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

And what physicians say about hectic fever is applicable here: that at the beginning a disease is easy to cure but difficult to diagnose; but as time passes, not having been treated or recognized at the outset, it becomes easy to diagnose but difficult to cure.––Niccolo Machiavelli

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 colleagues1 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.1 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 disease‐free 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, endothelium‐dependent and ‐independent vasoconstriction was evaluated using the same method via the infusion of N^G‐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, endothelium‐dependent 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 enhanced angiotensin II rise at exercise peak.2, 3, 4 Two points are unique in this study, however. First, the recognition of these abnormalities in individuals with an exaggerated blood pressure response to exercise was observed simultaneously, uncovering the multifactorial nature of blood pressure hyper‐responsiveness to exercise. Second, and likely more important, the above‐mentioned abnormalities were detected in young healthy men free of any cardiovascular disease or cardiovascular risk factors, suggesting that these abnormalities appear early in life and well before the onset of cardiovascular disease.

Exaggerated blood pressure response to exercise has been associated with target organ damage5 and hypertension in special populations.6, 7 We have previously shown that a disproportionate blood pressure response to exercise was the strongest predictor of left ventricular hypertrophy in individuals with prehypertension.5 Moreover, an exaggerated blood pressure response to exercise has been associated with incident hypertension,8 highlighting the potential detrimental cardiovascular sequelae of hyper‐responsiveness to exercise.

The study is limited by its small sample population and all male participants, a limitation appropriately discussed by the authors. Finally, the authors have not adjusted their findings for fitness status (because of the small number of study participants) claiming that fitness has little if any effect at relatively low workloads. However, we have shown that fitness or exercise capacity affects blood pressure response to exercise even at low workloads. Indeed, blood pressure levels at five metabolic equivalents during treadmill exercise were significantly lower in fit compared with unfit prehypertensive individuals.5

The findings of the study raise several interesting perspectives:

• Will aggressive lifestyle modification attenuate or even reverse these abnormalities in this patient population? We have shown that following 16‐week aerobic exercise training, systolic blood pressure levels of hypertensive individuals at the absolute workload of five metabolic equivalents were more than 30 mm Hg lower when compared with pretraining levels.9 Moreover, arterial stiffness that is increased in sedentary individuals is beneficially affected by exercise and healthy diets.10, 11, 12 Additional support for exercise‐related cardiovascular health benefits comes from studies in indigenous populations with a lifestyle characterized by high levels of physical activity (gatherer‐hunter lifestyle). Blood pressure and arterial stiffness were significantly lower in these populations when compared with individuals adhering to a westernized lifestyle.13, 14 Prospective studies with aggressive lifestyle modification in individuals with exaggerated blood pressure response to exercise are needed to evaluate the potential benefits.

• Will it prove useful to perform a submaximal exercise test early in life to detect individuals with exaggerated blood pressure response? Such an approach is simple and seems feasible for the general population but needs hard data before gaining wide application.

• Study findings1 and other data5 suggest that these patients are at increased risk for target organ damage. Is it then beneficial that submaximal exercise testing be administered early in life to identify individuals who exhibit an exaggerated blood pressure response? Moreover, when such individuals are identified, what type of therapy would be appropriate? Would antihypertensive therapy be beneficial for this population? According to the Trial of Preventing Hypertension (TROPHY), candesartan therapy in prehypertensive patients significantly delayed incident hypertension.15 Given that angiotensin II is implicated in the pathogenesis of exaggerated blood pressure response to exercise,1, 4 will renin‐angiotensin system inhibition be more beneficial in this patient population than in individuals with normal blood pressure response to exercise?

• Finally, our previous work over the years suggests that moderate‐intensity aerobic exercise training results in lower blood pressure at rest and during exercise.16, 17, 18 Perhaps we should consider a shift in the paradigm and consider increased fitness as a viable option to reverse the silent and insidious ascent of blood pressure.