Symptomatic angina pectoris refractory to medical and interventional therapies is a highly prevalent and debilitating medical condition. It poses a significant public health challenge, negatively impacting the quality of life of millions of patients globally. ^,, Refractory angina is prevalent in patients with advanced CAD and limited options for conventional revascularization, in patients following successful revascularization and in patients with nonobstructive CAD with associated microvascular dysfunction. ^,, The prevalence of refractory angina is 25% after 1 year and up to 45% two years after successful revascularization. Refractory angina might be the presenting symptom of a wide range of clinical conditions, including obstructive CAD, coronary microvascular disease with patent epicardial coronary arteries, hypertrophic cardiomyopathy, and left ventricular diastolic dysfunction. ^,, The long-term mortality of patients with chronic refractory angina due to epicardial coronary disease is not different from that of other patients with stable chronic ischemic heart disease. Therefore, therapy goals for these patients should prioritize improving quality of life and alleviating chest pain rather than reducing mortality. ^, Furthermore, refractory angina also incurs increased emergency department visits, cardiovascular hospitalizations, and significantly increased healthcare costs. ^, Coronary sinus (CS) narrowing has emerged as a safe and effective way to address the healthcare needs of patients with refractory angina. ^,,, In this article, we review the history of CS interventions for the relief of myocardial ischemia, the current clinical evidence base, the mechanistic basis by which this intervention may improve myocardial ischemia, and future directions for this innovative technology.

The concept of narrowing the CS to improve coronary perfusion into ischemic territories of the myocardium and to relieve symptoms of angina was developed more than 85 years ago by Claude Schaeffer Beck. The original open chest surgery he developed has been adapted years later through technological innovation to enable this procedure to be performed percutaneously. ^,, Beck intensively investigated methods of delivering additional blood to the heart muscle in the presence of coronary artery occlusion. The ‘‘Beck I operation’’ was first performed in humans in 1935, following extensive laboratory experiments. In a canine model of acute circumflex coronary artery ligation, narrowing of the CS decreased mortality by 43%, reduced infarct size, and doubled the degree of retrograde backflow from the distal stump of a severed left circumflex coronary (LCX) artery. In a clinical series of patients with severe disabling angina, Beck performed an open-chest surgical procedure to create a 60-70% narrowing of the CS to achieve a final 3 mm residual lumen diameter. Between the 1950s and 1960s, Beck performed this procedure in more than 100 patients and reported significant relief of angina symptoms, improved functional class, and reduced 5-year mortality rate. ^,,, Improvement in angina was assessed primarily on subjective self-reported information by the patients with no objective evidence demonstrating improved myocardial ischemia. The advent of coronary bypass surgery (CABG) and percutaneous coronary interventions (PCI) as successful treatments for angina combined with pharmacologic therapy have largely dominated the therapeutic approach for patients with obstructive CAD during the following decades, and the Beck’s operation had been abandoned and forgotten.

Since 1980, percutaneous transcatheter transvenous procedures to narrow or increase CS pressure have been investigated and developed for clinical use. First, the Pressurecontrolled Intermittent Coronary Sinus Occlusion (PiCSO) system was developed to address specific challenges in the management of myocardial ischemia and reperfusion. The initial development of PiCSO was rooted in the understanding that better outcomes in myocardial infarction could be achieved not only by epicardial revascularization, but also by addressing the complexities of microvascular perfusion and reperfusion injury. While early trials showed promise, technological and procedural challenges limited its widespread adoption. ^,,

Later, in 2004, the CS Reducer was developed to create controlled focal narrowing in the proximal segment of the CS and reproduce the Beck-I open chest surgery using a minimally invasive transcatheter approach.

The CS Reducer is a stainless-steel mesh designed to create a focal 3 mm narrowing in the lumen of the proximal segment of the CS to generate a pressure gradient across it ( Figure 1 ). ^,, It is implanted percutaneously via the right jugular vein into the CS. In a controlled preclinical study using a swine model of myocardial ischemia, CS Reducer implantation markedly reduced the extent and severity of dobutamine-induced myocardial ischemia. A small safety feasibility first-in-human study demonstrated improvement in angina score at 6-month and 3-year following Reducer implantation, without major adverse events or safety concerns. The long-term patency of the device was demonstrated using computed tomography angiography at 12 years postimplantation ( Figure 2 ).

The stainless-steel device, inflated on a balloon, conforms to the tapered coronary sinus anatomy. The center narrowing is 3 mm in diameter, and the length is 22 mm.

Computed tomography angiography (CTA) of the heart 1 year after Reducer implantation. LA = left atrium; LV = left ventricle; CSR = coronary sinus reducer; PLB = posterior lateral branch; MCV = middle cardiac vein.

The paucity of effective therapies for refractory angina is reflected in the latest guidelines on chronic coronary syndromes from the European Society of Cardiology, where the Reducer is the only device-based therapy that is recommended for the treatment of recurrent or refractory angina/ischemia . Of note, CSR implantation has been given a class IIb, level of evidence B recommendation, such that this intervention may be considered for patients with debilitating anginal symptoms who have exhausted all options for medical therapy and mechanical revascularization. Furthermore, a recommendation was provided by the National Institute for Health and Care Excellence in the UK in 2021 for coronary sinus Reducer implantation in patients with refractory angina to provide symptomatic relief, reduce the need for anginal medications, and improve quality of life.

These guidelines have been driven by the wealth of data, including 2 multicenter, randomized, sham-controlled trials and multiple prospective registries with long-term follow-up showing the safety and efficacy of the CS Reducer for patients with refractory angina and obstructive CAD. ^,,,,, In the landmark COSIRA trial, patients with obstructive CAD deemed unsuitable for revascularization, suffering from severe refractory angina (CCS class 3–4), despite optimal medical therapy and with objective evidence of ischemia, were randomized for CS narrowing or sham procedure. Narrowing of the CS was associated with significantly reduced angina and improved quality of life compared to the sham procedure. There was no difference in the rate of adverse events between the treatment group and the sham control group. A second randomized sham-controlled clinical trial (ORBITA-COSMIC) demonstrated that patients treated with CS Reducer had a significantly lower number of daily angina episodes and a better quality of life than sham-treated patients.

The REDUCER-1, a postmarket, nonrandomized, multicenter European clinical trial, enrolled 400 patients suffering from chronic angina, CCS Class 2-4, who were unsuitable for further revascularization and were treated with the Reducer. The cohort included 47% diabetic patients, 85% hypertensive patients, and 74% who had previous CABG surgery, PCI, or both. The results demonstrated a sustained significant improvement in angina severity, quality of life, exercise duration, and 6-minute walk test distance, and a marked reduction in emergency department visits for chest pain in the year following Reducer implantation compared with the year before treatment. Interestingly, 60 patients enrolled in REDUCER-1 had angina with nonobstructive CAD. The effect of CS narrowing in these patients was similar, or even more marked than in patients with obstructive disease. The RESOURCE multicenter observational retrospective registry included 658 patients from 20 medical centers. At a median follow-up of 502 days (IQR 225–1091), 39.7% of patients improved by ≥2 CCS classes (primary endpoint), and 76% improved by ≥1 class. A meta-analysis of nine prospective studies assessing the effects of CS narrowing demonstrated that 76% of treated patients improved by ≥1 CCS class, and 40% improved by ≥2 CSS classes. postprocedural SAQ scores and the 6MWT distance were significantly improved.

The long-term durability of angina improvement in patients treated with Reducer, with sustained symptom relief and improved quality of life, was also reported.

The Reducer is implanted percutaneously through the right jugular vein into the CS. The semicompliant delivery balloon comes in a single size, with the final expanded diameters depending on the inflation pressure. The Reducer is designed to accommodate the range of anatomies found in most patients and is compatible with CS diameters of 7.5 to 13 mm at the proximal implant site. The proximal and distal parts of the device are shaped to different diameters based on balloon expansion, allowing the device to conform to the tapered anatomy of the CS, with the center consistently narrowing by 3 mm in diameter. Implantation involves intentionally oversizing both wide ends of the device by 10–30%. This oversizing is crucial for anchoring the struts into the elastic vessel wall, helping to prevent migration and initiating a process of injury-induced tissue proliferation. Within 4–6 weeks after implantation, tissue growth should bridge the gaps between the metal struts to establish the pressure gradient across the device’s narrow center.

The precise mechanism by which narrowing the CS and modulating myocardial venous outflow alleviates angina and myocardial ischemia remains under investigation. The leading hypothesis is that the increased backward pressure resulting from CS narrowing redistributes arterial blood flow from the less ischemic subepicardial layers of the myocardium to the ischemic subendocardium. This redistribution is particularly beneficial because the subendocardium, with its higher metabolic demands and greater extravascular compressive forces during diastole, is more susceptible to ischemia. By directing blood flow to these vulnerable subendocardial regions, the intervention alleviates angina symptoms and enhances myocardial function in areas previously deprived of adequate blood supply. In a canine model of acute ischemia, Ido and colleagues showed that CS pressure elevation may be associated with increased regional myocardial blood flow into the ischemic subendocardium by redistributing blood from less ischemic territories of the myocardium into the ischemic subendocardium. The endocardial/epicardial blood flow ratio, which was low (0.5) in the ischemic heart, improved and returned to the normal ratio (1.2) when the CS pressure was elevated. The corresponding endocardial/epicardial intramyocardial pressure ratio, which was elevated in the ischemic zones, decreased when the CS pressure was elevated. They concluded that CS pressure elevation potentially enhances coronary collateral flow and preserves the ischemic myocardium, especially in the endocardial layers of the left ventricular myocardium. Elevation of CS pressure in the ischemic heart is associated with improved coronary blood flow into the ischemic subendocardium as was demonstrated in animals by Ido and his colleagues and was recently demonstrated in humans.

The ORBITA-COSMIC sham-controlled clinical trial demonstrated that the group of patients treated with the Reducer exhibited a significant improvement in subendocardial blood flow to the ischemic myocardium, as evidenced by perfusion cardiac MRI.

In a small blinded, sham-controlled, crossover, randomized clinical trial, Ullrich and colleagues demonstrated that acute CS pressure elevation led to a decrease in both resting coronary resistance and hyperemic coronary resistance. They enrolled 20 patients with angina pectoris (CCS class 2-4) due to coronary microvascular dysfunction and nonobstructive epicardial CAD to undergo inflation of an undersized balloon placed in the CS or a deflated balloon in the right atrium (sham). Increased coronary venous pressure led to an immediate reduction in microvascular resistance and improved coronary flow reserve.

The results of other small nonrandomized clinical trials support the redistribution of myocardial blood flow toward the hypoperfused myocardium. In these trials, the effect of the Reducer on quantitative global and regional myocardial perfusion in patients with refractory angina secondary to advanced CAD was evaluated using rubidium-82 (Rb-82) positron emission tomography (PET) and perfusion cardiac MRI.

Mechanistically, this may be explained by increased backward venous pressure resulting from CS narrowing, which forces a slight increase in the diameter of the subendocardial microvasculature which are under external compression from the high left ventricular diastolic pressure (LVDP). The slight increment in the microvasculature diameter results in a significant reduction in microvascular resistance and improved coronary blood flow into the ischemic subendocardium. ^, The relief of subendocardial ischemia enhances LV contractility, which further decreases LVDP. A reduction in the LVDP lessens the external pressure that compresses the subendocardial microvasculature during diastole, allowing further dilation of the microvasculature and further decreasing resistance to blood flow. While our understanding of the mechanism of action by which CS narrowing relieves angina and improves coronary blood flow into the ischemic subendocardium is growing, potential mechanisms remain hypothetical and may differ in obstructive and nonobstructive CAD.

Angina and nonobstructive coronary artery disease (ANOCA) represent a unique, challenging clinical scenario. It affects up to 50% of patients who undergo clinically indicated invasive coronary angiography for suspected ischemic heart disease. Recently, there has been increased awareness of this clinical entity, leading to increased adoption and utilization of invasive and noninvasive diagnostic tools. ^,,, The ESC guidelines for the treatment of chronic coronary syndrome advocate for invasive diagnostic procedures, including CFR measurement to assess coronary microvascular function in patients with angina and nonobstructive coronary arteries. These assessments are crucial for accurate diagnosis and guiding appropriate management strategies. The diagnosis of these patients is associated with reduced economic burden and has the potential to improve angina symptoms and quality of life. There are, however, limited therapeutic options for patients with ANOCA and coronary microvascular dysfunction (CMD). Preliminary clinical data show that CS narrowing may improve microvascular function, quality of life, and relief of angina and effort intolerance symptoms in patients with and without obstructive CAD. ^,,,, Recently, Lerman and colleagues showed that chronic narrowing of the CS improves endothelial-dependent and independent coronary flow reserve, improves symptoms and quality of life in 30 patients with ANOCA due to coronary microvascular dysfunction. Several other ongoing clinical trials are evaluating the potential role of CS narrowing in improving coronary microvascular function, which will further help guide clinical practice.

As the Reducer seems to mediate its effect at the level of the microcirculation, hence, treating patients with primary disorders of the microcirculation with Reducer is plausible. The ongoing REMEDY trial is a randomized, double-blind, sham-controlled trial of the CS Reducer in patients with ANOCA. The effect of CS narrowing on coronary microvascular function is evaluated by measuring the change in myocardial perfusion reserve on quantitative stress perfusion by cardiac MRI as well as by invasive coronary microvascular blood flow evaluation. Two additional prospective clinical trials to evaluate the effectiveness of the Reducer in patients with ANOCA are currently enrolling patients. A multicenter prospective, randomized open-label controlled superiority trial (the COSIMA trial) in the department of cardiology of the University Medical Center in Mainz Germany by Tommaso Gori, and a single center prospective Reducer ANOCA trial at the Tel Aviv University Medical Center, By Drs Maayan Konigstein and Shmuel Banai. The clinical implications of these small but compelling studies are profound. CMD represents a critical unmet clinical need in daily practice associated with significant quality of life burden and healthcare costs. These studies offer a potential path that may change the way this vulnerable population with coronary microvascular dysfunction is managed.

Chronic total coronary occlusion (CTO): CS narrowing should be considered a treatment option for patients suffering from angina due to coronary CTO. This is especially true for patients in whom interventions for CTO fail, those who are at high risk, or those who continue to suffer from angina following successful CTO intervention. The high-risk nature of CTO-PCI and the limited geographic availability of high-volume operators has led to a significant number of patients struggling with refractory angina. The Reducer offers a low-risk option to alleviate chest pain in patients with multiple comorbidities, who may be at high risk for percutaneous revascularization. Moreover, underlying microvascular dysfunction may contribute to anginal symptoms in patients with CTO, further supporting a role for the Reducer in these patients who may experience continued angina despite epicardial revascularization.

Angina with nonobstructive CAD (ANOCA) : The motivation to diagnose microvascular dysfunction has been hampered by limited therapeutic options. With recent preliminary published data supporting the role of CS narrowing in improving coronary MVD, and the anticipated results of the currently enrolling clinical trials, we anticipate an increased focus on larger clinical trials to explore the role of such therapies for patients with ANOCA.

If CS narrowing proves to be an effective way to improve coronary MVD, it might also open new possible exciting treatment options for early-stage diastolic dysfunction and myocardial ischemia secondary to hypertrophic cardiomyopathies.