Collateral vessels reduce mortality.

Christian Seiler, Pascal Meier, and their co-workers of the University Hospital in Bern, Switzerland, well known for their pioneering clinical work on the collateral circulation of the heart, have described a meta-analysis of 12 studies involving 6529 patients of the role played by the collateral circulation in mortality. The authors come to the conclusion that the ‘coronary collateralization has a relevant protective effect’. Mortality is reduced by 36% in patients with, compared with those without, demonstrable collaterals. This is a very important statement about a situation that most cardiologists believed that they knew from anecdotal evidence: patients with all three epicardial arteries occluded but without infarctions, in some cases even without typical ischaemic symptoms, die from an unrelated cause and with the post-mortem finding of long-standing major coronary artery disease, again without sign of infarction. 4 However, the relevance of such observations was sometimes disputed: since collaterals develop in response to arterial stenoses and occlusions, it is quite clear that more collaterals can often be demonstrated in hearts with more advanced coronary artery disease, and indeed the conclusion was put forward that collaterals are the harbingers of a worsening course of the disease. Only a few but prominent clinicians clung to this view, but this is now roundly refuted. Backed by their analysis, Seiler and his co-workers state, that ‘the results of this study highlight the importance of finding new means to induce collateral growth’. With the evidence of the lifeprolonging effects of collaterals at hand, it is time to make a giant leap forward and increase efforts to prolong the lives also of the have-nots. This is a timely reminder for the pharmaceutical industry to increase activities in this direction, which have so far been virtually absent. Two reasons may be put forward for this: the disaster which occurred with the industry’s brief love affair with angiogenesis, which early on showed promise for patients and profits but which ended in disappointment and huge losses in investments. Secondly, the industry is reluctant to stimulate vascular growth because of its potentially cancerogenic effect. However, since the molecular pathways of arteriogenesis are now sufficiently well known (Figure 1), this should facilitate industrial development of very specifically acting new drugs. The questions arising from that are: how feasible is the task of arteriogenic stimulation, are these vessels stimulatable at all, and will they stay enlarged after cessation of therapy? A further question is why is it that in so many patients collaterals do not develop? To answer the first question: yes, collaterals can be stimulated to grow and to develop. Collaterals develop best when two conditions are met: increased fluid shear stress plus attraction of bone marrow-derived mononuclear cells that attach to stressed endothelium but also enter the adventitial space from leaky small veins. Stimulation of these cells by peptide hormones was shown to be successful in patients. Stimulation by increased fluid shear stress is probably the strongest stimulus for vascular growth. The fate of forced growth will finally depend on the tissue’s need for oxygen and nutrients. All excess will be trimmed. Another essential factor is the presence of proteases necessary for outward remodelling. Without proteases all new growth will clog the lumen. Peptide growth factors, mitogens for endothelial and smooth muscle cells, are probably not the answer because clinical studies were generally disappointing and animal experiments by the group of Keshet have shown that cardiac endothelial overexpression of vascular endothelial growth factor leads to overproduction of shed endothelial cells that clog the arteries and cause tissue ischaemia, i.e. the opposite of the intended result. It was shown that inhibition of the nitric oxide (NO)-producing enzymes inhibits arteriogenesis, but we showed that one relatively recently developed NO donor (detaNONOate) indeed stimulated collateral development in the vascular periphery. Several reasons can be discussed to explain why collaterals do not develop in a number of patients.