Response to: Paz Y and Shinfeld A. Mild increase in coronary sinus pressure with coronary sinus reducer stent for treatment of refractory angina. Nat Clin Pract Cardiovasc Med 6: [doi:10.1038/ncpcardio1475]

Original article: Mohl et al. (2008) Is activation of coronary venous cells the key to cardiac regeneration? Nat Clin Pract Cardiovasc Med 5: 528–530

“Nothing is more powerful than an idea whose time has come.” Victor Hugo French dramatist, novelist, & poet (1802 - 1885)

We thank Dr Paz for his commentary on our claim that physiologically applied periodic coronary sinus pressure elevation (PICSO) via inborn molecular pathways induces regeneration.1 We recently published an editorial on the legacy of coronary sinus interventions and it seems that we touched a sensitive area deserving further investigation.2 Among the proven effectiveness of significant infarct size reduction in different species, a relationship between pressure amplitude and salvage could be established.3 In contrast to the coronary sinus reducer stent (CSRS), which employs a permanent pressure elevation in the ischemic microcirculation, our concept employs a physiologic adaption of this pressure rise. We evaluated different occlusion/release timings to optimize the treatment according to the situation in the coronary circulation not to impede coronary perfusion because of the coronary reflexes reported in the past.4,5,6,7,8

Paz and colleagues' findings, however, indicate improvements in myocardial ischemia after permanently reducing coronary venous outflow with a CSRS introduced into the silent zone of the great cardiac vein.6 Their data are impressive; however, our own experience with coronary sinus pressure elevations warrants extreme caution. So, what is the discrepancy between these two studies? On the one hand, the concept of cautious (physiologic?) optimization of the timing of pressure elevations without negative effects on coronary circulation, and on the other, a permanent, although limited, pressure rise induced by a reduction in the lumen size of the great cardiac vein producing a gradual pressure gradient in the coronary venous system. We think that the scientific difference lies in the fundamental question asked. Whereas increments of perfusion into a deprived coronary microcirculation is the achievable goal of the CSRS, the concept has advanced into a complex hypothesis of activating venous endothelium, which influences regenerative pathways. The positive effects of both concepts support and legitimatize further research in this area.

Ever since arterialization of the coronary sinus was developed and applied clinically, controversy on a potential negative impact on normal coronary perfusion has hampered scientific acceptance. There are numerous reports on coronary sinus reflexes and severe interactions with normal coronary circulation contradicting positive reports on improvements in myocardial ischemia.9

As always in biology, dichotomy exists and seeming controversies are the result of a lack of human comprehension. It is our present working hypothesis that pulsation and activation of the venous endothelium results in beneficial effects, such as alleviating myocardial ischemia–reperfusion injury and its consequences. The effects can be summarized as “embryonic recall” since, in mammals, unusual recapitulations of organogenesis seem to be reanimated.

As many reports indicate, dose-dependency is key in this regard. So how can these contradicting results be integrated. Again a holistic perception of complexity between disease and treatment helps our understanding. The more severe and diffuse the diseased coronary arteries are, the more they will limit normal perfusion, the better the chance for any treatment. So it is a matter of the quantity that allows the biological system to turn allowing freedom to operate. This implies even total reversal of flow from coronary veins to coronary arteries as it is often used in cardiac surgery for myocardial protection.

As in all medical therapies, however, there is a dose response relationship and therefore under normal circumstances with patchy flow distribution, as in ischemic cardiomyopathies, ultimate effectiveness relies on a physiologic approach. We feel that this is best realized in an optimized periodic pressure rise to activate the endothelium and to prevent permanent impedance of coronary venous flow.

In summary, we feel that the comments and results from Paz and colleagues on the effects of the CSRS are an important contribution in the treatment of myocardial ischemia, but more insight is needed to discriminate between the two polarities of activation of coronary venous endothelium and reversal of flow. The good, the bad and the ugly of coronary sinus interventions—as they span from activation, claiming regeneration, and the experience of simultaneously occurring negative reflexes and severe side effects on coronary circulation in rigorous restrictions in venous flow remain—and warrant further investigation.