Effects of Interval Physical Training on Expiratory Flow Limitation in Recent Myocardial Infarction

Effects of Interval Physical Training on Inflammatory Markers, Cardiac Autonomic Modulation at Rest, Expiratory Flow Limitation and Respiratory Efficiency in Recent Myocardial Infarction

Introduction: Expiratory flow limitation (EFL) and ventilatory inefficiency during dynamic exercise have been identified in patients with recent myocardial infarction (RMI) with preserved ventricular and pulmonary function. However, it is not known what is the prevalence of EFL in this population and what are the effects of physical and respiratory training on this limitation. Objectives: To evaluate the prevalence of EFL and ventilatory inefficiency during dynamic exercise in individuals with uncomplicated RMI, and to evaluate the effects of interval physical training (IT) in addition to inspiratory muscle training (IMT), exclusive IT and absence of cardiopulmonary rehabilitation (CR) on EFL and ventilatory efficiency. Methods: 54 patients will be included, divided into three groups with 18 participants each. All will be submitted to evaluations of heart rate variability, hematological and biochemical profile, erythrocytes membrane deformability and stability, inflammatory markers, respiratory pressures, plethysmography, spirometry, carbon monoxide diffusion capacity, ankle brachial index, electrical bioimpedance, echocardiogram, quality of life questionnaires, cardiopulmonary exercise testing and constant load tests. Then, groups 1 (IT) and group 2 (IT + IMT) will participate in a physical training program for 12 weeks and will be re-evaluated after this period. In addition, they will be monitored for a 6 month period after discharge, with returns every two months to measure the energy expenditure through an accelerometer, and at the end of this period they will repeat all the tests again. Group 3 (absence of CR), will consist of patients who do not live in the city or those who can not participate in the CR program for any other reason, and will only participate in the evaluations.

Patients with coronary artery disease (CAD) attended by the Sistema Unico de Saude (SUS) in the city of Uberlandia and region are routinely referred to Hospital de Clinicas - Federal University of Uberlandia after acute myocardial infarction (AMI) for coronary angiography and other exams, receiving appropriate clinical or surgical follow-up. After the resolution of the clinical condition, the patient is released from the hospital with a medical referral to the Cardiorespiratory Rehabilitation Program offered by the institution. These patients are contacted by telephone by the team of the rehabilitation sector, and invited to attend for a pre-entry evaluation for inclusion in treatment. In this telephone contact the secretary of the sector clarifies that the hospital does not have transportation services for the patients who accept to be part of the program, and afterwards the evaluation is scheduled. The initial anamnesis will be performed by a multidisciplinary team. In this screening are collected complaints, past and current history of possible diseases, personal and family history, life habits, medications in use, exams performed pre-hospital discharge and physical examination, collected from an individual anamnesis form. At the end of the evaluation the patient receives a card with the scheduling of training days that occur three times a week and dressing and feeding instructions prior to training. All volunteers who fit the study criteria will be invited to participate in the study, being informed about the experimental procedures to which they would be submitted. They will also be clarified that all the information collected during the accomplishment of the work will be kept confidential, protecting their identities. Individuals who agree to participate in the study will sign an informed consent according to National Health Council (466/12) guidelines, and a next return will be scheduled to begin physical testing and blood collection. At that moment, the Research Participant Identification Card will be filled in, which will be kept in a confidential place separated from the other evaluations, with restricted access to the researcher, and a code will be given to the participant. In case of refusal to participate in the study, the participant will receive the same care offered to other patients routinely referred to the rehabilitation sector, being included into the conventional rehabilitation program that also lasts for 12 weeks. Considering that the patients enrolled in the research will have to attend for evaluation and monitoring related to the study, all the displacements related to these additional activities will be refunded to the participants during the entire period of the study. The evaluation procedures that will be performed in 2 days will consist of: Step 1 - ankle brachial index, heart rate variability at rest, respiratory pressures (maximal inspiratory and expiratory pressures), cardiopulmonary exercise test (incremental and constant load tests), spirometry and quality of life questionnaires (SF-36 and MacNew QLMI); Step 2 - blood collection (hematological and biochemical profile, erythrocytes membrane deformability and stability, inflammatory markers), plethysmography, carbon monoxide diffusion capacity and echocardiography. After these exams the participant will be randomized to a training group: Group 1 - interval training (IT) or group 2 - IT + inspiratory muscle training (IMT), and will participate in the cardiorespiratory rehabilitation program for a period of 12 weeks, three times a week. Group 3 will consist of those participants who for any reason do not agree to participate in the rehabilitation program, such as those who do not live in the city, and will remain without intervention. During the 6 months of discharge, participants will be monitored monthly, by telephone contact to verify possible changes in medications in use and general health status. At the end of the 2nd, 4th and 6th month of discharge, in the last week of each period, the patient will be invited to return to the rehabilitation sector for placement of an accelerometer, a monitor that quantifies free activities and sedentary lifestyle. The selected equipment (activPAL3 ™ micro, PAL Technologies Ltd, Scotland, UK) makes use of algorithms properties to quantify periods of sitting, orthostatism and walking. This information will be used to estimate the daily energy expenditure in the period and will store information of seven consecutive days during the selected weeks. The re-evaluations will consist of all the exams mentioned above (steps 1 and 2), and will be performed at the beginning and at the end of the training period and after 6 months of the program's discharge.

Recent Myocardial Infarction, Interval Physical Training, Inspiratory Muscle Training, Expiratory Flow Limitation, Ventilatory Efficiency, Inflammatory Markers, Heart Rate Variability

54 patients will be included, divided into three groups with 18 participants each. All will be submitted to several exams applied to the monitoring of cardiac and pulmonary function. Then, groups 1 (IT) and group 2 (IT + IMT) will participate in a physical training program for 12 weeks and will be re-evaluated after this period. In addition, they will be monitored for a 6 month period after discharge, with returns every two months to measure the energy expenditure through an accelerometer, and at the end of this period they will repeat all the tests again. Group 3 (absence of CR), will consist of patients who do not live in the city or those who can not participate in the CR program for any other reason, and will only participate in the evaluations.

All participants will be submitted to several exams of cardiac and pulmonary functions. Then, group 1 (IT) will participate in a physical training program for 12 weeks and will be re-evaluated after this period. After discharge, they will be monitored for an aditional period of 6 months, with returns every two months to measure the energy expenditure (accelerometer). At the end of this period all the tests will be repeated. Each exercise session will last for 60 minutes and will be divided into three parts as follows: warm up (10 minutes); interval training (IT) - 30 minutes of IT performed in a cycle ergometer, divided into 6 levels of intensity based on the ventilatory anaerobic threshold found in CPET (70%, 80%, 100% and 110%); cooling down (10 minutes).

All participants will be submitted to the same evaluations before and after training, and 6 months after discharge. Group 2 (IT + inspiratory muscle training (IMT)) will participate in a 12 week physical training program. After discharge, they will be monitored for an aditional period of 6 months, with returns every two months to measure the energy expenditure. The group 2 will perform the IMT session at the end of the warm-up exercises, prior to the beginning of the IT on a cycloergometer. IMT session consists of 2 series of 12 inspirations with a 60% of MIP. Participant will be asked to inhale quickly and deeply, as quickly as possible, with a 2 minutes interval between series. All the others exercises will be identical between group 1 and 2.

Group 3 (absence of rehabilitation) will be made up of those patients who for any reason do not agree to participate in the rehabilitation program, such as those who do not live in the city, and will remain without intervention. All participants in this group will perform all the evaluations procedures, comprised of: heart rate variability, hematological and biochemical profile, erythrocytes membrane deformability and stability, inflammatory markers, respiratory pressures, plethysmography, spirometry, carbon monoxide diffusion capacity, ankle brachial index, electrical bioimpedance, echocardiogram, quality of life questionnaires (SF-36 and MacNew QLMI), cardiopulmonary exercise testing and constant load tests.

Each exercise session will consist of: warm up (10 minutes)- stretches and calisthenics exercises of low to moderate intensity; interval training (IT) - 30 minutes of IT performed in a cycle ergometer, divided into 6 levels of intensity based on the ventilatory anaerobic threshold (VAT) found in CPET: Level 1 - 5 minutes in moderate intensity, at 80% of power reached in VAT; Levels 2 and 4 - 5 minutes of moderate to high intensity, at 100% of VAT; Levels 3 and 5 - 5 minutes of moderate to high intensity, 110% of VAT; Level 6 - 5 minutes in moderate intensity, at 70% of VAT. cooling down (10 minutes) - stretching, and breathing exercises. An CPET will be performed every four weeks to adjust the intensity of training.

The IMT session will take place just after the warm-up exercises and consist of 2 series of 12 inspirations with a 60% of Maximal Inspiratory Pressure (MIP) with the equipment POWERbreathe Plus Medic® (POWERbreathe International Ltd, Warwickshire, UK). The patient will be instructed to remain seated with a nasal clip during the IMT series to avoid nasal air leakage and will be asked to inhale quickly and deeply, as quickly as possible, with a 2 minute interval between series. The training load will be adjusted weekly by a new evaluation of MIP to maintain the intensity of the exercise within the proposed value. All the others exercises will be identical between group 1 and 2.

Two constant workload exercise tests (CWET) will evaluate the EFL and the ventilatory strategy at the VAT and VAT + 25%, with rest interval of 30 to 60 minutes between tests. Duration: 20 minutes each test. Patients will be monitored with optoelectronic plethysmography and transthoracic electrical cardioimpedance. After a 2-minute rest period in a cycle ergometer (clinical evaluation, metabolic, cardiovascular, ventilatory and gas exchange records, and Borg), the effort will start at zero load (60 rpm). The pre-established intensity corresponding to VAT and 25% above VAT will be placed in the 3rd minute of exercise by single increment for ten minutes. In the last four minutes the flow-volume loops will be measured. After each test there will be an active recovery for 3 minutes, and 2 minutes of rest. EFL will be evaluated by comparing tidal flow-volume loops, obtained after an inspiratory capacity maneuver, with the resting maximal flow-volume loop measured before each CWET.

Change from baseline EFL, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation program

To this exam will be used a Doppler ultrasound (Portable Vascular Doppler; DV610B; MEDMEGA, Brazil), gel and sphygmomanometer. Volunteers will be instructed to remain at rest in the supine position for ten minutes. The cuff will be positioned 3 cm above the cubital fossa in the upper limbs and 3 cm above the medial malleolus in the lower limbs, considering the correct alignment to the arterial path. A 45 to 60º angle will be observed between the skin and the Doppler transducer in the opposite direction to the blood flow in order to amplify the sound of the signal. Systolic arterial pressures will be measured in the 4 limbs: right brachial artery; right posterior tibial and dorsalis pedis arteries; left posterior tibial and dorsalis pedis arteries; and left brachial artery. The ABI will be calculated as the ratio between the highest of the two systolic pressures below the ankle (posterior tibial and dorsalis pedis artery) with the highest brachial portion pressure.

Change from baseline ABI, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation program

This test will evaluate the autonomic modulation of the heart rate response from its variability (HRV) during rest in the supine, orthostatic and sitting positions. For this, the volunteers will be monitored with a cardiofrequencymeter (Polar Electro ™, V800 ™, OY, Kempele, Finland) and thoracic belt. Participants will be instructed to remain at rest, with a normal quiet breathing and not to talk during the examination. After 600 seconds of supine rest, HR will be collected for another 600 seconds in each position: supine, standing and sitting positions. Data recorded will be transferred to a computer via FlowSync ™ software. The data will be inspected visually, and for each volunteer, the sequence of RR interval (ms) with 256 consecutive beats will be selected at the time of greater signal stability. Subsequently, the linear and non-linear analysis of the HRV will be performed.

Change from baseline HRV, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation program

A digital manovacuometer (MVD300®, Globalmed, Porto Alegre, RS, Brazil) will be used to perform the respiratory pressures, with an operating range of ± 300 cmH2O. The volunteer will be seated with feet resting on the floor, and will receive instruction on how to proceed during the test. A nasal clip will be positioned five seconds before performing the maneuver to avoid air leaks, and the patient will be asked to press the cheeks with the hands. The volunteer will be instructed to close the lips firmly around the buccal, to exhale all the air until reaching the residual volume (RV) and to make a forced inspiration for approximately one to two seconds. Each patient will perform three maneuvers with 2-minute rest intervals between the replicates. If the last maneuver is greater than the previous ones, a further measurement will be made. The highest value will be used for the analyzes. Static values lower than 60% of predicted will be considered as respiratory muscle weakness.

Change from baseline MIP, once a week during the training period, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation program

The equipment for performing MEP will be the same as described for MIP, as well as patient positioning. The PE max will be measured from the total lung capacity (TLC), using a nasal clip, and the volunteer will be asked for a maximal expiratory effort sustained for one to two seconds. At least three maneuvers with 2-minute rest intervals between the replicates will be performed, using the highest value for the analyzes. If the last maneuver is greater than the previous ones, a further measurement will be made, and so on until the last value is not greater than the previous one. MEP minimum value of normality for men is 150 cmH2O.

Change from baseline MEP, once a week during the training period, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation program

Objective: evaluate the aerobic power; identify the VAT and the HR response. Variables measured respiration by respiration, will be: oxygen consumption, carbon dioxide production, respiration exchange ratio, minute ventilation, respiratory rate, ventilatory equivalent (O2 and CO2), end-tidal tensions of oxygen and carbon dioxide, inspiratory and expiratory time and total time of respiratory cycle. Duration: 8 - 12 minutes. After a 2-minute rest period (clinical evaluation, metabolic, cardiovascular, ventilatory and gas exchange records, and Borg evaluation), the effort will start at zero load (60 rpm) and increase at the 2nd minute of exercise until the maximum tolerance. Exhaustion will be noticed as malaise, lipothymia, nausea, extreme dyspnea (Borg 10) or chest pain expressed by the patient. The test will also be ended in the presence of fatigue (< 60 rpm) or maximum HR. After interruption of the increment, will start a 3-minute period of zero load and 2 minutes of rest.

Change from baseline CPET, every 4 weeks during the training period, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation

Before and after each constant workload exercise tests (CWET), spirometry will be performed using the Clinical Pulmonary Function-Spirometry (CPF-S™, Medical Graphics Corporation, St. Paul, MN- USA). Pre-CWET spirometry will be used to identify the reference variables at rest for the maximal flow-volume loop (MFVL) to allow comparison with the values during CWET. Post-CWET spirometry has the purpose to evaluate the presence of exercise-induced bronchodilation.

Change from baseline spirometry, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation

In the rest interval between the CWET, the quality of life questionnaires will be administered in the interview format. The generic SF-36 will be used in order to quantify the function and general well-being of the patient, allowing the comparison between different populations and studies. The questionnaire consists of the physical and mental components, encompassing a total of eight domains: physical component that involves (1) functional capacity (question 3), (2) pain (questions 7 and 8), (3) general health status (1 and 11) and (4) physical aspect (question 4); And mental component that includes (5) mental health (9B, C, D, F, H), (6) emotional aspect (question 5), (7) social aspect (questions 6 and 10) and (8) vitality (9A, E, G, I). Each domain has a final score of 0 to 100, with zero worse health status and 100, better health status.

Change from baseline SF-36, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation

In the rest interval between the CWET, the quality of life questionnaires will be administered in the interview format. The MacNew specific questionnaire will reveal functional symptoms and limitations attributed to the myocardial infaction, being more sensitive to changes in the clinical condition as results from the interventions. It consists of 27 items that fall into three domains: physical limitation (13 items), emotional function (14 items) and social function (13 items).

Change from baseline MacNew QLMI, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation

BIA aims to assess body composition by quantifying water in tissues. Before beginning the procedure, volunteers will be instructed to empty the urinary bladder and remove any metallic objects in contact to the body. They will then be placed in rest in the supine position for 10 minutes, with abduction of upper and lower limbs, forming an angle of at least 30 ° to avoid any contact between the limbs. The distal electrode will be placed in the right hand and right foot. The two distal electrodes (black clips) will be placed on the dorsal surface of the hand (metacarpophalangeal of the middle finger) and the foot (metatarsophalangeal of the middle finger), while current collectors (proximal red clips) will be applied in the styloid process, above the joint line of the wrist and between the medial and lateral malleoli of the ankle, above the joint interline. These proximal electrodes collect the voltage drop due to impedance, assigning values to the body composition.

Change from baseline BIA, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation

After a 12 hour fasting, the blood will be collected by venipuncture in evacuated tubes (Vacuntainer®) containing specific anticoagulants, and analyzed by the Clinical Analysis Laboratory of the Clinical Hospital - Federal University of Uberlandia (FUU). Hematological parameters: complete blood count, lipid profile, glucose, folic acid, CRP, glycated hemoglobin, vitamin B12, serum iron, ferritin, transferrin capacity index, uric acid, albumin, lactate dehydrogenase, reticulocytes, total, direct and indirect bilirubin.

Change from baseline Blood Collection, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation

After a 12 hour fasting, the blood will be collected by venipuncture in evacuated tubes (Vacuntainer®) containing specific anticoagulants. To erythrocyte membrane stability, a sample with EDTA will be sent to the Laboratory of Biophysiochemistry (FUU), and another to the Laboratory of Biochemistry (FUU) for analysis of oxidative stress.

Change from baseline Blood Collection, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation

After a 12 hour fasting, the blood will be collected by venipuncture in evacuated tubes (Vacuntainer®) containing specific anticoagulants, and analyzed by the Clinical Analysis Laboratory of the Clinical Hospital - Federal University of Uberlandia (FUU). A sample without anticoagulant will be sent to the Laboratory of Nanobiotechnology (FUU) for analysis of inflammatory markers and another to the Laboratory Eduardo Mineiro for homocysteine analysis. The required amount of blood for all the analyzes shall be 31 ml.

Change from baseline Blood Collection, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation

Static pulmonary volume measurements will be performed using the full-body plethysmography Elite Platinum DX system (Medical Graphics Corporation, St. Paul, MN, USA). The patient, within the hermetically sealed plethysmographic enclosure, will be instructed to make small, uniform, repetitive breathing movements against an obstruction at the airway opening at a frequency of 60 Hz. This maneuver aims to establish the starting point in functional residual capacity (FRC).

Change from baseline plethysmography, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation

The gas in the lungs is alternately compressed and decompressed, and such changes in thoracic volume are reflected by inverse variations of the thoracic cage, which is reflected by changes in pressure in the interior of the plethysmographic cabin. Indirectly, the residual volume (RV) is calculated using a vital capacity (VC) maneuver done immediately afterwards to estimate the lung capacity of each patient.

Change from baseline plethysmography, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation

The gas in the lungs is alternately compressed and decompressed, and such changes in thoracic volume are reflected by inverse variations of the thoracic cage, which is reflected by changes in pressure in the interior of the plethysmographic cabin. Indirectly, the total pulmonary capacity (TPC) is calculated using a vital capacity (VC) maneuver done immediately afterwards to estimate the lung capacity of each patient.

Change from baseline plethysmography, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation

DLCO analyzes the amount of carbon monoxide (CO) that diffuses to the pulmonary capillaries through the alveolar-capillary barrier. The system used for this evaluation will be Elite Platinum DX (Medical Graphics Corporation-MGC, MN, USA), applying the modified Krogh technique (single breathing). The patient will inhale a test gas (0.3% CO, 10% Helium, 21% O2 balanced with nitrogen) and will sustain in the lungs a volume corresponding to 90% of the VC for 10 seconds. During expiration, tracer gas (Helium) concentrations, with an inert (no diffusion) characteristic, and CO, will be continuously analyzed by a rapid response analyzer. Thus, the amount of exhaled CO is measured by determining the amount to be diluted in the lungs (estimated by tracer gas concentration), and thus the difference in relation to the inhaled concentration (previously known) indicates the total that will diffuse by the alveolar-capillary membrane.

Change from baseline DLCO, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation

Echocardiogram performed during hospitalization will be used as an inclusion criteria (LVEF ≥ 50%). The purpose of the exam will be to monitor the evolution of left ventricular function in response to the implemented therapies and to correlate it with the other tests performed. All ECHO will be performed in the Echocardiography Sector (FUU), by a properly trained professional of the institution.

Change from baseline ECHO, after 12 weeks at the end of the rehabilitation program and 6 months after release from rehabilitation

At the end of the 2nd, 4th and 6th month of discharge from the rehabilitation program, in the last week of each period, the patient will be invited to return for placement of an accelerometer, a monitor that quantifies free activities and sedentary lifestyle. The selected equipment (activPAL3™ micro, PAL Technologies Ltd, Scotland, UK) makes use of algorithm properties to quantify periods of sitting, standing and walking. This information will be used to estimate the daily energy expenditure in the period and will store information for seven consecutive days during the selected weeks. The microactivPAL3™ will be packed in a nitrile glove and attached to the skin by tegaderm™ (3M, Sumaré, SP) so that the patient can bathe with the device. The data will be transmitted to the computer via USB input (activPAL3 ™ micro USB port docking station, PAL Technologies Ltd, Scotland, UK) and analyzed by activPAL ™ software (PAL Technologies Ltd, Scotland, UK).

At the end of the 2nd, 4th and 6th month of discharge from the rehabilitation program, in the last week of each period.

Inclusion Criteria: Men Aged 35 to 80 years Recent myocardial infarction (RMI), between 15 and 45 days post-event, being the 1st MI event Left ventricular ejection fraction (LVEF) ≥ 50% Preserved respiratory muscle strength (Maximal Inspiratory Pressure > 60% predicted) Whether or not submitted to Percutaneous Transluminal Coronary Angioplasty (PTCA) Presence of expiratory flow limitation by incremental cardiopulmonary test Agreement to participate in the study after reading and signing the informed consent Non-inclusion Criteria: Body Mass Index (BMI) ≥ 35 kg / m2 Previous diagnosis of any musculoskeletal, neurological, respiratory or vascular diseases Ankle Brachial Index (ABI) < 0.90 and > 1.4 Diabetes mellitus Active or smoking cessation for less than six months Chronic organic dysfunction such as renal or hepatic impairment Patients submitted to Coronary Artery Bypass Graft Surgery (CABG) Inadequate response of systemic or electrocardiographic blood pressure during the cardiopulmonary exercise test (CPET) Presence of Chronic Obstructive Pulmonary Disease (COPD) or Interstitial Lung Diseases Presence of valvulopathies or Chagas disease Participants with pacemaker (PM) or implantable cardioverter defibrillator (ICD) Exclusion Criteria: Refusal to participate in the study Participants who do not complete all the steps proposed in the research Participants who request their exclusion at any time during the study, will be excluded

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