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Abstract

Introduction:

Hypertension links to a prothrombotic state driven by endothelial dysfunction, reduced fibrinolytic potential and platelet hyperactivity. We hypothesized that ramipril treatment would favourably modify the haemostatic response to a submaximal aerobic exercise session in hypertensives.

Methods:

Twenty-four hypertensive patients underwent a submaximal exercise test before and after 13±2 months of treatment with ramipril ± hydrochlorothiazide. Hypercoagulability (prothrombin fragments [PF1+2], thrombin– antithrombin complex [TAT] and D-dimers [Dd]), fibrinolytic activity (plasmin–a2-antiplasmin complex [PAP]), endothelial function (von Willebrand factor [vWf] and soluble thrombomodulin [sTM]), and platelet function (soluble P-selectin [sPsel]) were measured before, at peak and one hour after exercise.

Results:

Antihypertensive treatment resulted in an increase of PAP, vWf and sTM. During the first exercise, PF1+2 were mildly increased at peak exercise (p<0.05), while D-dimers, PAP and vWf varied significantly throughout the exercise (p<0.001). During the second exercise session, PF1+2 were decreased post-exercise (p<0.05), PAP was increased at peak and post-exercise (p<0.001) and vWf was increased at peak (p<0.05) and post-exercise (p<0.001).

Conclusions:

The haemostatic response to exercise in hypertensives after approximately one year of ramipril treatment is characterized by the attenuated activation of coagulation, enhanced fibrinolysis and endothelial activation.

Keywords

Essential hypertension acute submaximal exercise renin–angiotensin aldosterone system antagonists haemostasis endothelium

Introduction

Hypertension is considered a major risk factor for thrombotic events such as myocardial infarction and stroke, as there is strong evidence linking hypertension to a prothrombotic state driven by endothelial dysfunction, reduced fibrinolytic potential and platelet hyperactivity. A growing body of evidence indicates that the prothrombotic state can be induced by the activated renin–angiotensin system, which is more pronounced in hypertension.^1,2 Antihypertensive treatment and lifestyle modifications, with exercise being an integral component, are the cornerstone treatment for blood pressure (BP) control and prevention of cardiovascular disease (CVD) in hypertensive patients.^3,4 Beneficial effects of physical activity as well as of antihypertensive medical treatment that blocks the renin–angiotensin–aldosterone system (RAAS) seem to be mediated by mechanisms independent of BP lowering. Indeed, angiotensin-converting enzyme inhibitors (ACE-Is) in hypertensive patients have shown a beneficial or neutral effect on endothelial function, platelet function, fibrinolysis and hypercoagulability, depending on which of these drugs has been studied.^5
–8 However, whether treatment by an ACE-I modifies the exercise-induced acute changes in haemostatic markers in hypertensive patients has not yet been studied.

In a previous study, we demonstrated that a single bout of submaximal aerobic exercise in patients with recently diagnosed and never treated mild-to-moderate essential hypertension leads to enhanced fibrinolysis compared with a mild increase of coagulation indices.⁹ In the present study, we hypothesized that the haemostatic response to a submaximal aerobic exercise session could be modified favourably in hypertensive patients treated with an ACE-I, ramipril. The markers of hypercoagulability, fibrinolytic activity, endothelial and platelet function that were chosen as markers of haemostatic system activation represent in parallel novel risk factors of atherosclerosis and predictors of acute coronary events in the high-risk population.

Materials and methods

Twenty-four non-diabetic patients (53±10 years old, 18 men) with never-treated grade I–II essential hypertension attending the out-patient clinic of our department were recruited for the study. Diagnosis of hypertension was based on both repeated office measurements and 24 h ambulatory BP measurements, according to ESC/ESH guidelines.⁴ Echocardiography was performed in all patients at baseline evaluation. No signs of left ventricular hypertrophy were recorded.

Patients with secondary hypertension, congestive heart failure, previous myocardial infarction, cardiomyopathy, stroke, cardiac valve diseases, history of coronary artery by-pass grafting, rhythm other than sinus, renal insufficiency, overt proteinuria, diabetes mellitus or lung disease and patients under medication for non-cardiovascular diseases were excluded from the study. Patients who were not physically able to perform exercise testing as well as those involved in a structured exercise programme, defined as more than three 30-min workouts per week, were also excluded from the study. None of the hypertensive patients was being treated with a statin or cardioactive medication and none of the female patients was on hormone replacement treatment. Informed consent was obtained from all participants in the study while the protocol was approved by the ethical committee of our hospital.

The first phase of our protocol (pre-treatment period and first exercise test) is described in our previous study report.⁹ Briefly, in order to exclude coronary artery disease, all patients underwent a pre-treatment treadmill maximal exercise stress test (EST) according to the Bruce protocol. One week later, each patient underwent a submaximal exercise test on a bicycle ergometer and blood samples were drawn pre-exercise, at peak exercise and 1 h post-exercise. The second phase of our protocol consists of antihypertensive treatment with ramipril ± hydrochlorothiazide (HCTZ) commencing after the first submaximal exercise test. Patients were started on ramipril 2.5 mg and changed, if necessary (BP >140/90 mmHg), to either 5 mg ramipril or 2.5 mg ramipril + 12.5 mg HCTZ after 15 days of treatment. After a period of one month, patients were re-evaluated and, if necessary, either 25 mg HCTZ was added to 5 mg of ramipril, or 2.5 mg ramipril + 12.5 mg HCTZ was increased to 5 mg ramipril + 25 mg HCTZ. After this adjustment, all patients had BP <140/90 mmHg (16 patients on ramipril + HCTZ and eight patients on ramipril only). Patients were also advised to stop smoking, reduce salt intake and alcohol consumption, lose weight and start walking at least three times per week. We revaluated the patients regarding their BP control at 1, 3, 6 and 12 months after antihypertensive treatment initiation. After approximately 13±2 months of treatment, patients underwent a second submaximal exercise test. The exercise protocol consisted of 45 min submaximal exercise (65–70% of maximum predicted heart rate according to the Bruce protocol) followed by 6 min of recovery. BP and heart rate were recorded at baseline, every 10 min during exercise and every 2 min during the recovery phase. Again, blood samples were drawn pre-exercise, at peak exercise and 1 h post-exercise.

Blood samples were drawn by clean venepuncture (20-gauge needle) from an antecubital vein under controlled venous stasis: (a) after 30 min rest (pre-exercise), (b) immediately after exercise (peak exercise) and (c) one hour after exercise (post-exercise). All venipunctures were taken in a reclined position. Whole blood was collected in tubes containing sodium citrate anticoagulant 3.2% and within 30 min of phlebotomy, was centrifuged for 15 min at 2500g at room temperature.

Prothrombin fragments 1+2 (PF 1+2) and thrombin–antithrombin complex (TAT) served as markers of thrombin generation and D-dimers as markers of fibrin formation. Plasmin–a2-antiplasmin complex (PAP) was used as an index of fibrinolysis. Endothelial function was evaluated by the levels of both von Willebrand factor antigen (vWf) and soluble thrombomodulin (sTM). Platelet functional status was assessed by measuring the levels of soluble P-selectin (sPsel). Diurnal variation of haemostatic variables was avoided since blood samples were drawn for each patient at approximately the same time of day.

The supernatant plasma was removed, divided into aliquots, snap-frozen at −80°C and stored until assayed. PF1+2 (Enzygnost* PF1+2, Siemens, Germany), TAT (Enzygnost® TAT micro Kit, Siemens, Germany), PAP (PAP microElisa, DRG Diagnostics, Germany), sTM (Asserachrom^® Thrombomodulin, Diagnostica Stago, France) and sPsel (Human sP-selectin, Diaclone) were determined by enzyme-linked immunoassay (ELISA) with commercially available kits. D-Dimers (STA^®-Liatest^®-D-Di, Diagnostica Stago, France) and von Willebrand factor antigen (vWF Ag® Reagent, Siemens, Germany) were determined by immunoturbidimetricity in an STA analyzer. The intra-assay and inter-assay coefficients of variation for the parameters studied are as follows: PF1+2: 3.6–5.5% and 4.4–11.2%; TAT: 4–6% and 6–9%; D-dimers: 0.29–0.71 and 0.32–2.78; PAP: 2.1–6.3% and 3.5–11%; sTM: 4.8% and 8%, sPsel: (0.7–4.2%) and (1.6–7.5%) and vWf: (1.4–4.2%) and (0.9–4.2%), respectively.

Statistical analysis

A normality test was performed for all variables. No parameter followed a normal distribution during the first exercise session or the second exercise session, vWf levels excluded.

Repeated measure analysis of variance (repeated ANOVA) for normally and Friedman non-parametric test for abnormally distributed values were performed in order to investigate whether changes of markers studied were significant either between the two sessions (1^st and 2^nd exercises) or across all time points in the 2^nd exercise session (pre-exercise, peak exercise and post-exercise). Results are expressed as means ± SD and minimum–maximum values for parametric variables and as medians and interquartile ranges for non-parametric variables. The level of statistical significance was set at p<0.05. Data were analyzed using SPSS version 16.0 for Windows (SPSS, Inc, Chicago, IL).

Results

Demographic and clinical characteristics of all patients before initiation and after approximately one year antihypertensive treatment are shown in Table 1. Body mass index, body surface area and lipid levels did not differ within two groups. All participants completed uneventfully a treadmill exercise stress test without evidence of myocardial ischaemia or arrhythmia before the first submaximal exercise on the ergometric bicycle. Both exercise sessions on the ergometric bicycle were also successfully completed. Levels of markers of hypercoagulability, fibrinolysis, endothelial function and platelet function during the first exercise session are described in our previous study.⁹ In Figure 1, the exercise-induced changes in haemostatic parameters during both submaximal exercise sessions are described.

Table 1.

Demographic and clinical characteristics of patient population before and after treatment.

Parameters	Before treatment	After treatment	p
N	24	24
Age (years )	53.1 ± 10.6	54.1 ± 10.3	–
Men (%)	17 (70%)	17 (70%)	–
Current smokers (%)	7 (30%)	7 (30%)	–
BMI (kg/m²)	28.8 ± 3.8	28.3 ± 2.1	0.3
BSA (m²)	2.0 ± 0.2	1.98 ± 0.2	0.1
Systolic office BP (mmHg)	153 ± 19	132 ± 9	<0.001
Diastolic office BP (mmHg)	91 ± 12	81 ± 7	0.001
24 h systolic ABPM (mmHg)	143 ± 10	–	–
24 h diastolic ABPM (mmHg)	93 ± 7	–	–
Heart rate (bpm)	76 ± 8	74± 5	0.6
Total cholesterol (mg/dl)	208 ± 30	205 ± 51	0.7
LDL cholesterol (mg/dl)	130 ± 22	134 ± 30	0.6
Triglycerides (mg/dl)	134 ± 65	162 ± 73	0.1

BP: blood pressure, BMI: body mass index, BSA: body surface area, ABPM: ambulatory blood pressure measurement

Figure 1.

Acute exercise-induced changes in haemostatic parameters during two submaximal exercise sessions in hypertensive patients (first exercise session: before treatment initiation; second exercise session: after 13 ± 2 months of treatment). Solid lines: before antihypertensive treatment; dashed lines: after long-term antihypertensive treatment. PF1+2: prothrombin fragments 1 and 2; TAT: thrombin–antithrombin complex; PAP: plasmin–a2-antiplasmin complex.

Changes in haemostatic parameters compared with baseline

After a period of antihypertensive treatment, significant changes were observed in PAP, vWf and sTM compared to pre-treatment levels, while PF1+2, TAT, D-dimers and sPsel remained unchanged. In particular, there was a marked elevation of PAP complex while vWf and sTM were mildly increased in treated hypertensive patients (Table 2).

Table 2.

Exercise-induced acute changes in haemostatic parameters during two submaximal exercise sessions in hypertensive patients (1^st exercise session: before treatment initiation; 2^nd exercise session: after 13 ± 2 months of treatment).

	1st exercise session				2nd exercise session
	Pre-exercise	Peak exercise	Post-exercise	p	Pre-exercise	Peak exercise	Post-exercise	p
TAT (μg/l)	2.5 (2–2.9)	2.5 (2.2–2.8)	3.1 (2.3–3.6)	0.22	2.4 (1.4–2.6)	1.9 (1.6–2.5)	1.9 (1.6–2.5)	0.62
PF1+2 (nmol /l)	128 (113–157)	161 (132–196)*	149 (119–191)	0.01	150 (98–194)	156 (111–196)	137 (106–175)*	0.01
D-dimers (μg/ml)	0.1 (0.01–0.1)	0.11 (0.06–0.16)*	0.1 (0.05–0.16)*	<0.001	0.09 (0.05–0.11)	0.08 (0.04–0.13)	0.08 (0.05–0.11)	0.9
PAP (μg/l)	184 (165–225)	339 (256–553)**	295 (219–357)**	<0.001	363 (255–436)‡	590 (390–731)**	523 (282–571)**	<0.001
sPsel (ng/ml)	2 (1.1–5.6)	3.7 (2–4.9)	2.9 (1.9–8.6)	0.58	3.5 (1.9–4.7)	3.5 (1.4–5.29)	2.7 (1–4.9)	0.93
vWf (%)	106 (97–128)	143 (112–175)**	129 (116–166)**	<0.001	129 ± 50 (48–263)‡	148 ± 50 (61–271)*	146 ± 50 (61–279)**	<0.001
sTM (ng/ml)	6 (3.7–6.9)	5 (4.3–7.2)	4.7 (3.3–6.6)	0.74	7.5 (4.7–8.9)‡	7.3 (4.4–8.3)	7.6 (6.3–8.6)	0.46

PF1+2: prothrombin fragments 1+2, TAT: thrombin-antithrombin complex, Dd: D-dimers, PAP: plasmin-A2antiplasmin complex, vWf: von Willebrand factor antigen and sTM: soluble thrombomodulin. Values are expressed either as mean ± SD (minimum–maximum values) for parametric variables or as median-interquartile values for non-parametric variables. Sign ‡ represents p<0.001 when pre-exercise levels of haemostatic parameters were compared between the 1^st and 2^nd exercise session. Signs * and ** represent p<0.05 and p<0.001, respectively, when haemostatic parameters were compared with pre-exercise levels in the same exercise session; p values represents changes of haemostatic parameters across all time points in the same exercise session (pre-exercise, peak exercise and post-exercise).

Thrombin generation and fibrin formation

Variations in TAT were not significantly different between the two exercise sessions. On the contrary, PF1+2 changed significantly between the two exercise sessions. In the first session, a mild increase in PF1+2 was induced at peak exercise, which did not remain significantly elevated post-exercise. Interestingly, in the second session, PF1+2 levels were significantly decreased post-exercise compared with pre-exercise levels. Finally, D-dimer levels varied significantly throughout the first exercise session whereas they remained stable during the second session.

Fibrinolysis

Both exercise sessions bought about a significant increase in PAP complex levels. During the first exercise session a two-fold increase in PAP was observed at peak exercise which was almost sustained until post-exercise. In a similar way, during the second exercise session, PAP levels were increased 1.6-fold at peak exercise and 1.4-fold post-exercise, compared with pre-exercise levels.

Platelets

Levels of sPsel did not vary significantly in both exercise sessions. Interestingly, a trend towards a sPsel increase which was noticed at peak exercise during the first exercise session, disappeared during the second exercise.

Endothelium

Exercise-induced endothelial activation, as measured by an increase in vWf levels, was revealed during both exercise sessions. vWf release was significantly higher at peak exercise and post-exercise compared with pre-exercise levels in both exercise sessions. However, the thrombomodulin pathway was not influenced by exercise as levels of sTM remained unchanged throughout both exercise sessions.

Blood pressure

The BP response in treated hypertensives during submaximal exercise was not exaggerated (no one had a systolic BP response above 160 mmHg).

Discussion

To our knowledge, this is the first study which explores the effect of specific antihypertensive treatment on the haemostatic response to an acute submaximal exercise in patients with mild-to-moderate hypertension. Twenty-four newly diagnosed and never treated hypertensive patients participated in an exercise protocol which was repeated approximately one year later while being on antihypertensive treatment with ramipril. Our results showed that blocking RAAS for a year may lead to changes in some haemostatic variables at rest and have a favourable impact on the haemostatic response to exercise.

On pre-exercise measurements, no effect of antihypertensive treatment was revealed on markers of hypercoagulability. On the contrary, the fibrinolytic capacity was generally enhanced. Present data on the effect of RAAS inhibition on fibrinolysis remain conflicting.^10,11 This could be partially attributed to the fact that patients included in these studies are characterized by several phenotypes as well as various level of RAAS activation, which may lead to a different response to specific treatments. Moreover, markers used to evaluate fibrinolysis do not always reflect the endothelial fibrinolytic potential. Indeed, the TRAIN study failed to show any effect on plasminogen activator inhibitor-1 (PAI-1) antigen levels induced by a one-year treatment with fosinopril. However, the study included patients with a high cardiovascular risk profile, suffering from comorbidities such as diabetes mellitus and cancer that are known to decrease fibirinolytic capacity.¹²

Evidence on the improvement of endothelial function by antihypertensive drugs remains inconclusive.^13,14 Fibrinolytic capacity, sTM and vWf, which were evaluated in our study, represent three different aspects of endothelial function that are not regulated by the same metabolic and release mechanisms.^15,16 High vWf levels are an early marker of endothelial dysfunction and correlate with overall cardiovascular risk in hypertensive patients.² Scientific data concerning the relationship between levels of circulating sTM and endothelial function are less consistent, however.^17,18 While experimental data have shown that the release of TM parallels the extent of cell damage, clinical data remain conflicting. In the ARIC study, individuals whose sTM levels were in the highest quintile had a significant reduction of cardiovascular risk compared with those in the lowest quintile.¹⁸ It could be hypothesized that increased sTM levels might demonstrate their intact release from the endothelial cells while decreased sTM levels could be due to their consumption after thrombin binding in cases of excessive thrombin generation.

In our study population, stable levels of D-dimers, TAT, and PF1+2 before and after treatment demonstrate that there was no increase in thrombin generation at baseline and therefore no sTM consumption. It may be also assumed that the level of endothelial dysfunction characterizing our hypertensive patients is not sufficient to impair the antithrombotic and anticoagulant effects of sTM. However, we measured a further increase of sTM levels after antihypertensive treatment. Whether this increase could be attributed to the pleiotropic effects of antihypertensive agents remains to be studied. On the other hand, the simultaneous increase of sTM and vWf might reflect hypertensive disease progression and failure of the antihypertensive treatment to exert a beneficial effect on these facets of endothelial function. It should be noted that evidence regarding the effect of antihypertensive treatment on endothelial functional indices is scarce while it seems that the effect on vWf and sTM levels is rather neutral.^13,19 Nevertheless, our results need to be confirmed in a larger group of hypertensive patients.

Biomarkers of endothelial function have been associated with subclinical target organ damage (TOD) due to hypertension, representing either endothelial dysfunction (brachial artery flow-mediated dilation) or increased arterial stiffness (pulse wave velocity).²⁰ In a recent study, which included 46 never-treated hypertensive patients, vWF and sTM levels were significantly higher in hypertensives than in normotensive controls but only vWF was an independent determinant of arterial stiffness.²¹ On the other hand, long-term treatment with antihypertensive drugs targeting the RAAS, i.e. ACE inhibitors and angiotensin-receptor blockers (ARBs), improves TOD. Indeed, RAAS antagonists lead to a reduction in arterial stiffness, improvement in endothelial dysfunction and regression of left ventricular hypertrophy, independent of the level of BP decrease.²²

It has been reported that exercise can transiently increase the risk of acute ischaemic events, especially in high-risk patients, and that the risk seems to correlate with exercise intensity and duration.²³ In our study, treated hypertensive patients did not exhibit a hypercoagulable state after a bout of submaximal exercise. We should stress that the BP response during exercise was not exaggerated (no one had a systolic BP response above 160 mmHg). This is probably due to the fact that exercise was submaximal and the patients were well treated. However, when these patients were newly diagnosed, a small increase of thrombin generation associated with a mild increase in fibrin formation was evidenced by the increase of PF 1+2 and D-dimer levels, respectively.

Conversely, fibrinolysis was highly influenced in both exercise sessions. The plasmin–antiplasmin complex reflects plasmin formation and has a half-life of about 120 min. Even though the fibrinolytic capacity of endothelium was not measured directly, PAP complex represents the total fibrinolytic potential which is practically endothelium-driven. ¹⁶ It holds true that all biomarkers of fibrinolytic status have different limitations. Free tPA released into blood from endothelial cells has a short half-time and rapidly forms a complex with circulating PAI-1. Therefore, tPA antigen measures mainly inactive tPA/PAI-1 complexes. Moreover, measurement of plasma PAI-1 does not reflect the available PAI-1 because platelets contain approximately 90% of the total amount of PAI-1. Besides, it is still not clear whether total antigen or activity measurements better reflect the physiological situation.²⁴

In our study, PAP complex was found to be increased at peak exercise and to remain elevated post-exercise. Exercise-triggered generation of plasmin in treated patients occurred in the absence of fibrin formation, indicating tissue plasminogen activator (tPA)-induced rather than thrombin-induced fibrinolysis activation.^25
–27 It has been previously shown that in non-treated hypertensive patients tPA activity was higher immediately after exercise but returned to resting levels within 30 min whereas decrease of PAI-1 antigen occurred only after 30 min.²⁸ According to our results, exercise-stimulated tPA release is not impaired in hypertensive patients and this could have a protective role for acute cardiovascular events during exercise. Indeed, the ability of the endothelium to rapidly release tPA that can reach the thrombus in an active and unbound state is critical for the fibrinolytic process.²⁹

Exercise-induced endothelium activation was also evidenced by increases of the same magnitude of vWf antigen levels during both exercise sessions. Exercise promotes release of catecholamines which are known to trigger the activation of endothelial cells and raise vWF plasma levels acutely owing to exocytosis from Weibel Palade bodies.³⁰ Increase of vWf following an acute moderate or maximal exercise in healthy individuals has been demonstrated in various studies,^31
–35 while in patient population data are less consistent.^36
–39 It has been shown that acute intense exercise enhances shear-induced vWf binding to glycoprotein platelet 1b (GP1b) receptors, as well as platelet activation,^32,33 while acute moderate exercise suppressed these events.³⁴ Moreover, results from experimental studies in cultured endothelial cells suggest that NO, whose bioavailability increases during exercise training, is a possible inhibitor of endothelial vWF secretion.^40
–42 Further studies are needed in order to clarify whether exercise-related vWf release in hypertensive patients merely reflects the capacity of a healthy endothelium to respond to stress stimuli or whether it is another facet of a prothrombotic state that could be reversed by regular exercise training.

The sTM pathway was not activated during exercise, either before or after the treatment period. Scarce data exist on exercise-mediated changes in sTM levels. However, it seems that exercise intensity levels and mechanical factors may be involved in exercise-induced increases in sTM levels. It has been shown that one hour of maximal speed running, but not swimming or cycling, significantly increased sTM levels in male athletes.^35,43

P-Selectin is localized in the membranes of platelet a-granules and in Weibel Palade bodies of endothelial cells and mediates adhesion among leukocytes, platelets and endothelium. Raised levels of its soluble form imply platelet activation.⁴⁴ Available evidence suggest that short-term strenuous, but not moderate, exercise induces transient platelet aggregation, adhesiveness and platelet secretory activity.^{32
–34,45,46} However, in our study, moderate-intensity exercise in hypertensive patients, either un-treated or on antihypertensive treatment, did not manage to increase sPsel secretion.

Study limitations

One of the major limitations of this study is the relatively small number of patients. Additionally, since HCTZ was part of antihypertensive therapy in two-thirds of the study group, our results may be influenced by HCTZ co-administration. We should also state that endothelial fibrinolytic potential was only indirectly measured, as t-PA and PAI-1 were not evaluated in this study. However, the fact that fibrinolytic activity is our main interest in this study, may compensate for the indirect estimation of endothelial fibrinolytic potential by PAP levels. Finally, our study included middle-aged, non-diabetic subjects with mild-to-moderate hypertension. Therefore our findings may not be applicable to elderly hypertensive patients with more severe hypertension or with other co-morbidities.

In conclusion, in newly diagnosed, never-treated hypertensive patients, a small increase in thrombin generation and fibrin formation is evidenced as a response to an acute bout of submaximal exercise. Long-term treatment with ramipril seems to have a favourable impact on exercise-induced haemostatic response. The activation of the haemostatic system is attenuated while the endothelial fibrinolytic potential is unaffected, rapidly available after stimulus and preserved for at least one year after the initial diagnosis of hypertensive disease and treatment initiation. Increased fibrinolytic activity and endothelial activation are the dominant features of the submaximal exercise-induced haemostatic response in treated hypertensive patients, but their clinical relevance has not yet been clarified. It may be of interest to investigate the changes in haemostatic response to exercise after a longer period of training, as well as antihypertensive treatment.

Footnotes

Conflict of interest

None declared.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Long-term treatment with ramipril favourably modifies the haemostatic response to acute submaximal exercise in hypertensives

Abstract

Introduction:

Methods:

Results:

Conclusions:

Keywords

Introduction

Materials and methods

Statistical analysis

Results

Changes in haemostatic parameters compared with baseline

Thrombin generation and fibrin formation

Fibrinolysis

Platelets

Endothelium

Blood pressure

Discussion

Study limitations

Footnotes

Conflict of interest

Funding

References