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I greatly appreciate the thoughtful comment of Drs. Taegtmeyer and Razeghi. In my editorial to the study by Fang et al. (1), I described an “echocardiographic cascade” in the natural history of diabetic cardiomyopathy, with subtle, preclinical, possibly reversible changes in inotropic reserve, coronary flow-reserve, and ultrasonic tissue structure preceding more advanced, profound, and less, if at all, reversible changes in resting regional or global systolic function (2). No doubt that echocardiographic signs—however early—are only the consequences of the altered upstream metabolic and/or genetic condition. I proposed metabolic changes (with nonenzymatic glycation), according to what seemed to me (a metabolically and simple minded clinical cardiologist, I must admit) the most likely and proven explanation to date. There is little surprise to learn that knowledgeable experts propose a more sophisticated and elegant explanation: a genetically regulated disturbance in fatty acid metabolism that is present in both early and in more advanced phases of diabetic cardiomyopathy.
I do not know whether this is the only truth, but most likely it is part of it. In diabetic cardiomyopathy, disturbances in glucose metabolism coexist with alterations in fatty acid metabolism. Further upstream, there could be oxidative somatic DNA damage, which may co-generate and amplify the onset of clinical complications (3). Each of these components (genetic, metabolic, inflammatory, etc.) is part of a multifaceted and—at least for the clinician—still elusive pathogenetic entity. The quest for the holy grail of the metabolic source of diabetic cardiomyopathy cascade is still ongoing. Only by drying the (metabolic and/or genetic) source can we hope to halt the cardiomyopathy cascade that eventually leads the diabetic patient to heart failure and cardiac death. However, we are far from achieving this goal. The Romans used to have a term for this: Acta est fabula:“The game has just started.”
- American College of Cardiology Foundation