Interval Training in Cardiac Rehabilitation

Interval Training in Cardiac Rehabilitation: Effects on Cardiorespiratory Fitness and Platelet Function - A Randomized Controlled Trial

The purpose of this study is to determine whether high intensity interval training (INT) is more effective in suppressing platelet reactivity than continuous, moderate intensity training (CONT) in patients undergoing cardiac rehabilitation after percutaneous coronary intervention.

Background: Platelets play an important role in cardiovascular disease: First, they promote the development of atherosclerotic lesions, and second, platelets form vessel occluding thrombi on top of (ruptured) lesions, ultimately leading to thrombotic events like myocardial infarctions (MCI). Whereas acute, strenuous exercise causes platelet activation and transiently increases the risk for MCIs, long-term chronic exercise training results in a clear reduction of both platelet activation and MCI incidence. Exercise training plays a key role in cardiac rehabilitation, since improvements in cardiorespiratory fitness (CRF) are associated with decreased mortality in these patients. With respect to CRF improvements, high-intensity interval training has been demonstrated to be more effective than moderate-intensity continuous exercise. However, the beneficial effect of high-intensity interval training on platelet function in patients with cardiovascular disease has never been investigated. Scientific question: The aim of this study is to determine the effect of interval training in cardiac rehabilitation on platelet function. Hypotheses: Cardiac rehabilitation with interval training components (INT) reduces platelet activation and platelet reactivity at physical rest changes of platelet activation and -reactivity induced by acute, strenuous exercise to a greater extent than cardiac rehabilitation consisting exclusively of moderate-intensity continuous exercise training (CONT). Work program: 80 patients at the beginning of phase II cardiac rehabilitation will be randomly assigned to an interval group or to a control group. In both groups, patients will exercise 4x / week for 12 weeks. At the beginning, after 6 weeks and at the end an exercise test will be carried out. Blood will be taken before (platelet function at rest) and immediately after each exercise test (platelet function after acute, strenuous exercise). Basal platelet activation as well as platelet responsiveness towards a platelet agonist (platelet reactivity) will be analyzed.

Exercise, Interval training, Blood platelets, Platelet function tests, Physical fitness, Rehabilitation

5 min warm-up (40% Pmax*) 30 min high intensity interval training (1 min 100% Pmax, 1 min 20% Pmax, in alternating sequence) 10 min cool-down (30% Pmax) Pmax*: Maximal power output (Watt) achieved at the end of an incremental exercise test.

5 min warm-up (40% Pmax*) 30 min moderate intensity continuous training (60% Pmax) 10 min cool-down (30% Pmax) Pmax*: Maximal power output (Watt) achieved at the end of an incremental exercise test.

Platelet reactivity at physical rest: EC50 of TRAP-6 in terms of platelet CD62P expression. Unit of Measure: µM (Micromolar)

Platelet reactivity as measured by half maximal effective concentration (EC50) of the platelet agonist TRAP-6 (Thrombin receptor activating peptide-6; SFLLRN) in terms of platelet CD62P (P-selectin) expression, as described in Heber et al. 2016 (PMID: 26909532). The percentage of CD62P expressing platelets is quantified by flow cytometry without and with increasing concentrations of the platelet agonist TRAP-6. EC50 of TRAP-6 is estimated by fitting a four parameter logistic dose-response curve to flow cytometry data as a function of agonist concentration, aggregating multiple measurements to one reported value (EC50) with the unit µM. Treatment effects on platelet reactivity at physical rest after 6 weeks (INT vs. CONT) are estimated by ANCOVA, with baseline values as covariate.

Platelet reactivity at physical rest: EC50 of TRAP-6 in terms of platelet CD62P expression. Unit of Measure: µM

Platelet reactivity as measured by half maximal effective concentration (EC50) of the platelet agonist TRAP-6 (Thrombin receptor activating peptide-6; SFLLRN) in terms of platelet CD62P (P-selectin) expression. The percentage of CD62P expressing platelets is quantified by flow cytometry without and with increasing concentrations of the platelet agonist TRAP-6. EC50 of TRAP-6 is estimated by fitting a four parameter logistic dose-response curve to flow cytometry data as a function of agonist concentration, aggregating multiple measurements to one reported value (EC50) with the unit µM. Treatment effects on platelet reactivity at physical rest after 12 weeks (INT vs. CONT) are estimated by ANCOVA, with baseline values as covariate.

Inclusion Criteria: No regular exercise training within the last 6 months Dual anti-platelet therapy (low-dose aspirin plus ADP(adenosine diphosphate)-receptor antagonist) Status post percutaneous coronary intervention after recent acute coronary syndrome as underlying reason for current rehabilitation Eligibility for outpatient cardiac rehabilitation according to Table I in Niebauer et al. 2013 (PMID: 22508693) Exclusion Criteria: Type II diabetes mellitus Aortic aneurysm / dissection Uncontrolled hypertension (>180/110 mmHg) Pulmonary hypertension (>55 mmHg) Previously known hereditary platelet disorders Disorders of plasmatic coagulation Anemia (Hb < 13g/dl) History of end-stage liver or kidney disease

Niebauer J, Mayr K, Tschentscher M, Pokan R, Benzer W. Outpatient cardiac rehabilitation: the Austrian model. Eur J Prev Cardiol. 2013 Jun;20(3):468-79. doi: 10.1177/2047487312446137. Epub 2012 Apr 16.

Heber S, Assinger A, Pokan R, Volf I. Correlation between Cardiorespiratory Fitness and Platelet Function in Healthy Women. Med Sci Sports Exerc. 2016 Jun;48(6):1101-10. doi: 10.1249/MSS.0000000000000882.

Heber S, Fischer B, Sallaberger-Lehner M, Hausharter M, Ocenasek H, Gleiss A, Fischer MJM, Pokan R, Assinger A, Volf I. Effects of high-intensity interval training on platelet function in cardiac rehabilitation: a randomised controlled trial. Heart. 2020 Jan;106(1):69-79. doi: 10.1136/heartjnl-2019-315130. Epub 2019 Jul 17.