Abstract
den cardiac death (SCD) is rare among athletes. However, hypertrophic cardiomyopathy is the leading cause of SCD among those <35 years of age. Meanwhile, coronary artery disease (CAD) is the primary SCD cause among those≥35 years of age. CAD-induced plaque ruptures are believed to be a significant cause of cardiovascular diseases in middle-aged individuals who participate in extreme long-distance running activities such as marathons. A total of 1970 articles related to EIH were identified using search terms. Out of these, 1946 studies were excluded for reasons such as arterial hypertension, exercise-induced pulmonary hypertension, the absence of exercise stress testing (EST), and a lack of relevance to EIH. The study analyzed 24 studies related to both long- distance runners with exercise-induced hypertension (EIH) and the general public. Among these, 11 studies were quasi-experimentally designed studies used in randomized controlled trials (RCTs) on long-distance runners with EIH. Additionally, 12 studies utilized cohort designs, and one study with a quasi-experimental design was conducted among the general population. Recent studies suggest that an imbalance between oxygen demand and supply due to ventricular hypertrophy may be the actual cause of cardiovascular disease, regardless of CAD. Exercising excessively over an
used in randomized controlled trials (RCTs) on long-distance runners with EIH. Additionally, 12 studies utilized cohort designs, and one study with a quasi-experimental design was conducted among the general population. Recent studies suggest that an imbalance between oxygen demand and supply due to ventricular hypertrophy may be the actual cause of cardiovascular disease, regardless of CAD. Exercising excessively over an extended period can reduce endothelial function and increase arterial stiffness, which in turn increases afterload and leads to an excessive increase in blood pressure during exercise. Exercise-induced hypertension (EIH), which increases the morbidity rate of resting hypertension and is a risk factor for cardio-cerebro-vascular diseases, is more prevalent in middle-aged long-distance runners than in runners from other age groups, and it increases the prevalence of critical arrhythmias, such as atrial fibrillation or ventricular arrhythmias. EIH is associated with angiotensin II activity, and angiotensin II receptor blockers show promising effects in middle-aged runners. Further, guidelines for preventing excessive participation in races and restricting exercise intensity and frequency would be useful. This review identifies EIH as a potential risk factor for cardiovascular diseases and describes how EIH induces SCD. Keywords:exercise; hypertension; long-distance runner; cardiovascular disease; cardiac death 1. Key Points Sudden cardiac death (SCD), a result of excessive running in the middle-aged, may be caused by exercise-induced hypertension (EIH). EIH increases myocardial oxygen demand during exercise, increasing inflammatory reactions and the levels of vasoconstrictors and cardiac markers. In addition, EIH can result in the formation of plaque in the coronary artery and cause fatal arrhythmia, along with atrial expansion and myocardial hypertrophy. EIH can cause an imbalance in oxygen supply in the myocardium, rather than coronary artery disease, and act as a new potential risk factor for SCD. J. Clin. Med.2024,13, 2184.
J. Clin. Med.2024,13, 2184 2 of 23 2. Introduction Cardiovascular disease (CVD) is the leading cause of death worldwide, accounting for approximately 17 million deaths annually. Sudden cardiac death (SCD), defined as unexpected, sudden death, accounts for approximately 25% of cardiovascular mortali- ties [1]. Regular exercise can reduce the risk of CVD [2], hypertension [3], cardiovascular mortality [4], and glycated hemoglobin levels in diabetic patients [5]. It also improves the physical functioning of patients with heart failure [6], reduces all-cause mortality, and is a benefit to cardiovascular health [7]. Several studies have reported a reduced risk of chronic cardiac disease in long-distance runners, including full- and ultramarathon runners [8], suggesting that long-distance running may effectively reduce the risk of CVD [9]. However, several reports have suggested that excessive exercise may increase the risk of cardiovas- cular events, such as coronary artery plaque ruptures, and is associated with myocardial infarction and SCD [10–13]. The incidence of SCD among athletes is 0.13–0.75 cases per 100,000 [14]; among middle- aged individuals, the incidence is 6 per 100,000 [15]. Of 215,413 marathon runners in the United States with a mean age of 37 years, studied from 1976 to 1994, four experienced SCD. The incidence of SCD among marathon runners is 1 per 50,000 [11]. These numbers are surprising, as most runners experiencing SCD were found to be experienced athletes. Hypertrophic cardiomyopathy (hCMP) and congenital heart defects are the major causes of exercise-induced death (EIN) among those aged <35 years [16–18], while ischemic heart disease accounts for more than 70% of all EINs among those aged≥35 years [16–18]. The risk of SCD is 5 to 7 times higher during extreme forms of exercise, such as marathons, than during moderate exercise [8], acting to induce SCD with a history of myocardial ischemia or cardiac arrhythmia [19,20]. Thrombi resulting from exercise-induced atherosclerotic plaque ruptures are a suspected cause of SCD among older athletes [21,22]. Kim et al. also re- ported that the reason SCD occurs during long-distance running is not due to atherosclerotic plaque ruptures, but due to ischemia resulting from an imbalance in oxygen demand and
with a history of myocardial ischemia or cardiac arrhythmia [19,20]. Thrombi resulting from exercise-induced atherosclerotic plaque ruptures are a suspected cause of SCD among older athletes [21,22]. Kim et al. also re- ported that the reason SCD occurs during long-distance running is not due to atherosclerotic plaque ruptures, but due to ischemia resulting from an imbalance in oxygen demand and supply [23]. An increase in oxygen demand is a known cause of myocardial ischemia in patients with CVDs [24]. Exercise-induced hypertension (EIH), or the excessive elevation of blood pressure during exercise, can be defined as a resting SBP and diastolic blood pressure (DBP) < 140/90 mmHg and a maximal SBP≥210 mmHg in men and≥190 mmHg in women [ Recently, long-distance runners with EIH have been found to experience increased myocardial oxygen demand due to excessive increases in blood pressure during exer- cise [27], leading to an acute increase in the cardiac markers [28] expressed in myocardial infarction. Chronic endothelial dysfunction [29], decreased myocardial diastolic function and myocardial hypertrophy [30], fatal arrhythmia [31], myocardial ischemia on electro- cardiograms [32], and, crucially, an increased prevalence of coronary artery plaques [33] have been reported. The results of these studies suggest that EIH in long-distance runners may produce a significant possibility of developing SCD during exercise or competition. There is still no direct evidence that EIH causes SCD in long-distance runners. However, the following research results are already well known in the general population: EIH increases the incidence of resting hypertension [34] and is an independent risk factor for cardio-cerebro-vascular disease (CCVD) [35,36]. Therefore, based on the studies showing a high mortality rate in the general population with EIH, this study describes the need to review the cardiovascular side effects of long-distance runners with EIH and consider the possible mechanism behind SCD induction during excessive exercise. The purpose of this review is to suggest a potential mechanism for how EIH can lead to cardiovascular disease and assess the possibility of sudden cardiac death by examining various studies. The review will also examine the mechanisms responsible for excessive blood pressure elevations during exercise. In addition,
EIH and consider the possible mechanism behind SCD induction during excessive exercise. The purpose of this review is to suggest a potential mechanism for how EIH can lead to cardiovascular disease and assess the possibility of sudden cardiac death by examining various studies. The review will also examine the mechanisms responsible for excessive blood pressure elevations during exercise. In addition, it aims to propose a mechanism that could lead to SCD by reframing the association. This study also discusses the prevention and management of EIH in order to increase stability in middle-aged runners with EIH.
J. Clin. Med.2024,13, 2184 3 of 23 3. Methods We searched articles related to EIH in PubMed and MEDLINE, Google Scholar, and Web of Science and used the Research Information Sharing Service to search for domestic articles. The search keywords were as follows: exercise, hypertension, runner, athletes, cardiovascular disease, and sudden cardiac death. Similar keywords to those related to EIH, such as exaggerated blood pressure response and exercise hypertension, were also used. The articles were first reviewed based on the abstract, followed by an analysis of methods, results, and discussion sections to understand their content. We compared the results of our previous studies, examining dozens of cases of EIH in middle-aged individuals in relation to those at risk of EIH from 2012 to 2021. The definition of middle- aged in this review is between 40 and 60 years. Previous studies on middle-aged runners with EIH primarily examined marathon and ultramarathon runners. A total of 1970 articles related to EIH were identified using search terms. Out of these, 1946 studies were excluded for reasons such as arterial hypertension, exercise- induced pulmonary hypertension, the absence of exercise stress testing (EST), and a lack of relevance to EIH. Our research indicated that 11 quasi-experimentally designed studies were conducted in randomized controlled trials (RCTs) on long-distance runners with EIH, as presented in Table. Furthermore, Table experimental design for use on the general public. In total, we discussed and analyzed 24 studies related to this topic (Figure). Table 1.Cardiac markers, blood parameters, cardiovascular side Effects, and Training Characteristics of Middle-Aged Long-Distance Runners with Excessive Blood Pressure Elevation. Ref Aim Group ( n, age) Method Result Conclusion Kim et al. [31] To investigate the prevalence of CAD in middle-aged runners with EIH. NBPG (n= 22, 51.7±4.9) EIHG (n= 28, 54.5±5.0) Comparison of CAD prevalence in EIH and non-EIH groups according to GXT results EIHG had higher CAC scores (42.6±67.8) than NBPG (2.8±6.0). EIHG had a higher CAC score distribution than NBPG. EIHG had a higher prevalence of coronary artery plaque and maximum internal arterial stenosis than NBPG. Middle-aged runners with EIH are associated with an increased
EIHG (n= 28, 54.5±5.0) Comparison of CAD prevalence in EIH and non-EIH groups according to GXT results EIHG had higher CAC scores (42.6±67.8) than NBPG (2.8±6.0). EIHG had a higher CAC score distribution than NBPG. EIHG had a higher prevalence of coronary artery plaque and maximum internal arterial stenosis than NBPG. Middle-aged runners with EIH are associated with an increased prevalence of coronary artery plaques. EIH screening via GXT is recommended, followed by MDCT. Kim et al. [32] To assess the association between middle-aged runners with EIH and ATII. NBPG (n= 21, 53.6±4.9) EIHG (n= 35, 53.9±4.8) CHG (n= 14, 52.1±5.1) Blood collection before and after GXT, followed by RAAS and NO tests ATII activity and a reduction in NO were associated with endothelial dysfunction in runners with EIH. ATII inhibitors are appropriate antihypertensive medications for runners with EIH. Kim et al. [34] To compare cardiac markers and inflammation before and after a 100 km run between EIH and NOR runners. NOR (n= 10, 46.8±1.2) EIH (n= 10, 47.5±1.3) Blood collection pre-run and at 50 and 100 km CK: Increase in EIH with respect to NOR at 100 km NT-proBNP: Increase in EIH with respect to NOR at 50 and 100 km CRP: Increase in EIH with respect to NOR at 100 km Runners with EIH did not show myocardial damage following the 100 km run but had myocardial stress and active muscle damage due to epithelial dysfunction.
J. Clin. Med.2024,13, 2184 4 of 23 Table 1.Cont. Ref Aim Group ( n, age) Method Result Conclusion Kim et al. [35] To investigate the prevalence of abnormal ECG response and training characteristics of middle-aged runners with EIH. NEIHg (n= 268, 48.4±7.1) EIHg (n= 338, 49.9±7.2) Non-AERg (n= 569) AERg (n= 37) Comparison of abnormal responses in GXT and training characteristics EIHG had higher frequencies of ST segment depression and atrial arrhythmias than NEIHg. AERg had longer training history and greater total training time than non-AERg The high incidence of myocardial ischemia and atrial arrythmias among middle-aged runners with EIH is associated with excessive training. Kim et al. [36] To compare hemodynamic response and training characteristics between the abnormal response group (ARG) and the normal response group (NRG). NRG (n= 538, 49.0±7.3) ARG (n= 14, 49.2±7.9) Comparison of arrhythmias detected in GXT, hemodynamic response, and training characteristics Both groups had prehypertension and EIH in the resting state. ARG had lower DBP and higher VO 2max, a longer training history, and higher training intensity than NRG. Middle-aged long-distance runners exhibited prehypertension and EIH. ARG has high training intensity, a long training history, and high cardiorespiratory fitness and requires regular cardiovascular tests and adequate exercise prescriptions. Kim et al. [37] To investigate excessive exercise habits, resting and exercise blood pressure, and cardiac events. NBPG (n= 214, 49.1±7.7) HBPG (n= 357, 48.8±6.6) Comparison of training characteristics and cardiac events between a resting hypertension group and a non-resting- hypertension group based on GXT results HBPG had a shorter marathon history than NBPG but had higher training intensity, a longer daily training duration, and a higher drinking frequency. High training intensity and long training time can be used as new indices for potential resting and exercise hypertension for middle-aged long-distance runners. Yoon et al [38] To investigate the arterial stiffness of middle-aged runners with EIH NBPG (n= 17, 49.9±5.3) EIHG (n= 39, 51.7±5.0) CHG (n= 10, 50.8±3.3) Comparison of AIX, AIX@75bpm, and PWV between groups assigned based on GXT results CHG had higher AIX and AIX@75bp than EIHG and NBPG. EIHG had higher AIX and
exercise hypertension for middle-aged long-distance runners. Yoon et al [38] To investigate the arterial stiffness of middle-aged runners with EIH NBPG (n= 17, 49.9±5.3) EIHG (n= 39, 51.7±5.0) CHG (n= 10, 50.8±3.3) Comparison of AIX, AIX@75bpm, and PWV between groups assigned based on GXT results CHG had higher AIX and AIX@75bp than EIHG and NBPG. EIHG had higher AIX and AIX@75bp than NBPG. VO 2maxwas inversely correlated with MSBP during exercise, PWV, AIX, and AIX75@bpm High arterial stiffness can increase the risk of cerebrovascular diseases in runners with EIH. On the other hand, cardiopulmonary fitness is negatively correlated with exercise blood pressure and arterial stiffness. Further research on this correlation is necessary. Kim et al. [39] To compare cardiac markers and ET-1 before and after a marathon between EIH and CON runners. CON (n= 10, 52.5±7.9) EIH (n= 10, 50.6±7.5) Blood collection pre- and post-run cTnI, NT-proBNP, ET-1: Increased in EIH with respect to CON immediately after the run Increased vascular tone and blood pressure during a marathon increased myocardial stress and perfusion in runners with EIH.
J. Clin. Med.2024,13, 2184 5 of 23 Table 1.Cont. Ref Aim Group ( n, age) Method Result Conclusion Jee et al. [40] To compare inflammatory precursors in endothelial cells per section of a 308 km run between EIH and CON runners. CON (n= 8, 49.7±5.6) EIH (n= 8, 46.7±5.4) Blood collection pre-run and at 100 and 200 km sVCAM-1: Increased in EIH with respect to CON at 100 and 200 km sE-selectin: Increased in EIH with respect to CON at 100 km Leukocytes: Increased in EIH with respect to CON at 308 km Vascular resistance and shear force can increase during a 308 km run, damaging endothelial cells in runners with EIH. Kim et al. [41] To compare anti-inflammatory precursors and NO before and after a 100 km run between EIH and NCG runners. NCG (n= 8, 53.5±8.8) EIHG (n= 10, 53.7±4.3) Blood collection pre-run and at 100 km IL-10: Decreased in EIH with respect to NCG in the resting state NO: Decreased in EIH with respect to NCG at 100 km In EIHG, excessive exercise inhibits NO release by endothelial cells, causing blood pressure to rise excessively due to vascular constriction. Park et al. [42] To compare cardiac and inflammatory markers in the recovery phase following a 100 km run between EIH and NEBPR runners. NEBPR (n= 11, 51.7±4.3) EIH (n= 11, 52.9±3.8) Pre, 100 km CK, nTnI: Increased in EIH with respect to NEBPR at 100 km and 24 h NT-proBNP: Increased in EIH with respect to NEBPR at 100 km and 24 and 72 h hsCRP: Increased in EIH with respect to NEBPR at 24 h Increased inflammation and cardiac markers until the recovery phase can lead to volume and pressure overloads and restricted blood flow in the heart, leading to myocardial damage in runners with EIH. EIH, exercise-induced hypertension; NOR, normal; CK, creatinin kinase; NT-proBNP, n-terminal pro-brain natriuretic peptide; ET-1, endothelin-1; CON, control; sVCAM-1, soluble vascular cell adhesion molecule-1; sE- selectin, soluble E-selectin; NEBPR, normal-exercise blood pressure response; hsCRP, high-sensitivity C-reactive protein; NCG, normal control group; IL-10, interleukin-10; NO, nitric oxide; GXT, graded exercise test; NRG,
the heart, leading to myocardial damage in runners with EIH. EIH, exercise-induced hypertension; NOR, normal; CK, creatinin kinase; NT-proBNP, n-terminal pro-brain natriuretic peptide; ET-1, endothelin-1; CON, control; sVCAM-1, soluble vascular cell adhesion molecule-1; sE- selectin, soluble E-selectin; NEBPR, normal-exercise blood pressure response; hsCRP, high-sensitivity C-reactive protein; NCG, normal control group; IL-10, interleukin-10; NO, nitric oxide; GXT, graded exercise test; NRG, normal runners group; ARG, arrhythmic runners’ group; NBPG, normal blood pressure group; HBPG, high- blood-pressure group; CHG, complex hypertension group; EIHG, exercise induced-hypertension group; RAAS, renin–angiotensin–aldosterone-system; MDCT, multi-detector computed tomography; CAC, coronary artery calcium; AERg, abnormal ECG response group; AIX, augmentation index; PWV, pulse wave velocity. Table 2.Studies on Excessive Blood Pressure Elevation During Exercise and Its Associated Cardio- vascular Risks and Deaths. Ref. Aim Subject Method Result Conclusion Allison et al. [25] To assess the prognosis of subjects with exercise hypertension. A total of 150 healthy subjects 7.7±2.9-year follow-up High risk of major cardiovascular death in the EIH group. Healthy, asymptomatic subjects might be at a high risk of major cardiovascular events. Kurl et al. [28] To examine the association between exercise SBP and the risk of stroke. A total of 1026 subjects without cerebrovascular disease. 10.4-year follow-up The risk of stroke and ischemic stroke increased with MSBP in the exercise test and blood pressure at 2 min into the recovery phase increased. Exercise SBP tests are recommended as additional tools in predicting future strokes. Mundal et al. [29] To investigate whether casual blood pressure and exercise SBP can predict the morbidity and mortality rates of myocardial infarction in healthy men. Healthy males (n= 1999, 40–59 years). 31,984 patients Sixteen-year follow-up for males who were healthy from 1972 to 1975 Blood pressure during exercise is a stronger predictor of morbidity and mortality than casual blood pressure due to myocardial infarction. Blood pressure values measured during an exercise stress test can be used to differentiate between moderate and severe hypertension.
morbidity and mortality than casual blood pressure due to myocardial infarction. Blood pressure values measured during an exercise stress test can be used to differentiate between moderate and severe hypertension.
Description
This review discusses EIH as a potential risk factor for cardiovascular diseases in middle-aged runners.