Exaggerated Blood Pressure Response to Exercise: Will It Ever Be Ready for Prime Time?

In 1513, the Florentin diplomat Niccolo Macchiavelli wrote “De Principatibus” (About Principalities), a book on statecraft and the wielding of power, which is considered the first sample of modern political philosophy. In chapter 3 of this treatise, Machiavelli uses disease as a metaphor for the management of state affairs. When the evils that arise have been foreseen (by prudent rulers as the Romans), they can be quickly managed, but when the evils have been permitted to grow in a way that everyone can see them, there is no longer a remedy. Reversing the metaphor, the same logic applies with atherosclerotic vascular disease. It is difficult to diagnose but easy to manage at first, and easy to diagnose but difficult to cure at the end. Numerous indices of endothelial function and subclinical inflammation, genetics and epigenetics, the neurohormonal milleu, structural vascular abnormalities, and several others have been applied to identify atherosclerotic disease at its initiation and early stages, but none have gained wide application in everyday clinical practice. In this issue, Tzemos and colleagues use a simple method to detect early stages of cardiovascular disease. Specifically, the investigators in the current study explored the association between the blood pressure response to exercise, endothelial function, aortic stiffness, and neurohormonal response in healthy individuals. Study participants were free of overt cardiovascular disease (coronary artery disease, cerebrovascular disease, peripheral artery disease), traditional cardiovascular risk factors (hypertension, dyslipidemia, diabetes mellitus, smoking), and a family history for the latter disease conditions. This careful selection permitted for the identification and subsequent inclusion in the study of “truly healthy” individuals at a young age and diseasefree as could be determined by a routine clinical examination in everyday clinical practice. State-of-the-art methodology was used to evaluate vascular function. Endothelium-dependent and -independent vasodilatation was assessed by measuring forearm blood flow (strain gauge venous plethysmography) following the infusion of acetylcholine and sodium nitroprusside, respectively. Similarly, endotheliumdependent and -independent vasoconstriction was evaluated using the same method via the infusion of N-monomethyl-L-arginine and noradrenaline, respectively. Echocardiography was used to assess the proximal aortic wall compliance, and aortic distensibility was then calculated. All study participants underwent a submaximal, three-minute exercise step test, reflecting everyday activities. Neurohormonal evaluation (angiotensin II, catecholamines) was performed at baseline and exercise peak using appropriate methodology at a laboratory with time-long experience in this field. In total, 82 young sedentary men entered the study and half of them exhibited an exaggerated blood pressure response to exercise (systolic blood pressure >180 mm Hg at exercise peak). Therefore, two groups with similar baseline characteristics and equal number of participants were formed. Endothelium-dependent vasodilatation was significantly attenuated (by more than 30%) in patients with exaggerated blood pressure response to exercise compared with normal responders. Similarly, endotheliumdependent vasoconstriction was also significantly affected (by 20%) in hyper-responders to exercise. In contrast, endothelium-independent vasodilatation and vasoconstriction were not different between the two groups. Collectively, these findings point towards functional abnormalities in forearm resistance arteries in individuals with exaggerated blood pressure response to exercise. Two more significant findings are reported. First, higher levels of angiotensin II at exercise peak were observed in individuals with exaggerated blood pressure response to exercise, suggesting that angiotensin II is implicated in the pathophysiology of hyper-responsiveness to submaximal exercise. Second, higher aortic stiffness was observed in individuals with exaggerated blood pressure response to exercise compared with individuals with normal blood pressure response. The cross-sectional nature of the study does not allow definite conclusions about causality, ie, whether increased stiffness is the cause or the result of exaggerated blood pressure response. Prospective case-control studies are needed to clarify this issue. The findings of the study are not unique. Previous studies during the past decade have shown an association between an exaggerated blood pressure response to exercise endothelial dysfunction, aortic stiffness, and Address for correspondence: Michael Doumas, MD, PhD, VA Medical Center, 50 Irving Street NW-151-E, Washington, DC 20422 E-mail: michalisdoumas@yahoo.co.uk