Microcirculation

Microcirculation and diabetes

Hepatic microcirculatory dysfunction during cholestatic liver injury in rats

Coronary microcirculatory vasodilator function in relation to risk factors among patients without obstructive coronary disease and low to intermediate Framingham score

Microcirculation

The Circle of Life:
Heart disease is a killer. In fact, it is the number one killer in North America taking another life every 33 seconds!
Thousands of people with great cholesterol readings continue to die every year from heart disease. Women need to also pay close attention, as heart disease should not be considered just a “man’s disease”. In 1996, 52.7% of all female deaths were due to heart disease, compared to 47.3% for men. That is more deaths due to compromised circulation than the next 16 causes of death combined.
An alarming 800,000 North Americans die each year from heart disease. And people don’t die due to high cholesterol ‘numbers’. They die from the disease process that prevents your trillions of cells from getting sufficiently nourished and cleansed.
Ensuring proper circulation is essential. Your life is literally dependent upon your circulation. The vast majority of the vital functions of circulation are done in the microcirculation network of capillaries; where some of these are so small; it takes 10 of them to equal the width of a single human hair. This is where the oxygen and nutrition is transferred to vital organs and tissues, and where CO2 (carbon dioxide) and other waste toxins are removed. This is possible because the membrane walls are so thin, this exchange can easily occur in a healthy system.
Basically your cardiovascular health is totally dependent upon how efficient the arteries to your heart are at delivering oxygen and nutrient enriched blood through the arteries, into the capillaries and then returning this to start the cycle over and over again.

Hypertension (High Blood Pressure)
One in four North Americans suffer from overt diagnosed cardiovascular disease, and that does not include all the individuals yet to be diagnosed. Over 50 million suffer from increased resistance within their circulatory system, particularly the arteries and microcirculation, with the result being the risks associated with increased blood pressure.
It is important to note that a disproportionately large amount of blood pressure resistance arises from within your microcirculation. The overall health of your cardiovascular system is greatly impacted by even the smallest capillary. It can become blocked and affect the blood flow to all parts of the human body. This is just one example of the cascading affect of high blood pressure.
Complacency is dangerous when it comes to heart disease for virtually all of us have elevated blood pressure readings throughout the day depending on our stress levels. So, as your heart pumps 100,000 times day, any improvement that can be accomplished in lowering blood pressure by increasing the diameter within the arteries and capillaries can pay big dividends in decreasing wear and tear on the heart and the entire cardiovascular system.

Diabetes mellitus (Sugar diabetes)
We all know someone with diabetes, which is not surprising since it is the fastest rising cause of death in America. New cases of diabetes pile up at a rate of 798,000 annually and contribute to the cause of many deaths indirectly as well; including heart disease, high blood pressure, stroke, blindness, kidney disease, amputations, dental disease, nervous system disease, infections, and others.
Improved microcirculation can help mitigate some of the short and long term side effects of diabetes, since this disease is directly linked to decreased efficiency of microcirculation. This can arise in some diabetics simply from an increase in capillary resistance early on in the disease process, further damaging local tissues and vital organs such as the kidneys, which are all dependent upon capillary blood flow to function.
Diabetes cases are projected to surge in the next few years. The University of Maryland, School of Medicine states that more than 258,000 residents are estimated to have diabetes, yet only 129,000 have been diagnosed with it. The impact of early intervention can’t be over-emphasized, educating a friend or family member can be a life saving pursuit that rewards you and them for a lifetime.

Glaucoma
As was stated before, the cardiovascular system reaches and affects all areas and functions of the body, your eyes are no exception. Glaucoma is a common condition that arises from increased pressure within the eye which has now also been linked to vascular changes in microcirculation.
It is important to remember the eye is the only readily assessable window to view circulatory and neurological health. When a physician examines your eye with an ophthalmoscope the life sustaining arteries and veins can be clearly observed along with actual nerves, providing vital information to gauge vascular health.

Microcirculation and Smokers:
Individuals that have become addicted to nicotine require more help to protect and offset the detrimental effects on their microcirculation. Nicotine stimulates the sympathetic nervous system, which can lead to vasoconstriction (narrowing) of arteries and increased resistance in arteries and capillaries. The sum effect is more work for the heart from increased blood pressure, at the same time that the body has less oxygen and more waste products to cope with as a direct effect of smoking.
Stopping smoking is a challenge even for those with strong wills, but until success is achieved, offsetting side effects by improving micro-circulation is a good investment in yourself or someone you love. It should be noted that smoking increases the risk of dying from heart disease by 140% to 240% even in those that smoke lightly and an incredible 350% for heavy smokers.
Part of the challenge of successfully kicking this life threatening habit comes down to brain chemistry and proper brain circulation is essential for optimal production of neurotransmitter messengers linked to the addictive cycle that smokers find themselves.

Microcirculation and Alcohol
When drinking alcohol, a certain degree of free radical damage occurs. The classic signs of changes in circulatory health in consumers of alcohol are clear with the overt redness of the cheeks and nose, and frequently the visible appearance of blood vessels on the surface of the face. Numerous chemical processes are required to detoxify the body from the metabolism (breakdown) of alcohol. Therefore as with all forms of the clearing of waste products from the body, optimal circulation and microcirculation should be actively sought and enhanced.

Microcirculation and Stress:
The effects of this constant exposure to stress are numerous and include lowered immune function and diminished blood flow. Thus, with increased stress, the tissues of your body are asked to cope with a heightened level of alertness or readiness, commonly known as the “fight or flight response”. As a result, your micro-circulation particular to vital organs is detrimentally altered.
Millions of us exist in this state of high demand for abundant delivery of nutrients and oxygen to sustain our rapid lifestyle, yet our body must deal with drought-like conditions when it comes to proper circulation.
When pursuing peak performance nourishing the body with sufficient nutrients and oxygen is key, yet without the highways and by-ways that take the form of arteries within your body, the supply center may be full, yet your tissues can literally starve awaiting life-sustaining circulation.

Microcirculation Facts:
There are some 18,000 miles of capillaries within the body.
Peripheral vascular disease is the leading cause of amputation in this country.
Colds hand and feet can be a warning sign of poor circulation.
Numbness and tingling in the arms and legs can point to a lack of microcirculation.
Raynaud’s phenomenon results from too much contraction within the circulation network.
Healthy capillaries are so small that red blood cells must pass through single file.
Capillaries are how your body nourishes the trillions of cells (that equal you).

Steps to Improve Your Circulation:
Eating a proper and healthy diet can be essential in providing your body and microcirculation with vitamins, nutrients and antioxidants. Regular exercise can also greatly improve blood flow and increase the immune response to stress. In addition to regular exercise and proper diet, the additional steps you can take to help improve your microcirculation can be relatively simple.
Traditional Chinese Medicine (TCM) herbals like LingZhi Medicinal Mushrooms, plus Cordyceps have all been clinically shown to help strengthen and enhance microcirculation. They also support immune function, acting as antioxidants and helping to fuel the body with oxygen and nutrition.
LingZhi studies have reported positive blood thinning effects, antioxidant properties with cardiac protective potential, blood pressure lowering, cholesterol lowering, and clot protective properties. Each of these findings supports the inclusion of Lingzhi into a microcirculation promoting protocol.
Similarly, ongoing Cordyceps research has demonstrated blood pressure lowering, vasodilating (blood vessel expanding), protection against heart ischemia (lack of oxygen) and blood clot formation. These study findings strongly support the role of Cordyceps as a tool in the arsenal to augment and support healthier microcirculation. These properties are in addition to Cordyceps anti-fatigue and anti-stress effects that have also been noted in the medical literature.                                     

This article comes from: 

http://www.ihealthcast.com/Conditions/Microcirculation/tabid/462/Default.aspx

Microcirculation and diabetes

Many late complications of diabetes stem from damage to the microcirculation Changes in the microvascular wall, haemodynamic control and circulating blood may all contribute to impairment of capillary transfer function although the relative importance of the various possible mechanisms is unclear. Early functional disturbance appears more responsive to optimal diabetic control than established disease, and as microangiopathy becomes clinically apparent organ tissue damage is compounded by secondary mechanisms. Until more is learnt of the biochemical and cellular basis of the component pathogenetic mechanisms optimal diabetic control early in the disease remains the sole available primary prevention strategy, although evidence is emerging that manipulation of microvascular haemodynamics may have therapeutic potential.

This article comes from:

http://bmb.oxfordjournals.org/cgi/content/abstract/45/1/206

Coronary microcirculatory vasodilator function in relation to risk factors among patients without obstructive coronary disease and low to intermediate Framingham score

Aims The study aim was to evaluate the relation between the Framingham risk score (FRS) and the presence of coronary risk factors to coronary microcirculatory vasodilator function in patients with early coronary atherosclerosis.

Methods and results We evaluated 1063 patients (age: 50 ± 12 years, 676 (64%) females) without significant narrowing (<30%) on coronary angiography who underwent invasive assessment of coronary endothelial function. Coronary blood flow (CBF) in response to the endothelium-dependent vasodilator acetylcholine was evaluated as well as the microvascular (endothelium-independent) coronary flow reserve (CFR) in response to intracoronary adenosine. Coronary blood flow and CFR were analysed in relation to the FRS and the presence of traditional and novel risk factors. The estimated 10 years risk in this group was 5.4 ± 5.2%. Higher FRS was associated with lower CBF in men (P = 0.008), and was a univariate predictor of lower CFR (P = 0.012) in all patients. Multivariable analysis identified a higher FRS (P < 0.001), female sex (P < 0.001) and a positive family history of coronary disease (P = 0.043) as independent predictors of reduced CFR.

Conclusion
In patients without obstructive coronary disease, a higher FRS was an independent predictor of reduced CFR. The current study provides insight into the relation between cardiac risk profile and coronary microcirculatory function, and suggests that impaired microcirculatory vasodilator function may be present even in patients with a low to intermediate Framingham score

Introduction
Atherosclerosis and coronary heart disease (CHD) are the leading causes of morbidity and mortality in developed countries.1 Conventional risk factors for the development of CHD were defined by investigators from Framingham, MA, almost 50 years ago,2 and were later codified into global risk scores.3,4 The aim of the more global cardiovascular risk assessment was to match the intensity of treatment with the level of risk.
However, despite the established utility of the Framingham risk score (FRS), it may have limitation in certain patient populations such as young adults and women, and its applicability in the early stages of coronary atherosclerosis is unclear.5–8 The importance of identifying these patients is underscored by the observations that the majority of acute coronary syndromes occurs in non-obstructive coronary atherosclerotic (vulnerable) plaques, and it is possible that the coronary microcirculatory function may have an important role in the early stages of the disease.9,10
Assessment of coronary microcirculatory vasomotor function and endothelial function in patients without obstructive coronary artery disease may allow the identification of patients in the early stages of coronary atherosclerosis and at risk for cardiovascular events.11–15 The concept that endothelial and microvascular

Methods:Patient selection
The study was approved by the Mayo Clinic Institutional Review Board, and informed consent was obtained from all participants. All consecutive 1063 patients [mean age: 50 ± 12 years, 676 (64%) females and 387 (36%) males] who were referred for the evaluation of coronary endothelial function between 17 December 2001 and 7 February 2008 were included. Patients were referred if they did not have significant coronary artery disease (<30% diameter stenosis) on diagnostic coronary angiography. Coronary angiography was performed after an overnight fast, and all vasoactive medications affecting cardiovascular haemodynamics were discontinued at least 48 h before the study.

Risk factors and laboratory parameters included in analysisIn addition to the 10-year estimated risk of CHD derived from the FRS, we recorded the following known coronary risk factors: (i) diabetes mellitus (patient history and/or need for insulin or oral hypoglycemic agents), (ii) hypercholesterolaemia (total serum cholesterol level >240 mg/dL or treatment with lipid-lowering drugs), (iii) systemic hypertension (arterial blood pressure >140/90 mmHg or the use of antihypertensive medication), (iv) family history of CHD [CHD in first-degree relatives <55 (male) or <65 (female) years of age], and (v) smoking history (previous or current cigarette smoking). Low to intermediate FRS was defined as lower than 20% 10-year risk.4 Additional measurements related to coronary risk also evaluated were: vascular disease (peripheral vascular narrowing diagnosed by physical examination and confirmed by an imaging test), mean arterial pressure (pre-procedure) at baseline, the body mass index (BMI), estimated glomerular filtration rate (eGFR) (using the MDRD formula), lipid profile, fasting glucose, and glycosylated haemoglobin. The homeostasis model assessment (HOMA) was used to estimate insulin sensitivity [calculated as (fasting glucose × 0.0555 × plasma insulin)/22.5]. Blood samples were also tested for highly sensitive C-reactive protein (hsCRP), plasma homocysteine, l-arginine and the plasma brain natriuretic protein (BNP).

Assessment of coronary vasomotor function
After diagnostic coronary angiography and exclusion of significant obstructive coronary artery disease (and if vasoactive medications were discontinued >48 h), coronary vasoreactivity was assessed as described previously.Intracoronary bolus injections of incremental doses (18–60 mcg) of adenosine were administered until maximal hyperaemia was achieved (or the highest dose was given) to evaluate endothelium-independent microvascular coronary flow reserve (CFR). Subsequently, to assess endothelium-dependent vasoreactivity, by assessing slightly larger vessels (>150 μm) which may have an effect on downstream blood flow and transmission of pressure to the microcirculation,the endothelium-dependent vasodilator acetylcholine (Ach) was selectively infused at increasing concentrations (10−6, 10−5, and 10−4 mol/L) into the left anterior descending coronary artery. Coronary artery diameter (CAD) and average peak velocity (APV) were measured, and coronary blood flow (CBF) was calculated after each infusion of Ach. Coronary artery diameter was measured off-line by an independent investigator. CBF was calculated as π(CAD/2)2 × (APV/2). Endothelium-dependent CBF was calculated as the ratio of CBF in response to Ach vs. baseline.

Statistical analysis
Continuous variables with no/mild skew were presented as mean ± SD; skewed measures as median and inter-quartile ranges. Discrete variables were summarized as frequencies and percentages. Comparisons were made between tertiles using one-way ANOVA for continuous variables with mild skewness, the Kruskal–Wallis rank-sum test for skewed and ordinal variables, and by the Pearson χ2 test for categorical variables.
Univariate associations between the FRS, risk factors and the endothelial function measures were assessed by the Spearman correlation coefficient or a rank-sum test. Linear regression models were used to assess the association between the FRS, other risk factors, and the vasomotor function measures. Box–Cox transformations were used for dependent and independent variables to comply with the assumption of multivariate normal data. Variables which were associated with the endpoint at a 0.15 significance level were chosen as model covariates. Multiple linear regression models were fit on each of five multiple imputation data sets; the parameter estimates were then combined and standard errors calculated using SAS (version 9.1.3, SAS Institute Inc., Cary, NC, USA). The partial effect size (henceforth called the ‘effect estimate’) of the independent continuous variables was scaled to reflect the expected change in the (untransformed) response between the first and third quartiles of the continuous variable.

Previous SectionNext SectionResults
For the analysis, 1063 patients were included, of which 676 (64%) were female. Baseline characteristics in all patients and by gender are shown in Table 1. Overall, women were older, and men had a higher FRS and majority were smokers. There were 174 patients without Framingham risk calculated (16%), 262 (25%) with a risk of 1–2%, 345 (32%) with a risk of 3–5%, 180 (17%) with a risk of 6–10%, 87 (8%) with a risk of 11–20%, and only 15 (1.4%) with a risk over 20% (although some more patients had diabetes

Discussion
The results of the current study demonstrate that in a large cohort of patients without obstructive CHD, undergoing invasive coronary angiography and comprehensive assessment of coronary vasomotion, the conventional FRS was independently associated with coronary microcirculatory vasodilator function, specifically with the direct microvascular measurement of CFR. The current study demonstrated that impaired coronary microcirculation function may be present in patients with low to intermediate FRS (<20% 10-year risk) without obstructive CHD.
The current study is the largest series of patients reporting the relationship between risk factors and the invasive evaluation of coronary vasomotor function. This method allowed us to identify the degree of microcirculatory vasomotor function in relation to the FRS and CHD risk factors.
Evaluating the contribution of the various coronary risk factors and the applicability of the FRS to early atherosclerosis is clinically important because primary prevention protocols rely on risk assessment. Our findings show that even within a group of patients considered to be at low to intermediate risk of developing CHD, the FRS was still higher in the group of patients with abnormal CFR. Thus, our study demonstrates the usefulness of FRS in individuals with impaired microcirculatory vasodilator function even at the early stage of CHD. However, as a 1–2% difference in FRS may not necessarily translate into practical recommendation for the individual patient, it is possible that the assessment of coronary vasomotor function and/or the integration of new parameters to the current FRS may improve the diagnosis of early coronary atherosclerosis and potentially identify the patients at risk for adverse cardiovascular events.
The presence of systemic conventional CHD risk factors may indeed serve as a milieu for the development of abnormal microcirculatory vasomotor function. This has been already shown before for several risk factors.Those risk factors may play a role in the initiation and progression of early atherosclerosis by instigating oxidative stress and inflammation, and the first stage of the disease may actually be a functional abnormality. Structural abnormality affecting the microcirculation (e.g. arteriolar remodelling) cannot be excluded but this cannot be assessed in vivo with current imaging techniques.
It is possible that the pathophysiology of coronary atherosclerosis at the very early stages of disease involves the microcirculation, and only later epicardial involvement is apparent. This may explain why the FRS, which incorporates established risk factors, is still applicable at the early stages of CHD, but also why conventional (epicardial) coronary arteriography is of limited value.
In our study, other established risk factors (such as hsCRP) had no significant association with the functional abnormalities (abnormal CFR) in early atherosclerosis. The lack of independent correlation between the laboratory markers assessed and microcirculatory vasomotor function may suggest that other novel markers such as Lp-PLA2 or asymmetric dimethyl-arginine, which may be more specific to the vascular wall and involved in the process of vascular injury and repair, may be used as a risk marker at the early stages of the disease.Coronary microvascular dysfunction was shown to be associated with myocardial perfusion defects when using either myocardial scintigraphy or magnetic resonance imaging. Our findings now provide further insight into the link between CHD risk factors and microcirculatory dysfunction which may lead to adverse cardiovascular events.The observation that risk factors affect the function of microcirculation and induce abnormal CFR may explain the limited benefit of most imaging techniques to identify the very early stages of CHD.
The presence of coronary artery microvascular dysfunction, especially in women, may have additional clinical implications, as it is not uncommon for patients who present with acute coronary syndromes to have normal epicardial coronary arteries at angiography. Moreover, recent studies demonstrate the prevalence and the prognostic significance of the response to intracoronary Ach in patients with acute coronary syndromes. Our findings suggest that microvascular dysfunction may be the underlying mechanism of these events and that further assessment of microvascular function, and especially the CFR, might reveal the underlying source for symptoms, and help to assess prognosis in these cases.
While our focus was the coronary vasculature, previous evaluations of the peripheral endothelial function yielded conflicting results. It has been suggested that lipids, BMI and smoking are important determinants of vascular reactivity and that the FRS was predictive of agonist-stimulated, endothelium-dependent vasodilation and basal nitric oxide release. In patients with established (and stable) CHD, only age and diabetes mellitus were found to be associated with (peripheral) endothelial dysfunction.
The association between a positive family history of CHD and lower microcirculatory vasodilator function in our study (especially in men) is also of interest. Although the exact mechanism is unclear, a family history of CHD is an established and important CHD risk factor, and our findings suggest that a positive family history of CHD may actually represent an inherited physiological trait that may later lead to overt symptoms and future events. Interestingly, among the risk factors evaluated, smoking history by itself was not associated with abnormal CFR (Table 4), but paradoxically was a univariate associate of greater CBF (Table 2), which is in contradiction to endothelial dysfunction of epicardial arteries or microvascular dysfunction previously reported in smokers.

Limitations
The main limitation of the current study is the inherent deficiency of most of clinically oriented case-series trials which is ascertainment bias. Additionally, two-thirds of our patients were female. However, microvascular dysfunction is more important in women and its prognostic value has been demonstrated.Additional limitation is that in order to be included in the study, patients had to be referred to coronary angiography. Therefore, patients in the current study were more likely to be a cohort of selected patients with symptoms or positive stress tests, therefore with a higher likelihood to have coronary microvascular dysfunction when compared with the unselected group with risk factors or with asymptomatic patients.
Previous SectionNext SectionConclusion
In conclusion, the current study demonstrates that the FRS, female sex, and a family history of CHD were associated with impaired coronary microvascular function in patients at low to intermediate risk without obstructive CHD. Our study provides insights into the inter-relationships between traditional risk factors, FRS and coronary microcirculatory vasomotor function in a large group of patients with indications for coronary angiography but without obstructive coronary artery disease. Our findings also suggest that evaluation of the microcirculatory vasomotor function may help to better define the group of patients in whom the severity of early CHD may actually be greater than appreciated by their FRS.

This article comes from:

http://eurheartj.oxfordjournals.org/content/31/8/936.full#T1

Hepatic microcirculatory dysfunction during cholestatic liver injury in rats
　

The present study was conducted to elucidate the sequential alterations in the hepatic microvascular inflammatory response to extrahepatic biliary obstruction. METHODS:: The hepatic microvasculature in anesthetized Sprague-Dawley rats was studied by in vivo microscopy 3, 7, and 14 days after bile duct ligation (BDL) or sham operation. RESULTS:: The numbers of adhering leukocytes and swollen sinusoidal endothelial cells were significantly increased at 3, 7, and 14 days after BDL when compared with sham-operated controls. Concomitantly, the numbers of sinusoids containing blood flow were significantly and progressively decreased by up to 30%. The phagocytic activity of hepatic macrophages was significantly elevated during the development of biliary cholestasis. In particular, centrilobular phagocytosis at 14 days after BDL was significantly increased 1.4- to 2.0-fold when compared with that at 3 and 7 days after BDL. Electron microscopy also revealed evidence of activated Kupffer cells reflected by numerous filopodia and ruffles. CONCLUSIONS:: These results suggest that hepatic microcirculatory dysfunction subsequent to BDL contributes to cholestatic liver injury

This article comes from:http://www.ncbi.nlm.nih.gov/pubmed/14557825

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