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Curr Cardiol Rep (2016) 18: 35

DOI 10.1007/s11886-016-0710-4

ISCHEMIC HEART DISEASE (D MUKHERJEE, SECTION EDITOR)

Coronary Sinus Stent: Could It Help in Refractory


Chronic Stable Angina?
Wael ElMallah 1

Published online: 27 February 2016


# Springer Science+Business Media New York 2016

Abstract Refractory angina is a life-disabling disease, even infusion through the coronary sinus, since coronary sinus re-
with the discovery of antianginal drugs and the advances in mains free of disease even when atherosclerosis is extensive.
revascularization surgically or percutaneously to improve Attempts since the 1940s to improve myocardial perfusion
symptoms. Over the last decade a renewal of interest in an through the coronary sinus were withered by the lack of clin-
old surgical modality of narrowing the coronary sinus has ical significance or conflicting data and overshadowed by the
evolved. Although the surgical procedure idea was born in innovation in coronary artery revascularization techniques [3].
1940 it was overshadowed by the development of coronary Refractory angina entails persistent symptoms in the presence
artery bypass graft and percutaneous interventions. Recently, of objective evidence of ischemia despite maximally tolerated
a percutaneous approach of reducing the coronary sinus size medical therapy and with a consensus that revascularization,
has been developed and several clinical studies have been either surgically or percutaneously, cannot be achieved [4].
reported in refractory angina patients. We review the history Recently, interest in coronary sinus intervention as a path for
of coronary sinus intervention, and explore coronary sinus myocardial perfusion in refectory angina has been revived as
stent possible mechanism of action, device design, and the several trials reported favorable outcomes in refractory angina
clinical data supporting its use. cohorts [5]. Table 1 summarizes the different CSI modalities
[5, 6, 7].
Keywords Coronary sinus intervention . Refractory angina .
Coronary sinus reducer stent
History of Coronary Sinus Occlusive Therapy

Introduction The concept of coronary sinus occlusion was first reported in


1941, when Claude Becks described his first surgical proce-
Almost, two centuries lapsed between the first description of dure of coronary sinus reduction to a diameter of 3 mm [3]. In
the, coronary venous drainage by Adam Christian Thebesius 1948, Claude Becks described his second procedure of plac-
in 1703 [1], until the first reported coronary sinus intervention ing a vascular graft between the descending thoracic aorta and
(CSI) by Prat in 1893 [2]. The Prat experiment in hens proved the coronary sinus followed by ostial reconstruction of the
that heart nutrients can be provided through via retrograde coronary sinus ostium [8]. Experimental as well as clinical
data in 200 patients with refractory angina documented a tem-
This article is part of the Topical Collection on Ischemic Heart Disease porary improvement in symptoms. However, excessive mor-
tality and severe derangements, such as myocardial hemor-
* Wael ElMallah rhage and edema, coupled with a limited understanding of
wael.elmallah@ttuhsc.edu the mechanisms resulted in abandoning this surgical approach
[9].
1
Division of Cardiology, Department of Internal Medicine, Texas
In 1984, PICSO, was developed [10]. The concept involves
Tech University Health Science Center, 4800 Alberta Avenue, El inserting a balloon tipped catheter into the coronary sinus. The
Paso, TX 79905, USA balloon has a pressure sensor. The catheter is connected to a
35 Page 2 of 6 Curr Cardiol Rep (2016) 18: 35

Table 1 Summary of coronary sinus intervention modalities

Occlusion of the coronary sinus blood flow


PICSO Pressure-controlled intermittent Pressure controlled balloon occlusion of the coronary sinus over several
coronary sinus occlusion heart beats. The pressure wave redistributes blood from normally
perfused veins retrograde into the microcirculation of deprived
myocardium. Once, systolic pressure reaches a plateau, occlusion is
released, allowing sufficient drainage.
Neovasc Reducer (TM) Coronary sinus stent reducer Permanent occlusion of the coronary sinus
Retrograde reperfusion
Becks II procedure Surgical graft shunting blood from the aorta into the coronary sinus, and
ligation of the coronary sinus to ensure delivery of arterial blood into
ischemic zones.
Cardioplegia Retro infusion of cardioplegia during cardiac arrest in surgery.
PICVA Percutaneous in situ coronary Percutaneously redirecting arterial blood flow from the occluded,
venous arterialization offending artery into an adjacent coronary vein, thereby arterializing
the vein and providing retroperfusion to ischemic myocardium
SRP Synchronized retroperfusion Synchronized retroperfusion of arterial blood during diastole in settings
of myocardial infarction, through the coronary sinus.
SSR Synchronized Suctioning of blood followed by synchronized retroperfusion of arterial
Suction and retroperfusion blood during diastole through selective access of the local coronary vein
draining the ischemic area.

console controlling the whole system. The balloon is inflated pre-mounted on over the wire balloon and is delivered through
to occlude the coronary sinus over several heart beats and an internal jugular approach. After performing a right heart
once the coronary sinus pressure plateaus, it deflates the bal- catherization and coronary sinus angiography, the Reducer is
loon, terminating the obstructing to venous flow thus permit- deployed at 30 degree left anterior oblique angulation, 1-2 mm
ting drainage of cardiac venous return. Over the last three from the coronary sinus ostium, avoiding any side branch oc-
decades, abundant data has accumulated on myocardial sal- clusion (Fig. 1). The patient is preloaded with dual antiplatelet
vage in experimental ischemia, reperfusion injury, acute glob- therapy and continued on treatment for 3-6 months [13].
al ischemia, and heart failure. More recently, evidence regard-
ing PICSO use as adjuvant therapy during primary PCI has
been reported [11, 12].
Based on the same concept, the coronary sinus (CS) Animal Studies
Reducer (Neovasc Inc., Vancouver, B.C., Canada) was devel-
oped [13]. The balloon expandable stent reduces the size of The evidence for potential benefits and possible pathways of
the coronary sinus to a 3 mm diameter with the objective of action was driven mainly from PICSO studies, while only one
treating patients with refractory angina. We are going to re- animal study has investigated the CS Reducer safety and sug-
view the design and current evidence in support for its use in gested a possible mechanism of action.
refractory angina patients. Initially, the driving hypothesis beyond CSI, was that me-
chanical occlusion of the coronary sinus whether it is total
temporary or partial chronic occlusion, will result in redistri-
bution of flow within the venous compartment allowing
CS Reducer Design rertograde perfusion to the to deprived perfusion zones. The
occlusion of the coronary sinus will raise the coronary sinus
The CS Reducer is a stainless steel balloon-expandable stent. pressure resulting in a redistribution of venous blood and
It is deployed at 2-4 atmospheric pressures. At deployment plasma-dense fluid from normally perfused territories into
pressure, the stent assumes an hourglass shaped with a mid- underperfused areas. Consequently, blood will be squeezed
diameter of 3 mm and a 7-13 mm at both ends. The expansion into the microcirculation, reducing the areas of ischemia.
of the Reducer is asymmetric in such a way that the proximal During temporal occlusion as seen in PICSO procedures, a
end expands more than the distal end, to accommodate the phase of washout follows the filling of the venous compart-
tapering diameter of the coronary sinus. The mid stent ment [14, 15]. A meta-analysis of seven experimental trials of
narrowing can be abolished if balloon inflation pressure is PICSO in 125 test animals documented an inverse relationship
increased to 8 bars, completely opening the mid segment of between achieved coronary sinus systolic pressure, and dura-
the stent, which will then attain a tubular shape. The stent is tion of ischemia [16]. The analysis showed a significant
Curr Cardiol Rep (2016) 18: 35 Page 3 of 6 35

It was later that Weigel et al. explained the cascade leading


from coronary sinus narrowing to neo-angiogenesis (Fig. 2)
[19]. Miyasaka et al. postulated that chronic rise in venous
pressure will result in mechano-transduction and activation
of endothelium [20]. In a pig model of myocardial ischemia,
Weigel et al., proved that PICSO resulted in a fourfold in-
crease of heme oxygenase-1 gene expression (HO-1) in the
infarct area (P < .001), and a 2.5-fold enhanced transcription of
vascular endothelial growth factor (VEGF) in the infarct
(P < .006), border (P < .002), and remote (P < .02) areas [19].
HO-1, an anti-atherosclerotic molecule also known to be in-
volved in vasodilation, and VEGF, are associated with a better
cardiac function in 4 week follow up after experimental in-
farction. This upregulation of pro-angiogenetic molecules has
been observed in remote zones as well as in border zones and
also to some extent in ischemic zones. It is noteworthy that
that VEGF/VEGF2 and their receptor proteins were markedly
upregulated in myocardial cells in the remote zone but not in
the coronary sinus blood during experimental coronary artery
occlusion in pigs [21].
The Safety of CS Reducer was tested in nonischemic pigs.
These pigs were observed for up to a year. The implantation
procedure had no short or long term complications. The mean
Fig. 1 CS Reducer deployment in the coronary sinus. A, The left anterior
pressure gradient measured across the reducers was 3.71
oblique angiography of the coronary sinus during deployment. B, 1.75 mmHg immediately after implantation and 2.83
Diagram representing a posterior view of the balloon mounter CS 1.47 mmHg 6 months later [13].
Reducer positioning from the internal jugular vein through the SVC
into the coronary sinus. CS = coronary sinus, IVC = inferior vena cava,
SVC = superior vena cava
Clinical Trials

reduction in infarct size of 29.3 % in the PICSO group com- The first in-man application of the CS Reducer was reported
pared to the control group (p b 0.001; 95 % confidence inter- in 2007; in a multi-center trial conducted between centers in
val, 40.9 to 17.7). To explore the benefit of additional Germany, Israel, and India. In an open label use, 15 patients
retroperfusion of arterial blood during PICSO, dose depen- with symptomatic CAD and refractory CCS class II to IV
dence data showed that the amount of blood retro-perfused angina, underwent CS Reducer implantation. Patients were
had an inverse correlation to salvage (r = 0.97; p b 0.004) selected based on the presence of objective evidence of revers-
[10, 17]. So, the cyclic redistribution of venous blood into ible myocardial ischemia, determined by perfusion scan and/
the center of ischemia followed by washout, maintains basal or by dobutamine echocardiography, plus left ventricular ejec-
metabolism as well as vasodilation, collateral flow, and im- tion fraction >25 %. Exclusion criteria included patients with
proved perfusion to the border zone. The resulting increased an acute MI in the prior 3 months, revascularization in the
energy storage is thus the main factor of salvage in CSI [18]. primary 7 months, severe arrhythmias, decompensated heart
In a pig model of reversible myocardial ischemia, implanta- failure, severe valvular heart disease, CS devices, mean atrial
tion of the Reducer was associated with reduced mortality and pressure 15 mmHg or tricuspid valve replacement or repair.
improved ischemic parameters [13]. Whether the same theory The primary end point was device safety and the secondary
will hold true for the CS Reducer stent remains to be seen end point was technical success. In this small number of pa-
considering given that the occlusion is partial, chronic, and tients, the device met all primary and secondary endpoints. All
not associated with a period of washout. implantation procedures were completed successfully. All pa-
Early, histological data from Becks procedure, described tients were discharged from the hospital 1 to 2 days later
the formation of many vascular channels distal to the occluded without clinical complications. No major adverse cardiac
artery [8], which indicates neo-angiogenesis. Similar findings events had occurred during the periprocedural period or dur-
were observed after 8 to 12 weeks of coronary sinus ing the follow up period of 10 to 12 months (mean follow-up
narrowing by the CS Reducer in pigs, new macroscopic epi- 11 1.03 months). A postimplantation CT angiography anal-
cardial as well intramyocardial blood vessels developed [13]. ysis measured the mean diameters of the Reducers in the
35 Page 4 of 6 Curr Cardiol Rep (2016) 18: 35

Fig. 2 Summary of the pathways


by which coronary sinus
intervention and particularly
PICSO exert their effect through
regeneration, myocardial
protection, and improvement in
myocardial perfusion. IL-
6 = Interleukin 6,
VEGF = vascular endothelial
growth factor, HO = heme
oxygenase

proximal segment at 11 2 mm, distal segment at 7.2 1 mm, time to ST depression were prolonged (3:16 1:48 vs. 5:16
and mid segment at 3.0 0.2 mm. At 6 months, angina score 1:14 min, p = 0.05, and 1:47 1:12 vs. 3:57 2 min,
was lower in 12 of the 14 patients and remained constant in two. p = 0.59, respectively). There was a trend to improvement in
The average CCS class for the 14 patients was 3.07 at baseline METS and Duke Score (4 1.8 vs. 5 1.3 and 10.8 9 vs.
and 1.64 at follow-up (p = 0.0001). Ischemic burden was not 6.3 7, p = 0.17, respectively). Similarly, six months wall mo-
changed on stress testing. For the whole group, the average tion score index at stress improved significantly (1.9 0.4 vs.
double product and exercise duration were unchanged 6 months 1.4 0.4, p = 0.046), as well as ejection fraction during dobu-
after implantation compared with baseline (18,675 at baseline tamine infusion increased significantly from 48.9 % to 55 %
vs. 20,365 at 6 months [p = 0.18] and 7.08 at baseline vs. 6.79 at (p < 0.04). Thallium SPECT, summed stress score and
6 months [p = 0.59], respectively). Dobutamine echocardiogra- summed difference score were both significantly reduced,
phy showed improvement in eight out of 13 patients, while suggesting an improvement in the extent and severity of the
Thallium SPECT showed only improvement in four patients. ischemic segments (21.5 10 vs.13.2 9, p = 0.01, and 11.1
These results were maintained for three years [13]. 6 vs. 4.7 4, p = 0.007, respectively). Criticism was directed
To explore efficacy, 23 patients were recruited in an open to the patient selection process. During the follow-up period
label design; 14 patients from Israel and nine patients from four patients underwent coronary angiography due to angina.
Belgium. The same inclusion and exclusion criteria and study Two of these patients were treated by PCI for new coronary
design as the first in-man use trial. The Reducer implantation lesions, one patient was referred to CABG for progression of
was successful in 21 (91 %) patients. The procedure failed in his disease, and one patient was treated medically. [22]
two patients due to an unsuitable CS anatomy but no The Coronary Sinus Reducer for Treatment of Refractory
procedure-related complications were observed immediately Angina (COSIRA) trial was designed to examine whether
after the procedure and at one-year follow-up. Among the the implantation of the coronary-sinus reducing device
remaining 21 patients the procedure was uneventful and no could effectively improve refractory angina symptoms.
procedure-related complications were observed during a mean The trial was designed to overcome the shortcomings of
follow-up period of 11.4 5 months. The angina score de- the previous designs. It randomized patients from 11 clin-
creased significantly 6 months following Reducer implanta- ical centers on double blinded design to the Reducer stent
tion from a mean of 3.35 0.6 to 2.0 1 (n = 20, p < 0.001). versus the sham procedure. The selection of the patients
Seventeen (85 %) patients reported relief of symptoms follow- was more rigorous. A heart team approach decided on the
ing the procedure. Objectively, Exercise duration as well as revascularization appropriateness. Only patients who were
Curr Cardiol Rep (2016) 18: 35 Page 5 of 6 35

symptomatic after one month of maximum tolerable med- of Utrecht, reported their experience as a part of clinical care
ical treatment and Canadian Class III to IV angina were looking at angina improvement. Twenty-three, patients with
selected. Also, the trial was overseen by an independent objective evidence of myocardial ischemia and no option for
coordinating center, a steering committee, a clinical events revascularization were treated with CS Reducer. Procedural
committee, and a data and safety monitoring board. One success; defined as the successful placement of the device in
hundred and four patients with suitable coronary anatomy the CS without any periprocedural adverse events, was 100 %.
were randomized in 1:1 ratio to CS Reducer implantations After a median follow-up of 6 months there was a significant
versus a sham procedure. Successful implantation was improvement in CCS class. The average CCS class at baseline
achieved in 50 of the 52 patients (96 %) assigned to the was 3.35 0.49 and improved to 2.13 0.92 at follow-up
treatment group. A venous valve in the coronary sinus was (P = <0.001). The majority of patients (78 %) experienced an
the cause of failure in the remaining two patients as the improvement of clinical symptoms. Of the cohort 39 % by one
devices failed to cross the valves. Regarding efficacy, a CCS class, 35 % by two CCS classes, and 4 % by three CCS
significant change was observed in anginal class, quality classes. Nearly one fifth (22 %) of the patients had no clinical
of life, and mean exercise duration, but not in the angina improvement [25].
stability, or frequency. Of the patients in the treatment The data seem to be consistent. The CS Reducer is safe to
group 35 % had an improvement for at least two CCS implant and improves the CCS angina class. What remains to
classes compared to 15 % in the control group (P = 0.02). be seen is how the device exerts its action and whether it
The Reducer stent reduced the CCS class from a mean of improves objectively myocardial perfusion or not. Finally,
3.2 0.4 at baseline to 2.1 1.0 at 6 months of follow-up in why, does 20 % to 30 % of the patients selected based on
the treatment group, as compared with a reduction from the current protocol constantly fail to benefit from the device?
3.1 0.3 to 2.6 0.9 in the control group (P = 0.001). Of These questions dictate a need for a larger trial.
the fifty patients, 71 % had an improvement of at least
one CCS class, as compared with 42 % (22 of 52) in the
control group (P = 0.003). Although, the Seattle Angina Conclusion
Questionnaire total score was significantly higher in the
treatment group (17.6 points), as compared with 7.6 points Although, the current data is limited by the lack of device
in the control group (P = 0.048), angina stability did not specific animal investigation explaining the mechanistic ef-
significantly differ between the two groups (18.1 vs. 8.3 fect, the small number of patients enrolled in clinical and lack
points, P = 0.16) as well the frequency of angina (15.3 vs. of long-term follow up, nevertheless, continued use is clearly
11.0 points, P = 0.44). At 6 months of follow-up, the mean supported by : 1) the encouraging outcomes in all reported
exercise duration had improved by 59 seconds (13 %) in clinical evidences, 2) the safety profile of the device, 3) the
the treatment group and by 4 seconds (1 %) in the control lack of any alternative to improve the quality of life in refrac-
group (P = 0.07). When assessing ischemia objectively tory angina patients, and 4) the ease of implantation of coro-
there was a trend toward improvement that did not reach nary sinus stents. We need to refine the selection process and
statistical significance. On repeat stress test at six months, identify further cohort characteristics that may either improve
the mean time to ST segment depression was non signifi- or hinder the clinical benefit. Moreover, we need long term
cantly higher at 49 seconds in the treatment group when follow up to explore how long the clinical benefit will last. It is
compared to 18 seconds in the control group (P = 0.41). imperative to recognize that, these are not an alternative for
The dobutamine wall-motion index improved by 14 % in maximal medical treatment, life style modification or revas-
the treatment group and by 8 % in the control group cularization procedure. Furthermore, the selection process for
(P = 0.20). Concerning safety, one case of periprocedural these patients should be rigorous and may require a multidis-
mortality has been reported which was the first since the ciplinary approach involving the primary care physicians, the
device was used in humans. Adverse events did not differ non-invasive cardiologists, interventional cardiologists, and
between the two arms (64 % in the mean treatment arm vs cardiothoracic surgeons in a heart team approach.
69 % in the control arm, p = 0.68). There were three myo-
cardial infarctions and one death in the control group, and
there was one periprocedural myocardial infarction and no Compliance with Ethical Standards
deaths in the treatment group. CT angiography performed
only in 70 % of the treatment group but had no evidence of Conflict of Interest Wael ElMallah declares that he has no conflict of
interest.
device migration or occlusion in any of the patients. It was
concluded that the device was effective and safe [23, 24].
Human and Animal Rights and Informed Consent This article does
The device was approved for commercial use in 2013 (CE- not contain any studies with human or animal subjects performed by any
Mark). At Euro PCR 2015, the University of Medical Centre of the authors.
35 Page 6 of 6 Curr Cardiol Rep (2016) 18: 35

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