Insights Into Coronary Sinus Reducer Non-Responders

Background. Refractory angina affects an increasing proportion of the population with advanced coronary artery disease and microvascular dysfunction. Limited effective pharmacological and interventional therapies exist for this patient cohort. The coronary sinus (CS) reducer, recently recommended in the 2019 guidelines of the European Society of Cardiology for the management of chronic refractory angina, is a balloon-expandable, stainless-steel device designed for implantation in the CS. It acts by increasing CS pressure, thereby redistributing blood to ischemic myocardium, relieving symptoms, and improving quality of life. However, between 15%-30% of patients do not respond to this treatment. Six mechanisms appear to explain this poor response to CS reducer therapy: (1) inappropriate patient selection; (2) cardiac venous system heterogeneity; (3) CS size; (4) incomplete device endothelialization; (5) coronary artery disease phenotype and progression; and (6) limited myocardial ischemia at baseline. We hereby review these mechanisms in detail and highlight key areas that should be addressed in order to try and reduce the burden of non-responders following CS reducer implantation.

J INVASIVE CARDIOL 2021;33(11):E884-E889. Epub 2021 September 17.

Key words: chronic coronary disease, interventional cardiology, percutaneous coronary intervention, refractory angina

The recently published European Society of Cardiology (ESC) guidelines on chronic coronary syndromes rebrands the concept of stable coronary artery disease (CAD) in order to reflect its dynamic and often progressive nature.¹ Distinct clinical entities or syndromes have been identified along the spectrum of CAD. At the end stage of this spectrum lies chronic refractory angina, which is characterized by persistent symptoms despite escalation of anti-anginal therapy, with no further revascularization options. This cohort of patients is set to increase due to an increasingly elderly and comorbid population. Limited therapeutic options exist for these patients and the current technologies and interventions tested have demonstrated disappointing feasibility and efficacy to date (Table 1).^2,3

The coronary sinus (CS) reducer has demonstrated promising outcomes in one clinical trial and several prospective registries in terms of reduction in angina and ischemic burden and improvements in quality of life and functional capacity (Table 2).^4,5 Following this initial promise, reducer implantation is now recommended in the recent ESC guidelines for chronic coronary syndromes (class IIb). Current estimates suggest that over 1500 devices have been implanted worldwide, with very low complication rates. However, despite improvements in operator experience and careful patient selection, a significant cohort of patients (estimated to be between 15%-30%) derive minimal to no benefit and are deemed non-responders to treatment (Table 2).^4,5

As more patients are diagnosed with refractory angina and will undergo CS reducer implantation, this burden of non-responders is set to increase. Therefore, it is imperative to understand the underlying pathophysiological mechanisms accounting for these non-responders. In this review, we describe the mechanism of action of the CS reducer implant and highlight key anatomical, physiological, and technical reasons that may explain why some patients do not derive much benefit from CS reducer implantation, and discuss methods that can be undertaken to minimize the burden of non-responders.

History and mechanism of action. The concept of increasing CS pressure to ameliorate ischemia, especially in the territory of the left anterior descending (LAD) coronary artery, was first applied to patients with angina in 1941 by Claude Beck, who reported that partial surgical ligation of the CS to a diameter of 3 mm could improve symptoms and reduce mortality in patients with ischemic heart disease.⁶ Although initially promising, further development and progress were hindered by the advent of surgical coronary artery revascularization. In the early 2000s, Ido and colleagues studied myocardial blood flow redistribution after surgical ligation of the LAD in 38 dogs. Post ligation, occlusion of the CS resulted in an improved collateral perfusion to ischemic areas, as demonstrated by histological analysis of postmortem specimens.⁷ Following this, the CS Reducer System (Neovasc) was developed, comprising a balloon-expandable, hourglass-shaped, stainless-steel mesh intended for percutaneous implantation in the CS to create a controlled luminal narrowing. The device was designed to increase CS pressure and transmit it retrogradely along the coronary tree into the distal vascular bed, although the exact mechanism of action has yet to be fully elucidated. Increased recruitment and subsequent perfusion of the distal capillary bed with improved microvascular blood flow is hypothesized to improve myocardial ischemia, as observed with cardiac magnetic resonance,⁸ thereby reducing symptoms and improving patient quality of life.⁹

(1) Patient selection. As with any intervention, appropriate patient selection is a critical first step in optimizing response  to treatment. Current prerequisites prior to considering reducer therapy are presence of chronic refractory angina pectoris, classified as Canadian Cardiovascular Society (CCS) grade II, III, or IV despite optimal medical therapy, with limited surgical or percutaneous revascularization options along with evidence of reversible ischemia in the territory of the left coronary artery (LCA).⁹ Evaluating angina in these patients can be difficult and every effort should be made to exclude any potential alternative diagnosis for their symptoms. This is especially relevant in patients with chronic refractory angina, as they may attribute symptoms of non-cardiac origin to their underlying coronary disease, and because the degree of angina does not always correlate with the extent of ischemia, especially in subjects with multiple previous surgical and percutaneous interventions. Furthermore, referral of these patients to high-volume, specialized centers performing complex percutaneous coronary intervention and chronic total occlusion procedures is advisable in order to truly establish that the patient has no revascularization option.¹⁰ This is crucial given that reducer implantation is a single-use option, and once deployed cannot be removed, repositioned or replaced, with no provision to implant a second device within the CS.

(2) Cardiac venous system heterogeneity. The CS reducer aims to increase intracardiac venous pressure by partially obstructing drainage of venous blood through the CS. This effect can be influenced by the significant heterogeneity in the anatomy and physiology of the cardiac venous system,¹¹ as exhibited by the Thebesian veins, which provide direct connections between coronary vessels and cardiac chambers.  Thebesian veins “bypass” the CS and could account for the lack of CS pressure increase after reducer delivery, potentially dampening treatment response.^9,12 Their presence and extension can only be unmasked with selective coronary artery catheterization or with high-pressure intracardiac angiography, both of which are not part of the routine preprocedural screening before reducer implantation (Figure 1A). Recently, Baldetti et al described how the simple measurement of CS systolic wedge pressure, taken while the reducer delivery balloon is occluding the CS, could predict treatment response. According to these observations, high CS systolic wedge pressure could imply long-term remission from angina, while a low CS systolic wedge pressure would justify a minimal benefit from the treatment.¹³ While promising, these measurements were only reported in 2 patients; therefore, further studies are warranted to evaluate whether CS wedge pressure could be used as a predictor of poor response. Indeed, in patients with high CS flow and scarce alternative drainage systems, we expect a significant systolic wedge pressure increase during CS occlusion, in contrast with patients who have physiologically active Thebesian systems. Hence, if the systolic wedge pressure fails to rise as the delivery balloon fully seals the CS, one should not expect a pressure gradient across the neck of a deployed reducer; theoretically, these patients may not derive much benefit from reducer implantation.

(3) Large coronary sinus. The CS exhibits great anatomical heterogeneity in terms of its size and shape.¹⁴ Tzanis et al recently described how device implantation in large CSs (vessel diameter >13 mm) or in wider vessel segments could lead to treatment failure. CS size was significantly smaller among responders as compared with the non-responders (6.6 ± 1.6 mm vs 8.2 ± 1.4 mm, respectively; P=.04).¹⁵ Furthermore, CS size correlates well with myocardial perfusion increase at 4-month and 12-month follow-up as assessed by stress cardiac magnetic resonance (CMR) (r=-0.71; P<.01).

At present, reducer scaffolds only exist in one size, which can be slightly adjusted by modifying the delivery pressures, and either extremes in CS size could make device delivery or sizing difficult, impairing the aforementioned mechanics and resulting in poor device endothelialization (see below). A 10%-20% oversizing of the device relative to the CS is recommended to prevent device migration, and promote activation of injury-induced tissue growth that enhances subsequent device endothelialization.¹⁴ At present, CS size is not routinely assessed prior to reducer implantation. However, if subsequent studies confirm the impact of CS size on treatment response, then preimplant computed tomography (CT) or selective angiography should be considered, and potentially guide the selection of different scaffold sizes.

(4) Incomplete device endothelialization. Incomplete device endothelialization may partially explain the lack of clinical response in some patients, as reported in a case series by Zivelonghi et al.¹⁶ Five out of 43 patients who underwent CS reducer implantation had no improvement in their angina after 6 months of follow-up. In these 5 non-responders, CS angiography revealed free-flowing contrast though the reducer struts, suggesting incomplete device endothelialization (Figure 1B). Moreover, they performed a retrograde pressure recording from within the CS in 1 patient and did not demonstrate any pressure gradient across the device neck. This suggests the importance of device endothelialization in ensuring a retrograde venous pressure, and subsequent clinical benefit. Although this is a plausible hypothesis, similar pressure measurements were not repeated in the other 4 non-responders,¹⁶ and studies from histological preclinical pig models suggest otherwise. In these pigs, device endothelialization was only seen in the peripheral portions of the device, sparing the neck. This partial coverage of the peripheral struts was sufficient to redirect blood flow into the narrow neck of the device and generate a pressure gradient. Furthermore, in vivo, a pressure difference is measured immediately following device delivery, long before any tissue endothelialization has occurred.¹⁷ Therefore, it appears that the extent of device endothelialization, alongside additional factors such as device geometry and stent struts, vessel reactivity, and spasm, account for the observed hemodynamic effects and subsequent clinical response following reducer implantation.

(5) Coronary artery disease phenotype. In a cohort of 205 patients, Zivelonghi et al recently demonstrated a more significant reduction of anginal symptoms after CS reducer implantation among those subjects with non-revascularized CTO (n = 103)vs those with CAD other than CTO (n = 102), reporting a mean follow-up CCS class of 1.6 ± 0.9 vs 2 ± 1.1, respectively; P<.01) (Figure 1C).¹⁸ Accordingly, the proportion of non-responders was also significantly different, with 19.4% of patients in the CTO group experiencing no benefit after reducer implantation vs 33.7% in the non-CTO group (P=.03).¹⁸ Indeed, different “phenotypes” of CAD (ie, CTOs, diffuse disease, microvascular angina, high-risk single-vessel or double-vessel disease, etc) could predict different responses to reducer implantation.

Furthermore, the term “non-responder” could also apply to those in whom the device was initially successful in reducing their symptoms of angina, but subsequently their angina returned due to progression of underlying CAD rather than due to device failure. In these patients, the reducer exerted its effects for a certain period of time, but symptom recurrence was driven by CAD progression (Figure 1D).

Patients with complex CAD are at higher risk of disease progression as compared with the general population. In a previous study, we showed that 20% of patients with chronic refractory angina, treated with a reducer, required repeat PCI within 2 years due to CAD progression (30% acute coronary syndrome, 70% stable CAD).¹⁹ Therefore, patients who develop a recurrence of their angina following an initial benefit should undergo re-evaluation of their coronary anatomy to check for disease progression. If repeat coronary angiography does not reveal any significant progression in CAD, then repeat ischemia testing can be considered to look for the possibility of new-onset microvascular dysfunction. Alternatively, the possibility of a placebo effect accounting for the initial improvement in angina following intervention should be considered.

(6) Limited myocardial ischemia at baseline. Determining the presence of epicardial or microvascular myocardial ischemia is necessary prior to considering reducer implantation by means of dobutamine stress echocardiography, single-photon emission computed tomography (SPECT), or stress CMR.

The exact extent of ischemia required prior to considering reducer implantation has not been established, without a set ischemic threshold, and indication to treatment remains mostly clinical.

It was recently demonstrated that improvement in myocardial perfusion observed after reducer treatment was significantly greater in myocardial segments with elevated baseline ischemia as assessed by stress CMR.⁸ This suggests that patients with smaller ischemic areas, regardless of their initial burden of symptoms, may not derive as much benefit following reducer implantation. Studies are required to identify and validate a minimal ischemic threshold capable of discriminating between low and high probability of response to treatment. This is especially pertinent given that angina burden does not strictly correlate with CAD extension and myocardial ischemia. In the context of refractory angina evaluated for reducer implantation, all patients in the literature had CCS ≥II (mostly CCS III-IV),^4,5,20 but showed various degrees of CAD and heterogeneous burdens of myocardial ischemia.

Non-response to reducer therapy is a reality for a minor but constant proportion of patients (between 15%-30% across clinical studies). With the rate of implantations set to increase, especially after the 2019 ESC guidelines, non-response is an escalating problem that has not been fully addressed and described. Further work is warranted to explore these mechanisms to enable interventionists to refine their technique in order to minimize the burden of non-responders.

Key messages. (1) Further randomized trials are needed to fully evaluate the efficacy of this intervention and to describe the exact mechanism of action of this device. (2) Careful clinical evaluation of patient symptoms, presence and extent of baseline ischemia, as well as assessing the potential for further revascularization options using advanced contemporary techniques are critical steps in the selection of patients who would derive the most benefit from reducer therapy. (3)Intraprocedural evaluation of CS size and hemodynamics, as well as venous anatomy and identifying variants, should also guide implantation strategy. In line with conventional PCI, real-time evaluations should guide operative decisions to minimize implantation in patients with unfavorable anatomy or physiology. (4) Recurrence of angina after reducer implantation, especially following a period of clinical improvement, should warrant investigation of further coronary disease progression.