Review
European Heart Journal (2007) 28, 929–940
doi:10.1093/eurheartj/ehm015
Coronary sinus blood sampling: an insight into
local cardiac pathophysiology and treatment?
Rumi Jaumdally, Chetan Varma, Robert J. Macfadyen, and Gregory Y.H. Lip*
Haemostasis, Thrombosis, and Vascular Biology Unit, University Department of Medicine, City Hospital,
Birmingham B18 7QH, UK
Received 27 November 2006; revised 9 February 2007; accepted 15 February 2007; online publish-ahead-of-print 29 March 2007
KEYWORDS
Coronary sinus;
Circulating factors;
Myocardial ischaemia
Atherosclerosis remains the underlying cause of cardiovascular disease and is a dynamic process involving inﬂammation, haemostasis, endothelial dysfunction, and angiogenesis. Studies of circulating
factors from peripheral blood can provide an insight into this pathophysiology but may remain indicative
of a more generalized, systemic process. More localized interaction(s) within the heart may be better
studied from coronary blood samples. Indeed, an increasing number of prospective studies show good
correlation between indices of these processes and clinical outcomes. As local sampling offers a
unique way of assessing the local cardiac milieu, this may prove useful in the monitoring of both
local/systemic drug therapies and interventional technologies.
Cardiovascular disease (CVD) is the leading cause of death
and disability in the developed world.1,2 Of those aged
less than 65 years, CVD currently accounts for 30% of all
deaths3 and substantially contributes to the escalating
cost of health care.4 However, the differentiation
between coronary and linked vascular death attributable
to generalized atherosclerosis (for example, stroke) is less
well deﬁned. Population studies have developed scoring
systems in an attempt to deﬁne risk of future events but
these are frequently linked to generalized atherosclerosis
than speciﬁc coronary event rates. Thus these include generalized population vascular event rate associated with
both immutable [age, gender, and family history of premature coronary artery disease (CAD)] and modiﬁable factors
(such as hypertension, diabetes, smoking, and lipid
proﬁle).5
Atherosclerosis, the underlying cause of CVD, is a
dynamic process involving the pathophysiological processes
of inﬂammation, haemostasis, endothelial dysfunction,
and angiogenesis. Studies involving indices reﬂecting
these processes, both from peripheral and the cardiac
microcirculation, can provide an insight into this pathophysiology with potential prognostic beneﬁts. One problem
with the measurement of blood indices from the peripheral
circulation is that measured levels may not reﬂect intracoronary levels and, instead, can be indicative of a more
generalized, systemic process. Other methods to reﬂect
the coronary (or intracardiac) micro-environment are
therefore needed.
* Corresponding author. Tel: þ44 121 507 5080; fax: þ44 121 554 4083;
E-mail address: [email protected]
In order to focus more clearly on the coronary vasculature, selective catheterization of the coronary circulation
may be one approach. Coronary sinus (CS) catheterization,
for example, is well established as a method to compare
proposed myocardial protection strategies in cardiac
surgery.6 In routine electrophysiological studies,7 access to
the CS allows for diagnostic and therapeutic manoeuvres.
Dependent upon their circulating kinetics and responsiveness, assays of these various pathophysiological indices
obtained at CS sampling may offer enhanced sensitivity or
speciﬁcity for coronary events, from assessments of the
local intracardaic milieau to a lack of dilution effects. In
this review article, we examine the role of measuring
plasma indices (biomarkers) of inﬂammation, haemostasis,
endothelial damage/dysfunction, and angiogenesis from
the coronary circulation in the pathogenesis, treatment,
and prognosis of myocardial ischaemic events.
Search strategy
We performed a search using electronic databases
(MEDLINE, EMBASE, CINAHL, and DARE) between 1966 and
2005. Medical subject headings ‘sinus’, ‘circulation’,
‘venous’, ‘intracardiac’, ‘sinus catheterisation’ were combined with ‘biomarkers’, ‘inﬂammation’, ‘thrombogenesis’,
‘angiogenesis’, ‘endothelium’ and ‘coronary’ ‘myocardium’,
‘heart disease’, and ‘atherosclerosis’, ‘atheroma’, ‘plaque’
and ‘ischaemia’. The search was limited to papers published
in the English language and excluded studies involving electrophysiology only with no blood parameters quantiﬁed. The
reference list of identiﬁed studies was scrutinized and
relevant citations examined.
& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: [email protected]
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Introduction
930
Methods to study the local cardiac circulation
Figure 1 Anatomy of the coronary sinus and major cardiac veins. CS, coronary sinus; GCV great cardiac vein; PLVV, posterior left ventricular vein; ADV,
anterior descending vein; MCV, middle cardiac vein; ACV, accessory cardiac
vein; SCV, small cardiac veins.
cardiac biology, the technique leaves scope for signiﬁcant
loss of sensitivity, which can inﬂuence biomarker deﬁnition.
Myocardial ischaemia and angiographically
normal coronary arteries
Patients with cardiac syndrome X are complex but well
deﬁned and presumed to have recurrent ischaemia despite
angiographically ‘normal’ vessels, although some have evidence of subintimal or non-obstructive atheroma.13 The
pathogenesis of this clinical symptomatic subgroup remains
unclear. Microvascular coronary dysfunction has been postulated as a potential mechanism of recurrent ischaemia.14 A
range of surrogate investigations, such as magnetic resonance spectroscopy15 and positron emission tomography,16
reveal some supportive evidence of focal abnormalities of
coronary perfusion (i.e. nuclear perfusion defects and
restrictive regional blood ﬂow patterns, respectively) in
these patients.
Buffon et al.17 used a panel of circulating coronary biomarkers to provide an insight into this phenomenon by analysing the differences between CS and aortic levels of
hydroperoxides and conjugated dienes (which are two sensitive markers of ischaemia-reperfusion oxidative stress) in
cardiac syndrome X patients.17 In this study (n ¼ 9), rapid
atrial pacing was used to produce electrographic ST
changes, with sustained release of these markers in the
local circulation compared with a control group consisting
of ﬁve asymptomatic patients with normal ECG, left ventricular volume, and normal coronary angiogram.17 Similarly,
increased plasma concentrations of the powerful vasoconstrictor, endothelin-1 (ET-1), have been reported in the coronary circulation of such patients in response to atrial
pacing, correlating with coronary microvascular dysfunction.18 Thus, these patients appear to react adversely in
terms of their coronary efﬂux metabolism with signs of
Figure 2 Accessory venous pathways of the heart.
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Though the venous system of the heart comprises variable
anatomical branches, drainage is primarily via the CS into
the right atrium (RA) (Figure 1). In addition to electrophysiological mapping and pacing, the CS can be cannulated and
used to study changes in ﬂow, temperature, and, more commonly, blood sampling. In this respect, it is important in the
ﬁrst instance to note that alternative venous pathways exist
(Figure 2); they are generally not thought to contribute to
signiﬁcant venous drainage and thus, cannulation of the CS
can give access to blood sampling and monitoring of heart
metabolism. Sampling from the CS is usually achieved by
retrograde cannulation of a central venous system (subclavian, internal jugular, brachial, or femoral vein). Further
manipulation within the RA generally requires ﬂuoroscopic
imaging to allow for selective engagement of the main CS
trunk. Speciﬁc catheters, some with heparin bonding and
distal side-holes, together with transfemoral sheaths8–10
have been developed to facilitate cannulation and/or
blood withdrawal from the CS without admixture with RA
blood. The positioning of the catheter can be veriﬁed and
recorded with anterograde and retrograde left coronary
arterial contrast injection11 (Figures 3 and 4), although
this does not guarantee RA admixture. Other methods used
to conﬁrm CS cannulation involved distal pressure assessment at the catheter tip, oxygen saturation, and blood
ﬂow analysis. It is therefore assumed that a CS blood
sample thus obtained reﬂects venous cardiac metabolism.
In particular, during regional ischaemic injury, sampling of
CS blood does appear to deﬁne early and accurate measurements of myocardial metabolism, in contrast to concomitant
peripheral blood assays which show no change.12 The accuracy and validity of these assumptions are critically dependent on careful techniques, selective cannulation, and
avoidance of admixture. Sadly, this is rarely tested or conﬁrmed in published reports.
In summary, although selective coronary sampling appears
simple and safe and clearly appropriate to deﬁne regional
R. Jaumdally et al.
Coronary sinus sampling and pathophysiology
Figure 3
931
Radiographic views of the coronary sinus without and with anterograde contrast injection (antero posterior view).
pacing induced a marked lactate release when intracoronary
N (G)-monomethyl-L-arginine (a NO synthesis inhibitor) was
infused, but this effect was not seen systemically.25 Thus,
localized regional sampling was able to deﬁne the metabolic
ischaemic response to regional infusion and revealed the
higher NO dependence of the coronary circulation in hypertensive patients.25
Reversible myocardial ischaemia with
stable coronary plaque
Stable atherosclerotic CAD results in patients with chronic
exertional chest pain owing to reversible myocardial ischaemia from an unmet oxygen demand secondary to an obstructive coronary stenosis.26 The biology of plaque formation is
complex and results from an interaction of trigger factors
and localized cellular endothelial damage/dysfunction
and haemorrheological and inﬂammation abnormalities,
together with modiﬁed lipid inﬁltration of subintimal
tissues.23 Each of these mechanistic processes can contribute to a variable extent in individual coronary patients
and each might be better deﬁned by regional rather than
generalized blood sampling.
Endothelial function
An intact vascular endothelium plays an important role in
preserving arterial homeostasis by modulating NO production from its precursor, L-arginine, via the enzymatic
action of endothelial NO synthase.27 This pathway regulates
regional vascular tone via a wide range of mediators (such as
prostacyclin, bradykinin, endothelin, and angiotensin II)
that have vasodilatory or vasoconstrictive properties. NO
also inﬂuences coagulation, platelet aggregation, and
smooth muscle cell proliferation and migration.7,28,29 In
addition, NO can act to inhibit the degenerative oxidation
of low-density lipoprotein cholesterol,30 which is a key
step in plaque inﬁltration and destabilization.
Regional analyses of endothelial responsiveness speciﬁc to
the coronary circulation might intuitively provide a more
sensitive measure of the role of endothelial dysfunction
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regional ischaemia, presumed to be due to abnormal ﬂow.
How this relates to a standard exercise stress test, which
is quite distinct from RA pacing-induced stress, is
unknown. Importantly, this study did not reveal changes in
the peripheral circulatory levels of these metabolic
markers.
Several studies have examined the thrombotic balance in
the so-called cardiac syndrome X or linked presentations.
For example, Oshima et al.19 found higher plasma ﬁbrinopeptide A levels (reﬂecting an impaired local coagulation
system), with evidence of increased platelet activation in
CS sampling in patients with vasospastic coronary disease.
In a later study, the same group reported that intracoronary
acetyl-choline led to an enhanced CS-arterial gradient of
measured soluble P-selectin (a marker of platelet activation) in patients with angiographically normal coronary
arteries compared with those with visible atheroma.20
They suggested that the change in platelet activation seen
on coronary sampling was associated with the level of
cardiac ischaemia and even possibly, with myocyte necrosis.
Abnormal endothelial-dependent and endothelialindependent relaxations,21,22 as well as glucose metabolism23 in the coronary circulation have also been described
in symptomatic patients with exertional chest pain yet
angiographically normal coronary anatomy, using local
haemodynamic and rheological parameters. In the 1970s,
Goldberg et al.24 compared two groups of patients with
negative exercise test (one group had atypical pain and controls with no chest pain) and found a signiﬁcant increase in
cardiac arteriovenous lactate production (a measure of
metabolic performance) and in blood ﬂow in the former
group with focal coronary artery spasm.24 Thus, despite
near-normal angiography in both cohorts, CS indices provided a sensitive method to assess focal dysfunction in
those with arterial vasospasm.
Given the rapid intracardiac circulation, neurohormonal
effectors, such as short-lived endogenous nitric oxide (NO,
an endothelium-dependent vasodilator), can be estimated
from CS samples but not from peripheral blood. For
example, in one study of 12 patients with left ventricular
hypertrophy and normal coronary angiography, rapid RA
932
Visualization of coronary sinus os during left coronary arterial angiography.
and underlying coronary vasomotor regulation in stable
patients.31,32 Both baseline levels and response to pharmacological vasodilators on epicardial vascular bed can be
studied using CS oxygen saturation analyses.33
In patients with chronic symptomatic CAD, studies of CS
efﬂuent suggest raised intracardiac levels of soluble thrombomodulin34 in addition to other markers of endothelial
damage/dysfunction.35 In some studies, these biomarker
levels were correlated to the presence and angiographic
severity of CAD, but this was not the case with peripheral
blood sampling of the same markers. The functional
response of the endothelium to chronic ischaemic stress
can also be assessed using plasma levels of ET-1; for
example, after prolonged pacing-induced ischaemia (mean
6 min), local levels of ET-1 were signiﬁcantly elevated compared with peripheral blood, indicating localized cardiac
synthesis and regional metabolic changes.36
Angiogenesis
Chronic vascular disease involves well-deﬁned stimuli to a
range of vascular growth patterns characterized by new
vessel proliferation. In CAD, these responses are intimately
linked to the presence of viable but ischaemic myocardium
and are controlled and mediated by a distinct range of
biomarkers.37 One key growth factor associated with angiogenesis is vascular endothelial growth factor (VEGF). Circulating peripheral plasma levels are widely documented as
elevated in CAD38 and diabetic atherosclerosis.39 Endogenous cardiac release of angiogenic growth factors has been
described in patients with stable chronic occluded and collateralized coronary arteries—ﬁndings not seen in peripheral
samples.
In one study, for example, CS sampling from seven
patients with left coronary arterial occlusion revealed a
four-fold increase in local VEGF levels compared with
patients with non-occlusive coronary stenoses.40 Lambiaise
et al.41 also showed an association of increased CS VEGF
levels to coronary collateral ﬂow index (a measure of
degree of collateralization in the presence of single-vessel
stenosis). Intracardiac sources of earlier precursors (circulating endothelial progenitor cells) were also found to be
reduced in the presence of inadequate collaterals,42 and
no such relationships were seen in peripheral blood
samples. In acute myocardial injury and ventricular remodelling, the role of circulating VEGF appears less
conclusive.43 This seems hardly surprising, as many other
factors relating to the presence of occult collateralization
are likely to dominate the ventricular response to
infarction.
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Figure 4
R. Jaumdally et al.
Coronary sinus sampling and pathophysiology
Thrombogenesis
Other atherosclerotic risk factors
Cardiovascular risk factors such as hypertension, obesity,
and impaired glucose metabolism are linked with CAD and
myocardial ischaemia, with complex range of underlying
pathophysiological mechanisms. Several metabolic and
neurohormonal markers relevant to one or more of these
states have been assessed in patients, using CS sampling.
Adiponectin is a protein secreted by adipocytes with both
anti-inﬂammatory properties56 and the potential to suppress
atherosclerosis in relevant animal models.57 Systemic levels
of adiponectin are lower in the presence of type 2 diabetes
or CAD.58 Intracardiac adiponectin levels have also been
shown to be reduced in diabetic patients (samples from
the aortic and CS sites), with some evidence of transcardiac
metabolism of adiponectin.59
With respect to regional circulatory control of coronary
perfusion, CS cannulation may provide information on the
direct role of factors of the renin–angiotensin–aldosterone
system (RAAS) in vasomotor regulation.60 Fairly predictably,
local measurement of angiotensin II, together with intracardiac epinephrine levels, was associated with vasoconstriction during inducible ischaemia in patients with chronic
CAD.61 Assessment of coronary blood ﬂow responses conﬁrms
a role for angiotensin-converting enzyme inhibition therapy
in mediating coronary vasodilatation, independent of the
presence or absence of CAD.62 Finally, measurement of CS
blood may help in the deﬁnition of regional cardiac autonomic tone and sympathetic nervous responses, which
appear to correlate with sudden death or worsening
cardiac function in patients with pre-existing left ventricular failure.63
Myocardial ischaemia and unstable
coronary plaque
The factors which trigger coronary plaque destabilization
and promote plaque rupture are of critical importance.
Again with population studies, peripheral blood sampling
has deﬁned a range of indices reﬂecting pathophysiological
processes, but the relative importance of each to individualized coronary events is less clear. As with stable disease,
indices of activity within autonomic/neural, thrombotic, or
inﬂammatory tone are likely to be more sensitive if
derived from the relevant regional circulation, particularly
if sampled during deﬁned ‘disease instability’ (e.g. acute
coronary syndromes) without the overt myocardial
damage/loss seen with acute infarction.
Plaque rupture is believed to be preceded by cap thinning
and/or exposure of a core of lipid-laden activated macrophages which are highly thrombogenic to circulating
platelets.64 The degree of plaque disruption (erosion,
ﬁssure, or ulceration) and the extent of overlying mural
thrombus are key factors in the thrombogenic signal generated from a local arterial site. In addition, activation of
macrophages, T-lymphocytes, and smooth muscle cells
leads to the release of additional mediators, including
adhesion molecules, cytokines, chemokines, and growth
factors. The end-result may be myocardial ischaemia and
infarction, depending on the duration of the thrombosis
and the location of the associated endothelial dysfunction
and vasoconstriction.
Investigations using regional CS blood sampling have
played an important role in providing a quantitative assessment of the various systems involved in the pathogenesis of
acute coronary syndromes and help in identifying/optimizing new potential therapy areas. The key studies involving
endogenous platelet activation and thrombogenesis under
acute ischaemic conditions that have been conducted
using CS samples are summarized in Table 1. It is well recognized that exposure of tissue factor, a cell-surface protein
expressed by cells within a vulnerable plaque, can lead to
activation of the coagulation/ﬁbrinolytic pathways. In an
investigation of patients with ACS, levels of tissue factor
pathway inhibitor (TFPI) can be objectively measured on
the basis of difference noted between aortic and CS
levels, thus reﬂecting the intracoronary environment, and
can be used in addressing future treatment.65 This ‘consumption’ of TFPI within the coronary circulation contributes directly to and regulates intracoronary thrombus
activation.
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The association of abnormalities in thrombosis and vascular
disease is well established.44,45 However, the speciﬁc
linkage of peripheral blood sample changes in platelet function, coagulation, and ﬁbrinolytic pathways to the stability
and responses within the local coronary circulation is much
less clear. Although systemic analysis of these systems has
been widely investigated in CAD, their role in more regional
sampling in patients may reveal more relevant associations.
The difﬁculty with many haemostatic indices, whether of
platelet or thrombotic origin, is that they are widely recognized as being abnormal in peripheral blood in a range of
vascular diseases, independent of speciﬁc coronary involvement. The list of associations is large and crosses a range of
conditions linked to CAD, such as peripheral arterial disease,
diabetes mellitus, and myocardial infarction.46–48
Peripheral blood analyses of markers of platelet or
thrombin activation in patients with CAD undergoing acute
exercise stress do not show any changes in measured
levels.49 In contrast, regional analyses of CS blood, from
studies in the 1980s, conﬁrm a potential role of regional
platelet activation, prostaglandin production, and the
effects of aspirin therapy in chronic stable CAD
patients.42,50,51 Similarly, higher levels of thromboxane
(associated with platelet activation), but not components
of complement activation, were also found in this setting
but not in peripheral blood.52
CS sampling also facilitates the analysis of regional therapeutic response to platelet inhibition. Montalescot et al.53
reported that CS blood assays of platelet-activating factor
are unchanged during pacing, potentially eliminating its
participation in thromboxane release; there was good
thromboxane inhibition with low-dose aspirin (50 mg/day)
both at rest and during reversible and brief ischaemic
episodes.54
Furthermore, intracoronary assay of ﬁbrinolysis has been
studied in the context of cornary events in smokers compared with those who do not smoke. A lower level of
tissue plasminogen activator activity (impaired local ﬁbrinolysis) appears more pronounced in smokers with established
coronary atheroma on vascular ultrasound, in keeping with a
potential mechanistic link between smoking and CAD
event.55
933
934
R. Jaumdally et al.
Table 1 Examples of key studies analysing platelets activation and thrombosis markers during coronary sampling
Reference
Cases
Hypothesis investigated
Clinical implications
Craft et al.120
19 PCI
Rauch et al.121
30 PCI
Heparin use led to a #PMP and contrast led to an "PMP;
effect seen in the regional arterial samples only
CS level of CD15 following PCI correlates with ISR
Johansen et al.122
26 PCI
Platelet activation using PMP in
coronary circulation
Interaction of leucocyte and
platelets using adhesion
molecule CD 15
PDGF and BTG
Watkins et al.123
21 PCI
Thrombin activity using
Fibrinopeptide A (Fib A)
Platelet activation using beta
thromboglobulin
Impaired local ﬁbrinolysis
Platelet activity (PDGF)
Combination effect following PCI
Coagulation pathway using TF, TAT
complex, and pro-PF
Fornitz et al. 124
19 PCI
Mizuno et al.
125
43 PCI
Mizuno et al.
126
35 PCI
Coagulation and ﬁbrinolysis
23 UA, 16 CSA
Platelet and neutrophil interaction
using CD62P
Patel et al.
127
" levels of both PDGF and "BTG seen in aortic root and CS
following PCI; only arterial changes correlate ISR
" Fib A levels seen following heparin cessation in PCI and
in AMI (effect seen earlier and disproportionate in CS
sample)
Regional BTG levels did not vary following PCI irrespective
of heparin therapy
Impaired cascade with "PAI-1/#tPA seen centrally
PDGF" seen centrally
Combination of above after PCI correlates with ISR
All " ( TF, TAT, PF) with PCI; association of local
coagulation cascade (TF level at 24 h) correlates
with ISR following PCI
All " (TF, TAT, PAI-1, tPA) in PCI; transient effect seen
centrally with atherectomy
" in platelet expression (CD62P) in an unstable plaque
Effects of interventions
Different modalities such as balloon angioplasty, stent use,
and atherectomy during percutaneous intervention can
lead to differing patterns of platelets activation, coagulation, and ﬁbrinolysis.66 For instance, plasma levels of
tissue factor, thrombin–antithrombin III complex, plasminogen activator inhibitor, and tissue plasminogen activator are
elevated up to 24 h after all coronary procedures, whereas
only mechanical atherectomy seems to induce signiﬁcant
(though transient) platelet activation seen in CS samples.
There is a potential link to in-stent restenosis,67 whereas
abnormal intracoronary ﬁbrinolytic cascade may also
affect adverse modelling and restenosis.68
Plaque burden and coronary sinus sampling
Imaging techniques, such as vascular ultrasonography,
electronbeam-computed tomography, and magnetic resonance imaging, have made differing contributions to the
estimation of plaque burden and characterization.69 The
relationship of CS measures to each of these imaging
methods will vary, dependent on their ability to deﬁne the
extent of disease burden and/or its relative biological stability. CS catheterization complements these with the added
beneﬁt of quantifying the degree of local activation at vulnerable atherosclerotic plaques in the coronary beds.
In unstable angina, activation of neutrophils and platelets
was accurately assessed in the coronary circulation and compared with stable CAD.70 Furthermore, white cell expression
of the CD11b/CD18 adhesion receptor in the CS,71 as indices
of granulocyte and monocyte activation, further reﬂects
enhanced inﬂammation in unstable atherosclerotic
plaques. In acute myocardial infarction, differing platelet
reactivity and aggregability with subsequent effect of prostacyclin inhibitors therapy within the coronary artery are
well documented.72
Renin–angiotensin–aldosterone system
Angiotensin II is an important mediator of interleukin (IL)-6
expression by vascular smooth muscle cells and vascular
cell adhesion molecule-1 and MCP-1 expression by endothelial cells in vitro.73
In keeping with the many clinical trials of renin–angiotensin blockade in preventing cardiovascular events, a possible
direct effect on the myocardium has been postulated given
that CS assays show a local cardiac production of angiotensin.74 By further analysing CS gradient of angiotensin II and
its messenger RNA, there is an enhanced production in
acute coronary syndrome, which is associated with the upregulation of intracardiac cytokines, such as tumour necrotic
factor (TNF-a), IL-6, and interferon-gamma.75 This is in
contrast to the lack of a signiﬁcant change in the activity
of peripheral levels of RAAS measured in the same cohort.
C-reactive protein and inﬂammation
Produced in the liver, C-reactive protein when deﬁned using
high-sensitivity analysis is now recognized to have a potentially direct pro-inﬂammatory role in acute coronary syndromes.76 The mechanistic links are numerous, but
C-reactive protein is intimately linked to IL-1b, IL-6, and
TNF-a, as well as the expression of intercellular and vascular
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", increased level; #, decreased level; PCI, percutaneous coronary intervention; PMP, platelet microparticle; ISR, in-stent restenosis;PDGF, platelet-derived
growth factor; BTG, beta-thromboglobulin; AMI, acute myocardial infarction; CS, coronary sinus; CSA, chronic stable angina; UA, unstable angina; Fib A, ﬁbrinopeptide A; PAI-1, plasminogen activator inhibitor; tPA, tissue plasminogen activator; TF, tissue factor; TAT complex, thrombin–anti-thrombin complex; PF,
prothrombin fragment.
Coronary sinus sampling and pathophysiology
Endothelial (dys)function
Endothelial dysfunction is integral to the development of
atherosclerosis85 and correlates with serum C-reactive
protein in peripheral blood.86 Novel molecules could
potentially offer avenues to improve our recognition of
any early change within the coronary anatomy at a stage
before angiographically visible plaque.
For example, using immunologically deﬁned circulating
endothelial cells (CECs) shed from affected vascular beds
may be a novel technique for the assessment of the extent
or degree of endothelial injury. We have recently shown
that CEC levels in the peripheral blood 48 h following
acute coronary syndromes predict major adverse clinical
events at 1 and 12 months.87 The marked difference in
CEC count may be associated with a greater degree of vascular injury, and CEC release could potentiate pro-thrombotic
mediators and platelet aggregation.
Whether this marker is able to deﬁne a discrete coronary
endothelial response or a more generalized response of the
arterial (and/or venous) circulation is as yet unclear. During
angiography or angioplasty, CECs may also provide information as to the extent of intramyocytic release, though
no such data are available. Studies of regional response(s)
in peripheral and CS blood would be valuable to explore
this further.
Myocardial ischaemia and the development
of pre-conditioning
Intermittent periods of reversible ischaemia allow the
development of metabolic resistance to subsequent ischaemic stress and have the potential to reduce myocardial
loss at subsequent vessel occlusion. In animal models, a
technique of intermittent pharmacological retrograde perfusion of the CS during surgical ischaemia can allow
reduction of tissue hypoxia, impaired wall motion score,
and histological necrotic area.88 In stable coronary patients
undergoing percutaneous coronary intervention (PCI), the
lactate extraction ratio determined by simultaneous blood
sampling from the aorta and the CS reveals that repeated
balloon inﬂation can—in the short term, at least—enhance
ischaemic preconditioning without collateral recruitment.89
Various strategies aiming at minimizing myocardial injury
peri-CABG has been evaluated using similar surrogates
deﬁned in indices measured in the CS blood.90
Coronary retroperfusion, a technique involving CS cannulation, subsequent balloon occlusion, and retrograde venous
injection, has also been used in an attempt to enhance
ischaemic preconditioning and reduce complications
particularly in those undergoing PCI. Berland et al.91
successfully catheterized the CS (average time , 3 min),
with subsequent placement of an auto-inﬂatable balloon
catheter in the great cardiac vein. The protocol involved
synchronized retrograde perfusion using this catheter at
the time of intracoronary balloon inﬂation during the PCI
procedure. Of the 12 patients studied, fewer episodes of
chest pain were reported during the 101 (+ 36) s
of balloon occlusion, and quantitatively, electrographic
ST was reduced (10.4 + 7.8 mm compared with
18.8 + 10.6 mm in controls; P , 0.01).
Further studies are therefore needed to fully evaluate the
clinical impact and potential optimal use of procedural variables such as duration and frequency of balloon inﬂation or
stent type and deployment in ischaemic preconditioning
during PCI.
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adhesion molecule-1 and the induction of MCP-1 in endothelial cells—all these changes potentially destabilize
plaque structure. From peripheral blood samples, systemically elevated C-reactive protein levels are associated
with an increased risk of subsequent myocardial infarction,
admission with unstable chest pain symptoms, and recurrent
ischaemic events.77 In an angiographic study of patients with
acute coronary syndrome, a close correlation exists between
peripheral serum C-reactive protein levels, target lesion
complexity,78 and angioplasty outcome.79
Assays of C-reactive protein from the CS have been used
to compare the level within the coronary tree and systemically in differing clinical conditions. Techniques to harvest
blood using distal protection coronary devices have further
helped to elucidate the role of C-reactive protein during
the mechanical treatment of active coronary plaque
disease. Indeed, CS levels of C-reactive protein have been
found to be signiﬁcantly higher in patients with chronic
CAD and in patients with unstable angina,80 but interestingly, not in those with an acute myocardial infarction.
This is despite elevated markers such as IL-1b, IL-8, and
TNF-a found following coronary culprit lesion in the
setting of acute myocardial infarction.81
The precise reason as to why CS levels of C-reactive
protein are not elevated in occlusive coronary disease is
unclear. One possible explanation of this paradox is that
many cytokines, such as TNF-a and IL-6, are produced
in situ as a result of myocardial necrosis and, hence, are
an ‘after effect’ of the acute infarction process. In unstable
angina, a low-grade chronic inﬂammatory process exists, as
suggested by high-C-reactive protein levels that precede
cardiac troponin release and the ensuing activation of cytokines. Further in-depth understanding of the role of various
inﬂammatory cytokines has been gained by combining CS
site with intracoronary sampling. A recent study of 41
patients with acute myocardial infarction also conﬁrmed
similar ﬁndings from the site of plaque rupture and
suggested the origin (and role) of C-reactive protein as a systemic acute phase reactant.82 No increase or ‘consumption’
of C-reactive protein was seen before and after lesion in
these patients, whereas changes in IL-6 and TNF-a levels
correlated well with the extent of myocyte necrosis, as
measured by the level of troponin rise.
CS catheterization has also been utilized to evaluate the
extent of the inﬂammatory response within the coronary circulation during unstable symptoms. For example, Buffon
et al.83 found that the local response in acute coronary syndromes was not restricted to the unstable plaque but was
present throughout the coronary vasculature. Levels of neutrophil myeloperoxidase activity (with enzymatic depletion
mirroring enhanced inﬂammatory processes) were assayed
from aortic blood and segmental branches of the coronary
venous system, and activity was lowered in CS blood draining the site of coronary culprit lesion as well as non-affected
areas.84 Of course, these ﬁndings are dependent upon the
response moment and circulatory half life of the biomarkers
concerned, as well as being confounded by re-circulation.
935
936
Coronary sinus sampling during coronary
interventional procedures and outcomes
limited contemporary data with regard to PCI involving
DES, glycoprotein IIb IIIa inhibitors, or combination platelet
inhibition with clopidogrel and aspirin.
Responses to vascular growth therapies in CAD
Manipulating the growth factors regulating angiogenesis has
been widely studied as potential treatment to enhance coronary perfusion,106 particularly in patients not suitable for
conventional revascularization. Given the potential therapeutic application of vascular growth factors in coronary
heart disease,107 animal models have been mostly used to
demonstrate the efﬁcacy of percutaneous intramyocardial
delivery using CS.108 In one animal model,109 for example,
venous injection of radiographic contrast following balloon
occlusion of the CS led to inﬁltration of targeted myocardial
regions. This radiographic effect persisted for at least
30 min. Delivery of autologous bone marrow can be done
effectively in an animal model via the CS and transient
occlusion, resulting in improved angiogenesis in areas with
myocardial injury.110
Thus, the feasibility of percutaneous selective coronary
venous cannulation and injection provides the potential as
a novel approach for local myocardial drug delivery. This
aspect can be extended to include intracardiac monitoring
and possibly, tailoring of treatment. For example, in
Fabry’s disease (an X-linked inborn metabolic disorder
caused by deﬁcient activity of a-galactosidase A111),
assays of enzymatic delivery and customization of intravascular levels have been successfully performed using
samples from the CS.112 One case report also used the coronary venous system to ‘retrogradely’ perfuse ischaemic myocardium.113 In this patient—who had diffuse CAD, not
amenable to conventional revascularization—a percutaneous ﬁstula was created between the left anterior descending artery and the interventricular branch of the
coronary circulation with proximal occlusion of the vein.
This ﬁstula was still patent at 12 months, with subjective
improvement in symptoms.
The impact of systemic drugs on the coronary circulation
and, in particular, on PCI has been evaluated using CS
sampling. In a small number (n ¼ 9) of patients undergoing PCI,114 nifedipine CR has been shown to reduce the
intracardiac C-reactive protein level and vasospasm
periprocedurally.
Limitations of coronary sinus catheterization
A large body of literature is broadly supportive of CS
sampling as a better means of deﬁning both acute and
chronic cardiac responses to ischaemia and atheroma
(Figure 5). The invasive nature of CS cannulation carries a
small risk from the additional venous access site, transient
supraventricular arrhythmias, and failure to achieve a
stable catheter position with adequate exclusion of atrial
blood. Furthermore, activation of platelet and thrombin
production remains a potential drawback for CS cannulation
and manipulation, although this effect is attenuated using
heparin-bonded catheters.115 Though well recognized in
right-heart catheterization cases from the 1980s,116 CS
thrombosis is poorly documented with contemporary techniques and catheters. A recent review of over 10 000 CS
cannulations for the induction of retrograde cardioplegia
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PCI including stent placement remains the commonest
method of revascularization for CHD, in both the USA84
and the UK.92 By reducing the incidence of acute vessel
closure, recoil, and maintaining luminal patency, stent
deployment is now the preferred method when compared
with plain balloon angioplasty in PCI.93 However, the rate
of angiographic in-stent restenosis remains high, at up to
40% with bare metal stent94 and 25% with drug-eluting
stent (DES) in complex PCI.95 Furthermore, complications
such as subacute thrombosis can develop in both bare
metal-96–98 and DES-treated patients.99
CS sampling has been used infrequently to address potential markers of in-stent stenoses which may be distinct from
endogenous atheroma. In a study of plasma levels of inﬂammatory cytokines, as well as cytokine-generation capacities
of monocytes, before PCI and after 3–6 months follow-up
period in 34 consecutive patients, inﬂammatory indices
were signiﬁcantly decreased in patients without restenosis
compared with those with restenosis.100 CS levels of IL-6
are increased after PCI, and higher levels in response to
PCI have been associated with late restenosis.101 In
Indo-Asians undergoing PCI, platelet function or activity
with varying concentrations of adenosine di-phosphate was
assessed using a platelet aggregometer.102 In the patients
who developed restenosis, signiﬁcantly higher basal platelet
aggregability was found, though no signiﬁcant difference or
trend was noted over time in the small number (n ¼ 7)
investigated.
Plasminogen activator inhibitor-1 (PAI-1, an index of ﬁbrinolysis) activity changes immediately after PCI without stent
implantation may also be indicative of clinical restenosis.
Indeed, plasma levels of PAI-1 activity and ﬁbrin D-dimer
(a ﬁbrin degradation product) were evaluated in two
groups of patients who underwent either elective balloon
PTCA alone or with stent implantation.103 Following PTCA,
PAI-1 activity was higher in patients with subsequent clinical
recurrence with restenosis (P , 0.005 in both groups) than
in those without, whereas no differences were found in
ﬁbrin D-dimer levels.
The role of neutrophil adhesion molecules104 (using
CD11a, b, c and CD18 epitopes) in patients undergoing PCI
has also been studied in the process of restenosis. The
percent change in the expression of CD18 at 48 h after
PTCA (from baseline) and that of CD11b were signiﬁcantly
correlated (r ¼ 0.73, P ¼ 0.0008) in patients with restenosis. Similarly, activation of neutrophil adhesion molecule
Mac-1 at 48 h after PTCA may have value as a predictor of
subsequent restenosis.
CS levels of thrombin activity can be used to assess the
localized effectiveness of a given dose of heparin during
PCI. In one study,105 plasma levels of ﬁbrinopeptide A
(marker of thrombin activity) were elevated from the coronary and aortic root in patients with angiographic evidence of
thrombus. This seems to indicate that heparin-resistant
thrombin activity is associated with angiographic evidence
of intracoronary thrombus and potentially, with ischaemic
complications of PCI.
Although the majority of studies have shown the importance of intracoronary assays and linkage to the processes
of vessel or stent restenosis or thrombosis, there are
R. Jaumdally et al.
Coronary sinus sampling and pathophysiology
Figure 5
937
Coronary sinus assay of blood biomarkers—the pros and cons.
Conclusions
Even under stable clinical conditions, atherosclerosis
remains a dynamic process. Coronary circulatory measures
via the CS can be used to provide an insight into the intricate
pathophysiological processes underlying myocardial ischaemia. This invasive approach has helped in our understanding
of these factors at intracardiac level and hence, potentially
guides therapy during unstable plaque disease. Indeed, the
use of CS blood sampling can provide investigators a
method to assess the local changes in the myocardium,
including ‘downstream’ changes following local therapeutic
interventions, such as stem cell and drug administration.
Furthermore, the potential ability to study the change
along the different coronary circulation at different
branches of CS is a possibility. Access via the venous circulation of the heart has also been used for the administration of
drugs locally. Nonetheless, the invasive nature of this technique has limited its use in small study populations, and
serial measurements over time are impractical.
In conclusion, CS sampling offers a unique way of assessing
the cardiac milieu and may prove useful in the monitoring of
both local and systemic drugs and technologies. In future,
larger studies will be needed to correlate CS sampling of
various biomarkers with clinical outcomes.
Conﬂict of interest: none declared.
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