The Coronary Venous System: An Alternative Route of Access to the Myocardium

The epicardial coronary venous system has become the subject of renewed interest in recent years. There appear to be three main domains in which a thorough understanding of the venous system may lead to potentially useful clinical interventions. First is the use of percutaneous techniques to allow retroinfusion of arterialized blood into the coronary veins in patients deemed unsuitable for conventional revascularization. Second, the regional delivery of therapeutic agents such as cardioprotective drugs, cells or gene vectors, is possible. And finally, the use of the coronary venous system as a route of access to the myocardium for the cardiac electrophysiologist will be discussed. Historically, research on the vascular anatomy of the heart has focused on the coronary arterial system. The coronary venous system, by comparison, has been largely neglected. The venous system does, however, have key importance in the application of new technologies and techniques designed for the treatment of cardiovascular disease. In 1951, Tori¹ was the first to outline some of the larger veins by retrograde injection of contrast material into the catheterized coronary sinus. Since that time, it has been found that retrograde coronary venous perfusion can preserve myocardium during experimental coronary artery occlusion and has been used clinically to deliver oxygenated blood to ischemic myocardium during unstable angina³ or high-risk percutaneous transluminal coronary angioplasty.^4,5 Both global⁶ and selective⁷ surgical arterialization of the coronary veins have been shown to improve angina status. Percutaneous retrograde arterialization of the coronary veins in patients not suitable for conventional revascularization has been reported⁸ and will be discussed below. Targeted delivery of genes and stem cells to myocardium via the coronary veins, with rates of transfection superior to systemic or intra-arterial delivery, is another novel use for the coronary veins.^9–12 The venous system of the heart has also been used by cardiac electrophysiologists as conduits for the insertion of leads for left ventricular pacing in cardiac resynchronization therapy,¹³ radiofrequency catheter ablation,¹⁴ arrhythmia mapping¹⁵ and defibrillation.¹⁶ In this review, we will discuss the coronary venous anatomy and the potential for employing selective catheterization of the coronary sinus and coronary veins for therapeutic intervention. Coronary Venous System 1. Access to the coronary venous system Percutaneous cannulation of the coronary sinus and coronary veins and the potential applications of this technology have been recognized for some time.¹⁷ Several different guiding catheters have been used to successfully access the coronary veins via the coronary sinus. Right and left subclavian vein, right internal jugular vein and femoral vein approaches have been reported. Katritsis et al¹⁸ reported successful cannulation of the coronary sinus via the femoral vein using a modified 6-French gauge Judkins L5 catheter. More recently, experience using a left Amplatz-type catheter to access the coronary sinus for implantation of pacing leads has been reported. The authors report access to the coronary sinus in all 15 patients in whom the technique was tried, and a mean cannulation time of 3.34 ± 1.9 minutes.¹⁹ Complications of coronary sinus cannulation have been reported to include dissection of the vessel, hemopericardium and arrhythmia.²⁰2. Coronary venous anatomy There are two interrelated systems that drain the myocardium, the epicardial coronary veins and the Thebesian venous system. a. Anatomy of the epicardial coronary veins Detailed knowledge of the epicardial venous anatomy is necessary for successful catheterization of the coronary sinus and cardiac veins. The venous anatomy of the heart and its common variations has been described in detail in post-mortem, corrosion cast and in vivo studies,^14,21–25 The majority of blood returns to the heart by epicardial coronary veins that progressively join larger vessels and ultimately flow into the right atrium via the coronary sinus. Examination of coronary vein corrosion casts shows that myocardial collecting veins run perpendicular to the surface of the ventricles to enter the epicardial veins at right angles.²¹ The course of the anterior interventricular vein (AIV) is similar to that of the adjacent (left) anterior descending (LAD) artery as it runs in the interventricular sulcus towards the base of the heart. At the base of the heart, it is seen to turn laterally away from the LAD toward the circumflex artery in the left atrioventricular groove to become the great cardiac vein, and lies adjacent to the circumflex coronary artery. In imaging studies using electron beam computed tomography, the AIV is visualized in between 97%²⁶ and 100%²⁷ of subjects scanned. The course of the AIV was seen to run parallel to the left anterior descending coronary artery in 79% of subjects. The diameter of this vein was seen to be similar to the neighboring artery for the length of its course. The great cardiac vein usually receives tributaries from the left ventricular surface via the AIV, a left marginal vein (similar in position to a marginal branch of the circumflex artery) and a left posterior vein.²⁸ Inferiorly in the AV groove, the great cardiac vein drains into the coronary sinus, which itself then opens into the right atrium. The middle cardiac vein is seen to run in the posterior interventricular groove [often alongside the posterior descending artery (PDA) branch which usually arises from the right coronary artery] and drains directly into the coronary sinus. The coronary sinus is a superficial cardiac structure that lies in the coronary sulcus between the left atrium and the left ventricle. The coronary sinus is defined as the blood conduit that is a continuation of the great cardiac vein from the valve of the great cardiac vein to the ostium of the coronary sinus. The coronary sinus opens into the right atrium posteromedially, through the highly variable Thebesian valve — which may present an obstruction to selective cannulation of the coronary sinus. Although traditionally thought of as simply a conduit for venous return to the right atrium, careful examination of the coronary sinus reveals its structure to be similar to other cardiac chambers; demonstrating endocardium, striated myocardium and a specific conduction system — continuous with that of the right atrium. These findings suggest that the coronary sinus may also have a role in both normal and abnormal electrical conduction in the heart.²⁹ The venous drainage of the right ventricle is via the small cardiac vein and its tributaries directly into the right atrium. Recently, several groups have published descriptions of the coronary venous anatomy after detailed angiographic studies.^24,30 Although the venous pattern described above was found in most patients, the number and location of cardiac veins was found to be variable in these studies. In the work of Meisel et al, the anterior interventricular vein and middle cardiac vein were visible in 85 of 86 patients. The anatomy of the lateral marginal vein was, however, more variable, being present in 71 of 86 patients. This study also assessed coronary vein accessibility for the placement of defibrillation leads. A prototype lead was successfully advanced along at least 50% of the length of the anterior interventricular vein in 115 of 124 patients. b. Anatomy of the Thebesian venous system Early vertebrates (e.g., hagfish and lampreys) nourished the myocardium simply by absorbing blood from the lumen of their single-chambered ventricles. Simple diffusion is the classic method of nutrition and waste disposal for lower organisms lacking vascular systems. This has been confirmed in bacterial growth experiments.³¹ As mammals evolved, they outgrew the sponge-work interstices and sinuses that communicated directly with the ventricular lumen, and evolved the arterial and venous system.Superimposition of the vascular pattern on the primitive remnants of the local diffusion system has persisted in the mammalian heart. In the first years of the 18th century, Raymond Vieussens (1635–1713) and Adam Christian Thebesius (1686–1732) discovered the vasa cordis minima, today known as the Thebesian veins. These veins form a “lesser” venous system of the heart. Careful anatomical analysis has identified three distinct forms of these Thebesian vessels.^14,22,32 The first type of Thebesian veins drain blood from the capillary bed into the ventricular cavity.²² The second type, arterioluminal vessels, drain blood directly from the arteries into the ventricles without traversing capillary beds and thus have a larger diameter. The third type, the venoluminal vessels, form direct communications with the coronary veins, shunting blood from these vessels into the ventricular cavities.³³ Most of the Thebesian veins in the ventricles appear to be venoluminal in nature.¹⁴ The presence of an extensive Thebesian venous network, which in the healthy state carries 5–10% of the venous return, does allow for an alternative route of venous drainage of the myocardium. It has been established that the Thebesian veins are capable of carrying the bulk of venous return in situations where the epicardial coronary veins are compromised. Retrograde Coronary Venous Perfusion The coronary sinus and its tributaries provide an alternative route of access to myocardium subtended by occluded or severely stenosed coronary arteries. The early work of Pratt,³⁴ Beck,⁶ and Batson and Bellet³⁵ provided some documentation that reversal of flow in the coronary venous system could confer some nutritive benefit on the myocardium. By perfusing the coronary sinus, Pratt³⁴ was able to maintain contractions for 90 minutes in the otherwise devascularized feline heart. Gross et al³⁶ reported an attempt to increase coronary perfusion by partially occluding the coronary sinus in animals. These animals tolerated the ischemia of ligation of the left anterior descending coronary artery better than control animals that did not have partial coronary sinus ligation. The realization that the coronary venous system is not affected by atherosclerosis² encouraged further investigation of the coronary venous system as an alternative system for nutritive flow. Before the advent of coronary bypass surgery, surgeons experimented with arterialization of the coronary venous system. Beck et al⁶ refined this procedure during the 1940s. In an operation that was known as the Beck II procedure, they first occluded the coronary sinus by ligation. After 10–14 days, during which time the coronary sinus had fibrosed, an arterial segment or venous conduit was placed between the aorta and the coronary sinus. The initial experimental work on this procedure was performed in dogs. This revealed two important physiological features: the coronary sinus could tolerate arterial pressure over a long period of time, and there was no wide-open fistula effect from arterialization of the coronary sinus. Beck’s approach was termed “global retroperfusion” as it shunted oxygenated blood into the entire venous coronary system. Beck refined his experimental technique (known as the Beck II procedure), and in 1954, he and Leighninger⁷ reported a series of approximately 200 patients who had undergone this procedure. It was found, however, that the permanent obstruction of coronary venous drainage was associated with specific problems including myocardial edema, fibrosis and hemorrhage. A second means of venous revascularization, the selective method, in which blood flow is reversed only in the precise areas of ischemia caused by arterial disease, was proposed by Arelias.³⁷ Using this method, only a small portion of the venous drainage is reversed, with the epicardial and Thebesian venous systems in other territories continuing to function in their normal manner. Several other groups refined these procedures over the following years with encouraging results,^3,38,39 however, the advent of coronary artery bypass graft surgery meant that interest in this and related techniques declined. The advent of synchronized diastolic coronary retroperfusion allowed intermittent venous drainage from the myocardium to occur during retrograde perfusion. This technique has been shown to reduce episodes of pain in patients with unstable angina40 and to reduce complications in patients undergoing high-risk percutaneous transluminal coronary angioplasty.^4,41,42 However, the system has not become widely used due to its limited benefit and for various other logistical reasons. The number of patients felt to be poor candidates, or unsuitable, for conventional revascularization has steadily increased. This “no-option” group of patients has catalyzed renewed interest in the possible use of coronary veins to carry oxygenated blood to areas of myocardial ischemia. A novel percutaneous procedure for retrograde arterialization of the anterior coronary veins has been developed and recently performed in man.^8,43 This technique has been employed in patients with an occluded left anterior descending artery in whom the anterior ventricular vein has been arterialized, and the venous return occluded. The procedure was performed using specially-designed catheters which allowed an image of the cardiac vein to be obtained from within the coronary artery using intravascular ultrasound (IVUS). When the vein was adequately visualized, a hollow crossing needle was passed from artery to vein, which allowed passage of a 0.014-inch guidewire and subsequent deployment of a stent to connect the artery and vein. However, according to the authors, the procedure has been limited by technical issues, including the inadequacy of IVUS for imaging the target coronary vein, and problems with the choice of venous occlusion device. The authors also note that although the vein does have a similar course to the artery on the anterior ventricular wall, the anatomical relationship between the vessels is unpredictable. To overcome this, the authors have suggested the use of electromagnetic mapping/navigation technologies. The feasibility of using a similar technology in the lateral wall of the heart largely depends upon the presence or absence of an epicardial coronary vein mirroring the course of the circumflex coronary artery. Work at our institution using IVUS to ascertain the position and size of cardiac veins in the vicinity of the circumflex coronary artery suggests that there may be a target for retrograde coronary venous perfusion.⁴⁴ Percutaneous ventricle-to-coronary vein bypass is currently under assessment as a novel technique for patients unsuitable for conventional revascularization techniques. The procedure involves implantation of a PTFE-covered stent directly between the left ventricular cavity and the overlying coronary vein to provide systolic flow of arterial blood in the coronary vein, and also to allow diastolic drainage from the vein into the ventricular cavity. The procedure has been shown to be technically feasible and capable of maintaining cardiac function in the presence of a coronary artery. Clinical trials are awaited.⁴⁵ Retrograde Coronary Perfusion during High-Risk Percutaneous Coronary Intervention Patients with poor left ventricular function with large areas of at-risk myocardium subtended by a target vessel are deemed high-risk patients for angioplasty. In the 1980s, coronary sinus retroperfusion was used as a means of protecting the myocardium during angioplasty in this vulnerable group of patients. The technique was found to reduce both symptoms of angina during percutaneous coronary intervention (PCI) and also time to onset of ischemic ST changes after balloon occlusion.⁴ The technique was also found to be of benefit in patients with abrupt vessel closure.⁵ However, despite these findings, the use of coronary sinus retroperfusion remained limited. The main reasons for its underutilization appear to be that the coronary sinus retroperfusion equipment was awkward and time-consuming to set up. In addition, it was technically impossible in 10–20% of patients. Furthermore, the degree of myocardial protection, although of some benefit, was found to be limited, and the technique was only proven to be of use during left anterior descending artery interventions. Local Drug Delivery Numerous studies have investigated the efficacy of retrograde perfusion of pharmacologically-active agents into the coronary veins. In intact, nonischemic myocardium, drug concentration after retroinfusion is similar to that achieved when drugs are given by the intravenous route. However, in the setting of myocardial ischemia, retroinfusion achieves higher levels of drug concentration in tissue than intravenous delivery, with the advantage of lower peak systemic concentrations and reduced or absent systemic effects.^46–49 This increased level of tissue penetration is probably due to the improved access to low-pressure capillary beds, and less washout of drug in the presence of reduced anterograde blood flow. Thrombolytic agents, when given directly into the coronary veins, act more rapidly, improve functional recovery and reduce final infarct size more effectively compared with systemic delivery.¹² Gene, Growth Factor and Stem Cell Delivery The revolution in genomics and proteomics continues to progress, and the underlying molecular biology of several cardiovascular pathologies is becoming better understood. This understanding has, in turn, led to an increase in the number of potential molecular therapies that are available. The success of these therapies depends on many factors, not the least of which is the ability to deliver them to the target tissue. Some agents have demonstrated bioactivity when given systemically, however, it is assumed that most agents will be more effective and better tolerated if delivered locally. Thus, retrograde infusion into the coronary venous system route is attractive for several reasons: • Direct delivery of vector into the interstitium of the myocardium; • Minimal washout of vector; • Controlled dwell times, dependent on coronary vein balloon inflation time, for longer exposure; and • Coronary venous access is a relatively straightforward technique that uses conventional equipment. Gene Delivery Gene delivery to the heart has been attempted using viral and nonviral vectors. Adenovirus is the most effective viral vector used in vivo; however, adverse inflammatory and host immune responses may limit its usage. The direct injection of plasmid-based vectors into the myocardium has been reported, though the level of gene expression via this method is relatively low.¹¹ The delivery of genes to the myocardium by retrograde venous perfusion in a porcine model has been reported^9,10 and was demonstrated to be superior to surgical and percutaneous myocardial gene transfer.⁵⁰ Penta et al⁵¹ showed a plasmid gene delivery vector, hDel-1, known to have angiogenic activity in angiogenesis assays when introduced via the coronary veins. It was subsequently found in high concentrations in the myocardium, but was absent or in much lower concentrations in peripheral tissues. Growth Factor That angiogenic growth factors such as basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) induce the growth of coronary collaterals has been shown.⁵² Various methods of introducing these growth factors to the myocardium have been studied including direct injection to the myocardium,⁵² infusion into the coronary artery⁵³ and repeated intracoronary bolus administration.⁵⁴ Degenfeld et al⁵⁵ report selective pressure-regulated coronary venous retroinfusion of fibroblast growth factors in a porcine model of chronic ischemia. Venous delivery of growth factors compared favorably with intracoronary infusion, and also led to increased levels of tissue binding of FGF-2 and enhanced collateral perfusion. Stem Cells Recent studies have highlighted cell transplantation as an emerging treatment for patients with end-stage heart failure.^56,57 Two main methods for the delivery of stem cells to the myocardium have been investigated: these are direct intramyocardial injection⁵⁸ and intracoronary infusion.⁵⁹ Both of these methods have been shown to be effective, however, cells injected directly into the heart have been shown to form small islets that may be isolated from the native myocardium, and intracoronary infusion may not allow cells to reach ischemic myocardium. Suzuki et al¹² have reported a rat model retrograde venous perfusion of stem cells into the heart. This route of infusion was shown to allow cells to disseminate to all layers of the myocardium, with minimal myocardial damage seen during or after retrograde infusion. Cardiac Electrophysiology The coronary venous system has been exploited by the cardiac electrophysiologist, allowing access to the ventricle for pacing,⁶⁰ defibrillation, arrhythmia mapping¹⁵ and radiofrequency ablation.⁶¹ Cardiac resynchronization therapy incorporating a pacing lead placed in a left ventricular vein has been shown to improve quality of life in patients with severe symptomatic (NYHA III) chronic heart failure who are already receiving optimal medical therapy.¹⁶ The combination of biventricular pacing and an implantable cardiac defibrillator in patients with chronic heart failure has been shown to reduce all-cause mortality in follow-up studies.¹³ Conclusion The coronary veins provide an underexploited route of access to the myocardium for catheter interventions and the delivery of therapeutic agents. Despite the early promise of retrograde perfusion in patients undergoing high-risk PCI, this technique has not become routinely employed for the reasons outlined above. However, retrograde arterialization of the coronary veins is a potential new percutaneous treatment for “no-option” patients with severe symptomatic coronary artery disease. The use of the coronary veins as a conduit for therapies such as gene vectors and stem cells is gaining wider recognition, and will play an important role in the development of these treatments.

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