Hypertensive Response to Exercise in Athletes: Unremarkable Finding or Relevant Marker for Future Cardiovascular Complications?

Background In the general population, hypertensive response to exercise (HRE) predicts new-onset resting hypertension or other cardiovascular diseases. Methods PubMed was searched for English articles published between January 1st 2000 and April 30th 2020. Additional studies were identified via reference lists of included studies. 92 papers were selected for full text analysis, finally 30 studies were included. Results The results from 5 follow-up studies suggested an association between HRE and the risk of developing hypertension, while 10 studies reported a link with adverse cardiovascular events in the general population. Another study showed an association between HRE and future hypertension in athletes after a follow-up of 7 years. HRE in athletes was associated with left ventricular hypertrophy in three studies. Two other studies showed a link between HRE and focal myocardial fibrosis in triathletes and myocardial injury, respectively. One study found lower Apoliprotein-1 serum levels in athletes with HRE leading to a higher risk for cardiovascular disease. Only in one study no association with cardiovascular dysfunction in athletes with HRE was found. Conclusions Based on current evidence, HRE is not a normal finding in athletes. If detected, it should be interpreted as a risk factor for future cardiovascular complications. Future research should address the adequate follow-up and management of athletes with HRE.


Introduction
Overwhelming evidence shows that regular aerobic exercise is favorable for the cardiovascular system [1]. More specifcally, several studies have shown that physical activity including aerobic and resistance exercise lowers both systolic and diastolic blood pressure [2][3][4]. Tis efect is particularly strong in people with high resting blood pressure [3,5]. Moreover, exercise reduces the usual cardiovascular risk factors such as hypercholesterolemia, overweight/obesity, and type 2 diabetes (by reducing insulin resistance) [5].
As within the normal population, hypertension is the most common cardiovascular disease in athletes. Conditions typically associated with hypertension in athletes are high body mass index, positive family history, and unhealthy lifestyle. Other common factors include intake of anti-infammatory drugs, dietary supplements, abuse of anabolic steroids, and psychosocial pressure [6]. However, also the type of sport may play a minor role [7].
To increase the cardiac output, the systolic blood pressure physiologically raises linearly with the increment of load via increased sympathetic tone. Tus, the metabolic needs of the working muscles can be covered. Te diastolic blood pressure remains stable or decreases minimally [8].
To assess the efect of physical workload on blood pressure regulation, the type of workload should be considered. In terms of diferent sports disciplines, dynamic sports showed higher systolic blood pressure (SBP) values due to high workloads, whereas static sports showed higher diastolic blood pressure (DBP) values as a result of increased peripheral resistance [7].
It has been observed that some individuals respond to physical stress with an exaggerated increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP). Such a hypertensive response to exercise (HRE) has been also found in subjects without any previously known cardiovascular disease and may predict new-onset resting hypertension and/or future cardiovascular disease [8][9][10][11].
Currently, there is no consensus on how to defne the blood pressure limits for HRE. Te European Society of Cardiology (ESC) guidelines report reference values for SBP of ≥210 mmHg for men and SBP of ≥190 mmHg for women [12]. Caselli et al. reported slightly higher values of SBP, i.e., 220/85 mmHg for males and 200/80 mmHg for females [13].
Te pathophysiology of HRE is poorly understood. Several mechanisms related to endothelial dysfunction and vascular stifness have been demonstrated. Both may limit vasodilatation in response to exercise, leading to HRE. Endothelial dysfunction mainly results in HRE in younger individuals, whereas increased arterial stifness is more likely to be responsible for inadequate vasodilation during exercise in older individuals [11].
Since sedentary subjects with HRE have a higher risk of developing cardiovascular events, it has been questioned whether HRE in athletes should be interpreted as a normal adaptation to training, or whether it represents an imbalance between cardiac output and peripheral vascular resistance, and could therefore have a potential future clinical impact on hypertension, cardiovascular events, and mortality [14].
Here, we review the current knowledge of HRE and its possible clinical consequences with the focus on athletes. We hypothesize that HRE in athletes is a risk factor for future cardiovascular complications, due to several training hours a day with repetitively high blood pressure loads.
Further insights on previous literature have been presented in the online supplement.

Methods
Te following study designs were considered in this systematic review: prospective or retrospective cohort, crosssectional, and case-control. Studies that reported exercise induced blood pressure response and evaluated the clinical implications of HRE in the athletic and non-athletic population aged >18 years were included. Studies in English were considered. Papers analyzing HRE in a non-athletic population with previous diseases were excluded.
Te software EndNote was used for reference management.

Information Sources and Searches.
A systematic literature review was performed according to the procedure specifed by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [15]. For literature extraction, papers were searched within the PubMed database using following search terms: "exaggerated exercise blood pressure," "exercise-induced hypertension," "exercise-related blood pressure," and "hypertensive response to exercise in athletes." Animal and in-vitro studies were excluded. Papers published and those in publication process (i.e., in press and available in PubMed) between January 1st 2000 and April 30th 2020 were considered. In addition, references from identifed papers and suggestions for similar articles were hand-searched, screened, and analyzed.
Duplicates were systematically examined and removed. Relevant articles were identifed by screening the title and reading the abstract. For the fnal eligibility, full-text analysis was performed. Data extraction was performed for each eligible study by one independent author.
Information was extracted from each included study regarding the following aspects: characteristics of participants including gender, age, athletic condition, blood pressure response to exercise and observations associated with long-term outcomes such as hypertension, cardiovascular events, or cardiac remodeling.
Te literature search yielded a total of 881 papers. Of these, 17 were excluded after checking for duplicates and 789 after screening for title and abstract. Among the 92 articles selected for full-text analysis, 62 did not meet the inclusion criteria. In conclusion, 30 papers were considered relevant, among these, 10 were suitable to address the question whether HRE in athletes represents a risk factor for future cardiovascular complications ( Figure 1).

Patient and Public Involvements.
No patients were involved in this study.

Results
Characteristics of the included studies are described in Tables 1 and 2. From 30 included studies, 20 analysed HRE in nonathletes and 10 in athletes. Te calculated median age of nonathletes was 48.75 years, and the interquartile range (IQR) was 10. Te median percentage of men was 69, and the IQR was 44.15. Te calculated median age of the athletes was 38.95 years, and the IQR was 19. Te median percentage of male athletes was 86.5, and the IQR was 35.
Five prospective studies found a link between HRE and the risk of developing hypertension in non-athletes, while just one prospective study showed that athletes with HRE had a higher risk of developing arterial hypertension. 10 studies showed a relationship between cardiovascular events in non-athletes with HRE. In three diferent studies, an association between HRE in athletes and LV hypertrophy was found. Two studies reported a relationship between HRE in triathletes and myocardial injury with focal myocardial fbrosis. A cross-sectional study found lower Apoliprotein-A1 levels in athletes with HRE, suggesting a higher risk for cardiovascular disease. Only one study could not fnd any link between HRE in athletes and cardiovascular dysfunction.  [19]. Similarly, Kayrak et al. found a prevalence of 41% of masked hypertension in 61 patients with HRE, [17] and Sharman et al. found a prevalence of 58% for masked hypertension in 72 subjects with HRE [18]. Since masked hypertension is associated with increased mortality but cannot be diagnosed during ofce blood pressure measurement, Schultz et al. speculated that masked hypertension could be detected during low-intensity exercise testing as HRE has high specifcity and is more time-efcient than a 24 h ambulatory blood pressure monitoring [19]. In a more recent study, Schultz et al. found an association between elevated SBP during early stages of exercise stress test and hypertension that was only identifed by 24 h ambulatory blood pressure monitoring [20].

HRE and Risk for Cardiovascular Events.
Several studies reported increased cardiovascular events and mortality in subjects with HRE at moderate exercise compared to individuals without HRE. After a follow-up of 15 years Hietanen et al. found that an elevated ankle blood pressure in combination with elevated blood pressure levels during exercise was a signifcant independent predictor of coronary heart disease in subjects with normal resting blood pressure [25]. Kjeldsen et al. showed that an elevated SBP during moderate workload predicts cardiovascular mortality independently from other known cardiovascular risk factors, while no association was found for SBP at peak exercise and cardiovascular death [27]. Over a mean    Heart Study over 20 years and showed that HRE was associated with an increased risk for future cardiovascular disease beside resting blood pressure and other conventional risk factors [9]. Mottram et al. compared echocardiographic fndings in patients with HRE with and without resting hypertension with subjects with normotensive response to exercise and no history of hypertension: they report an association between HRE and subtle systolic dysfunction in HRE, while no correlation between HRE and left ventricular hypertrophy was observed [33]. Left ventricular diastolic dysfunction and exercise intolerance have also been observed in patients with HRE [21]. Using speckle tracking imaging, Yang et al. demonstrated longitudinal myocardial dysfunction among subjects with HRE. However, conventional echocardiographic examination did not show diferences in diastolic parameters, the left ventricular mass index, or ejection fraction between individuals with and without HRE [22]. Chung et al. found an association between female sex, arterial stifness, advanced diastolic dysfunction, and HRE. Even after adjustment for other risk factors, the association remained signifcant. Diferences were found according to sex and age [16].

HRE in Athletes.
Blood pressure response to exercise in athletes difers from non-athletes, as athletes present higher maximal exertion blood pressure values compared to non-athletes and, thus, could represent a physiological adaptation mechanism to higher loads [43]. Currie et al. showed that athletes with HRE did not have an impaired sympathetic reactivity, left ventricular dysfunction, or increased arterial stifness in contrast to untrained individuals with HRE and concluded that HRE in athletes is a compensatory mechanism to meet the higher demands of peripheral blood fow rather than as a dysfunction of the cardiovascular system [35]. Caselli et al. showed that the body mass index, resting SBP, and the type of training (i.e., endurance exercise) predict HRE in athletes [13]. Te same group showed that normotensive young athletes with HRE had an increased incidence (hazard ratio 3.6) of resting hypertension at 7 years of follow-up as compared to athletes without HRE (HRE: 13.5% vs. no HRE: 3.5%) [14]. During follow-up, no major adverse cardiovascular events and no signifcant cardiac remodeling was documented [14]. Leischik et al., documented left ventricular hypertrophy and left atrial enlargement potentially caused by HRE in 51 triathletes and speculated that HRE might play a role in sudden cardiac death, training-induced cardiac fatigue, and atrial fbrillation [37]. A signifcant and dosedependent relationship of left ventricular remodeling (myocardial thickening and higher left ventricular mass) to HRE was documented. Tahir et al. showed a dose-dependent higher incidence of focal myocardial fbrosis in competitive male triathletes with HRE [39]. Another study of the same group examined 30 master triathletes with and without myocardial fbrosis after an endurance race and showed lower left atrial ejection fraction, more elevated NT-proBNP values, and HRE in those athletes with myocardial fbrosis. Te authors speculated that HRE might have contributed to cardiac injury and myocardial fbrosis [40]. Bauer et al. investigated the SBP/metabolic equivalent of task slope in elite athletes and its relation to the BP response to a maximum exercise test in elite athletes and their performance. Te study showed that athletes with the lowest SBP/metabolic equivalent of task slope exhibit the lowest maximum SBP and achieved the highest absolute and relative workload, implying a better performance [41]. Kim et al. found an increase in left ventricular mass index, diastolic dysfunction, and elevated pulse pressure in marathon runners with HRE, compared to sedentary subjects with early-stage hypertension, with a positive correlation between elevated pulse pressure and diastolic dysfunction [42]. Malek et al. analyzed 30 male long-term ultra-marathon runners: athletes with high-normal resting blood pressure had an increased interventricular septal thickness and higher left and right ventricular mass index; those fndings were even more accentuated in subjects with high-normal BP and HRE. Athletes with isolated HRE did not show left ventricular hypertrophy [38]. Turmel et al. examined 44 endurance athletes (with and without HRE) using exercise testing, blood sampling during exercise and recovery, 24 h ambulatory blood pressure monitoring, and 24 h Holter electro cardiography monitoring. Athletes with HRE had lower levels of Apolipoprotein-A1 and showed higher SBP levels during 24 h blood pressure monitoring compared to athletes without HRE. As Apolipoprotein-A1 seems to be cardioprotective and a reduction in Apolipoprotein-A1 correlates with a higher risk for cardiovascular disease, this might be a sign of the detrimental efects of HRE in athletes on the cardiovascular system [36].

Discussion
In this systematic review, we collected current knowledge to answer the question whether HRE in athletes is associated with the onset of cardiovascular diseases. In summary, this is a hypothesis-generating review supporting the idea that HRE is associated with future development of hypertension and/or cardiovascular events in non-athletes and that in athletes may be associated with mild cardiac structural or functional abnormalities as well as future hypertension.
If a link could actually be demonstrated in further prospective studies, HRE would be an early and easily detectable marker in the long-term development of arterial hypertension, and other cardiovascular events-as exercise testing is routinely performed in athletes and would therefore have enormous prognostic meaning.

HRE in Athletes Is
Associated with Cardiovascular Implications in the Future. Caselli et al. found an association between HRE in athletes and new-onset hypertension. Over a follow-up period of almost 7 years, they did not report any major cardiovascular event nor signifcant changes in cardiac remodeling in athletes with HRE [26]. Terefore, the positive efects of exercise training and the consequently improved cardiovascular ftness likely outweigh the detrimental efects of HRE in athletes [14].
Caselli and Leischik report diferent fndings regarding the myocardial alterations due to HRE. In the study by Caselli et al., athletes did not develop signifcant cardiac remodeling during follow-up. Leischik et al., however, showed a positive correlation between HRE and myocardial thickening [37]. Tese discrepant fndings could be explained by the diference in intensity and frequency of the training: Leischik et al. examined triathletes competing for Ironman-distances, who had a much more vigorous training load than the athletes analyzed in the study by Caselli et al. Another reason is, that the population analyzed by Caselli et al. was young, and in 7 years of follow-up, signifcant events couldn't be expected. Kim et al. showed that HRE is correlated with an increased LV mass index, diastolic dysfunction, and elevated pulse pressure in athletes. Diferently, training-induced left ventricular hypertrophy in athletes is typically associated with normal cardiac function [42]. Tahir et al. observed that athletes with HRE were more likely to develop myocardial fbrosis [39]. Tese results provide further support to the hypothesis that HRE might cause myocardial injury and, therefore, cardiac dysfunction [40].
Turmel et al. observed higher SBP values of 24 h blood pressure monitoring as well as lower Apolipoprotein-A1 8 International Journal of Hypertension serum levels in athletes with HRE than in athletes with normal blood pressure response to exercise [36]. However, some studies do not support the evidence that HRE in athletes is associated with adverse cardiovascular events. Currie et al. assumed that HRE in athletes is a compensatory mechanism due to an increased peripheral blood fow under efort [35]. Malek et al. only found an association with LV hypertrophy when HRE was combined with high-normal blood pressure at rest, while HRE alone did not correlate with myocardial alterations and, as such, HRE in athletes may not be related to the onset of hypertension [38].
Most papers are cross-sectional studies and, as such, are not suitable to investigate any cause-efect relationship regarding adverse outcomes. Nevertheless, most of the authors speculate that the benefcial impact of exercise overcomes the negative efects of HRE in the long term. Overall, mostly men were analyzed in the included studies, so that a genderrelated efect cannot be excluded and further studies are required to determine the HRE incidence and its consequences in females, as well.
Te cause of HRE in athletes remains unclear at the moment. An endothelial dysfunction with lack of vasodilation leading to reduced peripheral resistance with consequent exaggerated blood pressure response could be an underlying mechanism, similar to non-athletes. At the same time, possible causes of hypertension such as the intake of antirheumatic drugs, adrenergic agonists, and other doping substances should be considered and excluded.
More research on this topic needs to be undertaken to understand the exact pathophysiology of HRE in athletes.

Clinical Relevance and Prognostic Value.
Despite methodological diferences such as threshold for HRE, time of onset of exercise-induced hypertension, and exercise testing protocol, the prognostic signifcance of HRE has been substantiated in several studies.
As mentioned in the introduction, a consensus on the defnition of HRE does not exist. Since athletes are capable of higher exercise performance, compared with the normal population, and thus achieve higher blood pressure values at maximal exercise, diferent thresholds should be used to diagnose HRE. According to diferent studies, we suggest cut-of values of ≥210/110 mmHg for men and ≥190/ 95 mmHg for women from the non-athletic population and values of ≥220/85 mmHg, respectively, ≥200/80 mmHg for athletes [14].
Based on current evidence, we propose an algorithm for a diagnostic and therapeutic approach in athletes with HRE ( Figure 2). If an athlete is diagnosed with HRE, he/ she should undergo 24 h blood pressure monitoring to detect a possible masked hypertension, which should lead to medical therapy according to current guidelines [44]. If the athlete has an isolated HRE, he/she should be screened regularly and treated for cardiovascular risk factors.
It is still debated whether a medical therapy in athletes with HRE is reasonable or not. Te aim of such a therapy would be to counteract HRE during training and competitions in order to limit the onset of aortic stifness or left ventricular hypertrophy. In athletes with high-normal resting blood pressure, life-style modifcations like weight reduction, alcohol and smoking restriction are recommended as frst-line interventions by the current guidelines of the sports cardiology section of the European Association of Preventive Cardiology (EAPC). Antihypertensive drugs should be started in athletes presenting with resting SBP values ≥180 mmHg or DBP ≥110 mmHg and/or at high risk for cardiovascular complications [44]. A similar approach has been recommended for athletes with known essential hypertension, with no restriction to sport participation needed [6].
Since angiotensin II infuences the vascular and myocardial response to exercise, angiotensin II receptor blocker (AT-I) or angiotensin converting enzyme inhibitor (ACE-I) could represent a frst-line therapy in athletes with HRE. However, at the moment, a pharmacological therapy is not indicated in neither population, unless a masked hypertension is discovered, as no evidence is yet available that antihypertensive treatment in HRE is in any way benefcial [11]. It is important to recognize that these two drugs do not afect exercise capacity nor are they listed as doping, while other antihypertensives are considered as doping substances. For some skill sports like archery and shooting, betablockers for example, are considered as doping, while exercise performance might be negatively afected for endurance sports. Diuretics are forbidden in all kind of competitive sports [44]. However, both AT-I and ACE-I are contraindicated during pregnancy and female athletes should be aware of this.
LV hypertrophy caused by endurance training is reversible after a detraining period. Diferently, cardiac remodeling triggered by hypertension usually responds well to antihypertensive medication, however, LV hypertrophy may not be reverted anymore, thus representing a rational to treat athletes with HRE [44].
Analogous, in non-athletes with HRE, a 24 h blood pressure monitoring should be sought to identify masked hypertension. Patients diagnosed with HRE should be allowed to perform high-intensity exercise even if they develop high SBP levels during exercise. Frequent physical activity with alternating workload intensity and lifestylemodifcations should be implemented to reduce the general risk of cardiovascular disease.
Further comments about the pathophysiology of HRE and the possible role of HRE as a precursor of cardiovascular diseases have been presented in the online supplement.   Figure 3: Scheme of possible future implications in athletes with hypertensive response to exercise. Tis fgure illustrates athletes with hypertensive response to exercise and the possible future cardiovascular implications throughout the years. At the beginning, the cardioprotective efects of physical exercise seem to outweigh the negative risk factors associated with HRE. Due to the repetitive pressure overloads during the years, the negative efects could predominately outweigh the benefts.

Conclusions
Te main goal of this narrative review was to summarize the actual knowledge about cardiovascular consequences of HRE in athletes. To date, there are several studies reporting an association between HRE in athletes and adverse cardiovascular events due to chronic exposure to pressure overload such as the onset of hypertension, adverse myocardial remodeling, or injury ( Figure 3). However, HRE is not a normal fnding, neither in the general population, nor in athletes. To establish a more casual relationship, further prospective studies are needed.

Conflicts of Interest
Te authors declare that there are no conficts of interest with respect to related consultancies, shareholdings, funding grants, research, authorship, or publication of this article.

Authors' Contributions
LW made data extraction and interpretation of the data, drafted the initial manuscript, reviewed, and revised the manuscript. PW revised the manuscript for important intellectual content and approved the fnal version to be published. VAR revised the manuscript for important intellectual content and approved the fnal version to be published. SC revised the manuscript for important intellectual content and approved the fnal version to be published. CMS revised the manuscript for important intellectual content and approved the fnal version to be published. DNEU revised the manuscript for important intellectual content and approved the fnal version to be published. DN designed the study, critically revised the manuscript for important intellectual content, and approved the version to be published. All authors approved the fnal manuscript as submitted and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Supplementary Materials
Online supplement includes an expanded introduction about the pathophysiology of athletes' heart and an expanded discussion about the current evidence of the pathophysiology of HRE, as well as an expanded discussion about the current evidence of HRE as a precursor of cardiovascular diseases. (Supplementary Materials)