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Diabetes, cardiovascular disease and the microcirculation

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality in people with type 2 diabetes mellitus (T2DM), yet a significant proportion of the disease burden cannot be accounted for by conventional cardiovascular risk factors. Hypertension occurs in majority of people with T2DM, which is substantially more frequent than would be anticipated based on general population samples. The impact of hypertension is considerably higher in people with diabetes than it is in the general population, suggesting either an increased sensitivity to its effect or a confounding underlying aetiopathogenic mechanism of hypertension associated with CVD within diabetes. In this contribution, we aim to review the changes observed in the vascular tree in people with T2DM compared to the general population, the effects of established anti-diabetes drugs on microvascular outcomes, and explore the hypotheses to account for common causalities of the increased prevalence of CVD and hypertension in people with T2DM.

Background

Type 2 diabetes mellitus (T2DM) and hypertension are established risk factors for cardiovascular disease (CVD), and people with T2DM and hypertension have an increased risk of cardiovascular (CV) mortality compared with those with either condition alone. This excess risk is suggested to be due to the synergistic effect on large and small blood vessels simultaneously, thereby reducing the potential for compensatory collateralization protecting organs from the adverse consequences of damage to either vascular bed. The principle role of the vasculature is to deliver oxygen and nutrients to the tissues—whether that is the heart, the brain, or the kidney. The functional changes occurring in T2DM and hypertensive conditions significantly alter the haemodynamic stress on the heart and other organs. However, the different physiology, mechanisms and changes at the microvascular level differ from those at the macrovascular level in T2DM and hypertension, which in turn have significant implications with respect to future CV risk.

Conclusions

Over the past few decades, epidemiological studies have elucidated the role of impaired microcirculation in people with diabetes and aetiopathogenesis of CVD. This has led to the recognition of the prevalence of microvascular disease. Furthermore, the prognostic value of incidence of microvascular disease in predicting CVD is now acknowledged. The focus of present-day epidemiological studies is to understand the association between pathological mechanisms and the risk factors to ascertain whether they are targets of therapeutic value or risk markers of CVD. These studies have contributed to the evidentiary framework in favour of clinical monitoring of microvascular function, and spurred the initiation of mechanistic studies by redefining our knowledge of vascular disease, particularly in people with diabetes.

HOW D’OXYVA CAN HELP?

Over the past few decades, epidemiological studies have elucidated the role of impaired microcirculation in people with diabetes and aetiopathogenesis of CVD. 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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My Neuropathy Story: This Is How My Diabetic Neuropathy Disappeared Forever

“I was first diagnosed with diabetes at a young age,” said Bryan, 50 years old. It was in his early 20s that he started to live with devastating pain in his legs from diabetic neuropathy and had deteriorating muscular degeneration. But today, Bryan can go jogging again, and even his vision is somewhat improving.

 

What happened?

“It’s simple, I started to look at my diet, did more research and found a new solution called D’OXYVA,” said Bryan.

 

Before D’OXYVA

Bryan was diagnosed with type 1 diabetes around 30 years ago. “I couldn’t believe when my doctor told me that my blood sugar levels are high,” he said, although he admitted that other risk factors were obvious, such as being overweight and the fact that diabetes runs in his family.

He ignored his diagnosis and paid little attention to diabetes. He was told to start eating healthy, yet he continued eating what he wanted and didn’t watch his weight.

“A few years ago, I started to feel tingling in my right foot, and it got worse day after day,” said Bryan. Soon, both feet felt numb and he began to feel the pain. It was so painful that he had a hard time taking a step.

At a routine checkup, his doctor wasn’t very happy with him ignoring his diabetes. His doctor told him that his blood glucose was dangerously erratic. From that time on, he became meticulous with managing his diabetes. He started using an insulin pump and other expensive technologies that he thought could help him. But despite all his efforts, Bryan’s health continued to decline, and the pain became more devastating. Despite his eye doctor’s best efforts, Bryan’s macular degeneration was not improving.

 

A solution called D’OXYVA

Bryan decided to do some research on his own. He remembered a patient he was sitting beside in the clinic talking about a product he had had success with. The product was called D’OXYVA.

From his research, he found out that microcirculatory dysfunction renders the diabetic foot unable to mount a vasodilatory response under conditions of stress, such as injury, and makes it functionally ischemic, even in the presence of satisfactory blood flow under normal conditions. Therefore, improving microcirculation to his feet would help with pain management and avoid further nerve damage.

 

D’OXYVA is noninvasive and uses an FDA-approved pharmaceutical-grade CO2. Additionally, it is a clinically validated blood flow and nerve stimulant for people suffering from neuropathy. In various clinical trials, D’OXYVA has been validated and demonstrated above-average results in improving a host of physiological functions at the same time.

 

It’s never too late to start a new journey

“I started off with their pro health set, and strictly followed twice a day D’OXYVA therapy as advised by their therapy expert after requesting for a customized treatment plan. They were very accommodating and professional. After 6 weeks, not only did the product help ease the pain, it got rid of the numbness. Plus, it didn’t cause side effects. My eye doctor also said he sees improvement in my vision,” said Bryan.

Now, Bryan and his wife are both in continuous D’OXYVA therapy as they found out that D’OXYVA, due to its microcirculatory enhancement capability, can help her with her varicose veins.

“I can’t wait to see how I will improve more after a few more months of using D’OXYVA,” Bryan said. He feels a new sense of vitality. He is now back on his feet, living free from the pain of diabetic neuropathy, and has better control of his blood sugar than he has ever had. He and his wife are looking forward to enjoying an active retirement full of exciting adventures and activities, including spending more time with their children and grandchildren.

“I see a new life and a new hope out there for you and for everyone who is experiencing the same,” said Bryan.

HOW D’OXYVA CAN HELP?

D’OXYVA® (deoxyhemoglobin vasodilator) is a novel, clinically validated blood flow and nerve stimulant for people suffering from neuropathy. In various clinical trials, D’OXYVA has validated leading independent research results and demonstrated above-average results in improving a host of physiological functions at the same time.

Subjects suffering from high blood sugar have reported neuropathy pain relief minutes after D’OXYVA was administered and long-term blood sugar level improvements in just a few weeks.

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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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Circularity Enters Talks to Close Institutional Financing Round, Announces Phase 3 Clinical Research and Human Trials of Diabetic Foot Ulcer Treatment and Microcirculation at Multiple Sites in Seven Countries

Published in PRWeb

Los Angeles, CA May 8, 2019.

Circularity Healthcare is emerging from a successful conference on Microcirculation in Maastricht, the Netherlands, organized by the European Society for Microcirculation (ESM-EVBO.) The company secured multiple new high-quality research projects that are planned to start in the near future in the United States, Canada, France, Germany, Holland, Sweden, and Hungary. In addition, management secured several high-profile commercial deals at the event, including one of the top equine groups in Europe.

The new studies will demonstrate the effectiveness of Circularity’s D’OXYVA (deoxyhemoglobin vasodilator) device. D’OXYVA is a novel non-invasive transdermal (over-the-skin) technology, which is the leader in the field of microcirculation and microvascular therapy in terms of the depth and breadth of the clinical evidence obtained by Circularity over the past six years. The clinical work has demonstrated outsized benefits results, laying the groundwork for a broad range of existing and potential commercial applications.

Prof. Ito Puruhito presents the Efficacy of Transdermal CO2 administration using D’OXYVA medical device to treat diabetic foot ulcers during a lunch symposium sponsored by Circularity Healthcare.
 

The company also announced at the Microcirculation event that it has recently appointed a leading global clinical research organization (CRO) called the Professional Education and Research Institute, Inc. (PERI) to launch a phase 3 human clinical trial. The trial will be performed under the leadership of Prof. David G. Armstrong, a world renowned expert in diabetic foot classification, treatments, and limb salvage. Dr. Armstrong has assembled an expert team with his colleagues at MIT, Yale, Harvard, and other top global research institutions to carry out the clinical trial at multiple sites, with the goal of obtaining FDA approval for applying D’OXYVA to treat and close diabetic foot ulcers.

“I look forward to this opportunity to conduct highly important and truly groundbreaking research with distinguished scientists. Our company’s institutional funding round under negotiations with a number of large private equity and corporate venture capital funds is focused around financing this critical new research, as well as translating our existing results into general practice at the bedside and in-home health care,” stated Circularity CEO, Norbert Kiss. “We may end up with a larger funding round than originally planned, sourced from multiple funds. This can only be a benefit, as it will provide additional resources for our teams to carry out Circularity’s mission to transform the delivery of critical health care with real measurable results to multiple massive patient populations that are currently underserved and in need of what D’OXYVA can provide.”

Prof. Ito Puruhito standing beside his presentation poster gallery.

Circularity’s Business Development Officer and CFO, Dr. Paul Kirkitelos added, “All the latest scientific evidence in microcirculation is pointing to the need for the underlying benefits D’OXYVA is already delivering to patients on a regular basis. Our path forward is to collect additional data to support the applications we have already studied and bring it to the scientific, medical, and consumer communities for the benefit of millions of diabetics suffering from chronic wounds and amputations with a high mortality rate.” 

Circularity Healthcare’s presence at the latest 3rd Joint International Microcirculation – ESM-EVBO 2019 – Conference in Maastricht, The Netherlands was a success. “Attending this kind of event is a great way to get top professionals in the Microcirculation scientific and medical field discover Circularity’s mission, giving people opportunity to interact with our brand which definitely impacts customer acquisition rates positively. It was also a great platform to build many relationships. Such distinguished long-term relationships are especially helpful as these connections can be the first step to improving our access both to repeat and new customers in a variety of markets,” said Jennifer Boadilla-Pelaez, Circularity’s Senior Sales and Marketing Manager and Creative Director.

Maastricht City Hall dinner function

Prof. Ito Puruhito said during his presentation at the event, “I am supporting the adoption of D’OXYVA in the university and hospitals in Surabaya and across Indonesia to benefit as many of our people as possible.”

Download Prof. Puruhito’s presentation delivered at the conference and get access to additional free educational material. (Warning: images of open wounds are included.) You can watch the 15-minute video recording of the presentation by simply registering your email, name, and occupation at this link.

Advertisement banners at the event.

About Circularity Healthcare

Circularity Healthcare, LLC, headquartered in Los Angeles, California in the U.S., is an emerging world leader in proprietary circulatory health and noninvasive delivery technologies, committed to helping significantly improve lives 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 pursuing regulatory approvals worldwide for device usage as a treatment of disease states related to cardiovascular and microcirculatory blood flow, immunological and autonomic nervous system disorders.

 

About ESM (European Society for Microcirculation)

The European Society for Microcirculation was founded in Hamburg in 1960 following a first meeting of interested scientists in Lund, Sweden in 1959, and now has 500-600 regular members. The aims of the Society are to advance understanding of the microcirculation by bringing together clinicians and scientists from a wide range of specialists, but including physiology, vascular biology, genetics and biophysics.

Since 1980, the Society has its own journal, the Journal of Vascular Research, an international publication of growing impact, through which the worldwide scientific community is informed of the Society’s endeavors.

 

About EVBO (European Vascular Biology Organization)

EVBO was launched in 2006, after discussion between European vascular biologists who recognized that there is a need for a democratic society to provide a united focus and forum for vascular biologists in Europe, primarily by organizing conferences but also by maintaining and enhancing an interactive network of researchers; evolving from the experience of the previous European Vascular Biology Association and building on the achievements of the FP6 European Vascular Genomics Network (EVGN).

 

About Professional Education and Research Institute, Inc. (PERI)

Professional Education and Research Institute (PERI), a global clinical research organization, was established in 2005 as a premier CRO with a goal to work closely with our sponsors throughout the world to manage Phase I through IV clinical trials in the most efficient and cost effective manner possible, while maintaining the highest standards in good clinical practice and human protection.

PERI offers top-quality facilities with a staff including regulatory and pharmacovigilance specialists, clinical research coordinators, as well as specialists in statistical analysis and data management.

 

 

 

For more information, please visit http://www.circularityhealthcare.com or http://www.doxyva.com or doctors (Rx only) visit http://www.doxyvaforwound.com and send your general inquiries via the Contact Us page. For specific inquiries contact Circularity Customer Care at info@doxyva.com info@circularityhealthcare.com or by phone toll free at 1-855-5DOXYVA or at 1-626-244-8090.

 

Forward-Looking Information

This press release may contain forward-looking information. This includes, or may be based upon, estimates, forecasts and statements as to management’s expectations with respect to, among other things, the quality of the products of Circularity Healthcare, LLC, its resources, progress in development, demand, and market outlook for non-invasive transdermal delivery medical devices. Forward-looking information is based on the opinions and estimates of management at the date the information is given and is subject to a variety of risks and uncertainties that could cause actual events or results to differ materially from those initially projected. These factors include the inherent risks involved in the launch of a new medical device, innovation and market acceptance uncertainties, fluctuating components and other advanced material prices, new federal or state governmental regulations, the possibility of project cost overruns or unanticipated costs and expenses, uncertainties relating to the availability and costs of financing needed in the future and other factors. The forward-looking information contained herein is given as of the date hereof and Circularity Healthcare, LLC assumes no responsibility to update or revise such information to reflect new events or circumstances, except as required by law. Circularity Healthcare, LLC makes no representations or warranties as to the accuracy or completeness of this press release and shall have no liability for any representations (expressed or implied) for any statement made herein, or for any omission from this press release.

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How does transdermal non-invasive CO2 infusion at the thumb cause improved blood circulation and cellular O2 levels in the foot?

How does transdermal non-invasive CO2 infusion at the thumb cause improved blood circulation and cellular O2 levels in the foot?

ABOUT THE AUTHOR

Judy Delp Ph.D.

Job Description

Professor of Biomedical Sciences

 

Education

B.S. Rockhurst University, Kansas City, Missouri

Ph.D. University of Missouri

 

Memberships

American Physiological Society

American Microcirculatory Society

American Heart Association

Toriyama et al.17 studied the effect of CO2 bathing in 83 limbs with critical ischemia and achieved limb salvage in 83% without surgery. They concluded that peripheral vasodilation from CO2 bathing resulted from an increased parasympathetic and decreased sympathetic activity. In the current study, treatment with transdermal CO2 in a localized area produced a sustained, remote vasodilation, and a lowering of systemic blood pressure.
 
These findings share some similarity with the hemodynamic changes that occur following an acute bout of exercise, in which both neural and vascular components contribute to a sustained decrease in vascular resistance and blood pressure that persists after cessation of exercise18. In the current study, the period of sustained vasodilation seen in response to transdermal CO2 was heightened in diabetic patients.
 
Interestingly, in hypertensive individuals, the period of post-exercise hypotension is of greater magnitude and duration as compared to that of normotensive individuals 18, 19. Paradoxically, the current findings in diabetic patients exposed to transdermal CO2 as well as previous findings in hypertensive patients post-exercise, imply that sensitivity to signals that mediate these cardiovascular responses increases in patients with pre-existing cardiovascular dysfunction19.
 
A sustained decrease in systolic blood pressure occurs post-exercise and here, following application of transdermal CO2, suggesting that neural mechanisms contribute to the observed reduction in systemic vascular resistance. The roles of efferent sympathetic nerve activity18-20, afferent nerve activity from muscle 21-24, and the baroreceptor reflex20, 23 in mediating post-exercise hypotension remain controversial.
 
Neural mechanism(s) could contribute to changes in skin SPP and systolic blood pressure induced by exposure to transdermal CO2. Future studies will need to monitor heart rate, heart rate variability, and sympathetic nerve activity during and after transdermal CO2 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.
 
Vascular conductance increases in both active muscle and inactive vascular beds following a bout of dynamic exercise 25, 26, suggesting that circulating factors contribute to this period of sustained systemic vasodilation. Vasodilation occuring independently of neural regulation constitutes more than 50% of the increase in systemic vascular conductance that occurs post-exercise; however, the mechanisms that underlie the post-exercise vasodilation have remained elusive.
 
Studies that have employed blockade of nitric oxide or evaluation of circulating nitric oxide metabolites have shown that the post-exercise vasodilatory response does not rely on circulating nitric oxide availability27, 28. A recent study by New and colleagues28 indicates that the nadir of post-exercise hypotension coincides with the peak of appearance of lipid hydroperoxides in venous blood, suggesting that reactive oxygen species with known vasodilatory properties29-32 contribute to the exercise-induced decrease in systemic vascular resistance. In the current study, transdermal CO2 was applied to the thumb, and a significant increase in SPP was measured at the toe.
 
Thus, a similar circulating vasodilatory stimulus may contribute to the remote, sustained vasodilation created by local transdermal application of CO2. Further investigations will need to focus on the identification of the mechanisms involved in both the local and remote factors that contribute to the sustained hemodynamic changes produced by exposure of the skin to CO2.
 
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 myocardium33-35, brain36, and kidney37, 38.
 
Although shown to be effective in various clinical and pre-clinical models 34, 35, 38-40, 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 conditioning38, 39, 41-43.
 
Basalay et al.41 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. In contrast, application of remote ischemic conditioning after myocardial ischemia also afforded protection against infarction, but was not altered by vagotomy or peripheral denervation41.
 
Remote ischemic conditioning has also been demonstrated to improve perfusion of transplanted kidneys, suggesting that remote conditioning confers protection that does not rely on intact neural circuitry38. Recently, Michelsen and colleagues42 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, possibly acting on opioid receptors, contributes to the cardioprotective effects of ischemic and exercise preconditioning.
 
Other reports in the literature have also shown evidence of a humoral substances that mediate protection against ischemia when remote ischemic conditioning is applied; however, these substance(s) remain to be identified. Application of transdermal CO2 produces a remote vasodilation that may be mediated through release of a circulating humoral agent.
 
Future investigations will need to focus on assessment of plasma samples during and following transdermal CO2 application.
This pilot study demonstrated an increase in measures of remote skin microvascular function with D’OXYVA, a simple commercially-available device to deliver transdermal CO2. The effects of the treatment were evident at all periods up to and including the last test period, 240 minutes post-exposure.
 
Although the sample size was small in this study, a clear increase in SPP and SPP/SBP ratio and a decrease in SBP and DBP continued for 4 hours post-treatment. The differences in skin perfusion and blood pressure responses detected between diabetic and non-diabetic subjects will require further examination in larger studies.
 
Click below to access Prof. Judy Delp’s Presentation on Transdermal Delivery of Carbon Dioxide Boosts Microcirculation.
 

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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“People are dying”: Diabetics rationing insulin amid rising drug prices

Drug manufacturers were grilled Wednesday about the skyrocketing price of insulin, which has doubled in the last five years and led some patients to ration the life-saving drug. One study finds the underuse of insulin could affect nearly 40 million people with diabetes by 2030.

“Nobody cared or nobody understood that without this next vial of insulin, I wouldn’t live to see another week,” said 28-year-old Kristen Whitney Daniels.

She started rationing her insulin after she was kicked off her parents’ insurance plan two years ago.

“I can’t really explain how isolating and how terrifying it is,” she said.

She’s now a patient at the Yale Diabetes Center, where a recent Journal of American Medical Association study found one in four patients reported “cost-related underuse.” Dr. Kasia Lipska treats patients at the clinic, and was the study’s lead author. She testified on Capitol Hill last week.

  • Woman says her son couldn’t afford his insulin – now he’s dead
  • Eli Lilly rolling out half-price insulin. Diabetics say it’s not enough

“This vial of insulin cost just $21 when it first came on the market in 1996. It now costs $275,” she said.

Some drug makers are already reacting to the outrage. On Wednesday, Sanofi announced it will cut the price of insulin for uninsured patients and those who pay cash to $99 per month. But that doesn’t eliminate advocate concerns.

“People are dying from lack of access to a drug that has been around for almost a century. I think it’s unconscionable,” Lipska said.

Insulin manufacturers told CBS News they’ve taken steps to address prices, including offering free medication to people who quality.

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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Circularity Healthcare Presenting D’OXYVA Diabetic Wound Healing Microcirculation Therapy Clinical Evidence and Sponsoring the 3rd International Microcirculation Conference – ESM-EVBO 2019

It is with our great pleasure to announce that we were invited by the organizers to participate in the 3rd joint ESM-EVBO 2019 and become a sponsor.

The 2019 ESM-EVBO (European Society for Microcirculation – European Vascular Biology Organization) Conference will be held on April 15-18 and hosted at the MECC in Maastricht, The Netherlands.

The conference focuses on advancing scientific research and medicine in all areas of vascular biology/medicine. Biennially, the ESM-EVBO hosts a four-day conference, where vascular enthusiasts from biology, preclinical and clinical research groups, and opinion leaders gather to share new fundamental scientific insights and current pre-clinical advances. Its network now has over 500 members worldwide, including representation in over 30 countries.

Besides being accepted into the poster sessions, Circularity is sponsoring the international symposium on Microcirculation.

Prof. Ito Puruhito, a distinguished thoracic vascular surgeon at Airlangga University, in Surabaya, Indonesia has been conducting several successful human clinical studies with D’OXYVA at the university over the past few years, and he is presenting some of his latest clinical evidence on diabetic foot ulcer treatment with D’OXYVA on April 17, 2019: http://esm-evbo2019.org/program/lunch-symposium/.

Want to stay updated on this event and what will happen next? Register your email for free now and follow the news about groundbreaking health discoveries!

About ESM (European Society for Microcirculation)

The European Society for Microcirculation was founded in Hamburg in 1960 following a first meeting of interested scientists in Lund, Sweden in 1959, and now has 500-600 regular members. The aims of the Society are to advance understanding of the microcirculation by bringing together clinicians and scientists from a wide range of specialists, but including physiology, vascular biology, genetics and biophysics.

Since 1980, the Society has its own journal, the Journal of Vascular Research, an international publication of growing impact, through which the world wide scientific community is informed of the Society’s endeavors.

About EVBO (European Vascular Biology Organization)

EVBO was launched in 2006, after discussion between European vascular biologists who recognized that there is a need for a democratic society to provide a united focus and forum for vascular biologists in Europe, primarily by organizing conferences but also by maintaining and enhancing an interactive network of researchers; evolving from the experience of the previous European Vascular Biology Association and building on the achievements of the FP6 European Vascular Genomics Network (EVGN).

 

About Circularity Healthcare

Circularity Healthcare, LLC, headquartered in Los Angeles, California in the U.S., is an emerging world leader in proprietary circulatory health and noninvasive delivery technologies, committed to helping significantly improve lives 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 pursuing regulatory approvals worldwide for device usage as a treatment of disease states related to cardiovascular and microcirculatory blood flow, immunological and autonomic nervous system disorders.

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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Have you heard of Tere’s inspiring diabetic story?

“My Doctor told me I have less than a year to live if I won’t let them amputate my leg, but I didn’t let them . . . here’s how I am still alive now!”

When doctors initially told 60-year-old Theresa “Tere” Schaufer that she had diabetes, she went into denial for 20 years.

“I was diagnosed with diabetes 20 years ago, and only when my doctor told me that they needed to cut my leg, did I realize that my diabetes was serious,” she says.

 

A major contributing factor

“Doctors told me the only way to survive this fight was to amputate my leg,” Schaufer says.  

She acknowledges that she had lived an unhealthy lifestyle for many years. Working in a restaurant as a cashier, she did very little exercise, ate fast food and drank sodas on a regular basis.

“If the doctor tells you you’re a diabetic, don’t ignore it. Don’t get to where I am. The sooner you accept things, the better it is for your health.”

Only after her doctor advised amputation did she realize the seriousness of her situation. Schaufer’s lifestyle had a hugely negative impact on controlling her diabetes. 

 

It was very painful!

Schaufer had puss from underneath her foot and necrotic toe. “After the doctor examined my foot, it was like decaying,” she says. “I couldn’t handle the pain. It was excruciating!” She was given less than a year to live because of her poor lifestyle.

 

I started to accept the situation.

Schaufer finally accepted her fate as a diabetic after the doctor told her that her leg would have to be amputated.

“I saw it coming. The pain was terrible. I could no longer handle it. At this point I was prepared; whatever came had to be.”

 

Unexpected turn of events

“I was browsing a support page I found on the web and read about a colleague’s experience with the microcirculation therapy she had tried. She noted that it had an amazing effect on her diabetic foot ulcer,” Schaufer says.

Right there on the support page, the woman raved, “There is this new technology you can buy online, D’OXYVA, which was voted one of the Top 10 Diabetes Care Solution Providers 2018! I didn’t have to amputate my leg because of this amazing product. In just four weeks, I can see my diabetic foot ulcer improving!”

“I read these words, and it gave me the hope I’d been praying for,” noted Schaufer.

She only had a month before her scheduled amputation, and without hesitation, she used the remaining days to try out D’OXYVA. She ordered the product online and closely collaborated with their in-house support.

“I was under D’OXYVA therapy for one month, taking it twice a day, once in the morning and once before bed as advised. It was very easy to use and non-invasive. In the first few days, I was skeptical as I wasn’t seeing any improvements, but I continued anyway and followed their suggested therapy guide,” Schaufer explains.

 

Thankful for D’OXYVA

When it was time for her to go back to her doctor and give her consent to amputate, her doctor was shocked to see her leg.

“What happened?” Those were the exact words my doctor asked upon seeing my leg after only a month. “Your wounds seemed to be healing from the inside,” my doctor said.

After a thorough check-up and the usual diagnostic check of my foot’s PI (perfusion index), he said the words that I never expected to hear. “We don’t need to amputate your leg anymore, but you need to continue whatever you’ve been doing for the past month.”

I then introduced him to D’OXYVA, and he was amazed by how this product had saved me.

 

Helping others

“I’m on my third month of D’OXYVA therapy, and it does amazing things for my health! I don’t think I have thanked D’OXYVA enough for this chance to live longer. I wouldn’t have the outlook on life that I have now,” Schaufer continues cheerfully.    

She is now also leading a healthy life. “This changed how I live my life, and I will continue sharing my experience as much as I can to help others.”

Schaufer often spends time with other “to-be-amputees” struggling to deal with their situation. “God gave me my situation to help others,” she maintains.

One of the ladies she counselled remarked how Schaufer had helped her tremendously. “She told me that I gave her her life back,” Schaufer says, breaking into tears.

“I’m in a way thankful for what I have been through with my diabetes because, without it, I wouldn’t have stumbled across my strength and my ability to help others.”

HOW CAN D’OXYVA 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.