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Function, metabolic, and flow heterogeneity of the heart: the view is getting better.

What controls the magnitude and distribution of blood flow in the heart is unknown. Since the early adenosine hypothesis,1 investigators have continued to look for metabolites or signaling pathways involved in the regulation of coronary perfusion. The trends have run through adenosine, neuronal influences, CO2, O2, pH, lactate, K+, myogenic responses, growth factors, nitric oxide, and others. No consensus has emerged with regard to a feedback or feedforward model for coronary perfusion regulation despite decades of research.

What is becoming clear is that a simple regulatory system on the basis of one metabolite or signaling pathway is unlikely. This is supported by many lines of experimental evidence,2 3 4 5 demonstrating complex interactions among most of the putative regulatory processes. To complicate this additionally, evidence has emerged that the coordinated functions of contraction, flow, and energy metabolism are highly heterogeneous. This heterogeneity, along with the assumed regional control processes, makes the mechanistic interpretation of mean flow data from the large veins and arteries difficult, even though this has been the major form of analysis in the past.

Labeled microspheres have documented heterogeneity of myocardial perfusion with 6- to 10-fold variations between regions.6 7 8 The heterogeneity is apparently not random; regions trend together with a similarity in the spatial correlation as a function of distance that has fractal characteristics.9 Most importantly, the magnitude of flow variation increases with decreasing sample size,8 9 suggesting a highly localized form of regulatory control. One factor contributing to the flow heterogeneity could be the branching network of the coronary vasculature.10 However, most studies suggest that the most important factor is the tissue itself, modifying flow to meet the metabolic need. Local metabolic activity correlates with regional flow.11 12 13 This is …