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The microcirculation is importantly involved in a variety of pathological conditions

The microcirculation is importantly involved in a variety of pathological conditions

Only recently, technology has been sufficient to assess microcirculatory function in intact humans. As a result, it is becoming apparent that the microcirculation is importantly involved in a variety of pathological conditions, and that microvascular dysfunction may herald, either as a marker or as a mechanism, the development of cardiovascular disease (CVD).

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This review will discuss the growing recognition that the microcirculation contributes to the development of atherosclerotic CVD, review regulation of the coronary microcirculation in humans, and discuss potential novel functions of the microcirculation, beyond regulating perfusion that might explain the intimate link to CVD.

Growing recognition that microcirculatory abnormalities contribute to cardiac prognosis supports the need for a more direct and focused understanding of how microvascular function is regulated in humans.

A number of conditions are closely associated with microvascular dysfunction. Diabetes mellitus manifests multiorgan pathology resulting from microvascular dysfunction. Nahser et al17 showed lower CFR and reduced metabolic dilation in diabetes mellitus, signs of impaired microvascular function. Di Carli et al18 expanded this observation by showing normal baseline flow but similarly reduced endothelium-dependent and endothelium-independent (dilation to adenosine) microvascular dilator capacity in young subjects with either type I or type II diabetes mellitus. Reduced dilation to adenosine persisted after controlling for duration of diabetes mellitus, insulin treatment, and autonomic neuropathy.18

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

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

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


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

Figure 1

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Summary and conclusion

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


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

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

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

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Improving Microcirculation for Weight Reduction in Obesity

weight loss obesity

Obesity, by definition, is a Body Mass Index (BMI) of 30 kg per square meter or greater. The prevalence of obesity has increased and is now thought to affect more than one third of the adult population.[1] Recent studies have shown that obesity has an adverse effect on microcirculation and is an important risk factor for the development of many health problems, such as metabolic syndrome (insulin resistance, elevated lipid levels, high blood pressure and increased abdominal girth), ischemic heart disease, heart failure, and other cardiovascular diseases.[2]

The following case demonstrates how improving microcirculation can help with weight reduction in obese people.

Brenda V was a 39-year-old white female patient with severe obesity and a BMI of 52.4 kilograms per square meter. Brenda’s past medical history was significant because it included a history of morbid obesity, high cholesterol, high blood pressure, diabetes mellitus, gout, and depression. She revealed that she could only walk for one block without severe shortness of breath and had to sleep on 2 pillows at night.

On physical examination, her weight was 340 pounds, and her height was 5 feet, 1 inch. Her blood pressure was 180/105, and her cardiovascular exam revealed severe pitting edema of both legs.

Brenda’s abdomen was distended and morbidly obese with decreased bowel sounds. Her laboratory exam showed a hemoglobin A1C level of 12.5% (normal is less than 5.7%) and a triglyceride level of 600 mg/dl (normal is less than 150 mg/dl).

Brenda was put on a regimen of diet, increased exercise, and the use of the peripheral deoxyhemoglobin vasodilator D’OXYVA[3] for 5 minutes per day, 5 times a week, for a 3 month period. After the regular applications, she had the following improvements:

  • Increased physical activity
  • Decreased blood sugar levels
  • Decreased blood pressure
  • Decreased triglyceride levels
  • Decreased HgbA1C levels
  • Increased cardiac function
  • Increased endurance
  • Increased physical fitness
  • Decreased depression
  • Massively decreased weight
  • Increased mobility


How Does Obesity Affect Microcirculation?

Microcirculation[4] refers to the body’s smallest branching blood vessels (arterioles, venules, and capillaries with internal diameters less than 100 microns) that supply oxygen to and remove wastes products from the body’s tissues.

Microcirculation responds to changes in metabolic demands or sympathetic nervous system activation by either expanding or contracting to increase or decrease perfusion levels.

Early in the course of obesity, dysfunctional changes begin to appear in microcirculatory endothelial lining cells”.

These changes are caused by oxidative stress and inflammation of the microcirculation[5] and are now thought to lead to both insulin resistance and hypertension.


Obesity has been found to lead to microcirculatory dysfunction, which causes severe health problems, such as metabolic syndrome, diabetes mellitus and various cardiovascular diseases. Reducing obesity through a program of strict dietary control, increased exercise and the use of D’OXYVA to enhance microcirculation can significantly improve general health and reduce the risk of potentially lethal health complications.



D’OXYVA is the only fully noninvasive, completely painless over-the-skin microcirculatory solution that has been validated 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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Did you know when used in a regimen, DOXYVA users have reported a number of health and cosmetic benefits?

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

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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


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Why Use D'OXYVA?

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

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

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

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

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Are Veiny Arms Really a Sign You’re Super Fit?

D'OXYVA | Cardiovascular, Diabetes Care, Pain Reliever in CA.

You’ve seen the crazy photo of cyclist Pawel Poljanski’s insane leg veins after his 70-hour Tour de France pump. And the Rock boasts a pretty impressive bicep vein, too. Plus, go to any bodybuilding competition, and you’ll see a whole slew of guys with impressive vascularity as well.

What all these veiny guys have in common is that they are in tremendous shape. But is vascularity really a sign of superb fitness?First, let’s take a look at the reason your veins pop in the first place.

Your arteries carry blood away from your heart to the tissues throughout your body, like your muscles. Your veins—which have thin walls and dilate easily—pump the blood back toward your heart.

“The venous outflow is slower than arterial inflow, causing a back-up of venous blood causing higher pressure in the veins,” says Doug McGuff, M.D., author of Body By Science. That increases pressure causes the veins to “pop” out. That’s the pump you get.

But what you’re doing also plays a role in the pop, too.

“Swelling in the muscles pushes the veins out to the surface,” says Spencer Nadolsky, D.O., author of The Fat Loss Prescription. “Your muscles swell when working out and push the veins closer to the surface of your skin, which makes them more pronounced.”

You probably notice your veins popping more during weight lifting than when you’re simply taking a walk or doing other kinds of light cardio.

In general, higher-rep weight lifting with fast concentric movements—say, the part of a biceps curl when you bring the weight up toward your arm—would trigger the biggest pump, says Dr. Nadolsky.

“High intensity interval work can produce this effect as well,” says Dr. McGuff. “Muscular loading and fatigue drive arterial inflow into the muscle, so exercise that triggers this will produce venous engorgement.”

Okay, so your veins tend to pop when you’re working out, but does how veiny you get actually depend on how fit you are? Well, sort of.

The leaner you are—meaning, the less subcutaneous fat you have covering your muscles—the more pronounced your veins will look, says Dr. Nadolsy.

But it’s not just about being lean: Having low body fat along with upped muscle mass is the magic combination for veins that pop, even when you’re at rest. So in some ways, pronounced veins are an indirect sign of fitness.


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Did You Know That Cellulite Is Also A Microcirculatory Problem?

D'OXYVA | Cardiovascular, Diabetes Care, Pain Reliever in CA.

The presence of cellulite is an aesthetically unacceptable cosmetic problem for most post-adolescent women. It is largely observed in the gluteal-fermoral regions with its ‘orange-peel’ or ‘cottage cheese’ appearance. It is not specific to overweight women although increased adipogenicity will exacerbate the condition. It is a complex problem involving the microcirculatory system and lymphatics, the extracellular matrix and the presence of excess subcutaneous fat that bulges into the dermis. It has been described as a normal condition that maximizes subcutaneous fat retention to ensure adequate caloric availability for pregnancy and lactation. Differences in the fibrous septae architecture that compartmentalize the adipose tissue have recently been reported in women with cellulite compared with men.

Weight loss has been reported to improve the cellulite severity by surface topography measures although in obese subject’s skin dimpling does not seem to change appreciably. However, histological analysis suggests that fat globules retract out of the dermis with weight loss. Cellulite has been treated with massage which decreases tissue oedema but it is also likely to have its effects at the cellular level by stimulating fibroblast (and keratinocyte) activity while decreasing adipocyte activity. In addition to massage, effective topical creams with a variety of agents were used to ameliorate the condition.

Nevertheless, only a few studies are reported in the scientific literature. Xanthines, botanicals, fragrances and ligands for the retinoid and peroxisomal proliferator-activated receptors appear to be giving some benefit. Reducing adipogenesis and increasing thermogenesis appear to be primary routes and also improving the microcirculation and collagen synthesis. Many agents are being investigated for weight management in the supplement industry [hydroxycitrate, epigallocatechin gallate, conjugated linoleic acid (CLA), etc.] and some of these agents seem to be beneficial for the treatment of cellulite. In fact, CLA was proven to ameliorate the signs of cellulite. One product, Cellasene, containing a variety of botanicals and polyunsaturated fatty acids also appears to provide some relief from these symptoms. Although more work is needed, clearly these treatments do improve the appearance of skin in subjects with cellulite. It is quite possible, however, that synergies between both oral and topical routes may be the best intervention to ameliorate the signs and symptoms of cellulite.


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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D’OXYVA on cellulite and fat reduction

D'OXYVA | Cardiovascular, Diabetes Care, Pain Reliever in CA.

Cellulite is a symptom of abnormal fat cell growth and an inflammatory response under the skin’s dermis layer. The skin’s dermis layer is known as the living skin, and it is composed of nerves, elastin, fats, blood vessels, and collagen fibers, which provide elasticity. With age, our skin produces less collagen, causing the skin to look wrinkled and saggy. Also, fat cell growth or expansion within the well-delimited hypodermis skin layers compromise effective O2 supply from the vasculature (microcirculation) and push the outer skin layers up while the fibrous septa pull it down. This physical action, which is due to fat cell overgrowth, causes the skin to have an orange-peel and cottage-cheese appearance.

Our body’s physiological response to hypoxia is well known. Hypoxia provokes an inflammatory response associated with the overproduction of adipokines, interleukins, macrophages recruitment, and increased glucose sensitivity (GLUT-1 expression). In other words, when cellulite appears in our skin, we have two major problems: disruption of the dermis skin layer architecture due to abnormal fat cell growth and an inflammation response caused by hypoxia. Substantial evidence suggests that hypoxia (low SpO2 ) is a protagonist in adipose physiology and in adverse bodily responses associated with obesity.

D’OXYVA gentle, super-saturated CO2 vapor causes instant artery microcirculation and venule dilation, thereby improving blood flow. By improving the skin layer’s blood flow, it allows our body to stimulate circulation, detoxify, balance, and increase O2 delivery. D’OXYVA® allows our body to self-heal, particularly by adjusting the fat cell microenvironment. As a result, fat cells decrease their growth rates through a reduction in glucose sensitivity and the promotion of catabolism. After D’OXYVA® administration, the inflammatory response decreases due to the elimination of the hypoxia state.

After adhering to a D’OXYVA® treatment plan, cellulite patients will find significant improvement in their skin’s appearance and feeling.


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 Big Pharma Is Struggling to Profit From the Obesity Epidemic

In a decades-long struggle to control her weight, Carolyn Mills joined the YMCA many times, signed up for the Jenny Craig diet program and tried fen-phen, the drug combination later found to damage heart valves. As her size yo-yoed down and back up, her health deteriorated.

She finally found the answer in a new class of medicines. Now, those drugs and changes to her diet have helped Mills cut her weight to 250 pounds (113 kilograms) from 300 pounds over the last six months. The drawback: her out-of-pocket expenses are almost $300 a month and may head higher. She says it’s worth the cost.


“Obesity haunts me,” said Mills, 62.

Mills highlights the difficulties big pharma faces as it seeks to profit from an epidemic that afflicts more than 600 million adults worldwide. Medicines like Novo Nordisk A/S’s Saxenda, the latest one used by the Boston resident, are safer and more effective than past treatments. Yet employers and insurers are reluctant to cover the drugs, meaning the cost often falls on patients’ shoulders, limiting the potential market.

Drugmakers such as Novartis AG, Novo and Sanofi are pushing ahead, testing even more advanced medicines they hope will deliver greater weight loss than the drugs available today. Once seen as a problem only in wealthier countries, obesity is on the rise in lower-income regions too, increasing the risks of diabetes, heart disease and cancer. That raises health costs and contributes to millions of deaths each year. More than a third of U.S. adults fall into that category.

“Given the public-health crisis around the world with obesity, if we can find a medicine that has strong efficacy and reasonable tolerability there’s no question there’s a very large market here and it would potentially have a big impact on health care,” said Vas Narasimhan, global head of drug development at Basel, Switzerland-based Novartis.

The industry faces hurdles over and above the lack of coverage. Modest weight-loss results and criticism of medicine as a way to treat obesity mean just 2 percent of excessively overweight people rely on drugs. The history in the field is also littered with failures, making some manufacturers leery.

In 2008, a Sanofi weight-loss drug was taken off the market in Europe amid concerns it could lead to depression and suicidal thoughts, while Pfizer Inc. and Merck & Co. ended obesity programs the same year. Those drugs were designed to suppress appetite by blocking the same brain receptor that makes marijuana smokers hungry.

“There’s a gold mine available,” said Ralph Abraham, a doctor at London Medical, a clinic in the U.K. capital that started a weight-management program incorporating Saxenda. “But it’s also been a graveyard in the past.”

Scientists are drawing lessons from treating a related disease: diabetes. Saxenda, which has a list price of more than $1,000 a month and has been sold in the U.S. for two years, has the same key ingredient as Novo’s diabetes medicine Victoza and works like a hormone the body produces naturally that regulates appetite.

Some doctors said they’re comfortable with Saxenda because they’ve been prescribing Victoza for years.
While Saxenda is relatively small today, its sales are forecast to climb to more than $1 billion within five years from about $240 million last year, according to estimates compiled by Bloomberg. Four other obesity drugs tracked by Datamonitor Healthcare—Contrave, Qsymia, Belviq and Xenical—accounted for just $280 million in sales in 2016. The global market for such drugs is projected to climb to about $24 billion in a decade from about $1 billion last year, London-based consulting firm Visiongain estimates.

The average weight loss of 5 percent to 10 percent that patients see with the existing drugs doesn’t “knock your socks off,” said Robert Eckel, a doctor and professor who focuses on obesity and diabetes at the University of Colorado. He said he’s only prescribed Saxenda “a couple of times because there are few people who are willing to pay that much for it.”

The next generation of medicines could work better.

Novartis has a treatment in mid-stage tests that could potentially help patients lose 10 percent to 15 percent of their weight, or even more, if trends seen in early studies continue, Narasimhan said. The company will decide how to proceed based on data due next year.

In the past “we could never thread the needle,” he said. “Now we have more mechanisms that we can take forward.”

An experimental drug Novo is developing showed in early studies it can achieve weight loss of as much as 14 percent, the company said last month. Combining it with other medicines could ultimately make it even more potent, leading to a possible reduction of more than 20 percent, Chief Science Officer Mads Krogsgaard Thomsen said in an interview.

Obese patients sometimes stop taking the drugs and regain weight when they see results plateau, and new and improved medicines may encourage people to stick with them, Thomsen said. Weight loss approaching 15 percent or 20 percent “would be a major breakthrough,” said Eric Ravussin, a specialist at Pennington Biomedical Research Center in Louisiana.

Sanofi is evaluating a drug in obese patients with diabetes that has potential to move closer to the results of surgery, said Stefan Oelrich, head of its diabetes unit. People who opt for bariatric surgery can lose more than 30 percent of excess body weight within six months. AstraZeneca Plc at the same time said it’s developing a diabetes treatment that may have potential in obesity and other metabolic diseases.

Louis Aronne, a doctor at Weill-Cornell Medicine in New York, compared obesity to hypertension, which was once regarded as a lifestyle issue and is now a field with scores of drugs. He predicted that every major medical institution would have a program focused on the disease within a decade.

Read more on the obesity epidemic: QuickTake

Several insurers in Canada have picked up Saxenda, and health authorities in the United Arab Emirates have agreed to pay for some patients in public hospitals, according to Novo. In the U.S., legislation was re-introduced in April aimed partly at improving access to weight-loss medicines for Medicare beneficiaries. It’s hard to predict how policies will play out as Republicans seek to overhaul the Affordable Care Act, but the Obesity Society, a research group, called the proposal a key step in tackling a disease that contributes to $200 billion a year in health costs.

Doctors are gaining a better understanding of the biology of the condition, increasingly seeing obesity as a disease, while there are signs that more insurers are covering medication, said Caroline Apovian, the Boston Medical Center specialist who treated Mills.

“We’ve learned a lot,” she said. “The treatment of obesity will prevent many other serious disorders that in the long term will save us money.”

Mills, an operations manager at a dental practice, said she’s swimming and trying to be more active to build on the progress she’s made with drugs.

“We’re reaching the tipping point with the percentage of people who are so overweight,” she said. “It’s my hope that the tide is changing and people are understanding it’s not just a matter of pushing yourself away from the table.”


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D'OXYVA | Cardiovascular, Diabetes Care, Pain Reliever in CA.

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.


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.


· 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.


· 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.


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.


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.


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.


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

D'OXYVA | Cardiovascular, Diabetes Care, Pain Reliever in CA.

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.

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.

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.


  • 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.

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.

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.

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.