EDITORIAL COMMENTARY Innovation in optical imaging: Looking inside the heart Igor R. Efimov, PhD From the Department of Biomedical Engineering, Washington University, St. Louis, Missouri. The evolution of cardiovascular physiology, as in all natural sciences, swings like a pendulum between the two extremes: reductionist and integrative approaches. 1,2 In the first case, investigators attempt to dissect a com- plex phenomenon and rigorously quantify their simplified models of a physiologic system. This approach yields breakthroughs in technology development and an under- standing of individual components of the system. How- ever, eventually a reductionist model fails to grasp the systemic complexity of the studied phenomenon and ends up being overwhelmed by the sheer number of complex quantitative relationships involved in the system. After that, the pendulum swings to the integrative approach, which follows and reestablishes the systemic view. It synthesizes the wealth of knowledge accumulated by reductionists of the preceding period and identifies new feedbacks and regulatory networks. However, it too eventually fails because of its inherent qualitative nature. The second half of the 19th century was the era of Ludwig’s integration, which was followed by the reduction- ist views of Starling. The pendulum again swung toward the integrative approach at the turn of the 20th century with the work of Wiggers, who dominated US physiology for nearly half a century. The discovery of ion channels has led to the dominance of the reductionist paradigm for the past half century and produced the channelopathy hypothesis of car- diac arrhythmias. However, this triumph also has signaled the end of the cycle. Whereas in some cases single molec- ular abnormalities have been linked to arrhythmias in a particular population of patients, limited progress has been made in addressing such gigantic problems as atrial fibril- lation and heart failure. Currently, new synthesis is needed to integrate the wealth of knowledge accumulated by the reductionist efforts of several generations. It appears that the period of paradigm shift is approximately 50 years, and the time has come to reestablish the synthetic complexity of the cardiovascular system using integration approaches. One of the major obstacles in advancing our understand- ing of the mechanisms of cardiovascular disease is a lack of comprehensive technologies to address the structure–func- tion relationship at the tissue-organ level. In order to com- prehend the complexity of the remodeling processes leading to diseases of the heart, one needs to investigate the mech- anisms of excitation, contraction, and their molecular basis in the same heart. Unfortunately, it usually is impossible because of the limitations of existing experimental method- ologies. Electrophysiology usually is studied in one group of hearts, anatomy and contractility in another, and molec- ular underpinnings in yet another group of hearts by three separate research laboratories often located thousands of miles apart. However, the intrinsic noise of a physiologic system as a result of heart-to-heart and species-to-species variability often obscures the importance of structural find- ings in the absence of functional data or vice versa. Molec- ular biophysical and imaging studies have low spatial or temporal resolution and lack correlation with tissue struc- ture/function, which often complicates extending these find- ings to heterogeneous physiologic systems, especially in the settings of dynamic remodeling associated with chronic disease. Thus, there is an urgent need for a methodologic frame- work that would allow investigation of all three fundamen- tal components of cardiovascular phenomena with a single synthesized set of tools that can be applied in comprehen- sive structure–function studies. These tools must be able to measure with high spatial and temporal resolution the struc- ture, function, and molecular substrates in the intact heart. Unfortunately, the state-of-the-art magnetic resonance im- aging (MRI) and computed tomography (CT) technologies of today do not provide means for electrophysiologic stud- ies. Biophotonic and electrode-based approaches remain the only current options for obtaining electrophysiologic mea- surements. The more mature electrode-based approach keeps deliv- ering impressive sets of tools for basic and clinical electro- physiology, including endocardial and noninvasive map- ping of the heart. 3 On the other hand, biophotonics is potentially a powerful approach; however, it struggles with breaking through to in vivo and even endocardial mapping. Recently, a number of interesting advancements have pro- vided assurance that biophotonics is capable of delivering high-resolution imaging tools to compete with electrode- based technology. Moreover, biophotonics may offer ad- vantages by providing a comprehensive set of tools to image Address reprint requests and correspondence: Dr. Igor R. Efimov, Department of Biomedical Engineering, Washington University, Cardiac Bioelectricity Center, 290 Whitaker Hall, One Brookings Drive, St. Louis, Missouri 63130. E-mail address: igor@wustl.edu. 1547-5271/$ -see front matter © 2007 Heart Rhythm Society. All rights reserved. doi:10.1016/j.hrthm.2007.04.006