High Interval Versus Moderate Intensity Continuous Training on Soluble st2 Biomarkers in Chronic Heart Failure
Phase: NA
Conditions: Heart Failure
Sponsor: Cairo University

HIGH INTENSITY INTERVAL TRAINING VERSUS 
MODERATE INTENSITY CONTINOUS TRAINING ON 
SOLUBLE ST2 BIOMARKERS IN CHRONIC HEART 
FAILURE 
BY 
DINA REDA ALI HASSAN 
M.Sc in Physical Therapy 2016 
11.09. 2022

Submitted in Partial Fulfillment for the Requirements of Doctoral 
Degree in Physical Therapy, Department of Physical Therapy for 
Cardiovascular/Respiratory Disorder and Geriatrics 
Faculty of Physical Therapy, 
Cairo University, 
2022. 
SUPERVISORS 
 
PROF. Dr. NESREEN GHAREEB ElNAHAS 
Professor and Head of department of Physical therapy for 
Cardiovascular/ Respiratory Disorder and GeriatricsFaculty of 
Physical TherapyCairo University 
PROF. Dr. HAZEM MOHAMED KHORSHID 
Assistant professor of cardiology 
Faculty of medicine 
Ain shams university 
DR. DONIA MOHAMED EL-MASRY 
11.09. 2022

Lecturer of Physical Therapy for Cardiovascular/ 
Respiratory Disorder and GeriatricsFaculty of Physical TherapyCairo 
University 
11.09. 2022

CHAPTER I 
INTRODUCTION 
Heart failure is not a single pathological diagnosis, but a clinical 
syndrome consisting of cardinal symptoms (e.g. breathlessness, ankle 
swelling, and fatigue) that may be accompanied by signs (e.g. elevated 
jugular venous pressure, pulmonary crackles, and peripheral 
oedema). It is due to a structural and/or functional abnormality of 
the heart that results in elevated intracardiac pressures and/or 
inadequate cardiac output at rest and/or during exercise (McDonght 
et al., 2021). 
Systolic heart failure or heart failure with reduced ejection 
fraction (HFrEF) is a complex clinical syndrome characterized by 
structural and/or functional impairment of the left ventricle, 
resulting in a decrease in heart pump function (left ventricular 
ejection fraction ≤ 40%), characterized by signs or symptoms of 
volume overload or manifestations of impaired tissue perfusion (such 
as dyspnea, edema, fatigue, or impaired exercise tolerance) (Bloom et 
al., 2017). 
The defining characteristic of heart failure with a reduced 
ejection fraction is decreased systolic function leading to reduced 
cardiac output and increased filling pressures. To date, no 
medications that directly enhance systolic function have improved 
outcomes. Cardiac myosin activators are a new class of myotropes 
that improve myocardial function by directly augmenting cardiac 
sarcomere function (Psotka and Teerlink 2017). 
           It has long been observed that heart failure (HF) is associated 
with measures of systemic inflammation. In recent years, there have 
￼1

been significant advancements in the understanding of how 
inflammation contributes to the pathogenesis and progression of HF. 
It has long been observed that heart failure (HF) is associated with 
measures of systemic inflammation. However although numerous 
studies have validated the association between measures of 
inflammation and HF severity and prognosis, clinical trials of anti-
inflammatory therapies have proven mostly unsuccessful with 
introduction of new clinical tries of anti-inflammatory therapy 
discussing its effect on the progression of heart failure (Sean et al., 
2020). 
ST2 is a member of the Toll-like/interleukin (IL)-1 receptor 
super family. Due to its cell-signaling capacities, IL-1 plays a central 
role in the regulation of immune and inflammatory responses and is 
linked to the processes of infection and inflammation. Through 
alternative splicing, there are 2 isoforms of ST2: a soluble or serum 
circulating receptor ST2 (sST2) and a transmembrane receptor ST2 
ligand (ST2L) (Pascual-Figal and Januzzi 2015).  
The expression of sST2 is largely inducible and almost 
ubiquitous in living cells, such as resting fibroblasts. It has been 
suggested that sST2 is produced by both cardiac fibroblasts and 
cardiomyocytes in response to injury or stress, and by macrovascular 
(aortic and coronary artery) and heart microvascular endothelial 
cells in response to diastolic load (Ghashghaei et al., 2016). 
Soluble ST2 has been evaluated in a number of clinical 
cardiovascular diseases CVD studies and is a Food and Drug 
Administration (FDA) approved prognostic biomarker of mortality in 
chronic heart failure patients. Previous meta-analyses have shown 
that sST2 has diagnostic value for heart failure and is prognostic for 
￼2

all-cause mortality in heart failure, coronary artery disease and 
following aortic valve replacement. However, there is a paucity of 
clinical studies on IL-33, which is likely due to difficultly measuring 
circulating levels (Liu et al., 2020). 
HF patients are often elderly and have many comorbidities, 
thus they are a challenging population to provide exercise training to. 
These patients have often been sedentary for a very long time, with a 
frequent  motion-limiting comorbidities. Exercise in heart failure 
increases the ability to perform sub-maximal activities in daily life, 
improving quality of life by implementation of different types of 
exercise (Beckers and Gevert  2020). 
Aerobic exercises can be continuous, of moderate intensity or 
intercalating high and low-intensity efforts. High-intensity interval 
training (HIIT) is currently one of the most effective methods for 
improving cardiorespiratory and metabolic function. HIIT involves 
repeated activities, from short to long ones, of high-intensity 
exercises combined with periods of active or passive recovery 
(Tschakert and Hofmann 2013).  
Moderate-intensity continuous training (MICT) is regarded as a 
successful approach to CR because of its efficacy and safety. Some 
studies found that MICT can reduce cardiovascular risk and 
cardiovascular mortality. MICT entails longer durations of moderate-
intensity continuous aerobic activity, maintaining intensity between 
60 and 80% (VO2peak or reserve heart rate) (Yue  et al.,2022). 
Recently reported that HIIT is superior to traditional 
continuous aerobic training in improving cardiac autonomic function 
and suggested that the effect verified on post-HIIT autonomic 
￼3

function was related to improve bar reflex modulation and vagal 
control (Kiviniemi et al. 2014). 
Several studies reported exercise-induced Moderate Intensity 
Continuous Training (MICT) favorable cardiac chambers remodeling 
in post-infarction and in heart failure (either with reduced or 
preserved ejection fraction) patients (Mueller et al., 2021). 
Statement of the Problem: 
Is there a significant difference between high intensity interval 
training versus moderate intensity continuous training on soluble 
ST2 biomarkers in chronic heart failure? 
The Purpose of the Study: 
To determine the effect of high intensity interval training 
versus moderate intensity continuous training on soluble ST2 
biomarkers in chronic heart failure. 
Significance of the Study: 
 A recent study of incident HF conducted between 1998 and 
2017 in the United Kingdom (UK), age-adjusted rates of first 
hospitalizations increased by 28% for both all-cause and HF 
admissions, and by 42% for non-CV admissions. The risk of HF 
hospitalization is 1.5 times higher in patients with diabetes compared 
to controls. AF, a higher body mass index (BMI), and higher glycated 
haemoglobin (HbA1c), as well as a low estimated glomerular 
filtration rate (eGFR) are strong predictors of HF hospitalizations 
(Lawson et al., 2019). 
Biomarkers have made a significant contribution to the 
diagnosis and prognosis of disease. Although strongly associated with 
￼4

inflammatory and autoimmune diseases, ST2 has also been found to 
play a role in the diagnosis and prognosis of CVD. As one of the 
isoforms of ST2, sST2 has recently become a promising prognostic 
indicator for patients diagnosed with HF and a useful tool for risk 
stratification. Due to its prognostic value, sST2 was recommended by 
the American College of Cardiology Foundation (ACC)/American 
Heart Association (AHA) as an important biomarker for monitoring 
HF patients in 2013 (Zhang et al., 2021). 
Several systematic reviews have compared the effectiveness of 
high intensity interval training (HIIT) and moderate intensity 
continuous training (MICT) in HF patients. All these studies 
investigated the changes of VO2peak in HIIT when compared with 
MICT. However, limited by a few numbers of included studies or a 
mixture of heart failure in CAD patients, the conclusion was 
constrained with high heterogeneity. In addition, regarding health 
outcomes such as other cardiorespiratory parameters, cardiovascular 
risk factors, left ventricular function and quality of life, there is a lack 
of investigations and the existing results remain inconsistent (Elliott 
et al., 2015). 
A systematic review and meta-analysis included the latest RCTs 
aims to evaluate the broad-spectrum physical health benefits of HIIT 
compared with MICT, with a specific focus on cardiorespiratory 
fitness, heart rate, blood pressure, blood lipids, left ventricular 
function and QoL in CAD patients without reduced LVEF or heart 
failure (Xie et al., 2017). 
A comprehensive review of the relevant literature is needed to 
resolve these limitations and determine the efficacy of HIIT versus 
MICT in HF patients. This would be helpful to develop a more 
￼5

targeted and efficient exercise prescription and contribute to more 
alterative choices in CR management (Liou et al., 2016). 
The current  study is expected to add important knowledge on 
the pathophysiology of HF and the clinical benefits of a training 
intervention as a novel treatment strategy in HF patients, which may 
help to improve both quality of life (QoL) and functional status in 
affected patients. 
Delimitations: 
This study will be delimited to the following aspects: 
Subjects:  
o
Sixty male patients with chronic heart failure grade 
NYHA I, II. 
o
Patients will be divided into two groups group A 
receiving HIITS and group B receiving MICT. 
o
Patients are ready to participate and cooperate actively in 
our exercise program.  
o
Patients who will meet one of the following criteria are to 
be excluded from the study: 
￼6

.1
Signs of acute heart failure, unstable angina or severe 
arrhythmia three months prior to enrolment in the study. 
.2
Pacemakers. 
.3
Chronic obstructive pulmonary disease. 
.4
Other disorders counteracting exercise testing conditions 
that limit lower limb mobility (for example, burns, 
fractures) 
.5
Pre-existing neuromuscular diseases (for example 
neuromuscular disorder). 
Basic Assumptions: 
It will be assumed that: 
1. The primary medical assessment will be done to every 
participating patient which includes: 
-Complete medical history (personal, present and past) 
- Referral from the physician. 
-homodynamic stability without need for vasoactive drugs. 
2. All patients will stick to the program and will follow instructions. 
3. All other factors which may influence the outcome such as noise 
and distraction will be controlled. 
Hypothesis: 
It will be hypothesized that there will be a significant difference 
between high intensity interval training and moderate intensity 
￼7

continuous training on soluble ST2 biomarker in patients with 
chronic heart failure. 
￼8

CHAPTER II 
LITRATURE REVIEW 
Heart Failure (HF) is a clinical syndrome characterized of 
typical symptoms breathlessness, ankle swelling and fatigue that may 
be accompanied by signs (e.g. elevated jugular venous pressure, 
pulmonary crackles and peripheral edema)   caused by a structural 
and/or functional cardiac abnormality, resulting in a reduced cardiac 
output and/ or elevated intracardiac pressures at rest or exertion 
(Ponikowski et  al., 2016). 
    	
Heart failure is a syndrome characterized initially by left 
ventricular dysfunction that triggers countermeasures aimed to 
restore cardiac output. These responses are compensatory at first but 
eventually become part of the disease process itself leading to further 
worsening cardiac function (Yancy et al., 2016). 
The American College of Cardiology and The American Heart 
Association ACC/AHA defines Systolic Heart Failure (SHF) as a 
complex clinical syndrome resulting from any structural or functional 
cardiac abnormality that impairs the ability of the ventricle to eject 
blood with manifestations of dyspnea, fatigue, exercise intolerance 
and fluid retention leading to splanchnic congestion and/or 
peripheral edema (Yancy et al., 2013). 
         Similarly, the ESC defines SHF as a clinical symptom 
characterized by typical symptoms of breathlessness, ankle swelling 
and fatigue that may be accompanied by signs of elevated jugular 
pressure, pulmonary crackles and peripheral edema caused by 
structural and/or functional cardiac abnormality resulting in reduced 
cardiac output. The two definitions further distinguish SHF from 
￼9

diastolic heart failure (DHF), the former resulting from impaired 
contractile function (defined by depressed ventricular ejection < 
40%) while the latter results from impaired ventricular filling, 
compliance or relaxation (defined by a mildly reduced or preserved 
ejection fraction > 50%) (Ponikowski  et al., 2016). 
In addition to routine clinical laboratory tests (including 
natriuretic peptides and cardiac troponins), other biomarkers are 
gaining attention for their utility in heart failure (HF) management. 
Among them, soluble ST2 (sST2) a novel biomarker integrating 
inflammation, fibrosis, and cardiac stress has been included in the 
2013 ACCF/AHA guideline for additive risk stratification of patients 
with acute and chronic HF (yancy et al., 2013). 
Soluble ST2 is an interleukin-1 (IL-1) receptor family member, 
is secreted into the circulation and functions as a "decoy" receptor for 
IL-33, inhibiting IL-33/ST2 signaling. Blood concentrations of sST2 
are increased in various diseases such as inflammatory diseases and 
heart diseases and are considered a valuable prognostic biomarker in 
both conditions. Soluble ST2 lacks disease specificity and, therefore, 
is not a valuable biomarker for the diagnosis of HF. In acute and 
chronic HF, however, sST2 is strongly associated with measures of HF 
severity and poor outcome. Several studies in patients with HF 
indicate that serial measurement of sST2 has prognostic value and 
could have a potential role in future biomarker-directed therapy 
(Dieplinger and Mueller 2015). 
In the issue of Circulation: Heart Failure, (Pascual-Figal et al 
2018) presents the first data indicating the production of soluble ST2 
protein by organs other than the heart and vessels. Using an 
experimental model of HF (permanent left anterior descending 
￼10

occlusion in a rat model); they measured soluble ST2 mRNA in lung, 
kidney, and liver tissue samples obtained at prespecified time-points. 
The liver and kidneys did not participate in ST2 production during 
any of the studied periods. Concentrations of sST2 have been 
implicated in the presence and severity of heart failure with 
particular value for prognostication.   It was reviewed the use of sST2 
as a prognostic biomarker in heart failure, including present and 
future directions in this exciting area (Bhardwaj and James 2010) 
          Much published work has examined and confirmed the 
beneficial physiological effects of aerobic physical activity or 
moderate intensity (55%–70% of maximal heart rate (MHR), rate of 
perceived effort (RPE) of 11–13 on the Borg scale) continuous 
training, known as MICT. World Health Organization (WHO) 
recommends a minimum of 150 min per week of aerobic physical 
activity at moderate continuous intensity to maintain or achieve 
health (Wood et al., 2019). 
         Exercise of high submaximal intensity performed in intervals of 
1 to 4 minutes, also called high-intensity interval training (HIIT), has 
been tested in a multiple studies on patients with heart failure with 
reduced ejection fraction, showing that HIIT was superior to 
moderate continuous training (MCT) in improving exercise capacity, 
quality of life, endothelial function, and left ventricular diameter and 
ejection fraction. The results were better than those observed in 
previous studies and meta-analyses of patients with chronic heart 
failure. They also prompted discussions of whether HIIT should be 
included in standard care of patients with chronic heart failure. 
Guidelines for rehabilitation in patients with cardiovascular 
disease (JCS 2014). 
￼11

Despite concerns regarding patient adherence, several studies 
have shown irrefutable advantages of HIT in patients with cardiac 
failure. It is interesting that HIT protocols, the total exercise volume, 
and time commitment have been significantly lower compared to 
moderate-intensity training, and yet its use still shows various 
positive physiological benefits that are at least comparable with 
moderate-intensity protocols. It is also important to note that HIT has 
been shown to be safe, tolerable, and enjoyable for patients with 
cardiovascular disease, eliminating any major concerns of an increase 
in adverse effect risk (Hussain et al., 2016). 
￼12

CHAPTER III 
PATIENTS AND METHODS 
The current study is designed to compare the effect of high 
intensity interval training versus moderate continuous training 
exercise on soluble ST2 biomarker level in chronic heart failure 
patients with New York heart association (NYHA) classification I, II. 
Patients: 
This study will be carried out on sixty male patients suffering 
from chronic Heart failure NYHA classification (I & II) with an age 
range from 50 to 60 years old. The patients will be selected from 
Aldmerdash hospital, Ain shams university and patients will be 
randomly assigned into two groups. The purpose, nature and 
potential risk of the study will be explained to all patients. 
￼13

Ethical considerations: 
• Approval of faculty ethical committee. 
• The study procedures will be explained for all participants. 
• Confidentiality will be assured. 
• An informed consent will be taken from each subject prior to 
participation (Appendix I). 
Criteria for the patient selection: 
Inclusion Criteria: 
The patient selection will be according to the following criteria: 
• They will have chronic heart failure (New York heart 
association class I& II) systolic left ventricular dysfunction. 
• Their left ventricular ejection fraction (LVEF) <40%. 
• Medical treatment will be optimized at least three months prior 
to study entry. 
• All patients didn’t participate in any rehabilitation programs 
prior to the study. 
Exclusion criteria: 
Patients who will meet one of the following criteria are to be 
excluded from the study: 
•
Signs of acute heart failure, unstable angina or severe 
arrhythmia three months prior to enrolment in the study. 
•
Pacemakers. 
￼14

•
Chronic obstructive pulmonary disease. 
•
Other disorders counteracting exercise testing conditions 
that limit lower limb mobility (for example, burns, 
fractures) 
•
Pre-existing neuromuscular diseases (for example 
Myasthenia Gravis). 
Patients will be assigned into two groups with a group A 
receiving HIIT and group B receiving MICT, both groups will receive 
their optimal medical treatment. 
•
 
All patients will be thoroughly evaluated before and 
after treatment protocol application. 
•
	
All patients will receive their prescribed medical 
treatment. 
Evaluation 
Primary outcome to be measured is soluble ST2 biomarker level 
Secondary out come to be measured is ejection fraction, quality of 
life and peak exercise response. 
.1
 Soluble ST2 biomarker  
The Presage(®) ST2 Assay 
 (Critical Diagnostics, CA, USA) is an in vitro diagnostic device that 
quantitatively measures soluble suppression of tumorigenicity 2 
(sST2) in serum and plasma by ELISA (Mueller and Dieplinger 
2013). 
￼15

Procedure: sample will be taken at the cubited vein at the beginning 
of the program and also at its end. 
.2
Echocardiogram. 
 Left ventricular systolic dysfunction will be assessed using the 
ejection fraction by 2D simpson method (the percentage of the end 
diastolic volume ejected during systole). 
Resting echocardiographic images will be acquired in accordance 
with American Society of Echocardiography guidelines by a cardiac 
sonographer, blinded to group allocation (Lang et al., 2015). 
Procedure:  A commercially available ultrasound system (Vivid 
S5 or E90, GE Medical Systems, Horten, Norway) equipped with a 2.5-
MHz multifrequency phased array transducer will be used to 
determine the echocardiogram variables by the physician. 
3. Minnesota Living with Heart Failure Questionnaire 
The questionnaire has 21 items. Assessing the impact of 
frequent physical symptoms of heart failure. Other items ask about 
the effects of heart failure on physical and social functions as well as 
mental and emotional functions. Since treatments might have direct 
effects on a patient’s life in addition to their effects on symptoms and 
functional limitations of heart failure, questions about side effects of 
medications, hospital stays and costs of care were included to help 
measure the overall impact of treatments for heart failure on 
patients’ quality of life. 
Procedures: When administering the Minnesota Living with 
Heart Failure Questionnaire to a subject, the instrument must be 
￼16

completed fully and it is crucial to explain to the patient why it is 
important to collect his opinions in order to reduce the number of 
missing data and therefore maximize the quality of the 10 data 
collected (Appendix  II ). 
4- Modified Bruce exercise test  
A symptom-limited graded treadmill exercise test (GXT) will be 
carried out prior to the exercise rehabilitation program to tailor the 
exercise training program using modified Bruce protocol .The 
following exercise parameters will be assessed: a) Exercise duration, 
b) estimated achieved metabolic equivalent of task (METs), c) basal 
heart rate (BHR), d) peak heart rate (PHR) and peak exercise 
response. The exercise test will be repeated after completion of the 3-
month CR program to assess the change in functional capacity of the 
patients with respect to the fore-mentioned parameters (Pescatello 
et al., 2014). 
Procedure: 
 Exercise will be performed on a treadmill. The leads of the ECG 
are placed on the chest wall. The treadmill is started at 2.74 km/hr 
(1.7mph) and at inclinator gradient of 10% after 3 min incline af the 
treadmill is increased by 2% and the speed increases. The test should 
be stopped when the subject cannot continue due to fatigue or pain 
or due to any other medical condition (Badawy and Muaidi 2019). 
￼17

Training  
Management procedures 
Group A 
 Patients will receive medical treatment and will be submitted to the 
cardiac rehabilitation unit receiving HIIT (pelliccia et al., 2021). 
•
Frequency:  HIIT, MCT will be in 2 supervised sessions per 
week for 12 weeks on treadmill. 
•
Intensity:  HIIT included 4 minute intervals aiming 60-85% of 
heart rate reserve separated by 3 min active recovery period of 
moderate intensity exercise 40-59%of heart rate reserve.  
•
Duration: The session lasts 30-40 min included warming up 
and cooling down at moderate intensity. 
Group B 
 Patient will receive medical treatment and will be submitted to the 
cardiac rehabilitation program receiving MICT (Mueller et al., 2021). 
•
Frequency: Moderate continuous training is scheduled 2 times 
per week for 12 weeks. 
•
Intensity: exercise will be applied on treadmill (40%-59% of 
heart rate reserve) 
•
Duration:  30-40 minutes per session. 
    Safety: all the procedures will be applied inside the cardiac 
rehabilitation unit. 
￼18

Only the patients who will complete the 3 month CR program 
attending >80% of the exercise training sessions will be included in 
this study. 
Data analysis: 
The collected data will be statistically analyzed using descriptive 
statistics (the mean and standard deviation). 
•
The paired t test will be used to determine the significance level 
between pre and post physical therapy treatment. 
•
The level of significance < (0.05). 
￼19

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Appendix I 
Sample consent form 
I am............................ freely and voluntarily consent to participate in this 
research study under the direction of the researcher Dina Reda Ali 
Hassan 
A thorough description of the procedures has been explained and I 
understand that I may withdraw my consent and discontinue 
participation in this research at any time without prejudice to me. 
Date: / / 20 
Participant/ 
 
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Appendix II 
￼
 
 .
Note: the questionnaire was taken by personal interviewing 
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