Effectiveness of Inspiratory Muscle Training for People With Ischemic Heart Disease Revascularized by Percutaneous Transluminal Coronary Angioplasty.

Myocardial ischemia According to the Spanish Heart Foundation, myocardial ischemia (MI) is the disease caused by atherosclerosis of the coronary arteries, responsible for providing blood to the heart muscle. Coronary atherosclerosis is a slow process of collagen formation and accumulation of lipids (fats) and inflammatory cells (lymphocytes) that causes narrowing of the lumen of the coronary arteries. This process begins in the first decades of life, but does not present symptoms until the stenosis of the coronary artery becomes so severe that it causes an imbalance between the supply of oxygen to the myocardium and its metabolic needs3. In this case, myocardial ischemia occurs, which may be chronic, known as chronic coronary syndrome or stable angina pectoris, or sudden occlusion due to thrombosis of the artery, which causes a lack of oxygenation of the myocardium that gives rise to coronary syndrome. Acute also called unstable angina and acute myocardial infarction. MI reduces force production, causes arrhythmias, and causes muscle damage, leading to acute ischemic contractile failure of the heart. Patients with chronic ischemic heart disease have lower evaluations of their social life and their coping with daily routine.

The consequence of the processes described above is that people who suffer from MI decrease their tolerance to exercise, functionality and performance in activities of daily living, which leads them to sedentary behaviors, worsening their quality of life. Furthermore, a vicious circle of inactivity and clinical and functional deterioration is established that produces a general worsening of physical condition and atrophy of peripheral and respiratory muscles. All of these circumstances lead to a decrease in functional capacity and therefore to a worse prognosis of the disease.

Regarding the risk factors that lead to the development of MI, there is a combination of socioeconomic, metabolic, behavioral and environmental risk factors. Among them are advanced age, high blood pressure, an unhealthy diet, high cholesterol, diabetes, obesity, smoking, a sedentary lifestyle, stress, family history and harmful consumption of toxins, among others. Most of these factors are modifiable and it is one of the fundamental pillars of their treatment to get affected people to change their lifestyle. The incidence is higher in men since women benefit from a hormonal protective effect during their fertile life. This circumstance disappears with menopause, which equalizes the cases in both sexes from 45-50 years of age.

Epidemiology It is estimated that in 2020 there were 244.1 million people living with MI worldwide. Of them, 141 million were men and 103.1 million were women. The regions of North Africa, the Middle East, Central Asia, South Asia and Eastern Europe had the highest prevalence rates. The global mortality rate was 112.37 per 100,000, this being also higher in the regions with the highest prevalence.

MI affects approximately 126 million people worldwide, representing 1.72% of the world's population. It is the main cause of death, with 9 million deaths annually. The incidence begins to increase in the fourth decade of life and is higher in men than in women. In developed countries, about a third of all deaths in people over 35 years of age are attributed to this disease. In the United States, it is estimated that almost half of men and approximately one-third of women will experience some symptoms of MI during their lifetime. In the European Union, cardiovascular diseases account for 40% of all deaths. Furthermore, the economic costs associated with MI are significant. The treatment of cardiovascular diseases constitutes 54% of total health expenditure, and contributes approximately a quarter of productivity losses.

Coronary heart disease is closely related to aging. Therefore, despite the decrease in its incidence observed in recent decades, all indicators suggest that its incidence will increase in the years to come. Coronary syndromes are expected to increase between 69% and 119% by 2049, mainly due to the growth of the population of patients over 75 years of age. For the group of patients between 25 and 75 years of age, the incidence is projected to remain stable in the coming decades.

Treatment

It usually consists of thrombolysis (revascularization of the artery or arteries whose flow is compromised) and can be done in two ways:

• By open surgery performing a bridge between two vessels that redirects blood to the affected myocardium.
• By performing a percutaneous transluminal coronary angioplasty (PTCA). This option is less invasive and uses a balloon at the tip of a thin tube, called a catheter, to widen the artery. A small spring is usually placed to keep the artery open.

Secondary prevention Once the first cardiovascular event has occurred, it is important to prevent it from happening again. This is called secondary prevention. In this regard, the non-pharmacological strategy with the most evidence at present to reduce mortality, cardiovascular disability, improve the quality of life of patients and prevent further cardiovascular events is cardiac rehabilitation programs (CRP). Moreover, their cost-effectiveness is well known. These include smoking cessation, control of other cardiovascular risk factors, health education, psychological therapy, and a multimodal exercise program (cardiovascular and strength training). Usually 2-3 training sessions are performed weekly for 8-10 weeks.

Inspiratory muscle training Specific inspiratory muscle training (IMT) consists of applying higher than usual workloads to the muscles responsible for generating the necessary negative pressure inside the thorax for air to enter the lungs. This overload induces adaptations that produce an increase in the strength of this musculature. It is widely used as part of the treatment of people with chronic respiratory diseases and people with heart failure (HF). It is a very safe intervention that reduces dyspnea and improves functional capacity and quality of life in these patients.

Overload is achieved by breathing in through specific devices containing a valve whose threshold can be regulated. In order to decide the pressure at which each individual will train, his or her Maximum Inspiratory Pressure (MIP) must be measured beforehand. Training protocols at high loads, between 50% and 80% of the MIP, are those that obtain the best results according to the available evidence for patients with HF and for patients revascularized with grafting by open surgery. Therefore, the intervention will be performed with loads of 70% of the MIP value, completing 3 sets of 10 repetitions, 4 days a week, with 3 minutes rest between sets, during the 8 weeks of the CRP.

Hypothesis and Objectives

Justification In view of the perspective presented above and the available literature, it is pertinent to conduct a low-risk randomized clinical trial evaluating the effectiveness of the addition of IMT to a CRP of people with IC with PTCA. A recently published review9 concludes that the quality of the evidence for inspiratory muscle training for the improvement of maximal oxygen consumption and expiratory muscle strength in this population is very low. However, it should be taken into account that most of the clinical trials carried out to date have been performed on patients who underwent open surgery, so that the literature is scarce in percutaneously operated patients. In this sense, the results of our study will be specifically focused on percutaneously revascularized patients, thereby increasing knowledge of the effects of this intervention in the subgroup of patients with IHD and PTCA on these and other variables. Although CRP have been shown to be effective there is limited evidence on the addition of an IMT in patients with IHD. Clinical practice guidelines do not routinely recommend IMT due to this lack of evidence, so we aim to shed light on its effectiveness.

Hypotheses The addition of inspiratory muscle training to a cardiac rehabilitation program for people with percutaneously revascularized ischemic heart disease will lead to better results in terms of functional capacity and muscle strength, in addition to social support, anxiety, depression, coping with the disease, sexual dysfunction, quality of life, quality of sleep, eating habits and body composition, after 16 sessions of intervention compared to the control group.

H2.- It is expected that a large proportion of the participants will present anxiety and depression, poor coping with the disease and poor control of cardiovascular risk factors.

H3.- There will be greater effects of the intervention on the variables in the subgroup of women, due to their greater degree of commitment to the intervention program.

Objectives

1. General objective

• To analyze the effectiveness of the addition of inspiratory muscle training to a cardiac rehabilitation program in people with percutaneously revascularized ischemic heart disease after 16 sessions of intervention, based on functional capacity, in addition to muscle strength, social support, anxiety, depression, coping with the disease, sexual dysfunction, quality of life, sleep quality, eating habits and body composition.

II. Secondary objectives

• To know the biopsychosocial profile of this population based on functional capacity, in addition to muscular strength, social support, anxiety, depression, coping with the disease, sexual dysfunction, quality of life, quality of sleep, eating habits and body composition.
• To analyze gender differences through subgroup analysis. Methodology

The present clinical trial has been previously approved by the Provincial Research Ethics Committee of Malaga with Code SICEIA-2024-001869 in its session number 9, held on 09/26/2024.

The characteristics of the proposed clinical trial are reported in accordance with the SPIRIT standards (Standard Protocol Items: Recommendations for Interventional Trials).

Study design Randomized, controlled (parallel), triple-blind, low-risk clinical trial.

Study Setting The study will be carried out at the Cardiac Rehabilitation Unit (CRU) of the Hospital Universitario Virgen de la Victoria de Málaga (HUVV).

Study Subjects Persons with Myocardial Ischemia (MI) referred to the CRU of the HUVV who have undergone PTCA.

Inclusion criteria: i) people with MI with PTCA; ii) both sexes; iii) over 18 years of age; iv) under 80 years of age; v) absence of cognitive deficit and/or physical limitations that would prevent them from performing physical exercise or completing the questionnaires necessary for participation in the study.

Exclusion criteria: i) Disease or condition that contraindicates exercise such as severe hypertrophic obstructive cardiomyopathy, severe aortic stenosis and/or dissecting aortic aneurysm; ii) Patients who refuse treatment or do not sign the informed consent.

Sampling, Sample Size and Randomization Consecutive sampling will be carried out with patients attending the HUVV CRU and meeting the criteria described above.

The sample size was calculated to detect differences between groups in our main variable, functional capacity measured by maximal oxygen consumption. According to the meta-analysis by Fabero-Garrido et al , people with ischemic heart disease who have undergone an inspiratory muscle training program have a mean difference of 2.18 ml O2/kg/min with respect to the control group and we want to find a deviation of 1 MET (3.5 ml O2/kg/min). The calculations were carried out with the statistical software G*Power 3.1, considering in all cases a confidence level of 95% and a power of 80%.

In view of the above, a sample size of 33 subjects per group (66 in total) was established. In addition, to minimize the impact of possible dropouts, the total sample was increased by 10% to 72 patients, which will lead to the final inclusion of 36 patients in each group.

Randomization of participants will be performed through a computer program that generates a sequence of random numbers.

Cardiac Rehabilitation Program.

The usual CRP will be carried out and supervised by the usual multidisciplinary team of the HUVV. It is composed of a cardiologist, a rehabilitation physician, a physiotherapist, a nurse and a psychologist. Prior to inclusion in the study, each participant will undergo a simple ergometry test to determine their maximum heart rate (MHR), observe their behavior at maximum effort and rule out conditions that contraindicate exercise. The study subjects will attend the cardiac rehabilitation room of the hospital 3 days a week. Two of these days will be dedicated to physical exercise sessions and the third to health education and a group psychological therapy session.

The health education session will deal with a different topic each week (basic knowledge of their pathology, proper medication, safe physical exercise, sexual dysfunction, healthy eating and control of cardiovascular risk factors).

On the other hand, those subjects suffering from erectile dysfunction will be offered the possibility of being seen in the urology office. The rehabilitation physician will perform a nutritional assessment by bioimpedanciometry and a morphological assessment of the quadriceps and another of abdominal fat, both by ultrasound. Participants with poorly controlled diabetes and/or morbid obesity will see the endocrinologist of the cardiac rehabilitation team.

The training sessions will last approximately 75 minutes. The structure will be as follows:

• Reception of patients, taking of constants (blood pressure, heart rate and glycemia in case of diabetic patients) and placement of telemetry.
• Warm up
• Strength Exercise: It will consist of different exercises with dumbbells and elastic bands involving various joints. We will work at 50% of 1 repetition maximum (1RM) measured indirectly with the method of 20 repetitions maximum (20RM). Three sets of 10 repetitions of the following exercises will be completed: elbow flexion, shoulder abduction and knee extension. The rest interval between sets will be 30 seconds.
• Cardiovascular Exercise: It will be performed on a treadmill or stationary bicycle. It will have a duration of 30 minutes. The first month the patient will be trained at 70% of the heart rate resulting from applying the Karvonen formula and the second month at 80%. The modality may be continuous or intervallic depending on the patient's tolerance.
• Relaxation and return to calm: patients will remain seated in chairs for 5 minutes during which a guided relaxation audio will be played.
• Checking of constants and farewell.

Patients will be weighed every week to monitor their evolution and rule out possible adverse effects of the training. The program will be extended for 8 weeks until completing 16 concurrent training sessions. At the end of the program, ergometry, blood analysis and the rest of the tests will be repeated.

Masking

None of the participants will know to which group they belong since they will all be given the same EEMI device. For the control group a load of 5 cmH2O will be set. This work intensity is below that necessary to achieve adaptations in the inspiratory muscles and will therefore function as a placebo.

The evaluators will also not know to which group the study subjects belong since they will not participate in the assignment or intervention process.

The analysis will be done independently since the data will be delivered coded.

Statistical analysis

Measures of central tendency and dispersion will be used for numerical variables, as well as relative frequencies for categorical variables to assess comparability between groups. All relevant variables will be examined for this purpose.

Exploratory data analysis will be performed to identify and address outliers that may affect the results. Appropriate corrections will be applied to mitigate their influence.

To contrast the differences between the control and experimental groups, the Student's t-test for independent samples or the nonparametric Mann-Whitney test will be used according to the normality of the data, measured with the Kolmogorov-Smirnov test. For pre- and post-intervention comparisons, Student's t test for paired samples will be used in case of normality or the Wilcoxon test, otherwise. In the case of qualitative variables, chi-square test will be used.

In addition to the aforementioned statistical analyses, possible complex and nonlinear relationships between variables will be explored by means of regression models or multivariate analyses, such as multiple regression or principal component analysis.

The analyses will be performed with the IBM SPSS v.24 statistical program. Anticipated risks and contingency plans

Anticipated risk Contingency plan:

Non-compliance of participants with the IMT Submission of paper log of compliance in the form of a diary

Incorrect performance of the IMT technique Weekly reinforcement session at HUVV

Doubts about the performance of the IMT by the participants The physiotherapist supervising the CRP physical exercise will always be available during the sessions to clarify any doubts.

Prospective It would be interesting to study in future clinical trials the specific training of the expiratory musculature (EMT) in these patients, both in isolation and concurrently with inspiratory training. There are studies that have shown benefits in postural stability and walking speed due to the strengthening of the central musculature of the body.

It would also be interesting to measure the medium- and long-term effects of EMT, as so far existing studies have not done so.

Justification of available resources The University of Cadiz, through its Library, will provide the bibliographic resources necessary for the development of this research project, such as access to the main publishers and indexed scientific journals.

The HUVV will provide the facilities and materials used by the CRP for this study.

The interviews and some of the pre- and post-intervention measurements will be carried out in the cardiac rehabilitation office of the HUVV. Its dimensions are 7m2 and it has the following materials:

• JAMARTm approved hydraulic dynamometer.
• Hogan Health Industries hand-held dynamometer, MicroFet 2 model.
• Measuring tape.
• Bioimpedance meter, Akern brand, Nutrilab model.
• MicroRPM® digital portable manometer.

Physical training, health education sessions, group psychology therapies and some measurements will be carried out in the cardiac rehabilitation room of the HUVV. It has an area of 80m2. and has the following equipment:

• 2 treadmills.
• 6 exercise bikes.
• Dumbbells.
• Elastic bands.
• Telemetry systems for patients.
• Computer with the necessary software to monitor electrocardiograms and heart rates (Mortaraâ system).
• Monitors where to observe the electrography in real time.
• Chairs for taking constants and for health education and relaxation sessions.
• Loudspeaker and playback system for relaxation audios.
• Blood pressure monitors, stethoscopes and glucometers to monitor patients' vital signs.
• Defibrillator and stretcher in case of adverse effects.
• 43" flat screen for health education sessions.

Ergometry tests will be performed by a cardiologist and a specialized nurse from the cardiology service of the HUVV in its exercise physiology laboratory. The laboratory is equipped with the following elements:

• Treadmill
• Sphygmomanometer, glucometer and phonendoscope.
• Computer with the appropriate software to perform the incremental exercise protocol.
• Defibrillator.
• Stretcher

This project is supported theoretically and technically by the TIC-256 Intelligent Social Knowledge Based Systems (IntellSOK) research group and the Pain Observatory of the University of Cadiz. Both entities have extensive experience in the development of research studies and have the technical resources and knowledge necessary for the proper implementation of the proposed project.

Ethical and/or biosafety implications of the proposed research. The present project will follow the ethical principles established for medical research on human subjects according to the Declaration of Helsinki.

The present clinical trial has been previously approved by El Comité de Ética e Investigación con medicamentos (CEIm) Provincial de Málaga (Spain), with communication/application code: SICEIA-2024-001869.

Since data from real subjects will be used, it is essential to guarantee their confidentiality, privacy and data protection. To this end, the participation of the subjects will be voluntary, and it is an indispensable requirement to sign the informed consent form for participation in the study. Participants will be able to withdraw from the study whenever they wish to do so. To safeguard the identity of the subjects, their names and surnames will be coded in the database.

This is a low-intervention clinical trial, since IMT is a very safe intervention, as it is routinely performed in other populations of chronic cardiac and respiratory patients without any relevant adverse effects having been reported.

In addition, patients will be scrupulously stratified according to their cardiovascular risk and the cardiac rehabilitation team at the HUVV has extensive experience in training this type of patient and its professionals are in constant training.

The damages incurred by the participants will be covered by the individual or collective self-insurance that the researcher in question has already contracted for the usual practice of his or her profession.

To publish the results of the project in international peer-reviewed journals and present the results at congresses worldwide, the Consolidated Standards of Reporting Trials (CONSORT) statement will be followed. In addition, as part of the knowledge translation strategy, we will disseminate the results on institutional websites and social media, contact news organizations and identify partner institutions interested in the results.