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Microcirculation in Hypertension, A New Target for Treatment?

The number of effective agents available for the treatment of hypertension is now substantial. However, in spite of this, most would agree that there is still considerable scope for improvement in the way hypertension is managed. In many countries, the great majority of hypertensive subjects still show imperfect blood pressure control.1 Furthermore, the reductions or improvements in end-organ damage seen during antihypertensive therapy do not always correlate well with the reduction in arterial blood pressure achieved. Thus, there seems to be a need for new therapeutic perspectives in the treatment of hypertension. One important new perspective might be provided by an enhanced appreciation of the importance of the microcirculation in the pathophysiology and treatment of hypertension.

 

The Microcirculation in Hypertension

In hypertension, the structure and function of the microcirculation may be altered in at least 3 ways. First, the mechanisms regulating vasomotor tone may be abnormal, leading to enhanced vasoconstriction or reduced vasodilator responses. Second, there may be anatomic alterations to the structure of individual precapillary resistance vessels, such as an increase in their wall-to-lumen ratio. Finally, there may be changes at the level of the microvascular network, perhaps involving a reduction in the density (rarefaction) of arterioles or capillaries within a given vascular bed. It is likely that the relative contributions of these factors will be different in different vascular beds and may vary between different forms and models of hypertension. Nevertheless, it is possible to discern a historical shift in the focus of antihypertensive therapy between these different mechanisms. Initially, antihypertensive therapy was directed mainly toward altering vasomotor tone and promoting vasodilation. More recently, attention was directed toward reducing or reversing changes in resistance vessel structure, and in the last few years, there has been a further evolution toward reducing or reversing microvascular network rarefaction. Interestingly, several antihypertensive agents that act acutely to reduce vasomotor tone are now known to have additional chronic actions on vessel and network structure, which may be more important in the long-term treatment of hypertension.

In this article, we review the animal and human evidence available for the role of the microcirculation during hypertension and the effects of therapy, focusing on those aspects that are likely to be common to most forms of hypertension and most organ systems.

Microcirculatory Abnormalities in Hypertension: Both Cause and Effect?

It has been known for many years that the diameter and structure of small resistance arteries can alter in response to changes in blood pressure and flow. There have been numerous reports of decreases in arteriolar diameters in experimental secondary hypertension.4 Increases in the media-to-lumen ratio of small arteries have also been widely documented in several forms of hypertension,4 consistent with the classic view that vessels maintain constant wall stress in the face of changing pressure. However, it is not clear whether similar changes occur in arterioles in primary hypertension. In SHR, arterioles have not been reported to show consistently reduced luminal diameter or wall thickening (reviewed by Struijker Boudier et al).4

A more consistent observation has been microvessel rarefaction. A reduction in the number or density of microvessels has been reported for many years in most forms of clinical and experimental hypertension. Several studies have documented microvessel rarefaction in SHR and after the experimental induction of secondary hypertension.4

It has been suggested that rarefaction may occur in 2 phases.9 The first phase of functional rarefaction involves microvessel constriction to the point of nonperfusion, possibly as a result of increased sensitivity to vasoconstrictor stimuli. The nonperfused vessels may then disappear, leading to the second phase of structural or anatomic rarefaction, which cannot be reversed by maximal vasodilation. In patients with primary hypertension, the reduction in density of capillaries in the skin of the dorsum of the fingers has recently been shown to be mainly a result of anatomic rather than functional rarefaction.10

It is therefore possible to view microvessel abnormality and rarefaction as responses to increased vascular pressure. However, this is clearly not always the case, because microvascular changes similar to those observed in hypertension can be found in conditions such as scleroderma, syndrome X, and hypertrophic cardiomyopathy in the absence of any elevation in arterial blood pressure. Furthermore, there is evidence that abnormalities in the microcirculation may cause or contribute to the elevation of blood pressure.

Targeting the Microcirculation to Prevent End-Organ Damage: Beyond Blood Pressure Reduction?

Numerous trials have demonstrated that antihypertensive therapy is effective in reducing major vascular events, including stroke and coronary heart disease. However, several forms of specific end-organ damage that primarily involve the microcirculation are thought to be secondary to hypertension, including nephropathy, retinopathy, lacunar infarction, and microvascular angina. Thus, it is to be expected that there will be additional benefits from targeting the microcirculation during antihypertensive therapy in terms of the prevention of or reduction in end-organ damage.

One of the most intensively studied forms of end-organ damage with microvascular involvement is microalbuminuria or increased urinary albumin excretion. Microalbuminuria is known to be a risk factor for cardiovascular disease and mortality in nondiabetic and diabetic individuals. In the Framingham study, proteinuria was 3 times more common in hypertensive than in normotensive individuals and was associated with a 3-fold increase in mortality.18 Importantly, hypertensive patients with microalbuminuria have an increased cardiovascular risk compared with normoalbuminuric patients with similar blood pressure.19

Although microalbuminuria may be an early marker of renal dysfunction, it is now clear that it can be reversible. A recent large-scale study of 6000 nondiabetic hypertensive patients showed that microalbuminuria can be reversed in many cases by antihypertensive therapy.20 In SHR, different antihypertensive agents have different effects on renal afferent arteriolar structure. ACE inhibition produced a greater increase in the diameters of distal afferent arterioles than a calcium antagonist of equivalent hypotensive effect.21

The heart is another organ that may suffer end-organ damage, and numerous studies have reported changes in myocardial microvessel structure and density in hypertension. During normal development, myocardial microvascular density increases during the first few postnatal weeks but then decreases, probably because angiogenesis fails to match the growth in myocyte volume.22 During the pressure-overload hypertrophy that often accompanies hypertension, the picture that emerges from studies in both animals and human patients is that microvessel growth is insufficient to prevent dilution because of the greater increase in other myocardial components; hence, microvascular density decreases.22 It has been argued that microvascular changes may make a substantial contribution to the development of cardiac failure in hypertensive patients.23

The risk of stroke is greatly increased by hypertension. Although there are multiple causes of stroke, the form that is perhaps most closely associated with small-vessel abnormality is lacunar infarction, the occurrence of small, deep infarcts thought to be caused by the occlusion or rupture of small vessels, largely as a result of hypertensive changes.

Hypertensive changes in cerebral arteriolar structure have been documented in animal models. In SHR, reductions in the external diameter and increases in the media-to-lumen ratio of cerebral arterioles have been reported.24 However, most reports conclude that neither cerebral arterioles nor capillaries undergo rarefaction in SHR or in other experimental models of hypertension. At least some forms of antihypertensive therapy can reverse structural changes in cerebral microvessels25 and can dramatically increase the lifespan of stroke-prone SHR.26,27

Conclusions

Abnormalities of microvessel structure and microvascular network density often accompany, and may be an important cause of, primary hypertension. Microcirculatory abnormalities are also likely to be central to many forms of hypertensive end-organ damage, including those involving the kidneys, heart, and brain. Optimal antihypertensive therapy should therefore be targeted at both large and small vessels. Available evidence suggests that the 2 longest-established classes of antihypertensive agents, diuretics and β-blockers, have no specific beneficial actions on the microcirculation. However, the results of numerous animal studies and a much smaller number of clinical studies indicate that the newer classes of antihypertensive agents and some combinations of agents offer considerable potential for improving microvessel structure and network density. It would therefore be predicted that more widespread use of these agents and combinations would enable substantial reductions in end-organ damage to be achieved, with consequent reductions in morbidity and mortality. Much further clinical research is needed to assess the extent to which this potential can be realized in clinical practice.

This article was written on behalf of the European Working Group for Microcirculation and Cardiovascular Disease. Other members are E. Agabiti-Rosei, University of Brescia, Italy; T.F. Lüscher, University Hospital, Zurich, Switzerland; G.A. MacGregor, St George’s Hospital Medical School, London, UK; and E. Vicaut, Hôpital Fernand Widal, Paris, France.

HOW D’OXYVA CAN HELP?

D’OXYVA is the only fully noninvasive, completely painless transdermal (over-the-skin) microcirculatory solution that has been clinically tested to significantly improve microcirculation.

The improvement of microcirculation, i.e., blood flow to the smallest blood vessels, benefits one’s health, immune system and overall sense of well-being in a variety of ways.

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Impaired Tissue Perfusion

What is Impaired Tissue Perfusion?

Ineffective tissue perfusion is a state in which an individual has a decrease in oxygen resulting in failure to nourish the tissues at the capillary level.

Tissue perfusion is a critical parameter for tissue survival and function, and both relative and absolute perfusion assessments are highly relevant for both diagnosis and evaluation of the therapy response.

Sometimes situations occur where this exchange of gases between the blood and the cells is disrupted, meaning the cells (and ultimately the tissues and organs) stop getting adequate oxygen supply. The body can’t function without oxygen, so obviously this is a problem. When tissues don’t receive enough oxygen through the capillaries, this is called ineffective tissue perfusion.

Many conditions can disrupt the exchange of oxygen and carbon dioxide, but diabetes, obesity, anemia, high blood pressure, and coronary artery disease are some of the more common risk factors that can cause ineffective tissue perfusion. We can further classify the type of ineffective tissue perfusion based on the part of the body affected. For example, there’s renal (meaning kidney), cerebral (meaning brain), cardiopulmonary (meaning heart and lungs), gastrointestinal (meaning digestive tract), and peripheral (meaning affecting the extremities) ineffective tissue perfusion.

Common Risk Factors

Small arteries in diabetic subjects, whether hypertensive or normotensive, exhibit severe hypertrophic remodeling, and histological analysis of skeletal muscle biopsy samples reveals capillary rarefaction in subjects with type 2 diabetes. Histological capillary density is inversely related to fasting plasma glucose and fasting insulin levels and positively related to insulin sensitivity in nondiabetic individuals. Microvascular permeability to large molecules such as albumin is increased in diabetes, a process that is linked to hyperglycemia and ROS

In humans, coronary flow reserve is significantly lower in obese than in nonobese subjects, and capillary recruitment is reduced in nondiabetic obese individuals compared with lean control subjects. Even in a sample of healthy children (11 to 14 years of age), microvascular function was negatively correlated with adiposity. Thus, obesity appears to have an independent effect on microvascular function.

Coronary flow reserve decreases progressively with age in subjects without coronary artery disease, from approximately 4 at 30 years to 3 at 65 years of age, largely due to increased basal myocardial blood flow.

Tobacco smoking acutely impairs capillary recruitment, and thus hyperemic blood flow increases in skin and coronary flow reserve is reduced in established smokers. Coronary flow reserve in smokers can be improved by administration of antioxidant vitamin C, which suggests that smoking-related oxidative stress is an important mechanism.

Individuals with hypercholesterolemia without coronary artery disease have reduced coronary flow reserve, and coronary flow reserve is inversely correlated with LDL cholesterol. A reduction in coronary flow reserve can be detected in healthy young men (mean age 31 years) with familial hypercholesterolemia, which suggests that microvascular abnormality is detectable early in the atherosclerotic process.

Given the relationships between individual cardiovascular risk factors with measures of microvascular status, it is not surprising that the overall Framingham risk score is inversely correlated with skin capillary recruitment, maximal skin capillary density, and coronary flow reserve.

Defining Characteristics

Ineffective Tissue Perfusion is characterized by the following signs and symptoms:

  • Abnormal arterial blood gases
  • Altered respiratory rate outside of acceptable parameters
  • Bronchospasms
  • Capillary refill >3 seconds
  • Chest pain
  • Chest retraction
  • Dyspnea
  • Dysrhythmias
  • Nasal flaring
  • Sense of “impending doom”
  • Use of accessory muscles
  • Altered mental status
  • Behavioral changes
  • Changes in motor response
  • Changes in pupillary reactions
  • Difficult in swallowing
  • Extremity weakness or paralysis
  • Speech abnormalities
  • Abdominal distention
  • Abdominal pain or tenderness
  • Hypoactive or absent bowel sounds
  • Nausea
  • Altered sensations
  • Altered skin characteristics (hair, nails, moisture)
  • Cold extremities
  • Dependent, blue, or purple skin color
  • Diminished arterial pulsations
  • Edema
  • Positive Homan’s sign
  • Skin discolorations
  • Skin temperature changes
  • Skin color pale on elevation, color does not return on lowering the leg
  • Slow healing of lesions
  • Weak or absent pulses
  • Altered blood pressure outside of acceptable parameters
  • Elevation in BUN/creatinine ratio
  • Hematuria
  • Oliguria or anuria

Damage, Complications, and Prognosis

Microvascular abnormalities that lead to impaired tissue perfusion appear to represent a generalized condition that affects multiple tissues and organs. For example, in hypertension, coronary flow reserve is correlated with the media:lumen ratios of small arteries in biopsies of subcutaneous fat. Dilatation of venules in the retina independently predicts progression of cerebral small-vessel disease, and in diabetes, reduced coronary flow reserve predicts the occurrence of retinopathy.

Impaired tissue perfusion may be involved in target-organ damage and complications that involve several vascular beds. For the coronary microcirculation, an obvious example associated with both hypertension and diabetes is the occurrence of myocardial ischemia and angina in the presence of angioscopically normal epicardial coronary arteries, also known as cardiac syndrome X. Impaired myocardial perfusion may also be an important factor in the development of hypertensive heart failure and may lead to localized ischemia and disturbed patterns of electrical activity that constitute a substrate for serious arrhythmias. In the case of renal disease, glomerular and peritubular capillary rarefaction has been noted in different animal models and in human progressive renal disease, and it precedes the development of impaired perfusion and chronic hypoxia. It has been suggested that hypoxia may be the common factor linking many forms of progressive renal disease.

Microvascular abnormality is also a predictor of prognosis. In hypertensive patients, the media:lumen ratio of peripheral small arteries is a strong independent predictor of cardiovascular events. Among individuals with normal or minimally diseased coronary arteries, reduced coronary flow reserve is an independent predictor of cardiovascular events within the next decade. Finally, in patients with chest pain and angiographically normal arteries, coronary flow reserve <3 is associated with a 6-fold increase in all-cause mortality risk compared with coronary flow reserve >3 during 8.5 years of follow-up.

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Did you know when used in a regimen, D`OXYVA users have reported a number of health and beauty benefits?

doxyva benefits

OPTIMIZE BLOOD CIRCULATION FOR A WIDE VARIETY OF SIGNIFICANT OUTCOMES

D’OXYVA® (deoxyhemoglobin vasodilator) in various clinical trials has validated leading independent research results and demonstrated above-average results in improving a host of physiological functions at the same time.

People using D’OXYVA® have recorded significant improvements in cardiovascular activity leading to much improved physical activity. As part of a healthy lifestyle, D’OXYVA may help significantly reduce the risk of high blood pressure, hypertension, cholesterol, and diabetes in just two or three months, with an average use of 5 minutes a day and 5 times a week.

Poor circulation is a gateway for a litany of ailments: slow healing, depression, poor complexion, sores, slow metabolism, and more.

D’OXYVA significantly improves sustained oxygen-rich microcirculatory blood flow locally and throughout the body. Its patented method of fully non-invasive, painless, and harmless transdermal delivery is unique only to D’OXYVA.

When used daily, D’OXYVA users have reported a number of health and beauty benefits, including but not limited to:

  • Relief from symptoms of microvascular complications
  • Significantly increased cardiac function, physical fitness, endurance and strength, muscle size, body tone, faster recovery from sports injuries and surgical trauma
  • Improved self-esteem via promoting healthy and radiant skin, complexion, dry skin relief, and acne reduction
  • Significant reduction in downtime from other skin treatments and cosmetic procedures when used in combination, reduction in the appearance of scars, cellulite, fat, spider veins and stretch marks
  • Promoting and maintaining a healthy weight, improving general mobility, deeper, more restful sleep
  • Significant improvement of mental acuity; concentration, problem solving, multitasking, eye-hand coordination, heightened stamina, energy, and focus while managing stress
  • Improved vitals across the board during checkups with zero adverse event reports after years of regular use by people with various health, demographic, and ethnic backgrounds

HOW D’OXYVA CAN HELP?

D’OXYVA is the only fully noninvasive, completely painless transdermal (over-the-skin) microcirculatory solution that has been clinically tested to significantly improve microcirculation.

The improvement of microcirculation, i.e., blood flow to the smallest blood vessels, benefits one’s health, immune system and overall sense of well-being in a variety of ways.

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Why post-menopausal women are prone to heart attack

Why post-menopausal women are prone to heart attack Read more: https://lifestyle.inquirer.net/296431/post-menopausal-women-prone-heart-attack/#ixzz5lzYlOezl Follow us: @inquirerdotnet on Twitter | inquirerdotnet on Facebook

Recently we had a female patient in her early 60s who suffered a heart attack and fortunately survived it.

All the time, she had been accompanying her husband to regular check-ups on his heart problem, without realizing she herself was a walking time bomb.

She has been a smoker most of her adult life. She has a strong family history of cardiovascular disease (CVD), with two male siblings undergoing heart bypass surgery in their early 50s.

Her blood pressure (BP) went on upward trend after menopause, with high cholesterol levels.

She showed no symptoms so she thought she was just fine, until she woke up in the middle of the night with severe chest tightness and shortness of breath.

She was rushed to the hospital, had an immediate declogging of the heart artery through angioplasty, and a small scaffolding-like metal called stent was inserted to keep the culprit coronary artery patent.

The same story happens so many times. Wife is so concerned about her husband with a heart problem and she neglects to have herself checked, or make sure that her lifestyle is not conducive to develop CVD.

Before menopause, women are protected by estrogen, the female reproductive hormone. This hormone has been shown to have a beneficial or cardioprotective effect on the inner layer of artery wall called endothelium.

After age 50

Endothelial dysfunction triggers the start of the atherosclerosis, which is the progressive narrowing of the artery. Estrogen prevents endothelial dysfunction, and helps maintain the flexibility of the blood vessels.

Flexible arteries can relax and expand to accommodate more blood and enhance the blood flow or circulation.

The onset of menopause is usually after the age of 50 (52 to 54 years of age on average). There are some who experience early menopause, signaled by the cessation of the monthly period at a much earlier age, even before age 40.

After menopause, estrogen decreases significantly and the heart protection is almost completely gone around eight to 10 years after menopause. This is usually when women are in their late 50s or early 60s.

Hence, the risk of developing a stroke, or heart attack, may increase and become higher in women compared to men at this age.

For those who have menopause at an early age, the increase in cardiovascular risk may occur at a much earlier age, when the women are just in their late 40s or early 50s.

Ovarian failure

The common cause is premature ovarian failure, but it may also be caused by damage to the ovaries as a result of cancer therapy and/or radiation treatments.

Another cause could be surgical removal of the ovaries if tumors in the female reproductive organs are diagnosed at a younger age.

The symptoms of premature menopause are pretty much the same as regular menopause, and include hot flashes, emotional instability or mood swing, vaginal dryness, decreased memory or comprehension, decreased libido or sex drive, and insomnia.

We have to clarify that menopause, by itself, does not cause CVD. It’s just that the levels of the heart-protective female hormones, particularly estrogen, decrease, and risk factors increase around the time of menopause.

These are increasing BP, high LDL (bad cholesterol) level, and low HDL (good cholesterol level. The triglyceride level, another bad type of fat, also increases after menopause.

A reckless lifestyle in the form of a high-carb and high-fat diet, being sedentary, smoking, and other unhealthy practices —which women could have earlier in life—starts to take its toll after menopause.

Guidelines from various heart associations remind women to really take stock of their health when they’re reaching menopause, so they can avert serious complications.

Since the cardiovascular risk in women peaks around eight to 10 years after the onset of menopause, women who are at high risk could be identified so that they could be treated more aggressively and monitored closely, preventing the complications which could occur years later.

A recently published study suggests that a relatively higher level of the male hormone called androgen or testosterone in postmenopausal women is associated with increased risks of cardiovascular complications.

The study, published in the Journal of the American College of Cardiology, followed up 2,800 postmenopausal women initially free of CVD. The women had their sex hormone levels measured at baseline.

The researchers reported that during an average of 12- year follow-up, CVD was diagnosed in 283 participants, plus clogging of the heart arteries (coronary heart disease or CHD) in 171, and heart failure in 103.

Adjustments were made to discount the effect of conventional risk factors and hormone therapy. The following findings were reported:

Male hormone

Higher total testosterone (male hormone)/estradiol ratio was linked with significantly increased risks for all cardiovascular outcomes.

Higher total testosterone appeared to significantly increase risks for CVD and CHD.
Higher estradiol (female hormone) was associated with significantly lower CHD risk, reaffirming its heart protective effect.

Does this study suggest that we should give post-menopausal women estrogen hormone therapy to prevent CVD or CHD?

I don’t think there’s good data to support that recommendation. There are also potential complications of aggressive hormone therapy which doctors are wary about.

The importance of this study is that we could identify the post-menopausal women who are at risk of suffering potentially serious cardiovascular complications, and implement risk-reducing strategies such as end to smoking, regular exercise and balanced diet.

Which type of diet is really good remains a big issue, in view of various fad diets claiming cardiovascular benefits.

The American Heart Association and Philippine Heart Association recommend eating a balanced diet consisting of: fruits, vegetables, whole grains, low-fat dairy products, poultry, fish and nuts, with less red meat and minimal sugary foods and beverages.

Aside from a healthy diet and lifestyle, adequate control of elevated BP is recommended; as well as the use of cardioprotective drugs like statins even if the cholesterol levels are not that high.

The important thing, too, is to get rid of the misconception that only men are vulnerable to heart disease, and women are spared from them.

A change of this wrong mindset is necessary so that the beloved women in our lives are not deprived of the medical care and attention they need to prevent heart attack, stroke and other cardiovascular complications.

HOW D’OXYVA CAN HELP?

D’OXYVA is the only fully noninvasive, completely painless transdermal (over-the-skin) microcirculatory solution that has been clinically tested to significantly improve microcirculation.

The improvement of microcirculation, i.e., blood flow to the smallest blood vessels, benefits one’s health, immune system and overall sense of well-being in a variety of ways.

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Being mindful of symptoms

LEWISTOWN–Dr. Maya Lichtenstein, neurologist at Geisinger-Lewistown Hospital, said that there are a myriad of potential symptoms that could be signs of a stroke. “Any sudden changes,” said Lichtenstein, “go the E.R.”

A stroke, according to Liechtenstein, is either the result of not enough blood flow to the brain, plaque in the blood vessels or heart, each resulting in a clot, or a hemorragic bleed, resulting in a bursted blood vessel in the brain. Classic symptoms of a stroke include numbness, tingling, weakness on one side of the body and changes in speech, but other sudden changes in in understanding language, vision, vertigo or clumsiness can also be symptomatic.

“It depends on what part of the brain is damaged,” said Lichtenstein.

Treatment options for a stroke vary, depending on the type of stroke.

“If you get seen fast enough,” said Lichtenstein, for a clot, a “clot-busting medication, a form of blood thinner” can be administered via I.V. A thrombectomy, a procedure, not an operation, said Lichtenstein, is another treatment option, similar to a cardiac catheterization. A bleeding stroke often leads to lowering the patient’s blood pressure and surgically relieving pressure on the brain. Taking aspirin can also treat a stroke.

Post-stroke, Liechtenstein said that rehabilitation is important, including physical, occupational, speech, and cognitive therapies. “Aggressive therapy can continue to improve people’s symptoms,” said Lichtenstein. “Everyone thinks they’re better if they can move their arms and legs.” Lichtenstein also encourages stroke patients to be aware of their mood and possible depression, encouraging them to accept all the help available.

To avoid a stroke, Liechtenstein said patients should see their doctors regularly for preventive care and that leading a healthy lifestyle is the key, including regular exercise to keep up the heart rate and eating a diet rich in fresh fruit and vegetables, lean proteins and whole grains. Lichtenstein also encourages patients to keep control of their vascular issues, such as high blood pressure and diabetes, as well as to quit smoking, if they smoke.

 

Reference: http://www.lewistownsentinel.com/news/local-news/2018/05/being-mindful-of-symptoms/

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The complexity of heart rate variability predicts outcome in intensive care unit admitted patients with acute stroke

BACKGROUND:

Heart rate variability (HRV) has been proposed as a predictor of acute stroke outcome. This study aimed to evaluate the predictive value of a novel non-linear method for analysis of HRV, multiscale entropy (MSE) and outcome of patients with acute stroke who had been admitted to the intensive care unit (ICU).

 

METHODS:

The MSE of HRV was analysed from 1 h continuous ECG signals in ICU-admitted patients with acute stroke and controls. The complexity index was defined as the area under the MSE curve (scale 1-20). A favourable outcome was defined as modified Rankin scale 0-2 at 3 months after stroke.

 

RESULTS:

The trends of MSE curves in patients with atrial fibrillation (AF) (n=77) were apparently different from those in patients with non-AF stroke (n=150) and controls (n=60). In addition, the values of complexity index were significantly lower in the patients with non-AF stroke than in the controls (25.8±.3 vs. 32.3±4.3, p<0.001). After adjustment for clinical variables, patients without AF who had a favourable outcome were significantly related to higher complexity index values (OR=1.15, 95% CI 1.07 to 1.25, p<0.001). Importantly, the area under the receiver operating characteristic curve for predicting a favourable outcome of patients with non-AF stroke from clinical parameters was 0.858 (95% CI 0.797 to 0.919) and significantly improved to 0.903 (95% CI 0.853 to 0.954) after adding on the parameter of complexity index values (p=0.020).

 

CONCLUSIONS:

In ICU-admitted patients with acute stroke, early assessment of the complexity of HRV by MSE can help in predicting outcomes in patients without AF.

HOW D’OXYVA CAN HELP?

D’OXYVA is the only fully noninvasive, completely painless transdermal (over-the-skin) microcirculatory solution that has been clinically tested to significantly improve microcirculation.

The improvement of microcirculation, i.e., blood flow to the smallest blood vessels, benefits one’s health, immune system and overall sense of well-being in a variety of ways.

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Improved Microcirculation Against Diabetes, Stroke and Several Other Diseases

Exercise has been shown to protect against diabetes, stroke and several other diseases and to improve our moods.

But does it also make us more likely to engage in other activities? Do people who exercise tend to have better social lives or achieve more of their goals?

All clinical evidence so far validates that the science of exercise physiology best explains the outsized and unmatched vast health benefits of D’OXYVA® (deoxyhemoglobin vasodilator) and opens up entirely new ways of thinking about the treatment of the underlying causes of the most severe and widespread medical conditions.

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D’OXYVA AND ITS POSITIVE IMPACT ON PATIENTS’ HEALTH

What is D’OXYVA?

The D’OXYVA®  device is a simple, commercially- available device to deliver transdermal carbon dioxide (CO2). It consists of a patented and patent-pending ergonomic polymer shell that is propelled by a patented single-use mini steel pressurized cartridge (45 psi) filled with pharmaceutical-grade (99.5%) liquid, purified CO2. The mini-steel cylinder is GMP-compliant, and recyclable.

D’OXYVA was identified by the IRB in a human clinical trial as a non-significant risk (NSR) device.

The D’OXYVA device is manufactured in the United States and other countries. D’OXYVA is an ISO-complaint device, which means that Circularity Healthcare, LLC has received a certification to certify that D’OXYVA fulfills all of the international requirements for medical device regulations, like risk assessment and maintaining effective processes for safe design, manufacture and distribution.manufacture and distribution.

 

WHO IS INVOLVED IN IMPROVING HEALTHCARE FOR PATIENTS?

CO2 is the protagonist in D’OXYVA’s revolutionary approach to improving healthcare and patients’ quality of life. The medical device causes controlled ischemia-like stress in a local area of the body to promote central nervous system activity and circulate humoral agents that favor micro-circulation, especially at the organ capillary beds.

Adequate blood flow in the capillary bed is essential for tissue survival and optimal organ function. If blood passes too fast or does not pass at all, the tissue cannot extract O2 efficiently and will generate what is known as capillary dysfunction, which is related to chronic pain, poor wound healing, diabetic neuropathy and Alzheimer’s disease, among other conditions.

 

WHAT DO WE USUALLY REMEMBER ABOUT CO2?

· It is a key player in regulating extracellular hydrogen concentrations and pH through various systems, like the respiratory system, kidneys and various buffers.

· Biochemistry: An increase or decrease in 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.
· It is attained by our body 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.

· CO2 can be delivered into our body through the skin (transdermal).

It is used in the medical industry to:

· Rapidly increase the depth of anesthesia when volatile agents are being administered—it increases the depth of respiration and helps to overcome breath holding and bronchial spasm

· Facilitate blind intubation in anesthetic practice

· Facilitate vasodilation and thus lessen the degree of metabolic acidosis during the induction of hypothermia

· Increase cerebral blood flow in arteriosclerotic patients undergoing surgery

· Stimulate respiration after a period of apnea

· Prevent hypocapnia during hyperventilation

 

It is also used in:

· Clinical and physiological investigations

· Gynecological investigations for insufflation into the fallopian tubes and abdominal cavities

· Tissue-freezing techniques (as dry ice) and to destroy warts by freezing.

· The CO2 concentration increment potentiates the S-shaped hemoglobin (Hb) to O2 dissociation curve. It helps Hb to unload O2 from 40% O2 dissociation under normal conditions to 70% O2 dissociation under increase CO2 concentration.

 

WHERE DOES CO2 VAPOR DELIVERED THROUGH THE SKIN TAKE ACTION IN THE BODY?

Transdermal delivery of CO2 has proved to improve local microcirculation (capillary beds) blood flow and tissue perfusion, but it also positively improves systemic blood pressure and TcpO2 (most likely due to the Bohr effect). As mentioned before, therapeutic medical-grade CO2 is used for vasodilatation in the medical field for several conditions and procedures.

Local, CO2 therapy has shown great success rates to improve the healthcare of patients through:

· Treatment for diabetic foot

· Increased microcirculation blood flow 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 to improve:

· The healthcare of patients with high blood pressure

· General vital organ function, like that of the: – Pancreas – Liver – Brain – Kidneys

We are currently finding clinical researchers who are interested in participating in clinical trials with our medical device. Our goal is to produce scientific evidence of D’OXYVA’s potential to improve healthcare.

 

OUTSTANDING CLINICAL RESEARCH RESULTS

More than two dozen research projects have been performed to test D’OXYVA potential and its capability to help patients obtain wellness. We have tested the efficiency, tolerability and safety of the D’OXYVA medical device in delivering a gentle, highly concentrated CO2 mist to the body through the skin and prove the reproducibility of its effects beyond doubt. To do so, we measured body CO2 concentration before and after treatment as well as the expected physiological response to CO2 treatment. In addition, we have partnered with healthcare leaders and clinicians to perform independent research studies.

Research end points:

1) Safety and tolerability  Up to date, no adverse side effects or negative healthcare responses have been recorded from our clients using D’OXYVA. Also, no participants in our research projects had any documented side effects from treatment. We encourage you to discuss with your healthcare professional if D’OXYVA medical device is right for you.

· Up to date, no adverse side effects or negative healthcare responses have been recorded from our clients using D’OXYVA. Also, no participants in our research projects had any documented side effects from treatment. We encourage you to discuss with your healthcare professional if D’OXYVA medical device is right for you.

· Measured transcutaneous carbon dioxide (TcPCO2)

· Within the first 5 minutes of D’OXYVA treatment, TcPCO2 increases in the body, followed by a decline slope that lasts approximately 240 minutes until returning to baseline values.

· In healthy individuals, D’OXYVA does not increase pCO2 beyond the body buffer’s manageable range, making it completely safe.

 

2) Efficiency CO2 delivery

a. Measured blood perfusion index (PI)
· The results of each research project consistently showed a significant increment on PI in 100% of participants within the first 5 minutes of treatment, peaking at 60 minutes after treatment. From 60 minutes after treatment until 240 minutes (our largest time period evaluated after treatment), PI decreased slowly to baseline levels. PI studies on diabetic patients has demonstrated a greater response to CO2 that in non-diabetic healthy individuals. Our studies have recorded that the PI change (from baseline) in diabetic patients was double the PI change recorded in healthy patients (Graph 1).
Graph 1: Skin perfusion index (SPP) in healthy and diabetic participants vs. time after using the D’OXYVA medical device

b. O2 concentration
 D’OXYVA has consistently reported increased free O2 molecules in our patients’ blood streams. The effective transdermal CO2 delivery allows the body to increment O2 availability through the Bohr effect, which helps hemoglobin cells to unload O2 more easily by decreasing its affinity.

c. Blood pressure
All of the research projects performed up to date have consistently recorded a significant decrease in systolic blood pressure (from the heart) and diastolic (return to the heart) blood pressure. These results have been consistent throughout all study time periods up to 240 minutes (our longest time period evaluated after treatment).

d. Diabetic ulcer
A research project focusing on D’OXYVA’s impact on diabetic ulcers recorded significant changes in wound healing, like significant granulation of tissue and improved ulcer borders, as soon as 1 week into the D’OXYVA treatment plan (Image 1).

e. Sports
Amateur and professional athletes are always searching for ways to improve cardiovascular function and increase the vascular transport capacity of skeletal muscle. Better vascular transport capacity translates to more O2 and nutrients delivered to our muscles, which means better performance in the field.
D’OXYVA research focusing on the perfusion index (PI) of superficial skeletal muscles has recorded excellent results. The most important findings demonstrate that participants who use D’OXYVA doubled their PI in comparison to the control group.

f. Blood alkalinity
Use of D’OXYVA has consistently been shown to improve local cellular homeostasis. It has the potential to improve body pH values by promoting an alkaline ambiance. A slightly alkaline microenvironment After 7 days of treatment with D’OXYVA (1x per day) – same wound dressing as before within the body promotes good health and optimal body organ performance.

 

WHEN WILL PATIENTS BEGIN TO PERCEIVE HEALTHCARE BENEFITS AFTER STARTING D’OXYVA?

The SENTEC digital monitor system has confirmed successful and constant CO2 transdermal delivery to the skin capillary bed after a 5-minute period of exposure to highly concentrated CO2 vapor produced by D’OXYVA.
The perceived healthcare benefits occur almost instantly, with local microcirculation improvements followed by an increment of SPO2 that last up to 240 minutes.

Nonetheless, adherence to a D’OXYVA regiment has demonstrated benefits to individuals suffering from difficult-to-heal skin wounds like diabetic ulcers, who demonstrated significant clinical improvements after two weeks of D’OXYVA.
Patients who achieved D’OXYVA device adherence for more than a month have shown wellness that persists in clinical trials.

Why can the D’OXYVA medical device and its capacity to produce highly concentrated CO2 vapor improve general health care? Judy M. Delp, Ph.D. in physiology and professor at the Florida State University, described D’OXYVA as a simple commercially available device used to deliver transdermal CO2 that has shown remote vasodilation, which may be mediated through the release of a circulating humoral agent.**

CO2 improves general healthcare in several ways:

· It has natural anti-inflammatory characteristics.

· It increases blood flow through microcirculation, by arteriolar/venous dilatation.

· It produces a rightward shift in the O2 dissociation curve.

· It enhances oxygen delivery at the cellular level in the muscles, organs, brain, skin and other parts of the body.

· It is a fat-dissolving compound.

· It naturally sedates and calms the central nervous system.

· It can be used to reconstruct functionally closed capillaries.

· It can improve venous response.

· It improves blood-flow properties.  It can be used to sedate the central nervous system.

 

IS D’OXYVA SAFE FOR MY PATIENTS (HUMANS AND PETS)?

Circularity Healthcare operates a state-of-the-art supply chain and quality management system (QMS) for manufacturing. Circularity has certificates of registration for IS EN ISO13485:2012 (European Union) and ISO13485:2003 under CMDCAS (Canada), which it has been implementing since 2013.

D’OXYVA is a CE-marked medical device (Class I, low risk) for delivery of medications via the skin. Circularity is seeking approval from the U.S. FDA and other countries for delivery of medical gases such as medical carbon dioxide (USP UN1013) via a novel, patented, non-invasive transdermal route with D’OXYVA to treat various widespread conditions.

Medical carbon dioxide is manufactured and delivered under applicable standards per each country’s regulatory requirements. In the United States, the Food and Drug Administration has cleared the use of medical carbon dioxide through inhalation for humans but not yet through transdermal delivery with D’OXYVA. Transportation of medical carbon dioxide via any postal or courier service requires a certification for handling dangerous goods (HAZMAT) by the U.S. Department of Transportation (DOT).

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Blood Circulation Problems

Blood is the carrier of the all-important oxygen molecule. Through a series of reactions in which oxygen is involved, energy is produced, which is necessary for driving our cells’ metabolic reactions. So when blood does not reach a part of the body, the conditions that result from it are the consequences of oxygen deprivation. The heart, through its pumping action, maintains the pressure required for the blood to reach all parts of the body. Under normal circumstances, arteries, veins and capillaries, through which blood travels, are quite flexible. When they harden or get blocked, blood cannot flow through them to reach the organs. Hardening or blocking of blood vessels occur due to many reasons. Deposition of cholesterol and fat, clumping of platelets to form clots, and inflammation, all of these can lead to the narrowing of the diameter of blood vessels.

Problems in circulation also occur if the heart cannot pump blood efficiently. This can occur due to a number of reasons, but mostly is due to the same factors that are involved in blood vessel narrowing. Here are some conditions in which the blood circulation of an individual may get compromised.

It is the leading cause of narrowed blood vessels that ultimately lead to all kinds of problems in the body. Atherosclerosis is a gradual process of hardening and loss of flexibility of the arteries as a result of deposition of cholesterol and fats inside their lumen. These deposits are called plaques. When this deposition reaches a significant level, the arteries become partially or fully blocked. Blood cannot flow with the same efficiency through them, and the organ to which they supply suffers ischemia, a condition of oxygen deprivation. Atherosclerosis is the cause of many diseases like myocardial infarction, brain strokes, renal stenosis, and pain and cramps in the hands or legs. The disease which a person gets, depends on which arteries have significant blockage in them. Cholesterol is needed and manufactured naturally by the body, and it also comes into the body by the consumption of food, and excess amounts are stored. The same goes for fat – especially trans fat. A high fat diet is therefore one of the main culprits in causing atherosclerosis, although other factors like genetics are also important.

Treatment
There is no easy way to get rid of atherosclerotic plaques, because they are quite tenacious. Lifestyle modification is an absolute necessity in preventing further damage to the arteries. In fact, nothing works as well as lifestyle modification in dealing with atherosclerosis. Other than this, the options available are for increasing the diameter of the narrowed arteries to restore normal blood flow.
  • Angioplasty – This procedure involves inserting a flexible tube in the artery and inflating it to increase its diameter.
  • Bypass Surgery – When the arteries supplying the heart (coronary arteries) are completely blocked, they are ‘bypassed” by using a blood vessel from some other part (e.g. leg). By surgically attaching this blood vessel to the heart, the blood supply is redirected via this, to the heart.
  • Preventive Measures – Changes in lifestyle, such as following a low-fat diet, exercising, reducing alcohol consumption, and cessation of smoking are necessary to avoid buildup of plaque in the arteries. Some drugs like statins can be used to lower cholesterol levels in the body, but they have many side-effects too.

This disease has two forms, a primary one, and a secondary form (called Raynaud’s phenomenon). The primary form does not occur in association with some other disease, but the secondary form does. In people suffering from this condition, some parts of the body such as the fingers, toes, nose, lips and ears feel very cold under conditions of low temperature or stress. This happens because some small arteries in these body parts constrict, reducing blood flow, causing the feeling of numbness and cold experienced by people suffering from this disorder. During an attack, the affected body parts blanch, and then turn blue. When blood flow is slowly restored, they turn red along with a burning, throbbing sensation. Many people with Raynaud’s disease experience all this only in their extremities. Its prevalence is greater among women as compared to men.

Treatment
People with Raynaud’s disease are advised to wear warm clothes and not expose themselves to cold. They are also advised to stay away from drugs that cause blood vessel constriction. Most treatment options aim at dilating the constricted blood vessels which lead to the symptoms of Raynaud’s disease. If a patient has secondary Raynaud’s disease, the treatment for the underlying condition encompasses the treatment for Raynaud’s disease. If the patient does not get relief from these, or if the symptoms are very severe, surgical intervention or some other options may be resorted to.

Drugs

  • Calcium Channel Blockers – These dilate blood vessels so that proper circulation to the extremities is restored. Some drugs in this category that are used are nifedipine, nicardipine and diltiazem.
  • Alpha-receptor Blockers – These drugs bind to alpha-1 receptors because of which norepinephrine is unable to bind to them. This prevents the constrictive effect of norepinephrine on the blood vessels. Some drugs in this class that are used are prazosin and doxazosin.

Other Options

  • Nerve Excision – Nerves that supply the blood vessels of the affected body part are cut so that they cannot cause them to constrict.
  • Amputation – Sometimes, gangrene develops in the part where the blood supply has been blocked. It needs to be surgically removed to prevent further spread.
  • Nerve Blockage – The nerves supplying the affected body part can be temporarily blocked to prevent blood vessel constriction.

Diabetes, as is well-known, is a complex metabolic disorder. The inability of the body to utilize glucose has system-wide effects, leading to all kinds of problems, from impaired wound-healing to neuropathies. One among the many problems stemming from diabetes is poor circulation. A high level of cholesterol and glucose in the blood, as well as high blood pressure, causes the blood vessels to thicken and lose their flexibility. This leads to insufficient blood supply to various organs, especially the hands and feet. The consequences of this reduced blood supply are many, like infections, delayed and impaired wound healing, numbness and coldness, tingling and difficulty in walking. If care is not taken, sores develop on the feet, which may advance to gangrene. Adding to the problem is the fact that diabetics often are overweight and have high blood pressure. All of these put them at an increased risk of heart problems as well. Diabetics often experience pain and cramping in the legs after a long walk or exercise. This is known as claudication.

Treatment
Mostly, preventive measures undertaken to deal with atherosclerosis are recommended to patients with diabetes, for improving circulation. Without these, no amount of medication is enough to prevent circulation problems.

  • Quitting Smoking – Smoking has been strongly associated in a number of studies with the development of atherosclerosis. Quitting smoking is one of the most important steps that people with diabetes need to take to stop atherosclerosis.
  • Exercise – Physical activity, such as a daily walk, and exercise under supervision, greatly helps with improving circulation.
  • Other preventive measures include a healthy diet, not exposing the extremities to cold, and checking the feet for injuries, regularly.

Also known as Thromboangiitis obliterans, it is a disease of unknown cause, that has a strong association with smoking or chewing tobacco. This disease is characterized by inflammation of the veins and arteries of the extremities. They become inflamed and swell up, restricting blood flow to the hands and feet. Blood clots also form and further block the blood vessels. It is believed that some factors trigger the immune system to attack the blood vessels and cause inflammation. Insufficient blood supply to the limbs has the same effect on the hands and feet, as in other diseases, resulting from such a deficit – greater risk of infections, gangrene and tissue damage.

Treatment
Most patients of Buerger’s disease are habitual tobacco users. Since tobacco use plays an important part in the genesis and progression of the disease, stopping smoking is the most important step in slowing the progression of the disease. Cessation of smoking improves the outcome of treatment, and slows the condition from aggravating further. Other than this, a treatment plan for Buerger’s disease involves therapies that increase blood flow to the limbs.

  • Streptokinase – This is an enzyme that is used to dissolve blood clots. It has been shown to be beneficial to a certain extent in patients of Buerger’s disease.
  • Synthetic Prostacyclin Analogues – Drugs belonging to this class, like iloprost, treprostinil and cicaprost, have been used with some success in dilating blood vessels in patients.
  • Surgery – Surgical options include sympathectomy (cutting off the nerve supply to the blood vessels), and in case of gangrene, amputation of the gangrenous part(s).
  • Some experimental therapies like the use of drugs to stimulate new blood vessels to grow are also being tried out.

There are a number of diseases that are caused due to formation of clots in the blood vessels, especially the veins. Valve defects, being on birth control pills for a long time, certain genetic conditions, injury, inflammation, certain congenital defects, some cancers, and many other factors predispose a person’s arteries or veins toward blood clot formation. These can be dangerous if not dealt with immediately.

Treatment
It depends upon whether the clots are in the arteries or the veins.

  • Arterial Clots – Aspirin and clopidogrel, both prevent the blood platelets from sticking to each other. This helps in preventing clot formation. Heparin and some thrombolytic agents are also used to prevent clot formation.
  • Venous Clots – Heparin and warfarin, both are used to prevent clot formation in the veins.


Although some conditions in which there is a problem with blood flow are genetic in nature, most are preventable by bringing about lifestyle changes, such as following a healthy high-fiber diet, giving up smoking, and reducing consumption of alcohol.