Exercise-induced hypertension is associated with angiotensin II activity and total nitric oxide

1. Introduction

Regular exercise ameliorates risk factors of cerebro-cardiovascular diseases^[1,2] while lowering mortality and promoting cardiovascular health.^[3] However, in runners participating in long-distance running such as marathon, arterial stiffness and pressure increased^[4] and the prevalence of critical arrhythmia such as atrial fibrillation, was significantly higher than the general population.^[5,6] Coronary atherosclerosis and myocardial damage has been also reported to have associated with marathon running in healthy runners.^[7–9] In prospective follow-up study of 10.4 years, running or walking decreased cardiovascular disease mortality risk progressively at most levels of exercise in patients after a cardiac event. However, the benefit of exercise on cardiovascular disease or ischemic heart disease related mortality was attenuated at the highest levels of exercise like running above 7.1 km/d.^[10]

Recent reports show that the incidence of exercise-induced hypertension (EIH) is high^[7] among long-distance runners and that runners with EIH show a greater elevation of cardiac troponin I, a marker for myocardial injury, and N-terminal fragment of the prohormone brain-type natriuretic peptide, a marker for myocardial volume-pressure, than normal runners during a marathon or ultramarathon,^[8,9] raising concerns for the risk of cardiac events during exercise. EIH is defined as a normal resting blood pressure (BP) of <140/80 mm Hg with a maximum systolic BP (SBP) ≥210 mm Hg.^[11] EIH increases the risk for future resting hypertension.^[10] and is an independent risk factor for cerebro-cardiovascular disease.^[12,13]

Furthermore, prehypertension and isolated or combined with exaggerated BP response affect cardiac remodeling such as myocardial hypertrophy or further left atrial enlargement in middle aged amateur marathon runners.^[14] Gabrielli et al reported athletes with more intensive training load had larger left ventricular mass and left atrial size with increased left atrial contraction. This increase in the left atrial contraction was related to the maximum oxygen consumption (VO₂) measured previous to the marathon and to performance in a highly demanding test.^[15]

Therefore, the preventive treatment for exercise induced hypertension is very important in the cardiovascular health of runners. Especially, the marathon race is an extremely vigorous and competitive exercise that requires regular and intense training. Nevertheless, the acute adverse effects of marathon race on arterial stiffness and clinical outcomes, as well as regulatory mechanism of BP, have not clearly been elucidated. A recent study found renin-angiotensin-aldosterone system (RAAS) involved in the elevation of BP and heart rate (HR) during exercise,^[16] and angiotensin II activity is associated with EIH in patients with dyspnea.^[17]

For this purpose, this study aimed to identify factors in the RAAS, which regulates BP, that are activated in addition to the responses of nitric oxide (NO), which has vasodilatory, antiplatelet, and antithrombotic action, in well-trained runners with EIH.^[18]

2. Materials and methods

3. Results

4. Discussion

This study examined the changes in RAAS and total NO, which are involved in BP regulation, after maximal exercise in middle-aged long-distance runners with EIH. The study participants were classified into the NBPG, EIHG, and CHG, and RAAS and NO measurements were taken before a GXT and 30 minutes after the GXT. The results showed that angiotensin II levels were significantly reduced from the baseline in the NBPG but remained at the baseline in the EIHG and CHG (Table 3 and Fig. 1B). This suggests that runners with EIH and CH showed persistent angiotensin II activity even in the recovery phase after exercise.

The NBPG showed no changes in NO in the recovery phase after exercise, but the EIHG and CHG showed reduced NO levels, with the EIHG showing a more significant reduction than the NBPG. Hypotheses explaining the reduction of NO after exercise involve elevated oxidative stress, shear rate, BP, baseline artery diameter, and SNS activity.^[20] Particularly, strenuous exercise increases the production of free radicals, such as superoxide, that cause oxidative stress, which substantially lowers the bioavailability and production of NO and diminishes epithelial functions and FMD.^[21] Further, NO eliminates free radicals, thereby decreasing NO availability.^[22] In general, oxidative stress increases with increasing exercise intensity,^[23] and this is related to an excessive reduction of FMD.^[24] A biphasic response occurs in which FMD declines 30 minutes to 1 hour after vigorous exercise, and this phenomenon is associated with the reduction of NO.^[20] High levels of BP lead to associated increases in shear that, over a prolonged period, may result in the decreased release of NO from the endothelium.^[25] As previously mentioned, the decrease in FMD immediately after exercise may be less apparent in trained individuals.^[26,27] However, in patients with EIH and general hypertension, they already have endothelial dysfunction, which is normal, because they lack protection against high shear rates due to increase in BP after exercise.

Therefore, the clear reduction of NO 30 minutes after maximal exercise in the EIHG and CHG and the relatively lower reduction in angiotensin II activity—which is involved in vasoconstriction—in the EIHG and CHG explain the impairment of vasodilation patients with EIH. We observed that the EIHG and CHG had higher BP than the normal group at 3 minutes of recovery after GXT. EIH occurs because of an increase in post load caused by increased arterial stiffness and arterial endothelial dysfunction.^[28,29]

In this study, we found that 50% of long-distance runners had EIH, and 20% of the participants had complex hypertension. It is unclear whether the high prevalence of elevated BP during exercise is caused by the higher exercise capacity of the participants or by a pathological factor such as increased arterial stiffness. Recent reports have shown a high incidence of EIH in long-distance runners, but the cause for this remains unknown.^[6,7] The incidence of atrial fibrillation,^[5] as well as sudden death^[30] and arterial stiffness^[4] is high among individuals who engage in vigorous exercise. In fact, runners who participate in intense exercises such as marathons engage in exercise 5 to 10 times higher than the recommended amount of exercise in the cardiovascular prevention guidelines,^[31] raising concerns for the potential side effects of excessive exercise. Individuals with EIH are 5 to 10 times more likely to develop resting hypertension,^[10] and although EIH is a risk factor for stroke and predictor of mortality,^[11] it is unknown whether this is also true for long-distance runners.

Recently, studies have confirmed the elevation of cardiac troponin I, which is expressed upon myocardial infarction, and the elevation of N-terminal fragment of the prohormone brain-type natriuretic peptide, which increases myocardial volume-pressure, during a 100 km ultramarathon in runners with EIH.^[8,9] This proves that runners with EIH participate in long-distance running with greater myocardial burden than runners with normal BP. In addition, in a study of 588 long-distance runners, Kim et al found that the group of runners with arrhythmia such as critical atrial fibrillation had higher VO₂max, greater exercise intensity, and longer exercise career than the group of normal runners, and that both groups had prehypertension and EIH.^[6] This evidence suggests that excessive exercise itself may adversely impact the cardiovascular system, and longitudinal studies are needed to investigate whether the incidence of future cardiac events such as myocardial hypertrophy, arterial stiffness, arrhythmia, and sudden death may be elevated among those with EIH.

Warner et al^[32] reported that the maximum SBP was lowered by 33 mm Hg in patients with exaggerated BP response by angiotensin II receptor inhibitors. Kim and Ha^[33] stated that angiotensin receptor inhibitors or ACE inhibitors can be recommended for patients with EIH. Moreover, Liakos et al reported that angiotensin receptor blocker were effective at suppressing the exercise induced acute phase inflammatory response.^[34] Our finding that runners with EIH and CH showed persistent angiotensin II activity even in the recovery phase after exercise could be accompanied by a significant clinical impact; it can be speculated that angiotensin receptor blockers can be suggested at protecting long distance runner with EIH against the triggering of acute coronary syndrome and the developing of sudden critical arrhythmia during vigorous exercise. Nevertheless, this suggestion needs to be proven by future studies with hard endpoints in terms of morbidity and mortality.

Some limitations of this study and recommendation for future studies were discussed. First, the size of sample was small and there was no randomization with groups, which would possibly affect generalizability of the findings. It is suggested that a larger sample size and randomization of the groups should be considered in the further studies. Secondly, the sample was only consisted of well-trained Korean healthy middle-aged runner, it is possible that results from this study may not be generalizable to various groups with other physical conditions. In the future, it is recommended involving a more various racial groups with different physical conditions. Thirdly, we were unable to adjust for the subjects’ family histories and control for their involvement in other exercises. Fourth, we also did not perform FMD testing before and after exercise. Absence of echocardiography to differentiate between the potential diseases affecting cardiac structure and functions and not using the 24-hour ambulatory BP test to accurately examine BP further limited the study. Finally, this study used only blood analysis for evaluation for arterial stiffness or hemodynamic changes. Follow-up assessments through diagnostic imaging test such as ultrasonography or computerized tomography scan would be suggested in future studies

Despite these limitations, this study has its significance by verifying the factors in the RAAS, which regulates BP, that are activated in addition to the responses of NO in well-trained runners with EIH.

In conclusion, angiotensin II and NO reduction, which hinder vasodilation, are involved in EIH among long-distance runners. Therefore, angiotensin II blockers should be considered for pharmacological therapy for them when necessary.

Author contributions

Data curation: Young-Joo Kim, Chul-Hyun Kim, Yongbum Park.

Investigation: Young-Joo Kim, Yongbum Park.

Software: Young-Joo Kim, Chul-Hyun Kim.

Supervision: Young-Joo Kim, Min Young Chun.

Validation: Young-Joo Kim, Chul-Hyun Kim, Yongbum Park, Min Young Chun.

Writing – original draft: Young-Joo Kim, Chul-Hyun Kim, Yongbum Park.

Writing – review & editing: Min Young Chun.