high fat diet. Furthermore, in obese swine, renal expression of tissue transglutaminase is increased, causing extracellular matrix crosslinking and vascular remodeling especially in conditions of sustained vasoconstriction.103 Moreover, microvascular media-to-lumen ratio is increased,104,108 and perivascular as well as tubulointerstitial fibrosis is observed in obese swine.104,108 The increased presence of renal M1-macrophages, and increased NF-κB expression, plasma/renal levels of TNF-α as well as activation of the TGFβ-system in the kidneys of obese animals, suggests that inflammatory cells play a central role in these processes.98–100,103,104,106

In conclusion, the increased fat or lipid deposition in and around the kidney acts as a promotor of a pro-inflammatory state with oxidative stress, endothelial dysfunction and microvascular remodeling as a consequence. Although these changes are initially reversible by switching to a healthy life style,104 as well as by interventions that lower lipids and/or oxidative stress,105,108 modulate the immune-system102 or prevent vasoconstriction,98,103 prolonged exposure results in irreversible alterations in the renal microvasculature. Indeed, although diabetes mellitus and hypertension are still the main causes of chronic kidney disease (CKD),112 it has been shown that obesity independently increases the risk of CKD and end-stage renal disease even in the absence of these known cardiovascular risk factors or nephropathy.113 As the kidney is important in clearing waste products and adipokines from the body, renal dysfunction in obesity and the ensuing increase in so-called uremic toxins, can further contribute to microvascular dysfunction in other organs and thereby contribute to development and aggravation of cardiovascular disease.114

Functional and structural changes in the pulmonary microvasculature as a result of obesity are less well studied as compared to their systemic counterparts. The comparison of the effect of obesity in the pulmonary and systemic microvasculature is of interest as the pulmonary vasculature receives the same cardiac output as the systemic vasculature and is exposed to the same circulating factors, such as glucose, cholesterol, adipokines, and inflammatory factors. Indeed, obesity is also associated with a variety of lung diseases including obstructive sleep apnea, hypoventilation syndrome, chronic bronchitis, asthma, and pulmonary embolism. Many of these diseases have an inflammatory component and it is likely that the change in circulating adipokines with obesity facilitates this pulmonary inflammation. Adiponectin exerts anti-inflammatory and protective effects against inflammatory lung diseases. In contrast, leptin is pro-inflammatory and leptin receptors are present on all inflammatory cell-types in the lung. An increase in leptin primes leucocytes for increased secretion of inflammatory cytokines and reactive oxygen species. However, exactly how a change in adipokine profile impacts pulmonary microvascular structure and function remains to be established.

An autopsy study in 1982 revealed a strong correlation between the size of atherosclerotic plaques in the aorta and the pulmonary artery. In rabbits on a high fat diet, the rate of cholesterol accumulation in the pulmonary artery exceeded that in the aortic arch initially, but at later stages of atherogenesis, the rate of cholesterol accumulation slowed in the pulmonary artery ultimately falling below accumulation rates in the aortic arch. Obesity is also associated with structural changes in the pulmonary microvasculature (Table 1). Increased medial thickness of both pulmonary small arteries and veins, and increased muscularization of pulmonary arterioles were observed in obese humans compared to controls at autopsy. Similarly, an increased wall to lumen ratio was found in pulmonary arterioles of obese rats as compared to lean control rats. Interestingly, adiponectin deficiency has been shown to result in pulmonary microvascular remodeling, with an increased muscularizaton of pulmonary microvessels.

These structural pulmonary microvascular changes in obesity resemble those found in post-capillary pulmonary hypertension. Indeed, the prevalence of pulmonary hypertension (PH) is increased in obese subjects, and is associated not only with sleep apnea and hypoxemia, but also with left ventricular diastolic dysfunction, resulting in increased left atrial pressure. The association between obesity and elevated pulmonary artery pressures has also been found in both obesity prone and overtly obese Zucker rats on a high fat diet and in obese FH-swine. Similar to humans, the elevated pulmonary artery pressure in the obese swine was mainly due to an increase in left atrial pressure as pulmonary vascular resistance was only mildly elevated. However, despite the mildly elevated pulmonary artery pressure and pulmonary vascular resistance at rest, the pulmonary vasodilator response to exercise was preserved in swine with hypercholesterolemia, at a time when systemic vasodilation was reduced.

The effect of obesity and high fat diet on pulmonary vascular function has only been assessed in experimental animals and may depend on the duration of exposure and the stimulus used to assess vascular function. Thus, pulmonary artery vasodilation in response to methacholine is enhanced in rabbits given a 2% cholesterol diet over a period of 2 weeks. Exposure of Zucker rats to high fat diet for 18 weeks has no effect on eNOS expression or acetylcholine-induced NO production in either conductance or resistance pulmonary arteries. Similarly, the increase in pulmonary vascular resistance in response to eNOS inhibition is comparable in healthy swine and in FH-swine on a high fat diet for 6 months, both at rest and during exercise, although ATP-induced NO mediated vasodilation was reduced. Also, the pulmonary vasodilator response to SNP is maintained in both obese Zucker rats and FH-swine exposed to high fat diet. In the latter group, vasodilation to PDE5-inhibition is also preserved. Altogether, these data suggest that pulmonary vasodilation through the NO pathway is well-preserved in obesity (Table 1).

In general, vasoconstrictor responses in the pulmonary microvasculature are reduced in obesity. Thus, vasoconstriction to KCl, phenylephrine, serotonin, and hypoxia are reduced in pulmonary resistance, but not conductance arteries of obese Zucker rats. In FH swine, endothelin receptor blockade did not reduce pulmonary vascular resistance, while it produced pronounced vasodilation in normal swine (Table 1). This loss of ET-mediated vasoconstriction was accompanied by slightly lower plasma ET-levels. These data suggest that reducing the effect of vasoconstrictors may serve as an early compensatory mechanism to maintain pulmonary vascular resistance as low as possible, to limit the workload of the right ventricle.

The term obesity paradox refers to the observation that although obesity is a well-known risk factor for the development of cardiovascular disease, mortality rate in many cardiovascular disorders, once established, is lower in obese patients. Thus, there is evidence suggesting that when CKD is present, mortality is higher in underweight patients and lower in patients with obesity class I, but not with class II or III. Similarly, in patients with established coronary artery disease, heart failure, or stroke, there are large cohort studies suggesting that mortality is reduced in patients with obesity class I, particularly in the short term. Also in patients with established PH, a recent study shows a strong inverse correlation between obesity and mortality, in that both in pre-capillary and out-of proportion post-capillary PH, obese patients had a significantly lower mortality (46% vs. 10% mortality in pre-capillary and 40% vs. 11% in post-capillary PH for lean and obese subjects). Moreover, BMI was the strongest predictor of mortality in a COX hazard analysis, followed by NYHA functional class.

However, there is also concern about selection bias, insufficient control for cardiorespiratory fitness, inadequate determination of body fat localization (i.e. visceral vs. subcutaneous), and underweight vs. normal weight subjects, in these studies. Indeed the overall consensus is that losing weight by for example exercise trainings confers protection against mortality in cardiovascular disease. A large part from these benefits of exercise training can be ascribed to improved microvascular function, and reduced inflammation. Another intriguing possibility is that exercise training results in secretion of ‘myokines’ from skeletal muscle and ‘cardiomyokines’ from cardiac muscle such as FGF21 and irisin, that act in an endo- and/or paracrine fashion on perivascular and epicardial adipose tissue, and induce a ‘browning’ phenotype.

Summary and conclusion

Obesity is a well-established risk factor for microvascular dysfunction throughout the body (Figure 1). This microvascular dysfunction is likely initiated by transient elevations of circulating free fatty acids, and perpetuated by changes in adipokines and inflammatory cytokines released from visceral as well as perivascular adipose tissue. These factors contribute to endothelial dysfunction as well as insulin resistance in the microvasculature, thereby affecting function of different organs not only by impairing tissue perfusion, but also through altering the release of paracrine factors from the endothelial cells. Thus, although the mechanisms can differ between regional vascular beds (Table 1), microvascular dysfunction is a central common pathway that may explain exercise-intolerance as well as the higher prevalence of chronic kidney disease, microvascular dementia, coronary microvascular angina, heart failure with preserved ejection fraction, and pulmonary hypertension in obese subjects.

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Why Use D'OXYVA?

Circularity has developed a one-of-a-kind, industry-leading, advanced metabolic weight loss, athletic performance, and injury recovery solution.Nitric Oxide (NO) is marketed all over for its benefits — yet, CO2 does far more for the body and until recently has been ignored.It wasn’t until Circularity Healthcare found a gentle, fast, and effective way to deliver CO2 over the skin and over-the-counter that the real benefits were realized.D’OXYVA is not considered doping according to the United States Anti-Doping Agency (USADA).

Yusuf Myers; a regular on the Dr. Oz Show on working out from home

In the middle of a global pandemic, prioritizing your health and wellness is one of the smartest moves you can make. That’s true for everyone, but for Black Americans, it’s critical as this group faces a disproportionate rate of COVID-19 hospitalizations and death, according to the Centers for Disease Control and Prevention.

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PROF. JUDY M. DELP, PHD on D’OXYVA’s Efficacy

Prof Judy Delp D'OXYVA how to increase blood flow in foot

Toriyama et al. studied the effect of CObathing in 83 limbs with critical ischemia and achieved limb salvage in 83% without surgery. They concluded that peripheral vasodilation from CObathing resulted from an increased parasympathetic and decreased sympathetic activity. Application of skin delivery COproduces a remote vasodilation that may be mediated through release of a circulating humoral agent.

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Recently, studies have documented that episodes of brief, non-damaging ischemia occurring in a tissue can induce systemic protection against ischemia-reperfusion injury in a remote organ. This phenomenon, termed remote ischemic conditioning, has been demonstrated to confer protection against ischemic events in the myocardium, brain, and kidney. Although shown to be effective in various clinical and preclinical models, the mechanism(s) of remote protection have not been clearly identified. Both neural and humoral mechanisms have been proposed to contribute to the protection against ischemic damage afforded by remote ischemic conditioning. Basalay et al. have shown that when remote ischemic conditioning is applied before induction of myocardial ischemia, sensory nerves and recruitment of a parasympathetic neural pathway are involved in reduction of infarct size.

Recently, Michelsen and colleagues have demonstrated that dialysate of human plasma from subjects who underwent either ischemic preconditioning or exercise preconditioning reduced infarct size in rabbit hearts, indicating that release of a humoral factor, contributes to the cardioprotective effects of ischemic and exercise preconditioning; however, these circulating substance(s) remain to be identified.

Future investigations will need to monitor heart rate, heart rate variability, and sympathetic nerve activity in order to more fully assess the role of the autonomic nervous system in mediating the sustained increases in SPP and systolic blood pressure reported in this initial study and focus on assessment of plasma samples during and following skin delivery COapplication. The D’OXYVA device is safe and can be administered at home. There are a lot of possibilities here and we are really excited about conducting future studies to determine what D’OXYVA may be able to provide to people with microvascular disease.

About Prof. Judy Delp

Prof. Judy Delp

Dr. Judy Delp is a Professor of Biomedical Sciences at Florida State University, she gained her PhD at University of Missouri. She is also a member of the American Physological Society, American Microcirculatory Society, American Heart Association. Prof. Judy Delp has co-authored 94 publications.

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Increasing demand for painless drug delivery, coupled with rising demand for self-administration of drugs, is anticipated to fuel market growth. D’OXYVA® (deoxyhemoglobin vasodilator) is the only fully non-invasive, non-irritating, non-opioid, and completely painless, over-the-skin delivery nerve stimulant and microcirculatory solution with over seven years of industry-leading research results.

D’OXYVA® has been demonstrating for years that it does not break the skin’s barrier, while it provides exceptional quality of life and health benefits quickly and affordably.

In short, based on current leading neurology, immunology, microvascular, and cellular oxygenation science, D’OXYVA® is leading the field by significantly lowering the risk of diabetes and cardiovascular complications and providing complete and significant improvement of difficult wounds together with major pain relief and improved quality of life.

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Children born at high altitudes may be stunted in growth and development, study finds

D'OXYVA for Kids

Children born at 5,000 feet or more above sea level are typically smaller at birth and more likely to remain stunted than those born at lower altitudes, according to new worldwide research published Monday.

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This was true even if the children were born into “ideal-home environments” defined as having good health coverage, higher living conditions and highly educated mothers, the study found, which meant stunting was unlikely to be due to common risk factors such as poor diet and disease.

Growth declined as altitude grew

Children living in ideal home environments grew at rates deemed standard by the World Health Organization until they lived at around 500 meters (1,650 feet) above sea level, the study found. At that altitude and higher, children’s height-for-age scores began to decrease.
At levels of 1,500 meters, or approximately 5,000 feet, above sea level, children were “born at shorter length and remained on a lower growth trajectory” than children who lived in cities at lower sea levels, according to the study published Monday in JAMA Pediatrics.
Prior research has shown growing shorter and slower at higher altitudes can lead to an increased risk of cognitive deficits and metabolic developmental impairments tied to chronic diseases in later life.

A worldwide study

The study looked at height-for-age data for more than 950,000 children in 59 countries.
“More than 800 million people live at 1,500 meters above sea level or higher, with two-thirds of them in Sub-Saharan Africa, and Asia,” said study co-author Kalle Hirvonen, a senior research fellow at the International Food Policy Research Institute, in a statement.
However, there are a number of cities in the United States that fall above 5,000 feet, including Butte, Montana; Cheyenne, Jackson and Laramie, Wyoming; Flagstaff, Arizona; Las Vegas, Albuquerque and Santa Fe, New Mexico; Mammoth Lake, Big Bear Lake and South Lake Tahoe in California; and about 37 cities in Colorado, among others.
In fact, Aspen, Breckenridge and Telluride in Colorado and Santa Fe in New Mexico are all above 7,000 feet above sea level.

Pregnancy highest risk

The study found most of the risk was in the period leading up to and immediately after birth and may be due to lower oxygen levels at higher altitudes.
“Pregnancies at high-altitudes are characterized by chronic hypoxia, or an inadequate supply of oxygen, which is consistently associated with a higher risk of fetal growth restriction,” Hirvonen said.
It was thought that genetic adaption to residing at high altitude over multiple generations might mitigate the stunting, but the study did not show that, Hirvonen said.

“After birth, the growth curve for children in areas 1,500 (meters) or more above sea level was consistently lower, implying limited catch-up to growth levels of children residing in areas lower than 1,500 (meters) above sea level,” the study found.
The results should educate health professionals to more closely work with pregnant women to control the effects of high altitude on the fetus, the study authors said.
“A first step is to unravel the complex relationship linking altitude, hypoxia and fetal growth to identify effective interventions,” said study co-author Kaleab Baye director of the Center for Food Science and Nutrition in Addis Ababa, Ethiopia.
“If children living at altitude are, on average, more stunted than their peers at sea level, then a more significant effort to address high altitude stunting is needed,” Hirvonen said.

physician-recommended easy to use daily

Why Use D'OXYVA?

D’OXYVA® (deoxyhemoglobin vasodilator) is an over-the-counter (OTC) device, which is the first biotech solution of its kind backed by widely-established groundbreaking Nobel Prize-winning science validated to significantly improve macro-, and micro-circulation of blood flow and certain nerve activities in the body such as the autonomic nervous system, which together are widely reported to form an effective solution option for many of the most severe and widespread health conditions.

D’OXYVA has proven itself especially effective for the most at-risk and complex cases in over three dozen human studies during its nearly decade-long clinical research and real-life results in over two dozen countries.

D’OXYVA’s eight years of comprehensive clinical research conducted by the world’s foremost medical experts has demonstrated massive improvements for the autonomic nervous system, heart rate variability, and oxygen-rich blood flow in many parts of the body for patients with a variety of neurological symptoms as well as other discomforts. No major adverse or negative effects have ever been reported about D’OXYVA as of today.

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Impaired microcirculation in patients with diabetes mellitus

Diabetes mellitus is a disorder of sugar metabolism. The blood sugar level is regulated mainly by the hormone insulin. If the amount of insulin produced is insufficient (type 1 diabetes), or if the effect of insulin is reduced (type 2 diabetes), blood sugar levels are chronically elevated. After some time, this results in significant damage to blood vessels. The term used for this is therefore diabetic angiopathy. If larger blood vessels are affected, the risk of heart attack and stroke is increased. The microvascular changes caused by diabetes can also cause serious complications.

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Impaired microcirculation in patients with diabetes mellitus

Among the most feared long-term consequences of diabetic angiopathy are damage to the eyes (diabetic retinopathy), the kidneys (diabetic nephropathy) and the nerves (diabetic neuropathy).

Diabetic retinopathy is the main cause of blindness in middle age in Germany and other industrialized countries. The retina is supplied with nutrients and oxygen through very fine microvessels. Over time, diabetes can damage the microvessels so that this supply is no longer sufficient. Affected persons at first see everything blurred, as though through a veil. In advanced stages, pronounced vision disorders and even blindness may develop. According to estimates by the German Diabetes Society, 20 to 40 percent of diabetics suffer kidney damage in the course of their disease. One of the tasks of the kidneys is to filter toxins and waste products out of the blood so they can be excreted in the urine. This work is done via tiny blood vessels in the renal corpuscles. Persistently high blood sugar levels damage these microvessels.

As a result, the filtering capacity of the kidney is reduced and the body is no longer sufficiently detoxified. If left untreated, this can lead to chronic renal failure so that renal functions must be replaced by dialysis or a kidney transplant. Approximately 30 percent of diabetes patients suffer nerve damage. One cause of this is impaired nerve cell metabolism due to high blood sugar levels. Another factor is reduced oxygen supply to the nerve cells due to the damaged microvessels supplying them. The most evident consequences are abnormal sensations like tingling, burning pain or numbness, especially in the hands and feet. In addition, tactile and temperature sensations, as well as pain perception, may be reduced. This latter factor favours the  development of diabetic foot syndrome since wounds are not noticed in early stages and – also due to impaired microcirculation – heal poorly.

LONG-TERM DAMAGE RESULTING FROM IMPAIRED MICROCIRCULATION IN PATIENTS WITH DIABETES
MELLITUS

• Damage to eyes (diabetic retinopathy) with vision impairments

• Damage to renal function (diabetic nephropathy), possibly mandatory dialysis

• Nerve damage (diabetic neuropathy) with abnormal sensations and impaired pain perception

• Impaired wound healing (diabetic foot syndrome)

HOW D’OXYVA CAN HELP?

Accordng to Dr. Michael McGlamry of  Forsyth Foot and Ankle Associates, Cumming, GA, D’OXYVA® (deoxyhemoglobin vasodilator) is a groundbreaking noninvasive, painless transdermal delivery system based on widely established, groundbreaking, Nobel Prize-winning science and is shown to increase oxygen-rich blood flow in the local microcirculatory system, which in turn leads to better blood perfusion and tissue oxygenation. The increased peripheral perfusion plays a significant role in enhancing the wound healing process, which may lead to a reduction in the influence of preexisting conditions in cases of a coronavirus infection.

D’OXYVA has shown significant promise for severe cases of diabetic foot ulcers. Its therapeutic effects have circulatory and neurological benefits as well.

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