Biomarkers of Cardiovascular Stress: A Historical Review.

Internal and external stress exerted by forces such as oxidative, xenobiotic, radiant, ischemic, mechanical, metabolic, neurohormonal, infectious, immunoinflammatory, emotional and psychological increases the risk of cardiovascular morbidity and mortality. Initiation and propagation of the explosive self-amplifying chain reaction of lipid peroxidation chain reaction (LPO) generates atherogenic and inflammatory toxic reactive oxygen species that cause cardiovascular tissue lesion that are the ultimate determinants of cardiovascular disease risk (CVD-R). Because the LPO toxins, cellular stress sensors and defenses, inter- and intracellular signaling, and pathogenic lesions are closely similar among these stressors, simultaneous exposure to multiple stresses can amplify LPO to accelerate accumulation of pathogenic lesions synergistically. Numerous blood tests measure LPO-derived toxins, stress-responsive metabolism and cytokines, which are used clinically as surrogate biomarkers of CVD-R. They can predict population risks quite well, but prediction of individual patient CVD-R using multiplex biomarker panels is hampered by lack of true independence between biomarkers, lack of understanding of their relative hierarchy in disease etiology or progression, and interference from comorbid diseases or acute-phase reactions. We present this historical review of landmark studies that led to the current clinical paradigms of CVD-R prediction to provide mechanistic and clinical context that will aid the development of integrated etiological biomarkers that reflect the multiple types of stress that promote CVD-R.