Abstract
Despite advances in primary percutaneous interventions (PPCI), management of microvascular obstructions in reperfused myocardial tissue remains challenging and is a high-risk procedure. This has led to renewed interest in the coronary venous system as an alternative route of access to the myocardium. This article reviews historical data describing therapeutic options via cardiac veins as well as discussing the clinical potential and limitations of a catheter intervention: pressure controlled intermittent coronary sinus occlusion (PICSO). Collected experimental and clinical information suggest that PICSO also offers the potential for tissue regeneration beyond myocardial salvage. A meta-analysis of observer controlled pICSO application in animal studies showed a dose dependent reduction in infarct size of 29.3% (p < 0.001).
Additionally, a 4-fold increase of hemeoxygenase-1 gene expression (p < 0.001) in the center of infarction and a 2.5 fold increase of vascular endothelial growth factor (VEGF) (p < 0.002) in border zones suggest that molecular pathways are initiating structural maintenance. Early clinical evidence confirmed significant salvage and event free survival in patients with acute myocardial infarction and risk reduction for event free survival 5 years after the acute event (p < 0.0001). This experimental and clinical evidence was recently corroborated using modern PICSO technology in PPCI showing a significant reduction of infarct size, when compared to matched controls (p < 0.04). PICSO enhances redistribution of flow towards deprived zones, clearing microvascular obstruction and leading to myocardial protection. Beyond salvage, augmentation of molecular regenerative networks suggests a second mechanism of PICSO involving the activation of vascular cells in cardiac veins, thus enhancing structural integrity and recovery.
1
Introduction
In recent years, the demographics of patients admitted for coronary interventions and revascularization procedures have changed, and there is an increasing need for complex high-risk interventional procedures (CHIP). Despite the development of sophisticated reperfusion strategies and the availability of logistic treatment networks for acute coronary syndromes (ACS), the management of obstructed myocardial microcirculation and subsequent myocardial deterioration remains challenging. Furthermore, there are large variations in reperfusion treatment across Europe; a substantial number of ST-elevation myocardial infarction (STEMI) patients in Eastern and Southern Europe are not receiving any reperfusion therapy . Although mortality from acute events has decreased, therapies to prevent or attenuate postinfarction left ventricular remodeling have changed little, leaving an increasing cohort of patients at risk of severe heart failure . Current routine therapies in ACS focus on the ischemic/reperfused microcirculation and on structural regeneration. Despite timely reperfusion, molecular, biochemical and immunological changes of the former deprived microcirculation persist, as well as areas of structural obstruction, particularly in the post capillary venules. Therefore there is a need for methods to further reduce microcirculatory obstruction, an important prognostic factor for morbidity, mortality and quality of life . In addition to restoring the microcirculation, cardioprotection and structural regeneration remain important in the treatment of ACS.
This article will discuss effective therapies and feasible catheter interventions using the back door of the heart for myocardial protection before, during and after the ischemic insult, particularly in the early reperfusion period.
2
The origin of coronary sinus interventions
The coronary venous route to access deprived myocardium and thus the obstructed microcirculation has a long history, beginning with retroperfusion of arterial blood in the late 19th century and progressing to the development of pressure-controlled intermittent coronary sinus occlusion (PICSO) in the 1980s ( Fig. 1 ) . Although there is little doubt that cardiac veins are useful access routes to jeopardized myocardium, few concepts have progressed to clinical development. The coevolution of interventional cardiology and cardiac surgery hindered widespread applications of coronary sinus interventions (CSI). However, the recent availability of novel interventional technologies has reversed this trend and revived interest in CSI.
The concept of PICSO, which uses the coronary sinus pressure for termination of obstructing venous flow in contrast to fixed timed ICSO, has recently been further developed using new technology. There are abundant data on myocardial salvage in experimental ischemia as well as in patients with lysis therapy during or following ischemia as well as reperfusion . Clinical data also support the use of PICSO in patients after global ischemia and in heart failure patients . Recently presented data detail the application of PICSO during primary PCI in the early reperfusion period .
The primary aim of coronary sinus interventions was retroperfusion of arterial blood to the myocardium, but preclinical and clinical data have suggested other beneficial effects, primarily redistribution of flow towards underperfused zones and subsequent washout as well as offering the potential to revive regenerative pathways, ultimately restoring structural integrity. The first clinical application of the concept of using the coronary sinus to access ischemic myocardium was in the 1940s . A series of pathophysiologic studies enhanced understanding of the reaction to elevated pressure in cardiac veins as well as reflexes originating from the endocardium close to the orifice of the coronary sinus . Further studies showed the effects of coronary sinus occlusion techniques on the behavior of the coronary microcirculation . Corday and Meerbaum developed interventional retroperfusion methods such as synchronized retroperfusion (SRP) and applied them clinically, forcing arterial blood retrograde via a catheter system during diastole into the ischemic microcirculation (see video 1) . Further research was halted following a combination of ambivalent results, unstable technology and the development of alternatives. Boekstegers refined the retroperfusion technology using a selective perfusion technique with subsequent suction that showed positive results in the clinical setting . Meerbaum achieved retrograde lysis of coronary artery thrombus by coronary venous streptokinase administration . In early clinical studies, pICSO (pressure observed intermittent coronary sinus occlusion without automatic closed loop, but observer control of pressure increase) was also able to enhance clot lysis significantly, even when given intravenously (p < 0.05) as compared to controls ( Fig. 2 ) . In addition, retroinfusion has been employed in stem cell research and gene therapy, showing favorable results when compared to other delivery routes .
2
The origin of coronary sinus interventions
The coronary venous route to access deprived myocardium and thus the obstructed microcirculation has a long history, beginning with retroperfusion of arterial blood in the late 19th century and progressing to the development of pressure-controlled intermittent coronary sinus occlusion (PICSO) in the 1980s ( Fig. 1 ) . Although there is little doubt that cardiac veins are useful access routes to jeopardized myocardium, few concepts have progressed to clinical development. The coevolution of interventional cardiology and cardiac surgery hindered widespread applications of coronary sinus interventions (CSI). However, the recent availability of novel interventional technologies has reversed this trend and revived interest in CSI.
The concept of PICSO, which uses the coronary sinus pressure for termination of obstructing venous flow in contrast to fixed timed ICSO, has recently been further developed using new technology. There are abundant data on myocardial salvage in experimental ischemia as well as in patients with lysis therapy during or following ischemia as well as reperfusion . Clinical data also support the use of PICSO in patients after global ischemia and in heart failure patients . Recently presented data detail the application of PICSO during primary PCI in the early reperfusion period .
The primary aim of coronary sinus interventions was retroperfusion of arterial blood to the myocardium, but preclinical and clinical data have suggested other beneficial effects, primarily redistribution of flow towards underperfused zones and subsequent washout as well as offering the potential to revive regenerative pathways, ultimately restoring structural integrity. The first clinical application of the concept of using the coronary sinus to access ischemic myocardium was in the 1940s . A series of pathophysiologic studies enhanced understanding of the reaction to elevated pressure in cardiac veins as well as reflexes originating from the endocardium close to the orifice of the coronary sinus . Further studies showed the effects of coronary sinus occlusion techniques on the behavior of the coronary microcirculation . Corday and Meerbaum developed interventional retroperfusion methods such as synchronized retroperfusion (SRP) and applied them clinically, forcing arterial blood retrograde via a catheter system during diastole into the ischemic microcirculation (see video 1) . Further research was halted following a combination of ambivalent results, unstable technology and the development of alternatives. Boekstegers refined the retroperfusion technology using a selective perfusion technique with subsequent suction that showed positive results in the clinical setting . Meerbaum achieved retrograde lysis of coronary artery thrombus by coronary venous streptokinase administration . In early clinical studies, pICSO (pressure observed intermittent coronary sinus occlusion without automatic closed loop, but observer control of pressure increase) was also able to enhance clot lysis significantly, even when given intravenously (p < 0.05) as compared to controls ( Fig. 2 ) . In addition, retroinfusion has been employed in stem cell research and gene therapy, showing favorable results when compared to other delivery routes .
3
The importance of pressure control during coronary sinus occlusion
Coronary sinus occlusion (CSO) techniques such as ICSO/PICSO and the Banai stent are based on changes in the pressure and flow relations in the normal and ischemic heart. During coronary sinus occlusion, redistribution of flow within the venous compartment allows access to deprived perfusion zones. During temporal occlusion as seen in ICSO/PICSO procedures, a phase of washout follows the filling of the venous compartment (see videos 2 and 3). In contrast, the Banai stent results in a chronic elevation of coronary venous pressure and may lead to severe side effects on coronary circulation including restrictions in venous flow and permanent reorganization of the venous outflow pattern .
During ICSO, the temporary occlusion of the coronary sinus (which collects about 70% of the myocardial outflow) induces a redistribution of venous blood and plasma-dense fluid from normally perfused territories into underperfused areas, such as severe atherosclerotic coronary arteries and in ACS with additional thrombus burden. The temporary increase of venous pressure in the coronary sinus induces a continuous rise and fall of pressure gradients in the microcirculatory bed, clearing debris and eliminating metabolic waste ( Fig. 3 ) . Reactive buffer systems and the action of osmotic, ionic and, most importantly, mechanical forces squeezing blood into the occluded microcirculation, reduce the area of the no reflow zones. Coronary sinus occlusion pressure reaches a systolic plateau resulting from the squeezing action of myocardial contraction. Since redistributed blood flow needs time to fill the venous compartment, these systolic pressure peaks rise constantly, reaching a plateau after several seconds. During pICSO and PICSO, this plateau level signals the reopening of venous drainage and enables optimal redistribution of venous blood ( Figs. 4, 5 ). The pressure in the occluded coronary artery fluctuates according to the pressure in the coronary sinus, and the arterial pressure decreases during coronary sinus release.
Several CSI techniques have undergone investigation. Animal research by Lazar et al. showed that PICSO was superior to IABP and that a combination of both methods enhanced the anti-ischemic effect during urgent surgical revascularization . The antiarrhythmic effects of pICSO have also been observed in animals . More recently, the historic concepts of ICSO and pICSO have been replaced by PICSO .
Currently the applications of PICSO have focused on ACS. In an experimental animal study, Jacobs et al. found that PISCO performed during reperfusion significantly enhanced myocardial salvage and postulated that PISCO may decrease heart rate by a reflex mechanism that is mediated by vagal afferents . A clinical study, the Prepare RAMSES trial (reperfusion after acute PCI in myocardial infarction and coronary syndromes: efficacy and clinical significance), which aimed to further analyze the salvage potential of this method, has recently been completed. This study followed the first-in-man study using new technology . Prepare PISCO included 15 patients with stable angina scheduled for PCI of the left anterior descending artery (LAD). Balloon occlusion of the LAD was performed twice, once with and once without PICSO and lasting maximally 3 minutes each, to document the effect of PICSO on coronary sinus pressure and LAD wedge pressure. PICSO resulted in a marked increase in coronary sinus pressure with no device-related adverse events reported . In a recently presented study of 32 heart failure patients undergoing resynchronization therapy, PICSO was performed on 8 patients for 20 minutes versus 24 controls. At 5 year follow-up, the metabolic, biochemical and molecular changes induced indicated that PICSO has regenerative potential beyond its acute effect on myocardial ischaemia .
In order to realize the full potential of this intervention, questions remain regarding the application of PICSO in ACS. There is also need for additional data to optimize the time window of PICSO to prevent/reverse reperfusion injury, to explore the potential to treat different ischemic perfusion territories and reduce the volume of obstructed microcirculation. Although early and recent clinical results are promising, there is also a need for long-term data from a propensity-matched trial to establish clinical significance.
However, there are major limitations associated with analyzing myocardial salvage in PICSO. It is known that PICSO interferes with edema formation and increases the energy in border zones by vasodilatation of the microcirculation . These findings demonstrate a reduction in the perfusion deficit and therefore reduce the evidence measured by magnetic resonance imaging (MRI), since it detects edema, which is claimed to be washed out, and positively influenced by PICSO. Myocardial salvage is assessed by MRI several days after the acute event and therefore includes PICSO effects on the area at risk, since deprived perfusion zones are normally measured experimentally before therapy starts. Therefore MRI data in PICSO research might blunt positive PICSO effects, reducing the perfusion deficit and enhancing washout. These effects of PICSO should be taken into account since recent data emphasize the importance and prognostic values of early changes in ischemic/reperfused microcirculation .
Stoller and colleagues reported that the reduction of ischemia in patients treated with brief ICSO periods depends on collateral flow . Variable levels of effectiveness of ICSO have been observed and seem to be dependent on the location of the balloon within the coronary sinus and therefore the amount of redistributed blood as well as the optimization of the pressure increase and cycling. A 2004 study on a sheep model showed that optimal timing significantly improves the effectiveness of the method . However, the fixed timings in ICSO occlusion/release cycle pattern prohibit optimal redistribution of blood, a limitation that has been demonstrated in several studies (see also Figs. 5,6 ) .
Inadequate duration of the coronary sinus occlusion release leads to an insufficient retroperfusion/drainage of the coronary sinus and hence decreases coronary artery inflow rather than resulting in washout and hyperemic response ( Fig. 5 ). The unadjusted fixed ICSO approach is unable to correct according to changes in CSP dynamics. Therefore an automatic closed loop method adapting to the dynamics of individuals was developed . In the majority of studies, pressure control was achieved by continuous observation and immediate, but observer controlled adjustment of pressure dynamics by the investigator (pICSO). A closed loop system for coronary sinus occlusion has been established that optimizes the beneficial effects of PICSO . The PICSO cycle adapts instantly (beat to beat) according to the physiologic state of the heart. Several parameters must be optimized in a PICSO intervention. In order to ensure sufficient coronary drainage, the release phase must be long enough to allow the next occlusion phase to be triggered by the end of the peak of hyperemic coronary arterial flow, which can be detected by observing venous flow (see Fig. 5 ). In addition, the occlusion phase must be set to ensure that the systolic coronary sinus pressure reaches a pressure plateau . Further developments have led to the implementation of proprietary algorithms used in the PICSO® Impulse System (Miracor Medical). These calculate the time of occlusion of the venous drainage via the coronary sinus versus the time of release of the balloon occlusion according to the coronary sinus pressure dynamics sensed over the fluid-filled line of the catheter.
Variations in coronary sinus dynamics can also be used as diagnostic parameters . Fig. 6 shows CSP dynamics as well as the rapid pressure increase following the opening of the coronary artery is opened in an ovine model . This was corroborated in a clinical evaluation of pICSO during the early reperfusion period. As soon as the bypass grafts were opened, the rise time in CSP shortened and systolic pressure increased significantly, thus reflecting surplus of myocardial inflow . This shows the importance of immediate response to the occlusion/release cycles during PICSO.
4
Optimization of PICSO therapy
In order to optimize PICSO therapy, the position of the occluding balloon redirecting blood in relation to side branches of the coronary sinus is of outmost importance. Exact positioning in an optimal region of the coronary sinus not only requires expertise, but is also a prerequisite of the effectiveness of the PICSO procedure. The easiest way to access the coronary sinus is the left jugular, subclavian or brachial vein. Since a routine anticoagulation regimen is used in ACS and to minimize the risk of bleeding, central venous punctures are avoided in several centers endorsing peripheral veins. The femoral approach has been extensively used and results in favorable catheterization times . The balloon catheter is positioned into the so-called “silent zone” of the coronary sinus (see video 4). Infrequently, an obstructing valve at the coronary sinus orifice hampers the positioning of the catheter within the silent zone of the great cardiac vein.
It is also important to stabilize the catheter system against the force of the outflowing blood, especially during the hyperemic response increasing the venous velocity ( Fig. 7 A, B ). The pressure within the pneumatic balloon catheter is monitored, avoiding any excessive force on the vessel wall and allowing maximal safety. Since the orifice of the coronary sinus is covered by endocardium and contains nerve endings, reflexes such as hypotension and bradycardia have been observed in animals . The squeezing action of the heart creates the pressure increase and forces the blood backwards into deprived zones; it is therefore important to collect as much inflow as possible from veins draining into the occluded section of the coronary sinus. The rate of rise gives an estimate of the capacity to be filled by retroperfused blood and is a summation of the venous compartment and the coronary microcirculation deprived from normal circulation. Epicardial flow into the deprived coronary vasculature and subsequent washout during the release phase therefore reduces the so-called ‘no reflow’ zones that are present in patients with ACS and allows a shift of blood towards the endocardium ( Fig. 4 ).
5
The salvage potential of PICSO
The significance of myocardial salvage by ICSO has been established in a meta-analysis of 7 experimental trials comprising 125 test animals that showed an inverse relationship between achieved (developed) coronary sinus systolic pressure, (i.e. occlusion duration and elevation of the coronary venous systolic pressure per minute multiplied by the application times of ICSO) and infarct size . The so-called “dose dependence” between optimized ICSO therapy and salvage has been documented in different species and different durations of ischemia .
Syeda et al. reported a significant reduction in infarct size of 29.3% in the pICSO group compared to the control group (p < 0.001; 95% confidence interval, − 40.9 to − 17.7), which correlated to the achieved (developed) coronary sinus pressure increase per minute (r = − 0.92; p < 0.007) . This dose-dependency has been recently confirmed by the Prepare RAMSES study, which showed a significant correlation (r = 0.70, p = 0.008) in reduction in infarct size and the cumulated coronary sinus pressure modulation over time . This has led to the development of an algorithm by Miracor Medical Systems that automatically calculates the PICSO quantity applied. The quantity is calculated as:
PICSO Quantity = ∑ n = 1 n = Total PICSO Cycles sCSP P n − dCSP P n * sCSP P n − CSPD A n * I H T n
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
