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First of all, what is blood circulation?
The circulation can be pictured as blood travelling
through the body in blood vessels. On average, we
have about 5 litres of blood travelling through our
circulatory system, delivering oxygen and nutrients
to all parts of the body.
On its return route to the heart, the blood picks up
carbon dioxide and waste products to be excreted.
Arteries carry blood away from the heart, in large
volume and under high pressure. Smaller arteries
branching off are called arterioles and eventually
lead to capillaries.
"The
microcirculation is the blood flow through blood
vessels smaller than 100 µm (i.e. arterioles,
capillaries, and venules). The main functions of the
microcirculation are transporting blood cells and
substances to/from the tissues, and as body coolant
in thermoregulation processes. It also contributes
to tissues color and stiffness."
Capillaries are the tiniest of our blood vessels.
Being small allows them to penetrate into every
corner of the body, bringing oxygen and nutrients to
the tissues and single cells.
Blood in the capillaries feeds the tissues before
travelling away from tissue and organs, flowing into
small veins called venules and then into larger
veins carrying blood back to the heart.
Microcirculation is the vascular network lying
between the arterioles and the venules, including
capillaries, as well as the flow of blood through
this network. Or in other words:
Microcirculation is the link between blood and
single cell. By this link, tissue and single cells
are supplied with oxygen and nutrients.
The importance of microcirculation:
A better supply of blood and therefore oxygen and
nutrients to a cell means:
The cell functions better;
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The organ works better;
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All organs work better;
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The whole organism works better;
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Result:
A person feels and is healthier!
 "Improved
blood circulation and supply of oxygen ensure that
the cells of the central nervous system are better
nourished, hence more efficient. Furthermore, the
circulation of the skin, therefore the functioning
of the finest capillaries, will be promoted. (...)
For when there is better blood circulation, the
entire body will benefit from a general cleansing
process." texts excerpted from The Nature Doctor
The microcirculation is a term used to
describe the small vessels in the
vasculature which
are embedded within organs and are
responsible for the distribution of
blood within tissues;
as opposed to larger vessels in the
macrocirculation which transport blood
to and from the
organs. The vessels on the arterial side
of the microcirculation are called the
arterioles,
which are well innervated, are
surrounded by smooth muscle cells, and
are 10-100 μm in
diameter. Arterioles carry the blood to
the capillaries, which are not
innervated, have no
smooth muscle, and are about 5-8 μm in
diameter. Blood flows out of the
capillaries into
the venules, which have little smooth
muscle and are 10-200 μm. The blood
flows from
venules into the veins. In addition to
these blood vessels, the
microcirculation also
includes lymphatic capillaries and
collecting ducts. The main functions of
the
microcirculation include the regulation
of 1. blood flow and tissue perfusion 2.
blood
pressure, 3. tissue fluid (swelling or
edema), 4. delivery of oxygen and other
nutrients and
removal of CO2 and other metabolic waste
products, and 5. body temperature. The
microcirculation also has an important
role in inflammation.
Most vessels of the microcirculation are
lined by flattened cells, the
endothelium and many
are surrounded by contractile cells the
smooth muscle or pericytes. The
endothelium provides
a smooth surface for the flow of blood
and regulates the movement of water and
dissolved
materials in the plasma between the
blood and the tissues. The endothelium
also produce
molecules that discourage the blood from
clotting unless there is a leak. The
smooth muscle
cells can contract and decrease the size
of the arterioles and thereby regulate
blood flow
and blood pressure.
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The microcirculation is comprised of arterioles,
capillaries, venules, and terminal lymphatic
vessels.
Arterioles
Small precapillary resistance vessels (10-50 μ)
composed of an endothelium surrounded by one or more
layers of smooth muscle cells.
Richly innervated by sympathetic adrenergic fibers
and highly responsive to sympathetic
vasoconstriction via both α 1 and α 2 postjunctional
receptors.
Represent a major site for regulating systemic
vascular resistance.
Rhythmical contraction and relaxation of arterioles
sometimes occurs (i.e., spontaneous vasomotion).
Primary function within an organ is flow regulation,
thereby determining oxygen delivery and the washout
of metabolic by-products.
Regulate, in part, capillary hydrostatic pressure
and therefore influence capillary fluid exchange.
Capillaries
Small exchange vessels (6-10 μ) composed of highly
attenuated (very thin) endothelial cells surrounded
by basement membrane ? no smooth muscle.
Three structural classifications: Continuous (found
in muscle, skin, lung, central nervous system) ?
basement membrane is continuous and intercellular
clefts are tight (i.e., have tight junctions); these
capillaries have the lowest permeability.;
Fenestrated (found in exocrine glands, renal
glomeruli, intestinal mucosa) ? perforations (fenestrae)
in endothelium result in relatively high
permeability.
Discontinuous (found in liver, spleen, bone marrow)
? large intercellular gaps and gaps in basement
membrane result in extremely high permeability.
Large surface area and relatively high permeability
(especially at intercellular clefts) to fluid and
macromolecules make capillaries the primary site of
exchange for fluid, electrolytes, gases, and
macromolecules.
In some organs, precapillary sphincters (a circular
band of smooth muscle at entrance to capillary) can
regulate the number of perfused capillaries.
Venules
Small exchange vessels (10-50 μ) composed of
endothelial cells surrounded by basement membrane
(smallest postcapillary venules) and smooth muscle
(larger venules).
Fluid and macromolecular exchange occur most
prominently at venular junctions.
Sympathetic innervation of larger venules can alter
venular tone which plays a role in regulating
capillary hydrostatic pressure.
Terminal Lymphatics
Composed of endothelium with intercellular gaps
surrounded by highly permeable basement membrane and
are similar in size to venules ? terminal lymphatics
end as blind sacs.
Larger lymphatics also have smooth muscle cells.
Spontaneous and stretch-activated vasomotion is
present which serves to "pump" lymph.
Sympathetic nerves can modulate vasomotion and cause
contraction.
One-way valves direct lymph away from the tissue and
eventually back into the systemic circulation via
the thoracic duct and subclavian veins (2-4
liters/day returned).
Microcirculation features original contributions
that are the result of investigations contributing
significant new information relating to the vascular
and lymphatic microcirculation addressed at the
intact animal, organ, cellular, or molecular level.
Papers describe applications of the methods of
physiology, biophysics, bioengineering, genetics,
cell biology, biochemistry, and molecular biology to
problems in microcirculation.
The journal also publishes state-of-the-art reviews
that address frontier areas or new advances in
technology in the fields of microcirculatory disease
and function. Specific areas of interest include:
Angiogenesis, growth and remodeling; Transport and
exchange of gasses and solutes; Rheology and
biorheology; Endothelial cell biology and
metabolism; Interactions between endothelium, smooth
muscle, parenchymal cells, leukocytes and platelets;
Regulation of vasomotor tone; and Microvascular
structures, imaging and morphometry. Papers also
describe innovations in experimental techniques and
instrumentation for studying all aspects of
microcirculatory structure and function.
This article comes from: http://www.cvphysiology.com/Microcirculation/M014.htm
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Background— A simple, reproducible invasive method
for assessing the coronary microcirculation is
lacking. A novel index of microcirculatory
resistance (IMR) has been shown in animals to
correlate with true microvascular resistance and,
unlike coronary flow reserve (CFR), to be
independent of the epicardial artery. We sought to
compare the reproducibility and hemodynamic
dependence of IMR with CFR in humans.
Methods and Results— Using a pressure-temperature
sensor-tipped coronary wire, thermodilution-derived
CFR and IMR were measured, along with fractional
flow reserve (FFR), in 15 coronary arteries (15
patients) under the following hemodynamic
conditions:twice at baseline;during right
ventricular pacing at 110 bpm;during intravenous
infusion of nitroprusside; and during intravenous
dobutamine infusion. Mean CFR did not change during
baseline measurements or during nitroprusside
infusion but decreased during pacing (from 3.1±1.1
at baseline to 2.3±1.2 during pacing, P<0.05) and
during dobutamine infusion (from 3.0±1.0 to 1.7±0.6
with dobutamine, P<0.0001). By comparison, mean
values for IMR and FFR remained similar throughout
all hemodynamic conditions. The mean coefficient of
variation between 2 baseline measurements was
significantly lower for IMR (6.9±6.5%) and FFR
(1.6±1.6%) than for CFR (18.6±9.6%; P<0.01). Mean
correlation between baseline measurements and each
hemodynamic intervention was superior for IMR
(r=0.90±0.05) and FFR (r=0.86±0.12) compared with
CFR (r=0.70±0.05; P<0.05).
Conclusions— Compared with CFR, IMR provides a more
reproducible assessment of the microcirculation,
which is independent of hemodynamic perturbations.
Simultaneous measurement of FFR and IMR may provide
a comprehensive and specific assessment of coronary
physiology at both epicardial and microvascular
levels, respectively.
Introduction
The state of the coronary microcirculation is an
important determinant of patient outcomes in a
number of clinical settings, including acute
coronary syndromes, percutaneous coronary
interventions, and cardiac transplantation–related
allograft vasculopathy.However, to date, a simple
and reproducible invasive method for assessing the
coronary microcirculation has been lacking. Current
techniques for evaluating the coronary
microcirculation are limited because they are
cumbersome, are qualitative, rely on complex
analyses, or do not independently interrogate the
coronary microcirculation.
Clinical Perspective p 2061
Guidewire-based measurement of coronary flow reserve
(CFR), either by Doppler flow or thermodilution
techniques, has become an increasingly important
invasive method for assessing the physiological
significance of coronary disease.However, use of CFR
to interrogate the microcirculation independently is
limited because CFR interrogates the flow status of
both the epicardial artery and the microcirculation
but does not allow discrimination between these 2
components.7 Furthermore, CFR is limited by its
dependence on heart rate and blood pressure, thereby
calling into question its reproducibility.
With recent technological advances, it is now
possible to measure pressure and to estimate
coronary artery flow simultaneously with a single
pressure-temperature sensor-tipped coronary wire. By
the thermodilution technique, the mean transit time
(Tmn) of room-temperature saline injected down a
coronary artery can be determined and has been shown
to correlate inversely with absolute flow. From this
technique, a thermodilution-based CFR can be derived
that has been shown to correlate well with Doppler
velocity wire-derived CFR and with absolute flow as
measured by a flow probe but that has the same
conceptual disadvantages as Doppler-derived CFR.
Using this thermodilution method, we reently
proposed and validated a novel index of
microcirculatory resistance (IMR) for assessing the
status of the microcirculation independent of the
epicardial artery. In an animal model, IMR, defined
as the distal coronary pressure divided by the
inverse of the hyperemic mean transit time,
correlated well with an accepted experimental method
for measuring microvascular resistance.
Unlike CFR, IMR is derived at peak hyperemia,
thereby eliminating the variability of resting
vascular tone and hemodynamics. We therefore
hypothesized that IMR would not only be a more
specific but also a more reproducible measure of
coronary microcirculatory status that may be less
subject to hemodynamic variation. This is especially
relevant in the catheterization laboratory,
particularly during interventional procedures,
during which changes in heart rate, blood pressure,
and cardiac contractility are likely to occur. The
goal of the present study was to evaluate the
feasibility, reproducibility, and hemodynamic
dependence of IMR compared with CFR in humans.
Methods
The study population comprised 15 patients over the
age of 21 years who were electively referred for
coronary angiography. Because severe epicardial
stenoses may affect measurement of microvascular
resistance, only coronary arteries without
high-grade epicardial stenoses (angiographic
stenosis 50% and fractional flow reserve [FFR]
>0.75) were included in the study. Patients were
excluded if they had significant renal insufficiency
(serum creatinine >1.5 mg/dL), recent acute
myocardial infarction (within 1 week), or congestive
heart failure. The study protocol was approved by
Stanford University’s Administrative Panel on Human
Subjects. Every patient provided informed written
consent.
All patients were brought to the cardiac
catheterization laboratory in a fasting state
without discontinuation of their cardiac
medications. After conventional diagnostic coronary
angiography was performed, 3000 to 5000 U of
intravenous heparin was administered, and a 6F
coronary guiding catheter was used to engage the
coronary artery of interest. Intracoronary
nitroglycerin (200 µg) was given. A 0.014-in
coronary pressure wire (Radi Medical Systems,
Wilmington, Mass) was calibrated, equalized to the
guiding catheter pressure with the sensor positioned
at the ostium of the coronary artery, and then
advanced to the distal coronary artery (at least two
thirds of the way down the vessel). CFR, IMR and FFR
were then measured under a variety of hemodynamic
conditions as described below.
Coronary Physiology Measurements
CFR, IMR, and FFR were measured by methods described
previously.Briefly, with commercially available
software (Radi Medical Systems) the shaft of the
pressure wire can act as a proximal thermistor by
detecting changes in temperature-dependent
electrical resistance. The sensor near the tip of
the wire simultaneously measures pressure and
temperature and can thereby act as a distal
thermistor. The transit time of room-temperature
saline injected down a coronary artery can be
determined with a thermodilution technique.Three
injections of 3 mL of room-temperature saline were
made down the coronary artery, and the resting mean
transit time (Tmn) was measured. Intravenous
infusion of adenosine (140 µg · kg–1 · min–1) was
then administered to induce steady state maximal
hyperemia, and 3 more injections of 3 mL of
room-temperature saline were made, and the hyperemic
Tmn was measured. Simultaneous measurements of mean
aortic pressure (Pa, by guiding catheter) and mean
distal coronary pressure (Pd, by pressure wire) were
also made in the resting and maximal hyperemic
states. CFR was calculated as resting Tmn divided by
hyperemic Tmn. IMR was calculated as the distal
coronary pressure at maximal hyperemia divided by
the inverse of the hyperemic Tmn. FFR was calculated
by the ratio of Pd/Pa at maximal hyperemia.
To investigate the effects of hemodynamic changes on
coronary physiology measurements, CFR, IMR, and FFR
were measured under 4 different hemodynamic
conditions: (1) Baseline: To study the intrinsic
variability of the coronary physiology indices,
measurements were made twice under baseline
conditions, once before any hemodynamic intervention
compared with a second measurement after all
hemodynamic interventions described below had been
completed. (2) Tachycardia: The measurements were
repeated during right ventricular pacing at 110 bpm
(with a 5F bipolar pacemaker lead introduced via the
right femoral vein). (3) Hypotension: The
measurements were repeated during intravenous
infusion of nitroprusside (0.5 to 2 µg · kg–1 ·
min–1) titrated to achieve a reduction of systolic
blood pressure of 20 mm Hg. (4) Increased cardiac
contractility: Measurements were repeated during a
5-minute intravenous dobutamine infusion starting at
10 µg · kg–1 · min–1, which then was increased to 20
µg · kg–1 · min–1 provided there was no significant
increase in heart rate at the lower dose (Figure 1).
After each intervention, heart rate, mean aortic
pressure, mean coronary transit time, and distal
coronary pressure were allowed to return to their
baseline values before the next intervention. In 4
patients, the resting blood pressure was too low to
allow nitroprusside infusion. In 4 patients, a
repeat baseline measurement after all interventions
was not performed:(who also underwent percutaneous
intervention during the same procedure) because of
excessive procedure time and because of a
combination of dyspnea arising from intravenous
adenosine infusion and prolonged procedure time.
Three patients were excluded from the dobutamine arm
because of concurrent ß-blocker usage. Hence, the
baseline variability protocol was completed in 11
patients; the effect of tachycardia was studied in
15 patients; the effect of nitroprusside was studied
in 11 patients; and the effect of dobutamine was
studied in 12 patients.
Discussion
In many patients presenting to the cardiac
catheterization laboratory, the status of the
coronary microcirculation, not just the epicardial
arteries, is of clinical and prognostic relevance.1
However, to date, there is no simple, specific, and
reproducible invasive measure of the status of the
coronary microcirculation. In the present study, we
compared a novel IMR with thermodilution-derived CFR
in terms of reproducibility and dependence on
hemodynamic changes. We also concurrently measured
FFR, an index specific for the degree of epicardial
coronary artery stenosis, under different
hemodynamic conditions.
The salient findings of the present study are as
follows: (1) IMR demonstrates less intrinsic
variability and better reproducibility at baseline
than CFR, and (2) whereas CFR is very sensitive to
hemodynamic changes, IMR is largely independent of
variations in hemodynamic state. Furthermore, FFR
(when simultaneously measured with IMR and CFR) is
highly reproducible and also largely independent of
hemodynamic state. These findings suggest that IMR
could be reliably applied in the catheterization
laboratory for interrogation of microcirculatory
resistance. Furthermore, simultaneous measurement of
FFR and IMR with a single pressure-temperature
sensor-tipped coronary wire may provide a simple
means for comprehensive and specific assessment of
coronary physiology at both epicardial and
microvascular levels, respectively.
In a recent study using a porcine animal model, we
found that IMR distinguished between normal and
abnormal microcirculatory function and correlated
well with true microcirculatory resistance as
measured by an external flow probe and pressure
wire.Furthermore, IMR, in its simplest form, was not
significantly affected by the presence of a moderate
to severe epicardial stenosis and is therefore a
specific measure of the state of the
microcirculation, unlike CFR. In more severe
stenoses, in which collateral flow may be
contributing to myocardial perfusion, a more complex
form of IMR, which incorporates the coronary wedge
pressure, is necessary to accurately determine
microvascular resistance.
Because IMR is derived at peak hyperemia, we
postulated that it would be independent of resting
vascular tone and hemodynamics. The present study
demonstrates that IMR is easily measured in humans
with a commercially available pressure-temperature
sensor-tipped coronary wire and that its values are
highly reproducible. Furthermore, variations in
hemodynamic status, including changes in heart rate,
blood pressure, and contractility, do not
significantly affect IMR measurements. During all
hemodynamic interventions in the present study
(rapid right ventricular pacing, nitroprusside
infusion, and dobutamine infusion), IMR exhibited
greater hemodynamic stability than CFR.
Use of CFR to evaluate the microcirculation is
limited by the fact that CFR interrogates the entire
coronary system, including the epicardial artery and
the microcirculation.7 For this reason, a patient
with epicardial disease but with normal
microcirculatory function can have an abnormal CFR,
which potentially limits the applicability of CFR
when assessing microvascular disease. Furthermore,
because CFR represents a ratio between peak
hyperemic and resting coronary flow, factors that
affect resting hemodynamics, such as heart rate and
contractility, may affect the reproducibility of
CFR. Previous studies have shown that Doppler flow
velocity–derived CFR is significantly reduced by
tachycardia and by increased contractility9 but is
not significantly affected by changes in blood
pressure due to compensatory changes in coronary
blood flow. Consistent with these previous studies,
the present study documents the hemodynamic
dependence of thermodilution-derived CFR. In the
present study, hypotension induced by nitroprusside
infusion had no effect on thermodilution-derived CFR.
In contrast, right ventricular pacing–induced
tachycardia and dobutamine infusion were both
associated with significant reductions in
thermodilution-derived CFR values, largely due to an
increase in resting coronary blood flow (and hence a
reduction in resting Tmn). Hence, like Doppler flow
velocity–derived CFR, interpretation of serial
measurements of thermodilution-derived CFR are
limited by a high degree of hemodynamic variability,
largely as a result of changes in basal coronary
blood flow.
FFR is measured during maximal hyperemia and
therefore is not prone to variability due to
fluctuations in baseline hemodynamic state. In the
present study, we show that when peak hyperemia is
induced by intravenous adenosine, the intrinsic
variability of FFR is very low (<2%) and may be
superior to that for FFR measured with intracoronary
adenosine, a route of administration that may not
induce as strong a hyperemic response and that is
associated with a very short half-life and hence is
potentially subject to greater variability. FFR
measurements, like IMR, demonstrated no significant
variation during any of the hemodynamic conditions
in the present study.
Study Limitations
IMR, FFR, and CFR are limited by their reliance on
the achievement of maximal hyperemia. Failure to
achieve peak hyperemia, by not achieving maximal
reduction in microvascular resistance, may result in
overestimation of IMR. Conversely, CFR will be
underestimated in the absence of maximal hyperemia.
In the case of FFR, if maximal hyperemia does not
occur, the pressure gradient across a stenosis will
be underestimated and the FFR overestimated. For
these reasons, intravenous adenosine, considered the
reference standard for induction of peak hyperemia,
was used for the present study. Use of less
effective hyperemic agents/protocols may affect the
reproducibility of these indices.
In the present study, dobutamine infusion was
associated with an increase in heart rate, which in
itself, can produce increased contractility.
However, although the influences of contractility
and heart rate were not divorced from each other,
the heart rate increase observed with dobutamine
infusion was much less than that observed with right
ventricular pacing, which suggests that an increase
in contractility had indeed been tested.
The effect of the severity of epicardial stenosis on
measurement of microvascular resistance is
controversial. Some have suggested that the minimum
achievable microvascular resistance increases with
the increasing severity of an epicardial artery
stenosis. In contrast, we and others have reported
that microvascular resistance is not affected by
increasing epicardial artery stenosis if collateral
flow is taken into account.13,15 In the present
study, all coronary physiological measurements were
made in arteries that were either normal or had only
minor angiographic stenoses. In cases with severe
epicardial stenosis, the simplified measurement of
IMR, as used in the present study, may overestimate
resistance because it does not account for
collateral flow, and a more complex measurement of
IMR that incorporates the coronary wedge pressure is
necessary.
Microvascular resistance has also been determined
invasively by measuring distal pressure and
estimating flow with a Doppler wire. Because of the
additional complexity of using a Doppler wire, we
did not test the reproducibility or hemodynamic
dependence of this technique.
Lastly, the distance of the pressure wire down a
vessel will impact the measured hyperemic transit
time and the IMR. The variability of IMR depending
on the distance of the wire down the vessel was not
tested in the present study, although in this study,
there was no correlation between transducer distance
and transit times.
Conclusions
Despite the importance of the status of the
microcirculation in determining clinical outcomes in
a wide variety of cardiovascular conditions, a
simple and reproducible method for invasively
assessing the state of the coronary microcirculation
has been lacking. Measurement of CFR for assessing
the coronary microcirculation has been limited by
its lack of specificity and its high degree of
hemodynamic variability. IMR is a new index for
specific and quantitative assessment of coronary
microcirculatory resistance that can be measured
easily in the cardiac catheterization laboratory.
IMR, by virtue of being more reproducible and less
hemodynamically dependent than CFR, appears to be
superior to CFR for assessing the coronary
microcirculation. Finally, simultaneous measurement
of FFR and IMR, by specifically quantifying the
status of the epicardial artery and
microcirculation, respectively, may provide a
simple, comprehensive means of evaluating the
physiological state of a coronary artery in the
catheterization laboratory. |
