Acute and subacute effects of strenuous exercise on platelet aggregation, coagulation and fibrinolysis in patients with stable coronary artery disease.

INTRODUCTION: Strenuous exercise may occasionally cause coronary thrombosis with myocardial infarction and sudden cardiac death. MATERIALS AND METHODS: Patients with stable coronary artery disease (CAD) (n = 164) and healthy individuals (n = 25) performed strenuous exercise on a bicycle ergometer. Blood was drawn at baseline, immediately after exercise and 2 h later. Platelet aggregation was measured with Multiplate® Analyzer. Thrombin generation was determined using a thrombogram and by measuring prothrombin fragment 1 + 2 (F1 + 2). A clot lysis assay was used to investigate fibrinolysis. RESULTS: From baseline to immediately after exercise, thrombin receptor activating peptide (TRAP)-induced platelet aggregation increased in CAD patients (Δ77 AU × min, 95 % confidence interval (CI): 46;107) and in healthy individuals (Δ153 AU × min, 95%CI: 75;232). Endogenous thrombin potential (ETP) was unaffected by exercise, whilst F1 + 2 increased (Δ17%, 95%CI: 11;24) in CAD patients. Fibrin clot lysis time increased by 9 % (95%CI: 1-17) in CAD patients and by 26 % (95%CI: 8;45) in healthy individuals. When comparing baseline to 2 h post-exercise, TRAP-induced platelet aggregation remained slightly elevated in both CAD patients (Δ53 AU × min, 95%CI: 22;84) and healthy individuals (Δ140 AU × min, 95%CI: 62;219). In contrast, ETP and F1 + 2 decreased in CAD patients (Δ-6 %, 95%CI: -10;-1 and Δ-8 %, 95%CI: -14;-2). Moreover, clot lysis time decreased (Δ-19 %, 95%CI: -27;-11) in patients with CAD and returned to baseline in healthy individuals. All p-values were <0.05. CONCLUSIONS: Platelet aggregation and F1 + 2 were substantially elevated immediately after exercise in CAD patients, indicating a pro-thrombotic state. After 2 h of recovery, they exhibited a markedly increase in fibrinolysis. Similar results were observed in healthy individuals.

The angiotensin-converting enzyme I/D polymorphism does not impact training-induced adaptations in exercise capacity in patients with stable coronary artery disease.

Systematic exercise training effectively improves exercise capacity in patients with coronary artery disease (CAD), but the magnitude of improvements is highly heterogeneous. We investigated whether this heterogeneity in exercise capacity gains is influenced by the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene. Patients with CAD (n = 169) were randomly assigned to 12 weeks of exercise training or standard care, and 142 patients completed the study. The ACE polymorphism was determined for 128 patients (82% males, 67 ± 9 years). Peak oxygen uptake was measured before and after the 12-week intervention. The ACE I/D polymorphism frequency was n = 48 for D/D homozygotes, n = 61 for I/D heterozygotes and n = 19 for I/I homozygotes. Baseline peak oxygen uptake was 23.3 ± 5.0 ml/kg/min in D/D homozygotes, 22.1 ± 5.3 ml/kg/min in I/D heterozygotes and 23.1 ± 6.0 ml/kg/min in I/I homozygotes, with no statistical differences between genotype groups (P = 0.50). The ACE I/D polymorphism frequency in the exercise group was n = 26 for D/D, n = 21 for I/D and n = 12 for I/I. After exercise training, peak oxygen uptake was increased (P < 0.001) in D/D homozygotes by 2.6 ± 1.7 ml/kg/min, in I/D heterozygotes by 2.7 ± 1.9 ml/kg/min, and in I/I homozygotes by 2.1 ± 1.3 ml/kg/min. However, the improvements were similar between genotype groups (time × genotype, P = 0.55). In conclusion, the ACE I/D polymorphism does not affect baseline exercise capacity or exercise capacity gains in response to 12 weeks of high-intensity exercise training in patients with stable CAD.Clinical trial registration: www.clinicaltrials.gov (NCT04268992).

Effect of regular exercise training on platelet function in patients with cardiovascular disease and healthy individuals: A systematic review.

INTRODUCTION: Regular exercise training is essential in prevention and treatment of cardiovascular disease (CVD), yet the beneficial effects of exercise remain only partly explained. Platelets play a key role in CVD and may be affected by regular exercise training. We aimed to systematically summarise studies investigating the effect of regular exercise training on platelet function in patients with CVD and in healthy individuals. METHODS: Studies were identified by PubMed, Embase and Web of Science May 16, 2022. We selected studies investigating markers of platelet function in relation to regular exercise training in patients with CVD and in healthy individuals. Regular exercise was defined as exercise training for four weeks or more. RESULTS: Of the included studies, 11 investigated patients with CVD and 29 were on healthy individuals. Studies were heterogeneous regarding design, study population and methodology, and the results were ambiguous. In total, 52 different markers of platelet function were investigated with platelet aggregation, soluble P-selectin, and thromboxane B2 (TXB2) as the most frequently examined. When evaluating between-group changes after regular exercise, two studies found a reduced platelet aggregation in the exercise group whilst three studies did not find a difference between groups. With respect to TXB2, three studies reported a reduction and two studies an increase in the exercise group. There were no between-group differences in the seven studies examining soluble P-selectin. CONCLUSION: Regular exercise training has no clear impact on platelet function in patients with CVD or healthy individuals. PROSPERO REGISTRATION: CRD42022350539.

Haemostasis and fibrinolysis after regular high-intensity interval training in patients with coronary artery disease: a randomised controlled trial.

IntroductionPatients with coronary artery disease (CAD) have prothrombotic changes compared with healthy individuals. Regular exercise reduces cardiovascular mortality in patients with stable CAD. However, the underlying mechanism for the beneficial effect is unknown. We investigated whether regular exercise would inhibit platelet aggregation and thrombin generation and increase fibrinolysis in patients with CAD. MATERIALS AND METHODS: Patients with CAD were randomised 1:1 to a supervised high-intensity exercise training programme or standard care for 12 weeks. Blood samples were obtained at baseline and after 6 and 12 weeks. Platelet aggregation was evaluated with the Multiplate Analyser, thrombin generation using the calibrated automated thrombogram and fibrinolysis employing a clot lysis assay. RESULTS: A total of 169 stable patients with CAD were randomised, and 142 patients (67±9 years, 83% males) completed the study; 64 in the exercise group and 78 in the standard care group. All but one patients received single antiplatelet therapy. From baseline to 12 weeks postintervention (Δ), no significant between-group differences were found in adenosine diphosphate-induced platelet aggregation (Δ-15 aggregation units (AU), AU×min, 95% CI -70 to 40 in the exercise group and Δ-26 AU×min, 95% CI -77 to 26 in the standard care group, p=0.44); endogenous thrombin potential (medians: Δ-5%, 95% CI -12 to 3 in the exercise group and Δ-6%, 95% CI -13 to 1 in the standard care group, p=0.26); nor in 50% clot lysis time (medians: Δ-9%, 95% CI -23 to 7 in the exercise group and Δ-17%, 95% CI -29 to -3 in the standard care group, p=0.60). CONCLUSIONS: Twelve weeks of high-intensity whole-body endurance exercise did not affect platelet aggregation, thrombin generation or fibrinolysis in patients with stable CAD. TRIAL REGISTRATION NUMBER: NCT04268992.

Feasibility and impact of whole-body high-intensity interval training in patients with stable coronary artery disease: a randomised controlled trial.

Exercise training reduces cardiovascular mortality and improves quality of life in CAD patients. We investigated the feasibility and impact of 12 weeks of low-volume high-intensity interval training (HIIT) in CAD-patients. Patients with stable CAD were randomized 1:1 to supervised HIIT or standard care. HIIT sessions were completed three times weekly for 12 weeks on a rowing ergometer. Before and after the 12-week intervention, patients completed a physiological evaluation of cardiorespiratory performance and quality of life questionnaires. Mixed model analysis was used to evaluate differences between and within groups. A total of 142 patients (67 ± 9 years, nHIIT = 64, nStandard care = 78) completed the trial. Training adherence was 97% (range 86-100%). Six patients dropped out because of non-fatal adverse events. Weekly training duration was 54 min with an average power output of 138 W. HIIT increased peak oxygen uptake by 2.5 mL/kg/min (95% CI 2.1-3.0), whereas no change was observed in standard care (0.2 mL/kg/min, 95% CI - 0.2-0.6, P < 0.001). In addition, HIIT improved markers of quality of life, including physical functioning, limitations due to physical illness, general health and vitality (P < 0.05). Twelve weeks of low-volume whole-body HIIT increased cardiorespiratory capacity and improved quality of life in patients with stable CAD compared to standard care. In addition, our study demonstrates that the applied vigorous training regime is feasible for this patient group.Clinical trial registration: www.clinicaltrials.gov . Identification number: NCT04268992.

Effect of remote ischaemic conditioning on platelet aggregation and platelet turnover.

Remote ischaemic conditioning (RIC) is a new beneficial treatment for patients with ST-elevation myocardial infarction. RIC may inhibit thrombus formation and, therefore, we investigated whether RIC affects platelet aggregation and turnover. 30 healthy male volunteers were subjected to intervention on day 1 (sham intervention, no aspirin), day 2 (RIC, no aspirin), and day 16 (RIC, treated 7 days with aspirin 75 mg/day). RIC was performed as four cycles of 5 min interchangeable inflation and deflation using an automated cuff. Blood samples were collected 5 min before, as well as 5 and 45 min after RIC. Platelet aggregation was measured by Multiplate® using collagen (COLtest), adenosine diphosphate (ADPtest), and arachidonic acid (ASPItest) as agonists. Platelet turnover was evaluated by flow cytometry. Serum thromboxane B2 was determined by ELISA to confirm aspirin compliance. We found no significant change in platelet aggregation at visit 1 (COLtest: p = 0.32; ADPtest: p = 0.24; ASPItest: p = 0.07), visit 2, except for ADP-induced platelet aggregation evaluated 5 min after RIC (COLtest: p = 0.39; ADPtest: p = 0.02; ASPItest: p = 0.39), or visit 3 (COLtest: p = 0.48; ADPtest: p = 0.61; ASPItest: p = 0.90). Platelet turnover was not influenced by RIC, neither on nor off aspirin (all p-values > 0.07). (1) RIC did not affect platelet aggregation in healthy young men. (2) RIC did not affect platelet turnover in healthy young men. (3) Aspirin did not influence the effect of RIC on platelet aggregation and turnover. (4) Future studies exploring the effect of RIC on platelet aggregation and turnover in patients with ischaemic heart disease are warranted.

Effect of long-term remote ischaemic conditioning on platelet function and fibrinolysis in patients with chronic ischaemic heart failure.

INTRODUCTION: Remote ischaemic conditioning (RIC) protects against ischaemia-reperfusion injury through cellular protective pathways, but may also modulate haemostasis. We aimed to investigate the effect of long-term RIC on platelet function and fibrinolysis in patients with chronic ischaemic heart failure (CIHF). MATERIAL AND METHODS: In a prospective, outcome-assessor blinded, paired study, 16 patients with CIHF and 21 age- and gender-matched controls without ischaemic heart disease (IHD) were treated with RIC once daily for 28±4days. RIC was performed as four cycles of 5min upper arm ischaemia and reperfusion. We evaluated collagen and arachidonic acid induced platelet aggregation (Multiplate® Analyzer), platelet turnover (Sysmex® XE-5000), platelet activation (plasma soluble-platelet-selectin) and fibrinolysis (clot lysis time, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1)). We compared blood samples assessed at baseline and following long-term RIC. RESULTS: Long-term RIC did not affect platelet aggregation, turnover or activation or PAI-1 in any study groups. Long-term RIC did not affect fibrin clot lysis time in patients with CIHF but reduced fibrin clot lysis time in matched controls without IHD (median: 773s (interquartile range: 689-936) vs. 658s (618-823), p=0.03). t-PA was increased following long-term RIC in CIHF patients (2.5 (1.7-3.4) vs. 2.9 (1.8-4.0), p=0.03) and in matched controls without IHD (1.5 (1.3-1.9) vs. 1.6 (1.4-2.3), p=0.03). CONCLUSIONS: While long-term RIC did not affect collagen or arachidonic acid induced platelet aggregation, platelet turnover or sP-selectin, fibrinolysis was increased although most consistently in matched controls without IHD. This finding suggests that RIC may stimulate fibrinolysis potentially reducing the risk of thrombosis.

Effect of remote ischaemic conditioning on coagulation and fibrinolysis.

INTRODUCTION: Remote ischaemic conditioning (RIC) reduces infarct size and may improve prognosis in patients with acute myocardial infarction. To explore the potential mechanisms, we investigated the effects of RIC on coagulation and fibrinolysis. METHODS: Interventional crossover study including 30 healthy drug-naïve males. Participants were exposed to a sham intervention (visit 1) and to RIC (visit 2 and 3) induced by intermittent arm ischaemia through four cycles of 5-min inflation of a blood pressure cuff followed by 5-min deflation. Prior to visit 3, all participants received aspirin 75mg daily for seven days. Blood samples were obtained at baseline as well as 5 and 45min after intervention. Whole blood coagulation was assessed by thromboelastometry (ROTEM®) and thrombin generation. Fibrinolysis was evaluated by clot turbidity-lysis, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1). RESULTS: No differences were found in clot initiation, clot propagation or clot strength evaluated by ROTEM® (all p-values≥0.98). During aspirin treatment, clot initiation and clot propagation decreased after RIC evaluated by ROTEM® EXTEM® clotting time (p=0.04) and ROTEM® EXTEM® maximum velocity (p=0.03). After sham and RIC, thrombin generation declined as evaluated by reduced endogenous thrombin potential (RIC: p=0.001) and peak (RIC: p=0.01). After RIC during aspirin treatment, changes in thrombin generation were inconsistent; increased peak (p=0.04) and time to peak (p<0.001) and a decrease in lag-time (p<0.001). Clot lysis time was prolonged both after sham and after RIC (p<0.001). After RIC, PAI-1 levels declined (p=0.03), but t-PA levels also declined after all interventions (p-values≤0.04). CONCLUSION: RIC did not have substantial effects on coagulation or fibrinolysis compared to sham. Overall, aspirin did not influence the results.