Download Effect of experimental coronary sinus ligation on myocardial

BASIC SCIENCE
Europace (2016) 18, 1897–1904
doi:10.1093/europace/euv431
Effect of experimental coronary sinus ligation on
myocardial structure and function in the presence
or absence of structural heart disease: an insight
for the interventional electrophysiologist
Osama Ali Diab 1*, Mohammed Said Amer 2, and Rania Ahmed Salah El-Din 3
1
Faculty of Medicine, Department of Cardiology, Ain Shams University, Cairo, Egypt; 2Faculty of Veterinary Medicine, Department of Surgery, Cairo University, Cairo, Egypt; and
Department of Anatomy, Ain Shams University, Cairo, Egypt
3
Received 3 October 2015; accepted after revision 23 November 2015; online publish-ahead-of-print 5 February 2016
Aims
To study the effect of coronary sinus (CS) occlusion on normal hearts and hearts with structural disease.
.....................................................................................................................................................................................
Methods
We included 32 dogs, divided into 4 groups: (1) CS ligation (CSL): subjected to CSL; (2) control group: no intervention;
and results
(3) MI-CSL group: subjected to myocardial infarction (MI) induction followed by CSL after 1 week; and (4) MI-control
group: subjected to MI induction, then open thoracotomy after 1 week without CSL. Electrocardiography, echocardiography, histopathology, and immunohistochemistry were done before and after CSL. In CSL group, there were no
significant electrocardiographic or echocardiographic changes after CSL, although there was interstitial oedema that
decreased after 1 week with the appearance of Thebesian vessels and positive staining for vascular endothelial growth
factor. In MI-CSL group, there was significant increase in left ventricular (LV) end-systolic diameter (P ¼ 02), decrease in
LV fractional shortening (P ¼ 0.0001), and LV ejection fraction (P ¼ 0.002) in comparison with MI-control group,
associated with severe myocardial degeneration.
.....................................................................................................................................................................................
Conclusion
Acute CS occlusion could be compensated in normal hearts, but may be detrimental in the presence of structural
heart disease.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Coronary sinus † Coronary sinus occlusion † Thebesian vessels
Introduction
Coronary sinus (CS) dissection and endothelial injury, with subsequent thrombosis, may occur during procedures that use access to
the right atrium, such as insertion of central venous lines,1 left ventricular (LV) lead placement during cardiac resynchronization therapy
(CRT), or endocarditis affecting the LV lead.2 Radiofrequency ablation
of accessory pathway using CS approach3 may result in CS occlusion.
Coronary sinus can be a target for ablation in some cases of persistent
atrial fibrillation (AF) and vein of Marshall tachycardia.4
The heart is drained by three separate systems: the coronary sinus, the anterior cardiac veins, and the Thebesian veins. The coronary sinus system drains 70 –80% of the total cardiac venous return.5
Since there are many anastomotic connections between the three
venous systems, the Thebesian veins that drain into all four chambers can drain up to 50% of cardiac venous return in full capacity.6
Since the flow in Thebesian veins is bidirectional, they are better to
refer to as ‘Thebesian vessels’. There are two distinct forms of Thebesian vessels. The first type is a large diameter arterioluminal system that drains blood directly from the arteries or capillary bed into
the ventricles bypassing the capillary beds, which is common in the
right ventricle. The second type is a smaller-diameter thin-walled
venoluminal system that shunts blood from coronary veins or capillary bed into the ventricular cavities bypassing the coronary sinus.5,6
A unique form of Thebesian vessels is ‘Thebesian sinusoids’. These
are irregular spaces, channels, or lacunae, formed of a single layer of
endothelium, larger than capillaries in diameter, located in the subendocardial region.7
Clinical course of CS obstruction remains unpredictable. Theoretically, no deleterious effects would be expected due to the presence of an alternative venous drainage. However, cases of CS
obstruction with massive haemorrhagic necrosis, pericardial
* Corresponding author. Tel: +2 0109 0555025; fax: +2 02 24820416. E-mail address: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2016. For permissions please email: [email protected].
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O. Ali Diab et al.
What’s new?
32 dogs
† The current study provides an insight to the interventional
electrophysiologist during techniques reported to be complicated with coronary sinus (CS) occlusion or possibly associated with this risk, the rarity of which should not hinder
highlighting its consequences that are still hazy among the
scientific community due to lack of follow-up studies.
† We are the first to thoroughly evaluate the effect of CS occlusion by electrocardiogram, echocardiography, histopathology, and immunohistochemistry, and to add a group with
structural heart disease.
† We demonstrated that CS obstruction alters myocardial
structure in both normal and diseased hearts, being more severe in the later. This could be compensated by normal hearts
with normal physiologic reserve, but not in diseased hearts.
† Based on our results, conservative treatment is recommended
if CS occlusion occurred in normal hearts, while CS stenting
may be considered in the case of structural heart disease.
Methods
Thirty-two apparently healthy mongrel dogs weighing 15 – 20 kg with
the age of 2 – 5 years of both sexes were used. The animals were vaccinated and guarded from internal and external parasites. All animals were
housed individually in metal cages and were fed once daily with a standard balanced diet.
Control group
N=4
CS ligation
No intervention
LAD ligation
1 week
ECG
Echocardiography
Morphology
IHC
Morphology
IHC
CS ligation
MI-CSL group
N = 10
MI-control group
N=8
LAD ligation
1 week
Thoracotomy
ECG
Echocardiography
Morphology
IHC
Figure 1 Study design. CSL, coronary sinus ligation; MI, myocardial infarction; LAD, left anterior descending coronary artery.
–
tamponade, LV dysfunction, and even sudden cardiac death have
been reported in the literature.1,8 Currently, little is known regarding the pathologic sequences of CS occlusion in the setting of normal hearts or in the presence of structural heart disease. With the
increasing use of CS access in cardiovascular interventions, it is useful to predict the consequences of incidental CS occlusion.
CSL group
N = 10
Myocardial infarction-control group (MI-control group): Included
eight dogs subjected to LAD ligation, followed by open thoracotomy without CSL after 1 week under the same protocol of general
anaesthesia used in MI-CSL group. Electrocardiogram and echocardiography were done before and after MI induction, and after open
thoracotomy prior to animal sacrifice. Animals were sacrificed at
24 h (3 dogs) and 1 week (5 dogs) after open thoracotomy.
Electrocardiographic assessment
Twelve-lead surface ECG was done before and after experimental procedure (prior to animal sacrifice) at 10 mm/mV and 25 mm/s. RR interval, QRS complex duration, QT and QTc intervals were measured. QT
interval was measured in lead II by tangent method from the average of
three cardiac cycles and was corrected to RR interval according to Frip
dericia’s formula (QTc ¼ QT/3 RR),9 which was preferred to Bazett’s
formula in dogs.10 Apart from non-specific T wave changes and premature beats, any ST segment shift ≥1 mm was considered significant
for myocardial ischaemia. Sustained or non-sustained arrhythmias, or
conduction defects following CSL were assessed.
Study design
Animals were allocated to four groups as follows (Figure 1):
–
–
–
Coronary sinus ligation group (CSL group): Included 10 dogs with
normal hearts subjected to CSL through open thoracotomy. Animals were sacrificed at 24 h (5 dogs) and 1 week (5 dogs) after
the procedure. Electrocardiographic (ECG) and echocardiographic
data before and after CSL were compared with each other. Morphologic examination and immunohistochemical (IHC) staining of
this group were compared with that of the control group.
Control group: Including four healthy dogs with no intervention,
which were sacrificed for morphologic and IHC examination.
Myocardial infarction-CS ligation group (MI-CSL group): Included
10 dogs with structural heart disease in the form of induced myocardial infarction (MI) through ligation of left anterior descending
coronary artery (LAD) after the first diagonal branch. Coronary sinus
ligation was done 7 days after MI induction. Surviving animals (9 dogs)
were sacrificed at 24 h (4 dogs) and 1 week (5 dogs) after CSL. Due
to possible remodelling with time, ECG and echocardiographic data
before and after CSL were compared with that of a control-sham operated group (MI-control group). Morphologic examination and IHC
were also compared with that of MI-control group.
Echocardiographic assessment
Echocardiographic examination was performed in lateral recumbent position through right parasternal window between 3rd and 5th intercostal
spaces 1 –8 cm lateral to sternum in conscious state.11 A phased-array
probe was used at a frequency of 2.5–3.5 MHz, attached to SAMSUNG
MADISON-SONO ACE R3 ultrasound machine with a depth of 15 –
30 cm. Parasternal short-axis view at the mid-ventricular level was selected for two-dimensional (2-D) and M-mode images to assess the LV
dimensions, diastolic wall thickness, fractional shortening (FS), and ejection fraction (EF). A simultaneous ECG was recorded for the correct timing of measurements within the cardiac cycle. At least three cardiac cycles
were measured, and the mean value for each parameter was obtained.
Preoperative preparation and general
anaesthesia
All experimental animals were examined preoperatively via routine
physical examination. Animals with any chest disease or cardiac murmurs on auscultation were not enrolled in the study. Dogs were administered intravenous (IV) atropine (0.04 mg/kg SC). Anaesthesia was
induced with IV ketamine (10 mg/kg) and diazepam (1 mg/kg). After
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Consequences of coronary sinus occlusion
intubation, dogs were maintained with isoflurane 1% and fentanyl
(0.25 mg/kg/min).
Experimental procedure
A standard left lateral thoracotomy was performed at the 5th intercostal
space. Incisions for all dogs extended from 2 cm ventral to the rib head
to just dorsal to the left internal thoracic artery. Finochietto retractors
were used for rib retraction. The pericardium was opened followed by
the proximal CS complete ligation using silk suture 3/0 near its opening
into the right atrium. In MI-CSL and MI-control groups, the LAD was
ligated after its first diagonal branch.
Animal sacrifice
Euthanasia was performed via an overdose (100 mg/kg) of IV thiopental
sodium. The heart was harvested and examined grossly after removing
of the pericardium. Specimens were taken from the anterior and lateral
walls of the LV. In infarcted hearts, specimens were taken from the viable
myocardium at least 1 cm from the infarct border.
Light microscopy
Specimens of the LV were fixed immediately in 10% formalin for 7 days.
They were processed and embedded in paraffin blocks. Serial sections
5 mm thick were sliced and stained with haematoxylin and eosin (H&E).
Immunohistochemistry
Immunohistochemistry staining was performed to assess vascular endothelial growth factor (VEGF) expression in the heart after CSL, using
rabbit polyclonal VEGF antibody; Cat. No. RB-9031-R7 (Thermo Fisher
Scientific, Inc., Fremont, CA, USA) at a dilution of 1:200. Avidin – Biotin
immunoperoxidase complex technique was used12 by applying the
super sensitive detection kit (Biogenex, CA, USA). The tissue sections
were fixed on poly-L-lysine-coated slides overnight at 378C. They were
deparaffinized and rehydrated through graded alcohol series. The slides
were placed in a target retrieval solution at a pH of 9.9, and antigen retrieval was performed overnight at 408C. After quenching in 3% hydrogen peroxide and blocking for 5 min, the sections were incubated at 48C
for 1 h. Biotinylated anti-mouse immunoglobulin and streptavidin conjugated to horseradish peroxidase were added. Then, 3,3′ -diaminobenzidine
as the substrate or chromogen was used to form an insoluble brown product. Haematoxylin was used as counterstain.
Statistical analysis
Statistical Package for Social Sciences (SPSS, Inc., version 21, Chicago, IL,
USA) was used. Continuous data were expressed as mean + standard
deviation. The D’Agostino– Pearson test was used to ascertain normality of data, then paired t-test was used to compare ECG and echocardiographic data before and after CSL in CSL group, and unpaired t-test was
used to compare data of MI-CSL with that of MI-control group. P-value
was considered significant if ,0.05.
Table 1 Electrocardiographic and echocardiographic
measures before and after coronary sinus ligation in
animals with normal hearts (CSL group)
Before CSL
After CSL
P-value
................................................................................
RR interval (ms)
459 + 51.73
QRS duration (ms)
55.5 + 8.95
QT interval (ms)
QTc (ms)
451 + 92.18 0.77
57 + 11.59 0.19
203 + 15.67
204 + 22.21 0.87
262.84 + 14.94 267.28 + 32.73 0.62
6.95 + 0.68
7.4 + 1.07
6.71 + 0.69
23.46 + 2.22
7.2 + 0.91
23.97 + 2.54
0.1
0.7
LVESD (mm)
13.96 + 1.85
14.78 + 1.77
0.26
FS (%)
EF (%)
39.88 + 5.24
72.6 + 6.76
37.83 + 5.58
69.98 + 7.16
0.29
0.28
IVSd thickness (mm)
LVFWd thickness (mm)
LVEDD (mm)
0.068
CSL, coronary sinus ligation; IVSd, interventricular septum in end diastole; LVFWd,
left ventricular free wall in end diastole; LVEDD, left ventricular end diastolic
diameter; LVESD, left ventricular end-systolic diameter; FS, fractional shortening;
EF, ejection fraction.
Histopathology at 24 h after CSL revealed congested epicardial
coronary vessels with interstitial and subendocardial oedema denoted by widened interstitial and subendocardial spaces, with intact
cardiomyocytes, nuclei, and intercalated discs. No abnormalities
were found in the control group (Figure 2).
Histopathology at 1 week after CSL showed Thebesian vessels
and sinusoids (Figure 3), with less interstitial oedema and intact myocardial tissue apart from vacuolar degeneration seen in two animals
(Figure 3C). No Thebesian vessels were noted in the control group.
Thebesian vessels were lined with a single layer of endothelial cells
with no media or adventitia. Luminal vessels opened directly into the
ventricular cavity; since they are lacking medial layer, they were considered as venoluminal vessels; some were guarded by a sphincteric
opening (Figure 3B), or a tiny valve formed of a thin endothelial layer
(Figure 3C). From the ventricular cavity to the Thebesian vessels, the
endocardium continued as an endothelial lining, while the subendocardial space that contains the Purkinje fibres disappeared at the venoluminal junction (Figure 3B). Thebesian sinusoids were seen in the
subendocardial region (Figure 3D), with irregular shapes, larger than
capillaries (the latter accommodate a single red blood cell), formed
of a single layer of endothelium with no media or adventitia.
Immunohistochemistry for VEGF in the myocardium showed
negative staining in the control group (Figure 3E) and positive staining in the CSL group at 1 week after CSL (Figure 3F).
Results
Myocardial infarction-coronary sinus
ligation group
Coronary sinus ligation group
There were no abnormalities in baseline ECG and echocardiography prior to MI induction. One out of the 10 dogs with induced
MI died intraoperatively during CSL due to bradycardia that progressed to asystole. There were no differences between MI-CSL
group and MI-control group regarding ECG and echocardiographic
measures before and after MI induction (Table 2). After CSL in
MI-CSL group or open thoracotomy in MI-control group, there
There were no abnormalities in baseline ECG and echocardiography. Following CSL, there were no deaths among this group until
animals were sacrificed. Electrocardiographic and echocardiographic measures after CSL did not significantly differ from that before
CSL (Table 1). There was no ST segment shift, sustained arrhythmia
or conduction defects following CSL prior to animal sacrifice.
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O. Ali Diab et al.
A
B
C
D
e
Figure 2 Light microscopic images (H&E) of a control dog (A) and CSL group (B – D) 24 h after CSL. (A) Normal appearance of the epicardial
coronary vessels with underlying compact myocardium. (B) Engorged epicardial coronary vein (right thick arrow) and artery (left thick arrow) with
widened interstitial spaces (thin arrows) denoting interstitial oedema. (C) Endocardium (e), Purkinje fibre cells (thin arrow), and widened subendocardial space (thick arrows). (D) High-power image showing intact cardiomyocytes with normal branching appearance, normal nuclei (thick
arrow), and intercalated discs (thin arrows).
were significant differences in left ventricular end-systolic diameter
(LVESD), FS, and EF (P ¼ 0.02, 0.0001, and 0.002, respectively).
Histopathologic examination of the non-infarcted myocardium of
the MI-control group was unremarkable (Figure 4A). Non-infarcted
myocardium of CSL-MI group at 24 h following CSL showed interstitial oedema with focal areas of hypereosinophilic necrosis
(Figure 4B). At 1 week, there was myocardial degeneration with
loss of contractile apparatus and loss of normal myocardial architecture (Figure 4C) and dilated congested Thebesian sinusoids
(Figure 4D). Immunohistochemistry for VEGF in the myocardium
showed negative staining of the viable myocardium in the MI-control
group 1 week after MI induction (Figure 4E) and positive staining
in the MI-CSL group 1 week after CSL (Figure 4F).
Discussion
Recent developments in cardiac device and ablation therapy required not only an orientation with CS anatomy, but also a thorough
knowledge of the consequences of possible CS occlusion in either
normal or diseased hearts.
Main findings
In the present study, acute CS occlusion did not significantly affect
normal hearts regarding ECG and echocardiographic parameters.
However, at the microscopic level, there was remarkable interstitial oedema that decreased by the 7th day post-CSL. This was concomitant with the appearance of Thebesian vessels and sinusoids,
and expression of VEGF. Echocardiographically, there was an increase in LV septal and free wall thickness, likely due to myocardial
oedema, which did not reach statistical significance. We studied
the left ventricle as the right side is normally rich in Thebesian vessels. The development of observable Thebesian vessels in the LV
after CSL suggests either dilatation of pre-existing vessels or
neovascularization.
It has been demonstrated that the Thebesian vessels are able to
carry out the majority of venous return in situations where the epicardial coronary veins are compromised.13 In the case of normal
CS pressure, the CS drains the majority of blood, but in the case
of high CS pressure, the blood is drained through the Thebesian
system. The small resistance Thebesian vessels can explain some
reports that retrograde delivery of cardioplegic solutions via the
coronary sinus at a pressure of 30 – 40 mmHg resulted in large
draining of solution into the ventricles without traversing capillary
beds.14
In the present study, we thoroughly combined electrocardiography, echocardiography, histopathology, and immunohistochemistry; and we added a group with structural heart
disease, with timed follow-up design. This may serve the field of
1901
Consequences of coronary sinus occlusion
A
cav
PM
B
cav
C
D
cav
E
F
Figure 3 Light microscopic images (H&E) of the LV myocardium of CSL group at 1 week after CSL. (A) Papillary muscle (PM) showing Thebesian
vessel at its base (rectangle). (B) Magnification of the rectangle in A, showing venoluminal vessel opening into the ventricular cavity (cav) through a
sphincter-like neck (large arrow), with some red blood cells inside. The junction between the endocardium and the vessel lining is marked with
disappearance of the subendocardial space (small arrow). (C) Thebesian vessel opening into the ventricular cavity (cav), guarded by a valve formed
of a thin endothelial layer (arrow). The surrounding myocardium shows vacuolar degeneration. (D) Thebesian sinusoids (arrows) seen in the subendocardial region, of irregular shapes, larger than capillaries in diameter, formed of a single layer of endothelium with no media or adventitia.
(E) Immunohistochemistry of the control group showing negative staining for VEGF. (F) Immunohistochemistry of CSL group 1 week after CSL
showing positive staining for VEGF.
electrophysiology and device therapy in which the effect of CS injury
is still questioned.
In one study, Miyahara et al. 15 induced CS thrombosis in dogs with
normal hearts through injection of thrombin in a balloon-occluded
CS. They reported histologic changes similar to that of haemorrhagic MI associated with cardiac enzyme elevation and ischaemic
ECG changes. The difference between their results and ours may
be explained by the following: (1) They induced CS thrombosis by
thrombin injection, which might leak into the capillary bed or into
the arterioles through Thebesian vessels. (2) They noticed the presence of fresh thrombi in the CS, great cardiac vein, and small vessels.
Thrombus could also be propagated back to the arterioles.
(3) Thrombus might embolize to the arterial side. In agreement
with our findings, no MI or haemorrhage were found on postmortem microscopic examination in a patient with CS thrombosis
due to injury by central venous catheter.8 As reported by the
authors, the cause of death in this case might be pulmonary embolism as evidenced by the presence of microemboli in both lungs.
However, we found two cases with myocardial vacuolar degeneration at 1 week after CSL in CSL group. This abnormality was
reported to occur in myocardial ischaemia.16 It has been demonstrated that CS occlusion may result in decrease in coronary arterial
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O. Ali Diab et al.
Table 2 Electrocardiographic and echocardiographic measures before and after MI induction and CS ligation in MI-CSL
compared with MI-control groups
Baseline
After MI induction
After CSL/open thoracotomy
.................................................. .................................................. ..................................................
MI-control
(n 5 8)
MI-CSL
(n 5 10)
P-value
MI-control
(n 5 8)
MI-CSL
(n 5 10)
P-value
MI-control
(n 5 8)
MI-CSL
(n 5 9)a
P-value
...............................................................................................................................................................................
RR (ms)
QRS (ms)
QT (ms)
QTc (ms)
IVSd (mm)
477.5 + 34.5
52.5 + 8.8
480 + 74.8
54 + 9.6
0.93
0.73
422.5 + 54.9
58.7 + 11.2
200 + 15.1
204 + 11.7
0.53
230 + 32
256.6 + 21.2
6.5 + 0.8
261.3 + 20.7
6.6 + 0.73
0.64
0.92
307 + 45.1
7.1 + 1.3
6.6 + 0.93
0.79
0.88
406.6 + 22.3
60 + 5.5
395.3 + 39.6
60 + 7.5
0.45
1.00
230 + 28.6
1.00
217.5 + 22.5
224.4 + 27.8
0.58
308.4 + 39.9
6.8 + 1.4
0.94
0.63
296.5 + 31.1
6.3 + 0.7
302.5 + 37.5
6.6 + 0.5
0.72
0.35
0.95
7 + 1.3
6.9 + 1.4
0.88
7 + 0.7
7.2 + 0.8
0.57
LVEDD (mm)
LVESD (mm)
23.5 + 1.8
13.8 + 1.9
23.1 + 2.2
14 + 1.7
0.69
0.88
27.3 + 3.7
21.3 + 4.1
26.3 + 4.5
20.1 + 4.6
0.59
0.55
26.7 + 3.2
20.1 + 1.7
27 + 2.8
23.1 + 3.1
0.86
0.02
FS (%)
37.1 + 4.9
36.5 + 4.5
0.78
21.1 + 9.1
24.4 + 9.9
0.48
19.6 + 2.8
13.8 + 1
0.0001
EF (%)
69.7 + 6.9
68.9 + 6.9
0.8
39.1 + 16.6
0.31
38.5 + 5.1
30.8 + 3.2
0.002
LVFWd (mm)
6.6 + 0.91
416 + 49.7
58 + 10.3
47 + 15.5
MI, myocardial infarction; CSL, coronary sinus ligation; IVSd, interventricular septum in end diastole; LVFWd, left ventricular free wall in end diastole; LVEDD, left ventricular
end diastolic diameter; LVESD, left ventricular end-systolic diameter; FS, fractional shortening; EF, ejection fraction.
a
One animal died intraoperatively.
blood flow. Nevertheless, it is unknown if this finding was due to CS
occlusion or pre-existing atherosclerosis. Owing to the relatively
few Thebesian vessels in canine LV, if any decrease in coronary
blood flow following CS pressure elevation occurred, it would be
compensated by an increase in oxygen extraction to maintain oxygen supply within normal range. Therefore, our findings should not
be interpreted as completely ‘harmless’ CS occlusion, but rather a
‘compensated harm’ in hearts with normal physiologic reserve.
On the other side, in the presence of structural heart disease,
MI-CSL group in the present study showed significant increase in
LVESD and deterioration of LV systolic function after CS occlusion,
in addition to a case with intraoperative death. At the microscopic
level, non-infarcted myocardium showed focal necrosis and marked
degenerative changes. This indicates that acute CS occlusion cannot
be tolerated by compromised hearts. In a similar context, Hazan
et al. reported a case with poor LV systolic function, post-mitral
valve replacement, who developed CS thrombosis that resulted in
acute clinical decompensation.17 Another case was reported to develop CS thrombosis with underlying chronic heart failure and EF of
10%, who was admitted with acute decompensation.18
Few cases with normal hearts, in whom CS thrombosis was life
threatening, were reported. Coronary sinus thrombosis in such
cases has resulted in cardiac tamponade or pulmonary embolism.1,8
If these conditions were properly managed, CS obstruction alone
would not likely to be fatal.
Onset of CS occlusion may influence the clinical outcome. Despite the presence of chronic heart failure, CS obstruction was tolerated in a patient with CRT, probably due to the gradual onset of
obstruction as evidenced by the gradual increase in LV lead threshold, likely due to fibrosis at the lead tip.2 Gradual CS obstruction
might give chance to collaterals to develop between CS, anterior
cardiac veins, and Thebesian vessels. From the available data and
our findings, we suggest that the clinical outcome of CS obstruction
is determined by the presence or absence of underlying heart
disease, and the onset of obstruction whether acute or gradual.
The worst-case scenario is an acute CS occlusion in a diseased heart.
Thebesian vessels
The coronary venous system has received little attention over many
decades; hence, little is known regarding the consequences of CS
obstruction. Thebesian system is made up of canals that open into
the cavity, or sinusoids that are located in the subendocardial layers
which lack the middle muscular layer in their walls.5 – 7 This was far
similar to our description of Thebesian system.
We demonstrated that the Thebesian vessels at their openings
into the LV cavity showed a valve or a sphincter-like outlet. Similarly,
Ratajczyk-Pakalska et al. 19 have observed the presence of a monocuspid valve, or sphincter, at the outlet of the Thebesian vessels. We
also demonstrate that Thebesian vessels that drained into the LV
cavity did not have medial layers. This is in agreement with what previously reported that the LV is lacking arterioluminal vessels that are
present only in the right chambers.5,6,13
We observed that the subendocardial space that contains the
Purkinje fibres is lost at the junction between the endocardium
and the endothelium of Thebesian vessel. This may help to differentiate between Thebesian vessels and normal endocardial recesses
associated with ventricular trabeculations.
In the present study, no Thebesian vessels were observed in any
of the control animals. Those vessels might be absent or collapsed
and open only when CS pressure increases. Thebesian system is
known to be poorly developed or absent in the left heart chambers.5,6,13 Although we observed Thebesian sinusoids in the subendocardial region, we did not observe the so-called ‘sponge-like’
appearance, which described large networks of Thebesian sinusoids
surrounding myocardial tissue islands; an assumption that was the
rationale behind transmyocardial laser revascularization (TMR)
which was abandoned.7
1903
Consequences of coronary sinus occlusion
A
B
C
D
S
E
F
Figure 4 Light microscopic images (H&E) of the non-infarcted LV myocardium of MI-control group (A) and the CSL-MI group (B – D). (A) Normal myocardial tissue appearance. (B) Specimen taken at 24 h after CSL showing widened interstitial spaces with focal areas of hypereosinophilic
necosios (arrows). (C) Specimen taken at 1 week after CSL showing myocardial degeneration with partial (small arrow) and complete (large
arrow) loss of the contractile apparatus and loss of normal myocardial architecture. (D) Specimen taken after 1 week of CSL showing a large
Thebesian sinusoid (S) filled with red blood cells (arrow) surrounded with degenerated hypereosinophilic myocardium.
(E) Immunohistochemistry of the non-infarcted myocardium of MI-control group at 1 week after MI induction showing negative staining for
VEGF. (F) Immunohistochemistry of the MI-CSL group at 1 week after CSL showing positive staining for VEGF.
Vascular endothelial growth factor
Vascular endothelial growth factor is the key cytokine in angiogenesis in myocardial ischaemia. In infarcted hearts, angiogenesis started
in the border zone and peaked at 7th day post-MI in the infarcted
zone.20 In CSL group in our study, VEGF was expressed in the myocardium after CSL by the 7th day, denoting certain degree of ischaemia, likely due to some decrease in coronary arterial flow being
compensated by angiogenesis. Hence, no significant ECG or echocardiographic changes occurred. In MI-CSL group in our study,
VEGF was expressed in the non-infarcted myocardium 1 cm from
the border zone, indicating that the stimulus of angiogenesis was
the same as in CSL group rather than MI itself, in which VEGF is
almost restricted to the infarcted and border zones.20
Conclusions
In normal hearts, CS occlusion did not result in significant ECG or
echocardiographic changes, although there were microscopic
1904
abnormalities that were compensated by Thebesian system, and
likely aided by VEGF expression. In the presence of structural heart
disease, an abrupt CS occlusion might have deleterious effects on
the myocardial structure and function.
All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the ethical committee of Faculty of Veterinary Medicine, Cairo University, Egypt.
No human studies were carried out by the authors for this article.
Conflict of interest: None declared.
Funding
The study was funded by our institute and we received no grants or
contracts from elsewhere.
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