i

THE CORRELATION BETWEEN BIOMARKERS OF INFLAMMATION AND LEFT

VENTRICULAR FUNCTION IN PATIENTS WITH HYPERTENSIVE HEART FAILURE

SEEN IN OBAFEMI AWOLOWO UNIVERSITY TEACHING HOSPITALS COMPLEX.

A DISSERTATION SUBMITTED TO THE NATIONAL POSTGRADUATE MEDICAL

COLLEGE OF NIGERIA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR

THE AWARD OF THE FELLOWSHIP OF THE COLLEGE IN INTERNAL MEDICINE.

SUBSPECIALITY: CARDIOLOGY

CANDITATE’S NAME: DR AGOKE ADEKUNLE KAYODE

MB,BS(UNILORIN) 2006

CANDITATE’S NUMBER: AF/009/14/098/040

NOVEMBER 2017

ii

DECLARATION

I hereby declare that this work is original unless otherwise acknowledged, and that it has

neither been presented to any other College for Fellowship award nor has it been submitted

elsewhere for publication.

-------------------------

DR A.K. AGOKE

iii

CERTIFICATION

This is to certify that this work was carried out by Dr. A.K. AGOKE in the Cardiac Care Unit

of the Department of Medicine, Obafemi Awolowo University Teaching Hospitals Complex,

Ile-Ife under our Supervision.

-----------------------------------------------

Prof M. O. Balogun (FMCP, FWACP)

Consultant Cardiologist

OAUTHC, Ile-Ife

--------------------------------------------

Dr O.E. Ajayi (FMCP)

Consultant Cardiologist

OAUTHC, Ile-Ife

------------------------------------

Dr T.R. Folorunso (FMCP)

Consultant Cardiologist

FMC, Owo

iv

ATTESTATION BY THE HEAD OF DEPARTMENT

I hereby certify that this work was carried out in the Cardiac Care Unit of the Department of

Medicine, Obafemi Awolowo University Teaching Hospitals Complex by Dr A.K. Agoke

under the supervision of Prof M. O. Balogun, Dr O.E. Ajayi, and Dr T.R. Folorunso.

----------------------------

Prof A. Sanusi (FWACP)

Head of Department

v

DEDICATION

To God Almighty, the author and finisher of our faith who gave me grace and strength from

the conception to the completion of this work.

vi

ACKNOWLEDGEMENTS

I am immensely grateful to my supervisors, Prof M. O. Balogun, Dr O.E. Ajayi and Dr T.R.

Folorunso for their highly cherished mentorship and painstaking supervision throughout the

execution of this work.

My sincere gratitude also goes to my other teachers and consultants in the cardiology unit, Dr

A. O. Akintomide, Prof R.A. Adebayo and Dr S. A. Ogunyemi for their guidance and support

during the execution of the work.

I also appreciate my esteemed trainers and consultants in the Department of Internal Medicine,

Federal Medical Centre, Owo for their support and encouragement especially to Dr Olatunde

L.O., Dr Ojo O.A., Dr Sumonu T.A., Dr Adeniyi B.O. and Dr Mrs Ojo O.A. for their selfless

input and corrections during the editing of the manuscript. I sincerely appreciate Dr Ilesanmi

in the Department of Community Medicine, Federal Medical Centre, Owo and Mr Opele J.K.

in Obafemi Awolowo University (OAU) for their advice on statistical analysis. My

appreciation cannot be completed until the contributions of Dr Adedeji, Dr Sola Jeje, Dr Busuyi

Sogo and the registrars in Chemical Pathology Department, OAUTHC are fully acknowledged

for their immense assistance in the storage, processing and analysis of samples of each

participant of this study.

I sincerely thank other senior registrars in the cardiology unit, OAUTHc namely, Drs Amjo,

Bamgboje, Olanipekun, Adebiyi and Oke. as well as the registrars and house officers who

assisted me during my data collection. I cannot but appreciate the senior registrars in the

Department of Medicine, Federal Medical Centre, Owo namely, Drs Ajiboye, Junaid,

Odeyemi, Akitikori, Adegboye, Owolabi, Akinwalere, Momoh and Bamiduro as well as the

medical officers and house officers who provided support and encouragement in the course of

this study. Special thanks go to other staff of the Cardiology unit, OAUTHC including Mrs

vii

Adebayo, Mr Jide Joraiah, and Miss Akinsete to mention a few, for their assistance during the

data collection.

My sincere appreciation go to all volunteers who freely gave their consent to participate in this

study without any inducement whatsoever.

I immensely appreciate the management of OAUTHC, Ile-Ife and that of Federal Medical

Centre, Owo for providing the much needed conducive environment and support for a

worthwhile residency training program.

My profound gratitude and appreciation go to my parents, Mr and Mrs Agoke who ensured that

I got all the necessary support throughout my education and career, and to my dear siblings

(Femi, Bolanle, Adedayo, and Olayiwola) for their unending love and support.

Last but not the least, I cannot stop appreciating my lovely wife, Omolola and my wonderful

children, Nifemi, Iremide and Timilehin for their reassuring smile all through the thick and thin

periods of residency training, and for their overwhelming love, support, encouragement and

prayers.

viii

TABLE OF CONTENTS

CONTENT PAGE

Title page i

Declaration ii

Certification iii

Attestation iv

Dedication v

Acknowledgements vi

Table of Contents viii

List of Tables and Figures ix

List of Abbreviations xi

Abstract xiii

CHAPTER ONE: INTRODUCTION 1

CHAPTER TWO: LITERATURE REVIEW 6

CHAPTER THREE: METHODOLOGY 33

CHAPTER FOUR: RESULTS 48

CHAPTER FIVE: DISCUSSION 76

CHAPTER SIX: CONCLUSION, RECOMMENDATIONS, LIMITATION 85

REFERENCES 86

APPENDICES 101

ix

ABBREVIATIONS

ACE = Angiotensin-Converting Enzyme

ACS = Acute Coronary Syndrome

AF= Atrial Fibrillation

ARB = Angiotensin-Receptor Blocker

BMI = Body Mass Index

BNP = B-type Natriuretic Peptide

CABG = Coronary Artery Bypass Graft

CAD = Coronary Artery Disease

CHARM = Candesartan in Heart Failure-Assessment of Reduction in Mortality and

Morbidity

CPAP = Continuous Positive Airway Pressure

CRT = Cardiac Resynchronization Therapy

CT= Computerised Tomography

DCM = Dilated Cardiomyopathy

DIG= Digoxin Investigation Group

ECG = Electrocardiogram

ESC= European Society of Cardiology

EF = Ejection Fraction

HF = Heart Failure

HHF = Hypertensive Heart Failure

HFpEF = Heart Failure with Preserved Ejection Fraction

HFrEF = Heart Failure with Reduced Ejection Fraction

x

HRQOL = Health-Related Quality of Life

HsCRP =Highly Sensitive C-reactive Protein

ICD = Implantable Cardioverter-Defibrillator

LBBB = Left Bundle-Branch Block

LV = Left Ventricular

LVDP= Left Ventricular Diastolic Pressure

LVEF = Left Ventricular Ejection Fraction

MI = Myocardial Infarction

Mmol/L= Millimole per Litre

NSAIDs = Nonsteroidal Anti-Inflammatory Drugs

NT-proBNP = N-terminal pro-B-type Natriuretic Peptide

OAUTHC= Obafemi Awolowo University Teaching Hospitals Complex

NYHA = New York Heart Association

RCT = Randomised Controlled Trial

RAAS=Renin-Angiotensin-Aldosterone System

SCD = Sudden Cardiac Death

SOLVD= Studies on Left Ventricular Dysfunction

SUA= Serum Uric Acid

TDI= Tissue Doppler Imaging

VAD = Ventricular Assist Devices

xi

Table Title Pages

Table 1 Classification of blood pressure according to JNC VII 39

Table 2 Classification of ejection fraction 46

Table 3 Demographics characteristics of the study population 49

Table 4 Summary of the medical history and treatment offered to HHF

subjects

51

Table 5

Table 6

Biomarkers result of the study population.

Laboratory findings of the study population.

53

57

Table 7 Two-dimensional and M-mode echocardiographic parameters of the

study population..

59

Table 8 Left ventricular systolic function parameters of the study population. 60

Table 9 Classification of the left ventricular ejection fraction. 61

Table 10

Table 11

Doppler echocardiographic findings of the study population.

Left ventricular geometry of the study population.

63

64

Table 12 12-lead ECG pattern of the study population. 66

Table 13 Summary of the Doppler echocardiography assessment of the left

ventricular diastolic function of the study population.

67

Table 14 Relationship between the biomarkers and the NYHA functional

classifications in HHF subjects.

69

Table 15 Relationship between the biomarkers and the left ventricular ejection

fraction in the HHF subjects.

71

xii

Figures Titles Pages

Figure 4.1 Bar chart showing frequency distribution of patients and controls. 50

Figure 4.2 Pie diagram illustrating frequency of patients in each NYHA class. 52

Figure 4.3 Bar showing the Hs-C reactive protein levels of the study

population.

54

Figure 4.4 Bar showing the serum uric acid levels of the study population. 55

Figure 4.5 Scatterplot showing a positive relationship between Hs-CRP and

NYHA functional class of the HHF patients.

72

Figure 4.6 Scatterplot showing a positive relationship between uric acid and

the NYHA functional class of the HHF patients.

73

Figure 4.7 Scatterplot showing a negative relationship between Hs-CRP and

the ejection fraction of the HHF patients.

74

Figure 4.8 Scatterplot showing a negative relationship between uric acid and

the ejection fraction of the HHF patients.

75

xiii

ABSTRACT

BACKGROUND

Heart failure is a common clinical syndrome associated with increased disease burden that

contributes greatly to enormous health cost, increased hospitalisation and mortality rates in

both the developed and the developing world. Hypertension is a major cause of heart failure in

the developing world. Inflammation plays an essential role in the pathogenesis and progression

of heart failure. Several studies on various biomarkers in relation to heart failure are being

carried out in the developed countries. In the developing world studies are still evolving and

for this reason, High sensitive C-reactive proteins (Hs-CRP) and serum uric acid (SUA) are

therefore used to determine the correlation between inflammation and disease severity of

patients in hypertensive heart failure (HHF).

Objective

This study set out to determine mean Hs-CRP and SUA in hypertensive heart failure patients

and compare same in control subjects. It was also set out to determine the relationship of Hs-

CRP and serum uric acid with the severity of HHF patients using New York Heart Association

(NYHA) functional classification and echocardiography parameter of left ventricular systolic

function based on the left ventricular ejection fraction.

METHODOLGY

One hundred and ten patients with hypertensive heart failure and One hundred and ten healthy

control subjects were recruited consecutively into the study. Hypertensive heart failure patients

in NYHA class II to IV were recruited. Baseline measurement of the biomarkers (Hs-CRP and

SUA) and transthoracic echocardiography were carried out.

xiv

RESULTS

The mean age of the hypertensive heart failure patients was 58.05±10.75 vs 56.46±10.01 years

for the control group. The median levels of Hs-CRP and mean SUA were significantly higher

in the hypertensive heart failure patients compared to the controls (Hs-CRP, patients 5(8.5) vs

controls 0.8(0.6) Mg/L p<0.001) (SUA, patients 485.54±114.95 vs controls 232.43±95.19

mmol/l p<0.001). The Hs-CRP and SUA levels were significantly higher in men than women.

There is a significant correlation between the two biomarkers and the NYHA functional

classification of the HHF patients. Also there is a significant correlation between the Hs-CRP,

SUA and patients with heart failure with reduce ejection fraction (HFrEF).

CONCLUSION

Heart failure affects the younger age group in this study more than the western countries. Levels

of Hs-CRP and serum uric acid are elevated in patients with hypertensive heart failure. There

is a proportionate increase in the biomarkers as the NYHA functional classifications worsened

and a significant relationship of the biomarkers with the left ventricular ejection fraction of the

HHF patients.

xv

CHAPTER ONE

1.0 INTRODUCTION

1.1 Definition

Heart failure is defined as an abnormality of cardiac structure or function leading to

failure of the heart to deliver oxygen at a rate commensurate with the requirements of the

metabolizing tissues despite normal filling pressures or only at the expense of increased filling

pressures1. It is a serious clinical condition which represents terminal stage of a myriad of other

cardiac diseases. Heart failure contributes largely to a major clinical problem worldwide. Heart

failure can simply be divided into two different types, though there are many other

classifications:

Heart failure with reduced ejection fraction (HFrEF), also known as heart failure due

to left ventricular systolic dysfunction or systolic heart failure. This is when the heart

muscle contracts poorly and blood is not adequately pumped out to the body. HFrEF

occurs when the ejection fraction is less than 40%2.

Heart failure with mid-range ejection fraction (HFmrEF) represent left ventricular

ejection fraction in the range of 40-49%2.

Heart failure with preserved ejection fraction (HFpEF), also known as diastolic heart

failure3.The left ventricular ejection fraction is 50% and above2,3,4. The heart muscle

contracts well but the ventricles do not relax as adequately during ventricular filling

1.2 Epidemiology

More than 20 million people have heart failure worldwide5. The prevalence and

incidence of HF are on the increase, largely because of growing life span by modern therapeutic

xvi

advancements, increase in the number of risk factors (hypertension, diabetes, dyslipidaemia,

and obesity) and improved survival rates from other cardiovascular disease like myocardial

infarction and valvular heart disease6.

Few epidemiologic data are available on the prevalence of heart failure in sub-Saharan

Africa. Recent data from the sub-Saharan African Survey of Heart Failure (THESUS-HF)

which was a multicentre study carried out in 12 university hospitals in 9 countries revealed a

prevalence of 3-7%7. In the study hypertension was the predominant cause of HF followed by

rheumatic heart disease and ischaemic heart disease.

In Nigeria studies from different geographical areas have shown hypertension as the

commonest underlying cause of HF. In a study by Obasohan and Ajuyah hypertension was the

commonest cause of heart failure in their series8. Adedoyin and Adesoye also revealed that, of

the 1004 cardiovascular disease patients seen between 1997 and 2001, those with heart failure

from hypertension were 35%9. In another study in southern Nigeria hypertension was revealed

as the commonest aetiological factor, responsible for 78.5% of cases of HF10. In the savannah

part of Nigeria, hypertension accounted for the commonest cause of heart failure11.

Furthermore, a study in Aminu Kano Teaching Hospital recorded hypertension as the

commonest aetiological factor accounting for 57% of cases12.

In developed countries, the mean age of patients with heart failure is 75 years old5. In

the United State of America only two to three percent of the population have heart failure, but

in those 70 to 80 year old, it occurs in 20% to30%5.A Nigerian study carried out in the southern

part revealed mean age was 56.6 ± 15.3 years. The study revealed men had a higher incidence

of heart failure, but the overall prevalence rate is similar in both sexes, as women survived

longer after the onset of heart failure13. Women tend to be older when diagnosed with heart

xvii

failure after menopause, they are more likely than men to have diastolic dysfunction, and seem

to experience a lower overall quality of life than men after diagnosis13.

1.3 Burden of heart failure

According to a report by World Health Organisation (WHO) cardiovascular diseases

account as the leading cause of death and disability worldwide14. In Africa cardiovascular

disease is recognised as a contributor of disease burden for many years14. Across various health

services in Africa, heart failure has been described as the fifth to sixth cause of hospital

admission15.A study in Abuja, Nigeria had shown HHF as a major cause of morbidity and

mortality among urban Nigerians16.

Heart failure contributes to a high burden of health expenditure, mainly because of the

cost of hospitalizations; which has been estimated to amount to 2% of the total budget of the

National health insurance in the United Kingdom, and more than $35 billion in the United

States17. People above the age of 65 years in HF have a higher frequency of hospitalisation18.

The need for hospitalization is an important indicator for poor prognosis especially

among people of the old age who are frequently re-admitted after hospitalisation19.CHARMS

trials, a study carried out among 7572 patients in chronic HF with reduced EF and preserved

EF showed the association of hospitalization and subsequent increase in mortality rates20.

Despite increase in mortality rates from frequent hospitalisations, intra-hospital mortality rate

has been on the decrease21. According to Framingham study, long-term mortality rates for

patients with HF have shown decline over the years21.

1.4 BIOMARKERS IN HEART FAILURE

Inflammation plays an essential role in the pathogenesis and progression of heart

failure. Thus, the interest in biomarkers of inflammation seemed to have dated back to decades

ago. The interest in the presence of inflammatory mediators in patients with heart failure began

xviii

in 1954 when a crude assay for C- reactive protein became available. There are several other

biomarkers which have since been discovered with their varying roles in HF, namely:

Interleukins (Interleukin-1, 6 and 18), TNF-α, biopyrrins, isoprostane, uric acid,

norepinephrine, BNP, NT proBNP, troponins, adrenomodullins and endothelins-1. Newer ones

of growing interest are chromogranin A, galectin-3, osteoprotogerin and adiponectin22.

C - reactive protein is a pentameric protein, whose gene in humans is encoded in

chromosome 1. Elevated levels of CRP have been observed in patients with heart failure23, and

activation of the immune response may play a role in heart failure through modifications in the

renin–angiotensin–aldosterone and sympathetic systems.

Increased levels of serum uric acid have been found to contribute to increased

cardiovascular risk in cardiac diseases such as hypertension, however the level varies with age

and sex24.There is increasing evidence that xanthine oxidase, which catalyzes the production

of two oxidants, hypoxanthine and xanthine, plays a pathologic role in heart failure. Ofori and

Odia in a study among hypertensive Nigerians reported a significant elevation in SUA and was

correlated with the severity of hypertension25.

1.5 JUSTIFICATION OF STUDY

Heart failure is a common clinical syndrome associated with increased disease burden

that contributes greatly to enormous health cost, increased hospitalisation and mortality rates

in both the developed and the developing world. In the developing world hypertension accounts

for the commonest aetiology.

Several studies have been done in the developed world on the use of various biomarkers

to relate with severity among patients with heart failure. However, only few researchers in this

part of the world have studied the relationship of biomarkers in heart failure patients. A Sub-

Saharan study in 21 health centres has identified the value of measurement of biomarkers to

xix

heart failure diagnosis, risk stratification especially at admission and discharge as well as in

prognosis26. This is the reason the study aimed to determine hs-CRP and serum uric acid as

biomarkers to correlate with the severity of hypertensive heart failure.

1.6 AIM

To assess the serum levels of high sensitive C - reactive protein and uric acid and

correlate them with the severity of hypertensive heart failure.

1.7 OBJECTIVES

1. To determine mean hs-CRP and serum uric acid in patients with hypertensive heart failure

and compare same in apparently healthy age and sex matched controls.

2. To determine the relationship of hs-CRP and serum uric acid with the severity of HHF using

the NYHA functional classification.

3. To assess the relationship of hs-CRP and serum uric acid with the severity of HHF using the

echocardiography parameter of left ventricular systolic function based on the ejection fraction.

CHAPTER TWO

2.0 LITERATURE REVIEW

xx

2.1INTRODUCTION

Heart failure is a common clinical syndrome representing the end-stage of a number of

various cardiac diseases. By definition, HF is a complex clinical syndrome that results from

any structural or functional impairment of ventricular filling or ejection of blood leading to

failure of the heart to deliver oxygen at a rate commensurate with the requirements of the

metabolizing tissues 1,27.

Although HF is not a heart disease itself, it is a heart condition with a high social and

economic impact. Hypertension has been noted as the commonest cause of heart failure from

studies carried out in Nigeria9,10,12.

Elevated blood pressure as defined by the Seventh Joint National Committee Report

(JNC7)28include:

Stage 1: Hypertension defined as; systolic blood pressure (SBP) of 140 –

159mmHg and/or diastolic blood pressure between 90-99mmHg.

Stage 2: Hypertension defined as; systolic blood pressure greater or equal to

160mmHg and/or diastolic blood pressure greater or equal to 100mmHg.

2.2 Classification of heart failure

HF is a complex syndrome, clinically characterized by signs and symptoms which are due to

abnormal cardiac function. The presentation may be classified as follow:

Systolic dysfunction or diastolic dysfunction

Heart failure with mid-range ejection fraction

Functional classification (New York Heart Association)

Stages of heart failure (American Heart Association/ American College of Cardiology)

xxi

Acute (New onset First presentation) or Chronic (in which patient may be persistently

stable, worsen, or decompensated)

Forward and backward HF

Right and left HF

High and low output HF

Preload and afterload

2.2.1 Systolic heart failure (HFrEF)

This refers to a weakened ability of the heart to contract in systole, and remains the

most common type of HF2. This reflects the prevalence of coronary heart disease (CHD) in the

Western world, although hypertension is still a significant contributor to systolic heart failure29.

HFrEF is when the LVEF is less than 40%2. Apart from the reduced LVEF, systolic HF (SHF)

is characterized as abnormality in systolic function, which manifest with cardiac chamber

dilation and mainly with left ventricular eccentric remodelling.

2.2.2 Diastolic HF (HFpEF))

It is characterised by a normal LVEF, normal LV end-diastolic volume, and abnormal

diastolic function, usually with concentric remodelling or hypertrophy30.It is also called “HF

with preserved EF” 2,3, 4, defined as HF with LVEF greater than 50%. It presents as impaired

diastolic filling of the left ventricle because of slow early relaxation or increased myocardial

stiffness resulting in higher filling pressures, with or without impaired systolic contraction. It

is commoner in the elderly.

2.2.3 Heart failure with mid-range ejection fraction (HFmrEF)

This is a newer classification of HF and this area is still very grey in the areas of research2. The

LVEF is in the range of 40-49%2.

xxii

2.2.4 Functional classification:

There are different scales used to assess functional status in HF, namely: New York Heart

Association which is commonly used. Also, there is the Medical Research Council scale.

New York Heart Association (NYHA) functional classification is based on symptoms and

exercise capacity. This classification has proven to be clinically useful and is employed

routinely in assessment of patients in the hospital31.

NYHA functional classification

CLASS I-No limitation of physical activity. Ordinary physical activity does not cause undue

fatigue, palpitation, or dyspnoea.

CLASS II-Slight limitation of physical activity. Comfortable at rest, but ordinary physical

activity results in fatigue, palpitation, or dyspnoea.

CLASS III-Marked limitation of physical activity. Comfortable at rest, but less than ordinary

activity results in fatigue, palpitation, or dyspnoea.

CLASS IV-Unable to carry on any physical activity without discomfort. Symptoms occur at

rest. If any physical activity is undertaken, discomfort is worsened.

2.2.5 STAGING OF HF

American College of Cardiology/American Heart Association working group introduced four

stages of heart failure31:

Stage A: Patients at high risk for developing HF in the future but no functional or structural

heart disorder.

Stage B: a structural heart disorder but no symptoms at any stage.

xxiii

Stage C: previous or current symptoms of heart failure in the context of an underlying

structural heart problem, but managed with medical treatment.

Stage D: advanced disease requiring hospital-based support, a heart transplant or palliative

care.

2.3 Epidemiology of Hypertensive Heart Failure

Congestive cardiac failure is an important cardiovascular event with increasing

incidence and prevalence worldwide7.The prevalence worldwide of HF has been rising during

the last few decades, which could be attributed to several factors: an increase in the incidence

of cardiovascular diseases; an aging population; better and more effective treatment of heart

disease, leading to a reduction in mortality and HF occurring over a longer time frame7.

The statistics of HF all over the world is of great significance. There are more than 20

million people diagnosed and being managed for HF worldwide6.In the United States of

America, HF affects 5.8 million people, and each year 550,000 new cases are diagnosed32. The

overall prevalence of HF in United States of America and Europe is between 2% and 3%6. The

prevalence in African-Americans is reported to be 25 percent higher than in the whites. The

incidence in men is higher than the women. However, there is similarity in the prevalence of

both the males and females13.

Although, notable differences in prevalence have been observed between studies in

different countries, HF is a common and severe condition in Africa, and remains the

commonest complication of hypertension33.A multicentre study across 9 countries in sub-

Saharan African region in a THESUS-HF study recorded prevalence of 3 to 7% of HF among

cardiovascular diseases7. In Nigeria, HF constitutes a huge burden of cardiovascular disease34.

In a study in southwest Nigeria, heart failure from hypertension represented 35% of

cardiovascular diseases that presented over a five-year period10. A study in the South-South

xxiv

region of Nigeria in University of Port-Harcourt Teaching hospital reported heart failure as the

commonest presentation among other cardiovascular diseases between the period of 1999 and

200535. Hypertension was regarded as the commonest cause of the HF 35. The mean age of

patients seen over the study period was 54.4 years. The study concluded with the observation

that heart failure from hypertension was the commonest cardiovascular disease presentation in

the region. This compared favourably with findings obtained in other parts of the country35.

2.4 Burden of heart failure

The burden of the disease is notably enormous on the patients mainly because of the

affectation of the aging population, frequent admissions and huge economic cost. In the United

States of America, HF accounts for 20% of all admissions among patients older than 65

years36.In various health services in Africa, HF is responsible for between the fifth to sixth

cause of hospital admission14. Patients older than 65years account for the highest age group of

HF admission18.

There are few data obtained on HF in the developing countries. Dokainish et al in a

study from Africa, Asia, the Middle East and South America showed different variations in age

group and severity of HF in these regions37. The study showed that participants from Africa,

closely followed by those from Asia heart failure affectation were of younger age group and

presentation in the hospitals were mostly in NYHA IV compared with participants from Middle

East and South America. The participants in South America and the Middle East were older

and hospital presentations were mostly in NYHA I37.

The health cost expended on HF on hospitalisation is estimated to amount to about 2%

of the total budget of the National Health Insurance in the United Kingdom, and more than $35

billion in the United States15,16.

2.5 AETIOLOGY

xxv

In the developed world, coronary artery disease and diabetes mellitus have become

increasingly responsible for HF while hypertension and valvular heart disease have become

less common due to improvements in detection and therapy38.Among the low to middle income

countries only few data are available on the causes of HF. In Africa untreated rheumatic

valvular disease, peripartum and idiopathic cardiomyopathy, and hypertension were the

predominant causes identified39. A study at the National Cardiothoracic Centre, Accra, Ghana,

over a four-year period with 572 patients with HF revealed hypertension (21.3%), rheumatic

heart disease (20.1%) and cardiomyopathy (16.8%) as main causes40.This observation is

consistent with results obtained from various parts of Nigeria. Hypertension is regarded as the

most common cause of HF in Nigeria9. Studies from the southern, northern and eastern Nigeria

showed hypertension as the commonest cause of HF accounting for 78.5%, 57% and 56.3%

respectively, of cases seen10,12,35. This is also in keeping with reports from several other centres

in Nigeria3,11,16.

The prevalence of coronary artery disease and other degenerative disorders in

developing countries remains low, but the situation is rapidly changing. However, the reason

for the reported low prevalence of CAD in sub-Saharan Africa may be due to a lack of

diagnostic facilities which limit its study14,41. Among the elderly several causes have been

identified as to why they are susceptible to the development of HF. Coronary heart disease and

hypertension are known to increase in incidence with age. There are also both structural and

functional changes that occur within the heart and vascular systems which may predispose to

this condition42.

2.6 PATHOPHYSIOLOGY

Heart failure is described as a progressive disorder that occurs following an index event

that either damages the cardiac muscle, with a consequent destruction of the cardiac myocytes,

xxvi

or, alternatively, affects the ability of the myocardium to generate force, thereby making the

heart unable to contract adequately. Overall, the changes associated with heart failure result in

a decrease in cardiac output. This results from a decline in stroke volume that is due to systolic

dysfunction, diastolic dysfunction, or a combination of the two28,29.

The index event that predisposes to HF may have a sudden onset, such as myocardial

infarction; it may have a gradual onset, as in the case of hemodynamic pressure or volume

overload; or it may be hereditary, as seen in genetic cardiomyopathies. The peculiar final

outcome that follows regardless of the initiating event is impaired the ability of the heart to

pump effectively27.

After this initial decline in pumping capacity, a variety of compensatory mechanisms

are activated. These compensatory mechanisms involve both the local cardiac and systemic

involvement. In a transient period, these systems are able to restore and sustain the

cardiovascular function to a normal homeostatic range with the aim of maintaining an

asymptomatic state in an affected individual. However, with continued progression of the

disease the sustained activation of these systems become overwhelmed and can lead to

secondary end-organ damage within the ventricle, with worsening left ventricular remodelling

and subsequent cardiac decompensation.

Adaptive mechanisms43 deployed by the body systems to sustain cardiovascular

functions overtime fail and then increase workload of the heart with consequent changes on the

heart:

Reduced force of contraction. In a healthy heart, increased ventricular filling results in

increased force of contraction by the Frank–Starling law of the heart and thus a rise in

cardiac output. There is failure of this mechanism in HF.

Reduced stroke volume.

xxvii

Increased in sympathetic activity

Myocardial hypertrophy

Myocardial remodelling

In addition, inflammatory changes occur with progression of HF whereby numerous

inflammatory markers play their varying roles in the pathogenesis. The inflammatory

mediators include the BNP, NT pro-BNP, C-reactive proteins and others24.

2.7 Clinical presentation

There are various algorithms for the diagnosis of heart failure, namely as follows:

Framingham Heart Study.

European Society of Cardiology (ESC)

For the purpose of this study clinical presentation of the patients will be interpreted

using the Framingham criteria.

Framingham criteria

Major criteria44 include the following:

Cardiomegaly on chest radiography

S3 gallop (a third heart sound)

Acute pulmonary oedema

Paroxysmal nocturnal dyspnoea

xxviii

Crackles on lung auscultation

Central venous pressure of more than 16 cm water at the right atrium

Jugular vein distension

Positive abdominojugular test

Weight loss of more than 4.5 kg in 5 days in response to treatment.

Minor criteria44 include the following:

Tachycardia of more than 120 beats per minute

Nocturnal cough

Dyspnoea on ordinary exertion

Pleural effusion

Decrease in vital capacity by one third from maximum recorded

Hepatomegaly

Bilateral ankle oedema

By the Framingham criteria, diagnosis of HF requires the presence of at least two major

criteria or one major criterion in conjunction with two minor criteria. The Framingham Heart

Study criteria are 100% sensitive and 78% specific for identifying persons with definite

congestive heart failure6.

2.8 Precipitating factors

Factors that may precipitate acute decompensation in patients with chronic heart failure

must be considered and include:

1. Dietary indiscretion-Excessive sodium and fluid intake may precipitate acute HF.

2. Myocardial ischemia/infarction

xxix

3. Arrhythmias (tachycardia or bradycardia)

4. Discontinuation/non-compliance with HF therapy

5. Infection (such as, pneumonia, viral illnesses)

6. Anaemia

7. Drugs

Calcium antagonists (verapamil, diltiazem)

Beta blockers

Non-steroidal anti-inflammatory drugs

Antiarrhythmic agents [all class I agents, sotalol (class III)]

8. Alcohol consumption

9. Pregnancy

10. Worsening hypertension.

11. Acute valvular insufficiency

12. Endocrine abnormalities (such as, diabetes mellitus, hyperthyroidism, hypothyroidism)

13. Pulmonary embolism

2.9 Investigative modalities

Investigation is imperative in any patient with suspected HF

The purpose of investigating CHF is to:

Confirm the clinical diagnosis

Determine the mechanism (LV systolic dysfunction, LV diastolic dysfunction, valvular

heart disease)

xxx

Identify a cause (CHD, hypertension)

Identify exacerbating and precipitating factors (arrhythmias, ischaemia, anaemia,

pulmonary embolism, infection)

Guide therapy

Determine prognosis.

2.9.1 Electrocardiogram

The electrocardiogram in HF is seldom normal, but abnormalities are frequently non-

specific. The most common are non- specific repolarisation abnormalities (ST–T wave

changes). A completely normal ECG makes a diagnosis of HF due to LV systolic dysfunction

unlikely45. However, it does not exclude other causes of CHF.

Conduction abnormalities may be seen, including:

Left bundle branch block

First-degree atrioventricular block

Left anterior hemiblock

Non-specific intraventricular conduction delays.

Other abnormal findings include:

LV hypertrophy

Evidence of pathological Q wave that denotes prior MI in patients with CHD

Sinus tachycardia (due to increased sympathetic activity)

Arrhythmia - Atrial fibrillation.

2.9.2 Chest x-ray

xxxi

A chest X-ray is important in making a diagnosis of CHF. Findings suggestive of HF

include cardiomegaly, cephalization of the pulmonary vessels, Kerley B-lines, bat wing

appearance and pleural effusions. The cardiac size and silhouette may also reveal features of

valvular disease (mitral stenosis or aortic stenosis).

2.9.3 Echocardiography

Transthoracic echocardiography (TTE) is a non-invasive imaging modality widely

available, rapidly performed, and safe which provide quantitative and qualitative evaluation of

cardiac anatomy (volumes, geometry46, and mass), wall motion, and valvular function.

Echocardiography is commonly used to assess the LV systolic and diastolic functions.

Measurement will be derived using the formulas proposed by the American Society of

Echocardiography.

Linear Measurements

Linear internal measurements of the LV and its walls by recommendation, is usually

performed in the parasternal long-axis view. Internal dimensions can be achieved with a two

dimensional (2D) echocardiography (2DE)–guided M-mode approach or directly from 2D

echocardiographic images.

Volumetric Measurements

LV volumes are measured using 2DE or 3DE. Volumetric measurements are usually based on

tracings of the interface between the compacted myocardium and the LV cavity from the apical

four- and two-chamber views.

Global LV function is commonly assessed by calculating the difference between the

end-diastolic and end-systolic value on M-mode, 2D, or 3D parameter divided by its end-

diastolic value. The end diastole is defined as the first frame after mitral valve closure or the

xxxii

frame in the cardiac cycle in which the respective LV dimension or volume measurement is

the largest. End systole is best defined as the frame after aortic valve closure or the frame in

which the cardiac dimension or volume is smallest.

LV systolic function

Ejection fraction (EF)

The EF is the volumetric decrease of the LV that occurs in diastole to systole. It

represents stroke volume as a percentage of end-diastolic volume. It can be estimated using the

Teichholz method47 and the modified Simpson’s rule. Teichholz method describes the left

ventricle as a simple ellipsoid with both orthogonal axes being equal. Modified Simpson’s rule

is based on summation of the smaller volumes in order to obtain the overall left ventricular

volume.

EF is calculated from end diastolic volume (EDV) and end systolic volume (ESV)

estimates, using the following formula:

Left Ventricular Ejection Fraction: (LVEDV-LVESV /LVEDV) x 100%

LV volume estimates may be derived from 2DE or 3DE. Reference for normal is >50%2.

Fractional shortening

Fractional shortening measures the percentage of the LV diameter change between

diastole to systole. Fractional shortening can be derived from 2D-guided M-mode imaging or

from linear measurements obtained from 2D images.

Left Ventricular Fractional Shortening: (LVIDd - LVIDs/LVIDd) X 100%

xxxiii

A study on HHF in Southern Nigeria showed majority of the patients presented with

LVEF <40%and FS <20%9. The predominance of those with depressed LV systolic function

was comparable to studies in other centres in Nigeria3,12,16.

Left ventricular diastolic function

Left ventricular diastolic function is evaluated by studying the filling dynamics of the

left ventricle. The mitral inflow velocities were determined from the apical four chamber view

with pulsed-wave Doppler and with the sample volume positioned at the tip of the mitral valve

leaflets. This inflow characteristics can be assessed by measuring the transmitral "E" wave

velocity (peak early mitral inflow velocity) and the "A" wave velocity (peak late atrial mitral

inflow velocity), the E/A ratio and the deceleration time (DT):(time interval of Peak E wave

velocity to its extrapolation to the baseline)48.

2.9.4Other important investigations that can be done include: Transoesophageal

echocardiography, stress echocardiography, cardiac magnetic resonance imaging, coronary

angiography, exercise testing and endomyocardial biopsy.

2.9.5 Blood tests

A complete blood count which may suggest concurrent or alternate conditions. Anaemia or

infection can exacerbate pre-existing HF.

Serum electrolytes, blood urea nitrogen, and creatinine may indicate associated conditions.

Renal impairment may be caused by and/or contribute to HF exacerbation.

Other Blood investigations that will be essential in HF are liver function test, fasting blood

glucose, fasting lipid profile and thyroid function test.

2.9.6 Biomarkers of heart failure

xxxiv

There are several biomarkers of HF which are helpful in diagnosis and prognosticating.

These biomarkers play important roles in the progression of HF and include: Interleukins

(Interleukin-1, 6 and 18), TNF-α, biopyrrins, isoprostane, uric acid, norepinephrine, BNP,

troponins, adrenomodullins and endothelins-1. The role of BNP and NT-proBNP have also

largely been studied and are related to increased cardiovascular risk, mainly HF. BNP and NT-

pro BNP - Brain natriuretic peptide (BNP) is a natriuretic hormone released primarily from the

heart, particularly the ventricles. The active BNP hormone is cleaved from the C-terminal end

of its prohormone, pro-BNP. The N-terminal fragment (NT-proBNP) is also released into the

circulation49.Newer biomarkers of growing interest include: chromogranin A, galectin-3,

osteoprotogerin and adiponectin23.

Several studies on biomarkers in cardiovascular diseases have been carried out in the

developed countries24,25. More studies on biomarkers are now emerging in the developing

world. Few studies in Nigeria have worked on relationship of biomarkers, particularly Hs-

CRP and SUA and cardiovascular diseases 24,25. The studies have related the elevation of the

biomarkers to increased disease severity in patients with HF and these are greatly related to the

effect of inflammation24,25.

Role of Hs-CRP in heart failure

C - reactive protein is a pentameric protein comprised of 5 identical units whose gene

in humans is encoded in chromosome 1. Inflammation plays a role in the initiation and

progression of HF through atherosclerosis. CRP is a product of inflammation whose synthesis

by the liver is stimulated by cytokines in response to an inflammatory stimulus. CRP activates

xxxv

the classic complement pathway and participates in the opsonisation of ligands for

phagocytosis.

Elevated levels of CRP have been observed in patients with heart failure24 and the

increase is connected to Interleukin-6. Interleukin 6 is a determinant of the hepatic production

of CRP, and is produced in monocytes/macrophages, endothelial cells, vascular smooth muscle

cells, fibroblasts, and cardiac myocytes under hypoxic stress in response to a wide range of

acute and chronic inflammatory conditions such as bacterial, viral, or fungal infections;

rheumatic and other inflammatory diseases, malignancy, and tissue injury and necrosis50. Left

ventricular dysfunction, liver or kidney damage caused by low cardiac output, hypoperfusion,

hypoxia, and venous congestion may all be sources of increased interleukin-6 and hence CRP

production50.

Several methods are used to measure CRP and these include ELISA,

immunoturbidimetry, rapid immunodiffusion, and visual agglutination. A high-sensitivity CRP

(Hs-CRP) test measures low levels of CRP using laser nephelometry.

Hs-CRP levels and risk of cardiovascular disease

High level of Hs-CRP has been related with increased risk of cardiovascular diseases51.

The cardiovascular diseases include hypertension, myocardial infarction, heart failure and

stroke. In a Framingham Heart study, the risk of heart failure was significantly elevated among

participants with CRP serum levels of ≥5 mg/L, even after adjustment for prevalent

cardiovascular disease and occurrence of myocardial infarction during follow-up were

considered51.Baba and colleagues in a study carried out in Obafemi Awolowo Teaching

Hospitals reported higher CRP levels among apparently healthy adult individuals who were at

increased risk of cardiovascular diseases52. CRP levels were elevated more in the females than

in the males. The increase was attributed to the gender difference of the body weight which

xxxvi

was higher in the females than in the males52. Another study in hypertensive patients reported

that elevated CRP levels were seen even among the normotensive subjects and were found to

correlate to increased risk of developing cardiovascular disease53.

Relationship between Hs-CRP and severity of heart failure

Hs-CRP have been used in several studies to relate with severity in patients with CCF51,

52. Clinical indexes that have been studied to determine severity had included relating the levels

of the elevated Hs-CRP with patient’s clinical and investigative parameters. The clinical

parameters had evaluated the functional class of the patients based on NYHA functional

classifications. Several investigative modalities had included 12 lead electrocardiography and

echocardiography. Some studies have evaluated roles of the biomarkers in predicting clinical

course, re-admission and mortality among CCF patients54, 55. Alonso-Martinez and colleagues

in a study reported a significant relationship between elevated Hs-CRP levels and NYHA

functional class III and IV. There was also significant relationship in HF patients with left

ventricular ejection fraction less than 35%. The limitation of the study was with the use of CRP

which had lesser sensitivity to identify cardiovascular diseases compared to Hs-CRP55.

Role of serum uric acid in heart failure

Patients with chronic heart failure exhibit elevations in serum uric acid56.UA is a

metabolic by-product of purine metabolism. Serum UA may increase in the failing heart

because of increased generation, decreased excretion, or a combination of the 2 factors. There

are several possible contributors to increased UA production in HF, including increased

abundance and activity of xanthine oxidase, increased conversion of xanthine dehydrogenase

to xanthine oxidase or increased xanthine oxidase substrate resulting from enhanced ATP

xxxvii

breakdown to adenosine and hypoxanthine. Xanthine oxidase is also known as one of the main

sources of free radicals and may contribute to oxidative damage in the myocardium55. A

chronic increase in myocardial oxidative stress is capable of causing subcellular abnormalities,

and may lead to cardiomyopathic changes, depressed contractile function and failure. Thus, an

elevated serum level of UA may relate to cardiac dysfunction and progression of heart failure

through oxidative stress by increased xanthine oxidase activity in patients with CHF56. The

roles of increased xanthine oxidase activity in inflammatory response are the focus of studies

in patients with chronic heart failure57,58.

SUA and risk of cardiovascular diseases

Several research works are emerging in recent years to study the contribution of UA in

cardiovascular diseases24, 25. Increased levels of UA have been found to contribute to increased

cardiovascular risk in cardiac diseases such as hypertension and heart failure24. Ofori and Odia

reported the significant contribution of elevated UA to the development of cardiovascular risk

in Nigerians with hypertension 25. In patients with heart failure SUA was shown to be elevated

and was strongly related to one of the circulating markers of inflammation which contribute to

increased cardiovascular risk57.

Relationship between SUA and severity of heart failure

Several research works have studied the relationship between SUA level and disease

severity in patients with HF using clinical and echocardiography parameters57,58. The clinical

parameters studied included the functional state of patients using the NYHA functional

classifications and echocardiography parameters of left ventricular systolic function. These

parameters have studied the contribution of SUA to prognostic outcome. In a study elevated

uric acid levels in patients with systolic heart failure was associated with impaired clinical and

xxxviii

hemodynamic profile. The study concluded that SUA levels might be used as a non-invasive

indicator of elevated left ventricular filling pressures57.In addition a study revealed that there

was a significant relationship between elevated SUA levels and HF patients with left

ventricular ejection fraction less than 40%. The study concluded that there was a negative

correlation between elevated SUA and HFrEF57.Also, some studies have shown significant

relationship between increased SUA levels and NYHA functional classifications of HF

patients57,58. These studies reported that the levels of SUA were increasing as the NYHA

functional class of the HF patients worsened from class I to class IV57,58.

2.10Treatment

Treatment focuses on improving the symptoms and preventing the progression of the

disease. Reversible causes and precipitants of heart failure also need to be addressed (for

example infection, alcohol ingestion, anaemia, thyrotoxicosis, arrhythmia, and

hypertension).There is a range of effective strategies available to support people with HF to

improve and prolong their lives and achieve a good quality of life.

These include:

1. Non-pharmacological interventions and management of co-morbidities

2. Pharmacotherapy

3. Surgical procedures and supportive devices (for example, coronary artery bypass graft

surgery and ICDs)

4. Post-discharge management programs (for example, home- based interventions).

2.10.1 Non-pharmacological management

1. Physical activity

2. Diet

xxxix

The adverse effect of being overweight or obese put increased demands upon the heart during

physical activity. Weight loss may improve physical activity tolerance and quality of life.

(I) Saturated fat

Saturated fat intake in all patients should be limited, especially in those who suffer from HF59.

(II) Fibre

Due to relative gastrointestinal hypoperfusion, constipation is common and a high-fibre diet is

recommended59.

(III) Undernutrition

Malnutrition, cardiac cachexia60 and anaemia are common problems that contribute to

debilitating weakness and fatigue. They are also associated with a much poorer prognosis.

(IV) Sodium

Reduced dietary sodium intake can result in beneficial clinical effects. For patients with

symptoms in HF (NYHA Class III/IV) requiring a diuretic regimen, a restricted intake of 2 g

per day should be applied.

(V) Caffeine

Excessive consumption of caffeine may exacerbate arrhythmia, increase heart rate and increase

blood pressure. The consumption should be reduced.

3. Alcohol

Alcohol is a direct myocardial toxin and may impair cardiac contractility59. It should be reduced

remarkably.

4. Smoking

xl

Cigarette smoking or chewing of tobacco is hazardous to health and must be stopped. Smoking

is atherogenic, reduces the oxygen content of blood, provokes vasoconstriction, impairs

endothelial functions and is arrhythmogenic.

5. Vaccination

Immunization with influenza and pneumococcal vaccines to prevent respiratory infections

should be given to patients especially the elderly.

2.10.2Pharmacological therapy

A systematic and expeditious approach to management of HF is required because many

patients will present in an acute state

Medical therapy for heart failure focuses on the following goals:

Preload reduction

Afterload reduction

Inhibition of deleterious neurohormonal activation

Improving myocardial contractility

Pharmacotherapeutic approach in management of chronic heart failure include the following:

(I) Diuretics

Diuretics remain an important part of standard therapy for acute heart failure. Examples are

furosemide, bumetanide, torsemide. Chronic diuretic therapy has not been shown to improve

survival. Diuretics are effective in preload reduction by increasing urinary sodium excretion

and decreasing fluid retention, with improvement in cardiac function, symptoms, and exercise

tolerance61.

xli

(II) Vasodilators

Vasodilators (for example, nitroprusside, nitroglycerin, or nesiritide) may be considered as an

addition to diuretics for patients with acute heart failure for relief of symptoms. Vasodilators

will decrease preload and/or afterload.

Sodium nitroprusside is a potent, primarily arterial, vasodilator resulting in a very efficient

afterload reduction and decrease of intracardiac filling pressures.

Nesiritide (human brain natriuretic peptide analogue) is a vasodilator and works by reducing

pulmonary capillary wedge pressure (PCWP), right atrial pressure, and systemic vascular

resistance but has no effect on heart contractility.

(III) ACEIs

ACE inhibitors have been proven useful in the treatment of symptomatic and asymptomatic

patients with a depressed EF (<40%)62. ACE inhibitors interfere with the renin-angiotensin

system by inhibiting the enzyme that is responsible for the conversion of angiotensin I to

angiotensin II.

ACEIs have been shown to:

Prolong survival in patients with NYHA Class II, III and IV symptoms62.

Improve symptom status, physical activity tolerance and reduce need for hospitalisation

in patients with worsening CHF62.

Increase ejection fraction.

(IV) Angiotensin II receptor antagonists

An overview of studies comparing the use of ACEIs and angiotensin II receptor antagonists in

heart failure shows similar outcomes63.

xlii

(V) Aldosterone antagonists

Aldosterone receptors within the heart can mediate fibrosis, hypertrophy and

arrhythmogenesis. A study carried out on spironolactone revealed it causes reduction in

mortality and symptomatic improvement in patients with advanced CHF64.

(VI) Digoxin

The cardiac glycoside, digoxin, inhibits sodium–potassium ATPase. Digoxin has shown

improved inotropic effect especially in systolic HF65. Digoxin may also sensitise

cardiopulmonary baroreceptors, reduce central sympathetic outflow, increase vagal activity

and reduce renin secretion65. Digoxin can lead to a small increase in cardiac output,

improvement in heart failure symptoms, and decreased rate of heart failure hospitalizations65.

(VII) Beta-blockers

Beta-blockers inhibit the adverse effects of chronic activation of neurohormonal system acting

on the myocardium. Three beta-blockers—carvedilol (beta-1, beta-2 and alpha-1 antagonist),

bisoprolol (beta-1 selective antagonist) and metoprolol (beta-1 selective antagonist) provide

survival benefits in patients with HF by both causing reductions in sudden death, as well as

death due to progressive pump failure. Beta blockers can lessen the symptoms of HF, improve

the clinical status of patients and reduce hospital stay66.

(VIII) Positive inotropic agents

Inotropic therapy aims to improve pump function by acutely increasing contractility. Inotropic

drugs are generally indicated for acute, transient support of a patient with myocardial

dysfunction, reduced stroke volume, cardiac output, blood pressure and peripheral perfusion

with increased ventricular filling pressure. Dobutamine is generally used as a positive inotropic

drug with vasodilator activity, while dopamine is used as a vasopressor with positive inotropic

xliii

effects when given in medium to high doses67.Milrinone is less frequently used in CHF because

of concerns about arrhythmogenesis.

2.10.3 Emerging anti-HF regimens

1. Angiotensin receptor neprilysin inhibitor (ARNI)LCZ696 (Sacubitril/Valsartan) in HFrEF

and HFpEF. Study has shown beneficial effect of LCZ696 when compared with enalapril68.

2. Finerenone in HFrEF is a non-steroidal mineralocorticoid receptor antagonist (MRA). In

heart failure patients with diabetes and/or chronic kidney disease, finerenone was no more

effective than the currently approved MRA eplerenone in reducing the severity of heart

failure69.

3. Ferric carboxymaltose in iron-deficient HFrEF. The benefits of iron therapy in symptomatic,

iron-deficient HF patients includes over a 1-year period sustained improvement in functional

capacity, symptoms, and quality of life. It may also be associated with risk reduction of

hospitalization for worsening HF70.

4. Serelaxin in acute HF, recombinant human relaxin-2, is a vasoactive peptide hormone with

many biological and haemodynamic effects. In the RELAX-AHF trial, serelaxin was associated

with relief of dyspnoea, but had no effect on readmission rate to hospital71

2.10.4 Management of refractory heart failure

Ultrafiltration

Uses of devices

Types of devices proven safe in the effective treatment of systolic heart failure are as follow:

Atrial-synchronised biventricular pacing (also called cardiac resynchronisation

therapy);

xliv

Implantable cardioverter defibrillators;

In highly selected patients, left-ventricular assist devices

2.10.5 Surgical intervention

Various cardiac surgical interventions are being exploited to manage patients who are in

refractory CHF.

Cardiac transplantation

Coronary revascularisation (CABG)

Valve repair or replacement

Surgical ventricular reconstruction or restoration

2.11Co-morbidities

Diabetes mellitus

The likelihood of developing HF in patients without structural heart disease is further increased

in the presence of diabetes mellitus72 and may impact adversely on the outcomes of patients

with established HF.

Sleep apnoea

Two types are commonly seen in patients with HF. Obstructive sleep apnoea and central sleep

apnoea. Obstructive sleep apnoea occurs due to upper airway collapse and is likely to aggravate

but not necessarily cause CHF73. Obstructive sleep apnoea impacts adversely on the heart in

that it has been shown to cause a reduced LVEF, lower LV filling rates, and a higher incidence

of CHF74.

Anaemia

xlv

CHF may be associated with a normocytic normochromic anaemia. It is important to exclude

other causes of anaemia such as chronic renal impairment, toxic effects of pro-inflammatory

cytokines, haemodilution and the use of drugs like ACEIs that tend to lower haemoglobin

levels75.

Chronic renal failure

The assessment of renal dysfunction and or renovascular disease should be considered in all

patients with CHF who are elderly, have a history of hypertension or diabetes mellitus. The

presence of renal impairment is associated with a worse prognosis in patients with HF76.Renal

diseases often cause excessive salt and water retention in which patients will require higher

doses of loop diuretics.

Arthritis

Patients with severe systolic dysfunction and/or hyponatraemia should not be treated with large

doses of both selective and nonselective cyclooxygenase inhibitors for arthritis, as they will

increase the risk of worsening CHF77.

2.12 Prognostic factors

Determination of prognosis in HF is complex and patient survival is influenced by many

factors. Some include aetiology, age, co-morbidities and inter-individual variation in

progression.

DEMOGRAPHY

xlvi

Effect of Age-Studies have shown patients who are aged 65 years to 74 years and or greater

than 75 years had an independent increase in one-year mortality compared to patients aged 25

years to 49 years78.

Effect of gender-The prognosis has generally been better in women than men with HF12.Data

collated from the Framingham Heart Study suggest that the median survival time after

diagnosis was better in women than men79.

Effect of race-The effect of race on the prognosis of HF is unclear with different studies

revealing contrasting findings:

Higher mortality in blacks was noted in a post hoc analysis from the SOLVD trial of enalapril

in patients with asymptomatic LV dysfunction or overt HF80.

CHAPTER THREE

3.0 METHODOLOGY

3.1 Study Location

The study was conducted in the Cardiology Units of Department of Medicine, Obafemi

Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun state. Ile-Ife is an ancient

Yoruba city in Osun State, South-Western Nigeria. The town lies at the intersection of roads

from Ibadan, Ilesha, and Ondo. It is located at latitude 7˚ 28N and longitude 4˚ 34E.

Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), a 1600

bedded complex, is one of the first generation of teaching hospitals established by the Federal

xlvii

government in 1972 to provide qualitative health care delivery to her people. The hospital serves

patients from Osun, Ekiti, Ondo and Oyo states.

3.2 Study Population

The study population was made up of patients who were of the age 18 years and above with

hypertensive heart failure diagnosed by the Framingham criteria42, who presented at the

Cardiology Unit of Department of Medicine and Adult Accident/Emergency (A/E) unit of

OAUTHC who satisfied the inclusion criteria. Equal number of age and sex matched healthy

controls were also recruited.

3.3 Study design

It was a descriptive cross sectional study. /

3.4 Study period

This study was conducted between October 2016 and March 2017.

3.5 Sample Size

Fisher’s Statistical formula was used for accurate sample size determination81 using a HF

prevalence of 7%8:

N = (Z2) X P ( 1-P )/ d2

N =Minimum sample size

Z = Significant level of effort tolerable for this study at 0.05 confidence level of 95%

Z = 1.96 (from Z table)

P = Best estimation of prevalence

d = Absolute precision of 5%

xlviii

Prevalence rate of 7% for heart failure8

Where P = 0.07, Z = 1.96, d = 5

(1.96)2 X 0.07 (1.0 – 0.07)

(0.05)2

3.8416 X 0.07 X 0.93

0.05 X 0.05

N = 99 subjects.

Adjustment for loss to follow up assuming an estimate of 10% using the formula below,

Adjustment factor for X% loss = 100/(100-x).

Where x=10.

Therefore, the total sample size X adjustment factor is

= 100x100/89

= 112.3.

At the end of the study, a net total of 110 hypertensive heart failure patients and 110apparently

healthy age and sex matched control subjects without HHF were evaluated having excluded

patients and controls with incomplete data and those lost to follow up

3.5 Sampling methods

A non-probability sampling method by consecutive recruitment of volunteers until the desired

sample size was reached was employed. Certain inclusion and exclusion criteria were used as

a guide in selection.

xlix

3.6 Ethical Consideration and consent

1) Approval of the Ethics and Research Committee of the OAUTHC was sought and obtained

before the commencement of the study (APPENDIX II).

2) Informed consent of the individuals for the study were obtained verbally and in written

form (APPENDIX III).

3.7 Inclusion criteria for patients

1. Patients who gave an informed consent.

2. All male and female individuals with heart failure secondary to hypertension who are 18

years and above and were managed within the hospital were recruited into the study.

3.8 Exclusion criteria for patients

Patients with the following:

1. Unwillingness to participate in the study

2. Infection, specifically presence of fever, productive cough, diarrhoea and urinary

symptoms

3. Pregnancy, use of steroids, immunosuppressive drugs and oral contraceptive pills

because these conditions affect the level of hs-CRP.

4. Malignancy.

5. Use of hypouricaemic medications such as Non-steroidal anti-inflammatory agents,

uricosuric drugs like allopurinol.

6. Clinical evidence of gout.

7. Chronic kidney disease

l

3.9 Inclusion criteria for controls

1. Adults aged 18 years and above without hypertensive heart failure were recruited from

among members of the hospital community and patient’s relations.

2. Healthy adults free of any illness within the previous three weeks.

3.10Exclusion criteria for controls

Apparently healthy controls with the following:

1. Unwillingness to participate in the study

2. Individuals who are hypertensive

3. Infection, specifically presence of fever, productive cough, diarrhoea and urinary

symptoms

4. Pregnancy, use of steroids, immunosuppressive drugs and oral contraceptive pills

because these conditions affect the level of hs-CRP.

5. Malignancy.

6. Use of hypouricaemic medications such as Non-steroidal anti-inflammatory agents,

uricosuric drugs like allopurinol.

7. Clinical evidence of gout.

8. Chronic kidney disease.

3.11 Materials, Equipment and Reagents

Materials

Sample bottles – plain, lithium heparinised, ethylene diamine tetraacetic acid

Needles

Syringes (5ml, 10ml)

Disposable gloves

li

Methylated spirit

Cotton wool

Equipment:

The equipment used for the study include:

- Littmann stethoscope

- Sphygmomanometer (Accuson) with blood pressure cuff 12X15cm

- Chest radiography machine

- 12 lead Electrocardiography (SCHILLER ECG machine)

- Transthoracic echocardiography GE medical system VIVID 7 dimension.

REAGENTS

- Enzyme immunoassay test kits for Hs-CRP and serum uric acid.

3.12 Data collection method

Protocol 1: History and examination

Data was obtained using a proforma (APPENDIX IV) that included demographic data, relevant

history and physical examination after an informed consent was given (APPENDIX III).

Clinical evaluation for diagnosis of HF was performed by the investigator. The following

information was obtained from each of the subjects; age, sex, residential address, telephone

numbers.

The patients were clerked and physically examined in detail by the investigator. Clinical

diagnosis of HF was based on the Framingham’s criteria of the concurrent presence of

two major or one major with two minor criteria44.

lii

The height was measured to the nearest 0.01 metre using a stadiometer. The weights of

the subjects were measured with light clothing on, using a secca scale to the nearest

0.5kgand the BMI calculated by the investigator using the formula: weight

(Kg)/[height(m)]2 . Classification of the weights was defined using the WHO criteria83.

The Pulse was determined at rest by palpating the radial artery with the tip of the fingers

compressing the vessel against the head of the radius, the forearm slightly pronated and

the wrist slightly flexed and counting the pulse for one minute. The rhythm and volume

of the pulse were also noted.

Protocol 2: Blood pressure and anthropometric measurements.

Blood pressure measurement

The blood pressure was measured sitting and standing with a Mercury column

sphygmomanometer after patients and controls were allowed to rest for an average of 5

minutes. Korotkoff phase 1 and 5 were used for systolic and diastolic blood pressure

respectively. Three consecutive measurements were taken at 5 minutes intervals and the

average values were recorded. Hypertension was defined as systolic BP ≥140mmHg and/or

diastolic BP ≥90mmHg or the current use of anti-hypertensive medications82.

The observed readings were classified according to 7th Report of the Joint National Committee

on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII)28.

Table 1: Classification of blood pressure according to JNC VII

BP CLASSIFICATION SYSTOLIC BP( mmHg) DIASTOLIC BP (mmHg)

Normal < 120 and < 80

liii

Prehypertension 120-139 and/or 80-89

Stage 1 Hypertension 140-159 and/or 90-99

Stage 2 Hypertension > or = 160 and/or > or = 100

Protocol 3: Functional Classification and Follow-Up

The functional class of every participant was assessed clinically using the New York Heart

Association Classification31.

NYHA functional classification

CLASS I-No limitation of physical activity. Ordinary physical activity does not cause undue

fatigue, palpitation, or dyspnoea.

CLASS II-Slight limitation of physical activity. Comfortable at rest, but ordinary physical

activity results in fatigue, palpitation, or dyspnoea.

CLASS III-Marked limitation of physical activity. Comfortable at rest, but less than ordinary

activity results in fatigue, palpitation, or dyspnoea.

CLASS IV-Unable to carry on any physical activity without discomfort. Symptoms at rest. If

any physical activity is undertaken, discomfort is increased.

Patients with NYHA classification II to IV were recruited into the study.

Protocol 4: Biomarkers and other test

Each participant had the following tests done: Hs-CRP and serum uric acid.

Biomarkers

liv

Hs-CRP – 5mls of venous blood samples were collected from both subjects and

controls and the samples were centrifuged to separate serum and stored at -40C.

PRINCIPLE: The Hs-CRP ELISA is based on the principle of a solid phase enzyme-

linked immunosorbent assay84. The assay system utilizes a unique monoclonal antibody

directed against a distinct antigenic determinant on the CRP molecule. This mouse

monoclonal anti-CRP antibody is used for solid phase immobilization (on the microtiter

wells).A goat anti-CRP antibody is in the antibody-enzyme (horseradish peroxidase)

conjugate solution. The test sample is allowed to react simultaneously with the two

antibodies, resulting in the CRP molecules being sandwiched between the solid phase

and enzyme-linked antibodies. After a 45-minute incubation at room temperature, the

wells are washed with water to remove unbound labelled antibodies. A

tetramethylbenzidine (TMB) reagent is added and incubated for 20 minutes, resulting

in the development of blue color. The color development is stopped with the addition

of 1N hydrochloric acid changing the color to yellow.

The concentration of CRP is directly proportional to the color intensity of the test

sample. Absorbance is measured spectrophotometrically at 450 nm (APPENDIX VII).

Procedure: Briefly, 10µl of appropriately diluted CRP standard, samples and controls

was dispensed into appropriately labelled microtitre wells shown in APPENDIX V (that

had been brought to room temperature i.e. 20-25oC) after which 100µl of enzyme

conjugate reagent was added, thoroughly mixed for 30 seconds and incubated at 20-

25oC for 45 minutes. The wells were later washed for 5 times with distilled water and

properly dried by striking sharply on absorbent paper. 100µl of tetremethylbenzidine

solution was added to each well, gently mixed for 5 seconds and then incubated at 20-

25oC for 20 minutes. Thereafter, 100µl of 1N hydrochloric acid (stop solution) was

added to each well, gently mixed for 30 seconds to stop the reaction and for the

lv

development of a yellow colour as shown in APPENDIX VI. The optical density of

each well was then determined with a microtitre well reader at 450 nm within

15minutes.

Calculation of results: The standard curve was created by plotting the optical density

values for stock, blank and for each standard on the x-axis against the concentration

(Mg/L) on the y-axis and a best fit curve was drawn through the points on the graph.

Results of subjects in this study were categorized into levels of Hs-CRP<1Mg/L, 1-

3Mg/L and Mg/L and were defined as low, intermediate and high risk according to the

American Heart Association and Center for Disease Control recommendations85,86.

Serum uric acid: This was determined by an enzymatic colorimetric method using an

auto-analyzer after 5mls of venous blood was collected. Mean value of uric acid in

cases was calculated and were compared with the controls. Reference value employed

as normal was 420umol/L for males and 360umol/L for females24. Values greater than

these levels were classified as having hyperuricaemia.

(i)Fasting blood glucose and 2-hour post prandial

After 10-12 hours of overnight fast without alcoholic drink and beverages, venous blood was

obtained from the subjects and analyzed for the fasting blood glucose. A second sample was

collected 2 hours post-prandial for blood sugar measurement. All samples were quickly sent to

Department of Chemical Pathology and analyzed immediately using the glucose oxidase

method. Diabetes mellitus and impaired fasting glucose were diagnosed according to the WHO

criteria87.

(ii) Fasting lipid profile

After 10-12 hours of overnight fast, venous blood was centrifuged and the serum immediately

separated and the concentrations of triglycerides (TG), total cholesterol (TC) and its fractions

lvi

[LDL-C, HDL-C] were analysed. The atherogenic Index of plasma (TC/HDL-C and

LDL/HDL-C) was calculated. The National Cholesterol Education Program Adult Treatment

Panel III (NCEP ATP III) cut off points were used to identify subjects with desirable,

borderline high and high levels of lipoprotein risk factors88.

(iii)Other laboratory tests that were done included packed cell volume for estimation of

anaemia, total white blood cells count and differentials to rule out evidence of infection.

Urinalysis to assess glucose and protein to rule out renal dysfunction. Also, chronic kidney

disease was ruled out with the calculation of the estimated glomerular filtration rate using the

National Kidney Foundation calculator.

Blood samples for serum sodium (Na), potassium (K), urea (U) and creatinine (Cr) were

collected in heparinized bottles and analysed in the Department of chemical pathology using

flame photometer (Na and K), diacetylmonoxime (U) and Jaffe (Picric) method (Cr).

Protocol 5: Imaging studies

12 lead ECG

A conventional resting 12 lead ECG (Schiller AG, Switzerland) with a long rhythm strip of

Lead II was performed in accordance with the American Heart Association (AHA)

recommendation for standardization of leads and specification for instrument89,90. The ECG

paper speed was adjusted to 25mm/mVs and amplitude of 10mm/Mv (APPENDIX X). All

ECGs were recorded in the supine position. The following parameters were analyzed from the

ECG strip;

Heart rate; with normal value considered to be 60 - 100 beats per minute. Values above 100bpm

were considered a tachycardia

lvii

Left ventricular hypertrophy (LVH); with changes in the QRS complex, the ST segment, and

the T wave. Voltage criteria using the Sokolow-Lyon criteria91SV1+ RV5 > 3.5 mV, Gubner

Ungerleider92(SIII + RI > 25 mm), Araoye code system93 (SV2 + RV6 > 35 mm in women or

> 40 mm in men or RI > 12 mm in both sexes), and Cornell’s criteria94 (SV3 + RaVL > 20 mm

in women or > 28 mm in men) were considered.

Echocardiography-

All subjects had 2 Dimensional (2D) derived M-Mode and Doppler (pulsed wave, continuous

wave and colour flow) transthoracic echocardiography with simultaneous ECG recordings

(APPENDIX VIII and APPENDIX IX). The echocardiography was performed according to

standard procedure95 by means of a standard ultrasound machine, GE medical system Vivid 7

dimension instrument with 5 MHz transducer.

Echocardiographic parameters

Left ventricular mass (LVM) was derived using the formula proposed by the American Society

of Echocardiography:

LVM (g)= 1.04[(LVIDd+PWTd+IVSd)3- (LVIDd)3] x0.8+0.6g

Where 1.04 = specific gravity of the myocardium

0.8 = correction factor

The normal LVMI is <100g/m for females and <125g/m for males²96.

LVIDd = left ventricular internal diameter in diastole [in centimeters (cm)]

PWTd = left ventricular posterior wall thickness in diastole (in cm)

lviii

IVSTd = interventricular septal thickness in diastole (in cm)

Relative wall thickness (RWT) was calculated using the formula:

RWT = (IVSTd+PWTd)/LVIDd.

RWT value <0.45 is indicative of normal left ventricular geometry or eccentric hypertrophy,

while a value of 0.45 or above indicates concentric left ventricular hypertrophy or

remodeling97.

Four left ventricular geometric pattern were described in this study: concentric hypertrophy

(elevated LVMI and RWT), concentric remodeling (normal LVMI and elevated RWT),

eccentric hypertrophy (increased LVMI and normal RWT) and normal geometry (normal

LVMI and RWT)96.

Where applicable, measurements were indexed for body surface area (BSA) which was

calculated with the Monsteller formula98:

Square root of [Weight (kg) x Height (cm)/3600]

Left ventricular systolic function

Left ventricular systolic function was determined with the following M-mode measurements

and parameters:

Left Ventricular Ejection Fraction: (LVEDV-LVESV /LVEDV) x 100%

Left Ventricular Fractional Shortening: (LVIDd-LVIDs/LVIDd) x100%

LVEDV-Left Ventricular end-diastolic volume

LVESV-Left Ventricular end-systolic volume

LVIDd-Left Ventricular internal diameter in diastole

lix

LVIDs-Left Ventricular internal diameter in systole

The software of the Teicholz formula was already factory-installed in the echocardiography

machine and automatically calculated the left ventricular volumes in end-diastole and end-

systole:

7/(LVID+2.4) x LVID3 100.

Where LVID = left ventricular internal dimension

The above formulae had been programmed by the automated facilities in the echocardiography

machine.

Stroke volume was gotten by calculating the difference between end diastolic volume (EDV)

and end systolic volume (ESV). Stroke Index(SI) is stroke volume divided by body surface

area, while cardiac output (CO) is stroke volume multiplied by heart rate. Cardiac index (CI)

is cardiac output indexed to body surface area.

Normal reference values for ejection fraction (EF) and fractional shortening (FS) are >50%2and

>20% respectively101.

Ejection fraction assessed for subjects recruited for this study were classified based on the table

below.4

Table 2: Classification of ejection fraction2

Ejection fraction (%) Interpretation

<40 HFrEF

40-49 HFmrEF

>50 HFpEF

lx

3.13 Statistical analysis

The data obtained were analyzed using the software Statistical Programme for Social Sciences

(SPSS) version 21. Data were tabulated in Microsoft excel worksheet and represented using

descriptive statistics such as tables, graphs, pie charts and bar charts. Discrete variables like

age and sex were represented in absolute numbers and percentages. Continuous variables were

presented as mean ± standard deviation or median ± interquartile range. Frequencies and simple

percentages of blood pressure were determined for both male and female subjects and controls.

Hs-CRP and serum uric acid levels were evaluated as dichotomous variables of elevated or not

elevated.

A statistical comparison was made with student t-test for quantitative variables, analysis of

variance for three or more variables and chi-square test for comparison of proportions.

Bivariate analysis was performed using Pearson Correlation Coefficient.

A p-value of less than 0.05 was taken as statistically significant and a confidence interval of

95%.

lxi

CHAPTER FOUR

RESULTS

4.00: Two hundred and twenty subjects participated in the study. Consecutive recruitment of

volunteers was carried out until a total of one hundred and ten (110) patients with HHF and

110apparently healthy age and sex matched controls were obtained to complete the study.

4.01.1: Sociodemographic characteristics of the Study population

The sociodemographic characteristics of the study population are summarised in table 3. The

hypertensive heart failure patients were matched for age and sex with their apparently healthy

controls counterparts. Each group comprised of 55 males and 55 females. The mean age of

both groups (HHF group, 58.05 ±10.75 vs control group 56.46±10.01, p =0.052) did not show

a significant statistical difference. Patients with HHF had no significantly lower mean body

weight compared to the controls (p = 0.003). There was also no significant difference in mean

height among the two groups (p =0.139).The mean BMI of the HHF patients compared with

the control group also did not show any statistically significant difference (p=0.369). Heart rate

at rest, systolic blood pressure and diastolic blood pressure were significantly higher in the

HHF group than the control groups (p < 0.001 in all cases).

lxii

Table 3: Demographic characteristics of the study population

Parameters HHF group

(mean±SD)

Control group

(mean±SD)

p value

Age (years) 58.05±10.75 56.46±10.01 0.052

Gender

Male

Female

55(50)

55(50)

55(50)

55(50)

1.000

Weight (Kg) 63.09±8.23 68.78±6.45 0.003

Height (m2) 1.65±0.05 1.68±0.67 0.139

BMI (Kg/m2) 23.12±2.96 24.20±2.92 0.369

BSA 1.73±0.15 1.78±0.11 0.256

PR (bpm) 96.65±12.54 80.74±10.48 <0.001

SBP (mmHg) 141.22±24.07 114.00±9.11 <0.001

DBP (mmHg) 88.85±14.81 75.65±7.54 <0.001

PP (mmHg)

50.87±15.12

37.65±9.39 <0.001

lxiii

KEY: BMI= Body mass Index; BSA= Body surface area, HR= Heart rate at rest; SBP=

Systolic blood pressure at rest; DBP= Diastolic blood pressure at rest. HTN=Hypertension

FIGURE. 4.1 BAR CHART SHOWING FREQUENCY DISTRIBUTION OF PATIENTS

AND CONTROLS

lxiv

This chart showed that the highest percentage of the HHF patients and the controls were in

the age group 50 – 59 years and the lowest percentage were those in the age group 30 -39

years.

4.01 Medical History and Treatment offered to HHF subjects

The table below shows the medical history and treatment offered to patients with hypertensive

heart failure. The percent of HHF patients on furosemide, spironolactone, digitalis, ACEi/ARB

and beta-blockers were 53.7%, 57.9%, 31.6%, 52.1% and 27.9% respectively. Twenty four

(21.8%) and 21(19.1%) gave a history of cigarette smoking and alcohol consumption

respectively.

Table 4: Summary of the medical history and treatment offered to HHF subjects.

Frequency Percent

Treatment

Furosemide 102 92.7

Spironolactone 110 100

Digitalis 60 54.5

ACEi/ARB 99 90

Beta-blockers 53 48.2

lxv

Medical History

Cigarette smoking 24 21.8

Alcoholic intake 21 19.1

KEY: ACEi= Angiotensin Converting enzyme inhibitor; ARB= Angiotensinogen Receptor

Blocker

4.02 FREQUENCY OF PATIENTS ACROSS NYHA FUNCTIONAL CLASS

The NYHA functional classes of the HHF patients were as follow: 50 patients (45.5%) were in

NYHA class II, 43 patients (39.1%) were in NYHA class III and 17 patients (15.4%) were in

NYHA class IV. These were represented in the pie chart below.

lxvi

FIGURE 4.2 PIE DIAGRAM ILLUSTRATING FREQUENCY OF PATIENTS IN EACH

NYHA CLASS

4.03.01Result of the biomarkers of the study population

Table 5 shows the laboratory findings of the study population. The median of the serum

levels of high sensitive C-reactive protein (Hs-CRP) (5.3(8.8) vs 0.8(0.7) Mg/L, p<0.001)

and the mean serum uric acid(SUA)(485.54±114.95 vs 232.43±95.19 umol/l, p<0.001)in

the HHF patients were significantly elevated compared with that of controls (p <0.001).

lxvii

Table 5: Biomarkers result of the study population.

PARAMETERS Cases

(mean±SD)

Control

(mean±SD)

p value

Hs-CRP(Mg/L)

All* 5(8.4) 0.8(0.6) <0.001

Males* 5.3(8.8) 0.8(0.7) <0.001

Females* 5.0(7.8) 0.8(0.5) <0.001

SUA(umol/l)

All 485.54±114.95 232.43±95.19 <0.001

Males 501.72±116.56 231.19±87.93 <0.001

Females 467.50±111.53 234.12±105.57 <0.001

KEY:Hs-CRP= High sensitive C-reactive protein, SUA= Serum uric acid.

*= median ± interquartile range

lxviii

Figure 4.3: Bar chart showing the Hs-CRP levels of the study population.

This chart showed that a higher percentage of HHF patients had Hs-CRP levels greater than 3

Mg/L and a higher percentage of the control subjects had Hs-CRP levels lower than 1 Mg/L

while the percentage of HHF patients and the controls with Hs-CRP levels between 1 and 3

Mg/L was below 20%.

lxix

Figure 4.4: Bar chart showing the serum uric acid levels of the study population.

This chart showed that a high percentage of the HHF patients recorded elevation in their

serum uric acid levels while a high percentage of the control subjects showed no elevation in

the serum uric acid levels.

4.03.02 Other biochemical parameters

lxx

The mean total cholesterol (TC) and low density lipoproteins (LDL) were elevated in the

HHF group compared to the control group. The difference was statistically significant

(p<0.001). High density lipoproteins (HDL) and triglyceride (TG) were lower in the HHF

group and the difference was statistically significant (p<0.001).

PCV of the population was not statistically significantly lower in the HHF group when

compared to the control group (37.04±5.87 vs 37.96±2.89%, p=0.051). In addition, HHF

group had no statistically significant lower serum sodium compared with the controls

(134.71±4.82 vs 136.67±4.26mmol/l, p=0.020). The serum potassium, chloride,

bicarbonate, creatinine and urea were all significantly higher in the HHF group compared

with the controls (p< 0.001 respectively). These are as shown in table 6.

Table 6: Laboratory findings of the study population.

lxxi

PARAMETERS Cases

(mean±SD)

Control

(mean±SD)

p value

FBS(mmol/l) 4.96±2.32 4.84±0.75 <0.001

2HPP(mmol/l) 6.43±1.14 6.56±1.40 <0.001

TC(mmol/l) 5.09±1.49 4.84±0.75 <0.001

HDL(mmol/l) 0.92±0.67 1.13±0.39 <0.001

LDL(mmol/l) 3.13±0.10 1.81±0.14 <0.001

TG(mmol/l) 1.36±1.70 1.88±0.45 <0.001

PCV(%) 37.04±5.87 37.96±2.89 0.051

WBC(cm) 6031.13±1778.43 6542.22±1711.76 <0.001

Creatinine(mmol/l) 106.05±21.06 110.81±23.78 <0.001

Urea(mmol/l) 8.12±2.44 5.77±2.88 <0.001

Sodium(mmol/l) 134.71±4.82 136.67±4.26 0.020

Potassium(mmol/l)

eGFR(mi/min/1.76m2)

4.01±0.47

85.41±22.50

4.18±0.67

102.32±34.3

0.018

<0.001

KEY:Hs-CRP= TC=Total Cholesterol, HDL= High density lipoprotein, LDL= Low density

lipoprotein, TG= Triglyceride, PCV= Pack cell volume, WBC= White blood cell, %=

Percentage, eGFR=estimated glomerular filtration rate.

4.04 Echocardiographic findings of the Study population

lxxii

Table 7 shows the two dimensional and M-mode parameters of the study population. The

mean left atrial dimension (LAD), aortic root dimension (AOD), right ventricular diastolic

diameter (RVD), left ventricular internal diameter in systole and left ventricular internal

diameter in diastole (LVIDD) were statistically significantly elevated in the HHF patients

compared with their control counterparts(p<0.001).

The mean inter-ventricular septum thickness (IVST), left ventricular posterior wall

(LVPWT), relative wall thickness (RWT) and left ventricular mass (LVM) as well as its

index were all significantly higher in the HHF group compared to the control group.

Table 7: Two-dimensional and M-mode echocardiographic parameters of the study

population.

lxxiii

Parameters HHF group

(mean±SD)

Control group

(mean±SD)

p value

LAD (cm) 3.09±0.49 2.85±1.15 <0.001

LADi (cm/m2) 2.44±0.43 2.03±0.41 0.090

AOD (cm) 1.91±0.31 1.64±0.38 <0.001

AODi (cm/m2) 1.68±0.52 1.58±0.62 0.081

IVST (cm) 1.14±0.19 0.90±0.26 <0.001

LVPWT (cm) 1.19±0.15 0.95±0.14 <0.001

RVID (cm) 2.54±2.36 1.64±0.37 <0.001

RVIDi (cm/m2) 1.14±0.78 0.93±0.25 0.257

LVIDD (cm) 5.74±1.17 3.87±1.04 <0.001

LVIDDi (cm/m2) 3.22±5.29 2.17±0.61 0.051

LVIDS (cm) 4.53±1.29 3.02±0.51 <0.001

LVIDSi (cm/m2) 2.24±0.79 1.68±0.0.32 0.103

LVM (grams) 173.32±19.79 171.51±17.95 <0.001

LVMi (grams/m2) 102.42±42.03 96.46±13.18 0.034

RWT 0.42±0.11 0.39±0.05 0.009

KEY: LAD=left atrial diameter; AOD=Aortic root diameter; IVSD=interventricular septal

thickness in diastole; LVPWD=left ventricular posterior wall thickness in diastole;

LVPWT=left ventricular posterior wall thickness in systole; RVID=right ventricular internal

dimension ;LVIDD=left ventricular internal dimension in diastole; LVIDS=left ventricular

internal dimension in systole; LVM=left ventricular mass; RWT=relative wall thickness, [‘I’,

where seen as suffix, represents that parameter indexed for body surface area]

4.05: Left ventricular systolic function parameters of the study population.

lxxiv

Table 8 shows the left ventricular systolic parameters of the study population. The mean left

ventricular ejection fraction (39.48±16.46 vs 62.70±10.81%, p<0.001) and the fractional

shortening (19.25±8.64 vs 29.57±5.15%, p<0.001) were significantly lower in the HHF group

compared with the control group.

The stroke volume was statistically significant in the HHF group compared with the control

(p<0.001) while the in-between group difference in cardiac output was not statistically

significant.

Table 8: Left ventricular systolic function parameters of the study population.

Parameters HHF group

(mean±SD)

Controls

(mean±SD)

p value

SV (ml) 76.55±24.12 87.92±19.29 <0.001

SI (ml/m2) 44.49±13.73 49.40±11.84 0.426

CO (Litres) 6.60±1.8 6.97±1.39 0.145

CI (Litres/m2) 5.81±20.35 3.91±0.83 0.450

LVEF (%) 39.48±16.46 62.70±10.81 <0.001

LVFS (%) 19.25±8.64 29.57±5.15 <0.001

KEY: HTN= hypertension, SV= Stroke volume; CO= Cardiac output; LVEF= Left

ventricular ejection fraction;CI=Cardiac index;LVFS= Left ventricular fractional

shortening, SI= Stroke Index.

4.06 Classification of the left ventricular ejection fraction of the study population.

lxxv

Table 9 below summarized the categories of the ejection fraction of the study population.

66.4% of the HHF group recorded ejection fraction less than 40% and none among the control

group. 8.2% of the HHF group had ejection fraction between 40 to 49% and 25.5% had EF

greater than 50%. 5.5% of the control group recorded ejection fraction between 40 and 49%

while 94.5% of the controls had ejection fraction greater than 50%. The ejection fraction was

statistically significantly higher in the HHF group compared with their control group.

Table 9: Classification of the left ventricular ejection fraction.

Ejection fraction (%) HHF group Control group p value

<40 73(66.4) 0 <0.001

40-49 9(8.2) 6(5.5)

>50 28(25.5) 104(94.5)

Total 110 110

4.07 Doppler echocardiographic findings of the study population.

lxxvi

Table 10 shows the Doppler echocardiographic findings of the study population. There was a

statistically significant difference between the two groups in all the parameters recorded. Early

transmitral inflow velocity (MV E vel.) and Isovolumic relaxation time (IVRT) and early

transtricuspid inflow velocity (TV E vel.)were significantly lower in the HHF group than the

control group while the late transmitral inflow velocity (MV A vel.), the ratio of early to late

transmitral inflow velocity (MV E/A), deceleration time (DT), late transtricuspid inflow

velocity (TV A vel.) and the ratio of early to late transtricuspid inflow velocity were

significantly higher in the HHF group than the control group.

The difference in the percentage of subjects in the HHF group who had mitral regurgitation

(MR), tricuspid regurgitation (TR), aortic regurgitation(AR) and pulmonary regurgitation (PR)

compared with the control group was statistically significant (p<0.001).

Table 10: Doppler echocardiographic findings of the study population.

lxxvii

Parameters HHF group Controls p value

MV E vel.(m/s) 0.81±0.28 0.85±0.00 <0.001

MV A vel.(m/s) 0.87±3.58 0.62±0.00 <0.001

MV E/A 1.69±0.94 1.38±0.11 <0.001

Dec. T (ms) 193±18 174.63±15.38 <0.001

IVRT (ms) 79.32±33.52 80.76±12.16 <0.001

TV E vel.(m/s) 0.54±0.19 0.74±0.16 <0.001

TV A vel. (m/s) 0.45±0.16 0.38±0.78 0.008

TV E/A 1.34±0.66 1.25±0.21 <0.001

MR n(%) 75(68.2) 3(3.8) <0.001

TR n(%)

AR n(%)

59(53.6)

33(30.0)

0

0

<0.001

<0.001

PR n(%) 44(40.0) 8(10.0) <0.001

KEY:; MV E vel= early transmitral inflow velocity; MV A vel= late transmitral inflow

velocity; MVE/A= ratio of early to late transmitral inflow velocity; Dec Time= early

transmitral flow velocity; DT= deceleration time; IVRT= Isovolumic relaxation time.TV

Evel= early transtricuspid inflow velocity; TV Avel= late transtricuspid inflow velocity; TV

E/A=ratio of early to late transtricuspid inflow velocity: MR=Mitral regurgitation; TR=

Tricuspid regurgitation; AR= Aortic regurgitation; PR= Pulmonary regurgitation.

4.08 Left ventricular geometry of the study population.

lxxviii

There was a statistically significant difference in the left ventricular geometrical pattern

between the HHF group and the control group. The percentage in the HHF group presenting

with left ventricular eccentric hypertrophy, left ventricular concentric hypertrophy and left

ventricular concentric remodeling were 69.1%, 24.5% and 6.4% respectively. The control

group with normal geometry was 91.1% while 9.9% had left concentric hypertrophy.

Table 11: Left ventricular geometry of the study population.

HHF group Control group p value

Normal - 101(91.1)

LV conc. Hypert. 27(24.5) 9(9.9) <0.001

LV conc. Remodel. 7(6.4) -

LV eccent. Hypert. 76(69.1) -

KEY: LV conc. Hypertrophy=Left ventricular hypertrophy, LV conc. Remodel.= Left

ventricular remodeling, LV eccent. Hypert.=Left eccentric hypertrophy. HHF=Hypertensive

Heart Failure.

4.0912-lead ECG pattern of the study population.

lxxix

The table shows the ECG pattern of the study population. The heart rate was increased in the

HHF group compared to the control population (97.03±16.71 vs 83.88±11.57 bpm). The

difference was statistically significantly (p<0.001).

Sinus rhythm was recorded in 48(44.5%) of the HHF group compared to 68(85%) of the control

group. Sub analysis of the rhythm abnormalities shows sinus tachycardia was present in 38.2%

and 3.8% in the HHF group and control group respectively. Sinus bradycardia was present in

3.6% and 3.8% in the HHF and control groups respectively.

Sub analysis of the supraventricular arrhythmias showed that 7.3% of the supraventricular

arrhythmias in the HHF group due to atrial fibrillation while PACs were seen in 1.8%.

Premature ventricular complexes (PVC) were recorded in 11(10%) and 2(2.5%) in the HHF

and control groups respectively (p=0.043).

1st degree AV block was recorded in 6.4% of the HHF group and 1.3% of the control group.

Only the HHF group recorded 2nd degree AV block in 1.8%. Complete AV block was seen in

3.6% of the HHF group alone.

LBBB and RBBB pattern were recorded in 7.3% and 1.8% in the HHF group respectively.

None was present in the control group.

LVH by voltage criteria was observed in 85.5% of the HHF group and 2.5% of the control

group and this finding was statistically significant among the groups (P <0.001).

Table 12: 12-lead ECG pattern of the study population.

lxxx

Parameters HHF group Control group P value

HR(B/M) 97.03±16.71 83.88±11.57 <0.001

Heart rhythm(%)

Sinus rhythm 48(45.5) 68(85.0) <0.001

Sinus tachy 42(38.2) 3(3.8) <0.001

Sinus brady 4(3.6) 3(3.8) 0.967

Svent arrhyth n(%)

PAC 2(1.8) 1(1.3) 0.756

AF 8(7.3) 1(1.3) <0.001

Vent arrhythn(%)

PVC 11(10.0) 2(2.5) 0.043

AV Block(%)

1st degree 7(6.4) 1(1.3) 0.216

2nd degree 2(1.8) 0(0) 0.225

Complete AV Block 4(3.6) 0(0) 0.085

Conduction block

LBBB n(%) 8(7.3) 0(0) 0.014

RBBB n (%) 2(1.8) 0(0) 0.225

LVH n(%) 94(85.5) 2(2.5) <0.001

KEY: HR=Heart rate; Sinus Brady=Sinus bradycardia; Sinus Tachy=Sinus tachycardia;

Svent Arrhyt= Supraventricular arrhythmias; Vent Arrhyt=Ventricular arrhythmias;

PAC=Premature atrial complex; AF=Atrial fibrillation; PVC=Premature ventricular

complex; AV block= Atrioventricular block; RBBB=Right bundle branch block; LBBB=Left

bundle branch block; LVH=Left ventricular hypertrophy.

4.10 Left ventricular diastolic function of the study population.

lxxxi

As seen in table 13, normal diastolic function was observed only in the control group. Grade

1 diastolic dysfunction was present in 46(41.8%) and 5(6.3%) in the HHF and control groups

respectively. Grade 2 diastolic dysfunction 6(5.5%) was seen only in the HHF group.

Restrictive pattern was seen in 58(52.7%) of the HHF group alone.

Table 13: Summary of the Doppler echocardiography assessment of the left ventricular

diastolic function of the study population.

HHF group Controls group p value

Normal 0 105(93.7) <0.001

Grade 1 LV diast.

Fxn

46(41.8) 5(6.3) <0.001

Grade 2 LV diast.

Fxn

6(5.5) 0 0.137

Restrictive

Total

58(52.7)

110

0

110

<0.001

KEY:LV diast. Fxn=Left ventricular diastolic function.

4.11 Relationship between the biomarkers and the NYHA functional classification in

HHF subjects.

lxxxii

One way analysis of variance (ANOVA) in the relationship between the baseline measurements

of biomarkers (Hs-CRP and serum uric acid) and the NYHA functional classification in the

HHF patients.

The median levels of the Hs-CRP in the HHF patients in NYHA class II, NYHA class III and

NYHA class IV were 3.0(4.0) Mg/L, 8(7.3 Mg/L and 10(21.1) Mg/L respectively. The

difference was statistically significant (p<0.001).

The levels of the mean SUA in patients with HHF in NYHA class II, NYHA class III and

NYHA class IV were422.80±92.00umol/l, 526.74±97.46umol/l and 565.88±124.25mmol/l.

The difference was statistically significant (p<0.001).

There was a further in-between analysis of the HHF patients with elevated Hs-CRP and SUA

in NYHA class II, class III and class IV. The result showed there was a statistically significant

relationship among the three groups (p<0.001) of HHF patients with elevated Hs-CRP and

SUA. These are as shown in table 14.

Table 14: Relationship between the biomarkers and the NYHA functional classifications

in HHF subjects.

NYHA functional class p value

lxxxiii

Class II Class III Class IV

mean±SD mean±SD mean±SD

1Hs-

CRP(Mg/L)*

3(4.0)a 8(7.3)b 10(21.1)c <0.001

2SUA(umol/l) 422.80±92.00a 526.74±97.46b 565.88±124.25c <0.001

KEY: NYHA=New York Heart Association, EF=Ejection fraction, Hs-CRP= High sensitive C-reactive protein, SUA= serum uric acid.

*= median ± interquartile range

1. Post Hoc . Bonferroni significance across the NYHA functional classes are significant.

2. Post Hoc . Bonferroni significance across the NYHA functional classes are significant.

4.12 Relationship between the biomarkers and the LVEF in HHF subjects.

One-way analysis of variance (ANOVA) in the relationship between the left ventricular

ejection fraction and the biomarkers (HS-CRP and serum uric acid) of the HHF patients.

lxxxiv

The median levels of Hs-CRP in patients with HHF in HFrEF (<40%), HFmrEF (40-41%) and

HFpEF (>50%) were 8.0(7.8) Mg/L, 3.5(8.0) Mg/L and 3.0(4.0) Mg/L respectively. The

difference was statistically significant (p<0.001).

The levels of the mean SUA in HHF patients in HFrEF, HFmrEF and HFpEF were

520.13±107.7umol/l, 421.11±57.91umol/l and 416.07±108.40mmol/l. The difference between

the three groups showed a statistical significant (p<0.001).

Further in-between analysis of the three groups of HHF patients with elevated Hs-CRP and

SUA. The groups are HHF patients with HFrEF, HFmrEF and HFpEF. The result revealed that

there was a statistically significant relationship between the group of patients with HFrEF and

the other two groups with HFmrEF and HFpEF (p <0.001). There was no statistically

significant relationship between patients with HFmrEF and HFpEF (p=1.000). The result was

similar in both HHF patients with elevated Hs-CRP and SUA. This is as shown in table 15.

Table 15: Relationship between the biomarkers and the left ventricular ejection fraction

in the HHF subjects.

Ejection fraction p value

<40% 40-49% >50%

lxxxv

mean±SD mean±SD mean±SD

1Hs-

CRP(Mg/L)*

8.0(7.8)a 3.5(8.0)b 3.0(4.0)c <0.001

2SUA(umol/l) 520.13±107.77a421.11±57.91b 416.07±108.40c <0.001

KEY: NYHA=New York Heart Association, EF=Ejection fraction, Hs-CRP= High sensitive C-reactive protein, SUA= serum uric acid.

*= median ± interquartile range

1. Post Hoc Bonferroni significance in HFrEF shows significance when compared with HFmrEF and HFpEF while the relationship between HFmrEF and HFpEF were not significant.

2. Post Hoc Bonferroni significance in HFrEF shows significance when compared with

HFmrEF and HFpEF while the relationship between HFmrEF and HFpEF were not

significant.

4.13 Bivariate correlational analysis between the biomarkers and the New York Heart

Association functional class of the HHF patients.

Bivariate analysis showing relationship between the biomarkers and the New York Heart

Association functional class. As seen in Figure 4.5 and 4.6, there is a positive relationship

between Hs-CRP and serum uric acid levels and the New York Heart Association functional

lxxxvi

class. There is a worsening of the New York Heart Association functional class as the levels

of the biomarkers increases.

There is a positive correlation between the biomarkers (Hs-CRP r 0.339 and serum uric acid r

0.247 and the New York Heart Association functional class . The relationship between the

two biomarkers and the New York Heart Association functional class was statistically

significant, p <0.001.

lxxxvii

Figure 4.5 Scatterplot showing the relationship between Hs-CRP and NYHA functional

class of the HHF patients.

There was a positive relationship between Hs-CRP and NYHA functional class of the HHF

patients

lxxxviii

Figure 4.6 Scatterplot showing the relationship between uric acid and the NYHA functional

class of the HHF patients.

There was a positive relationship between uric acid and NYHA functional class of the HHF

patients.

4.14 Bivariate correlational analysis between the biomarkers and the left ventricular

ejection fraction of the HHF patient.

lxxxix

Pearson’s correlation showing the relationship between the biomarkers and the left

ventricular ejection fraction. There is an inverse relationship between the biomarkers of

inflammation and the left ventricular ejection fraction of the HHF patients.

There is a negative correlation between the biomarkers (Hs-CRP r -0.129 and serum uric acid

level r -0.124) and the left ejection fraction. The relationship between the two biomarkers was

statistically significant with the left ventricualar ejection (p <0.001). These are as shown in

figure 4.7 and 4.8.

xc

Figure 4.7 Scatterplot showing the relationship between Hs-CRP and the left ventricular

ejection fraction of the HHF patients.

There was an inverse relationship between Hs-CRP and the left ventricular ejection fraction

of the HHF patients.

xci

Figure 4.8 Scatterplot showing the relationship between uric acid and the left ventricular

ejection fraction of the HHF patients.

There was an inverse relationship between uric acid and the left ventricular ejection fraction

of the HHF patients.

CHAPTER FIVE

xcii

DISCUSSION

The study of correlation between Hs-CRP and serum uric acid levels in hypertensive heart

failure patients involved 110 subjects diagnosed HHF and 110 apparently healthy age and sex

matched controls.

5.01 DEMOGRAPHIC DATA OF THE STUDY POPULATION

AGE AND GENDER DISTRIBUTION

The mean age of the patients with HHF was 58.05±10.75 years which is similar to findings

obtained in other studies from centres within the country3,9,10,14. The mean age of the control

group was 56.46±10.01years. The mean age of HF patients in this study is comparable to the

mean age of HF patients in other African countries as reported by Damasceno and colleagues

(52.3±18.3 years)7. This however contrasts with the mean age of HF patients in some other

countries. The mean age in United States of America, Europe and Asia are 75 years, 69.9

years and 67.3 years respectively105-107.

Studies have shown that cardiovascular disease including HF occurs at an earlier age in the

developing countries than the developed world.This finding may be attributable to both the

earlier occurrence of cardiovascular events and inadequate facilities required for the care of

these patients in developing countries. Furthermore, hypertension as aetiology of HF occurs

earlier in the developing countries107.

The genders of the HHF and control groups were made up of 55 males and 55 females.

5.02 PHYSICAL CHARACTERISTICS OF THE STUDY POPULATION

xciii

5.02.01 BODY WEIGHT AND BODY MASS INDEX

The patients in the HHF group had a significantly lower body weight compared to the control

group. The lower body weight in the HHF group can probably be explained by the severity of

the CHF which contributes to cardiac cachexia. The underlying mechanisms are multi-

factorial and include an increased resting metabolic rate, release of cytokines such as Tumour

Necrosis Factor (TNF), Interleukin-1 (IL-1) Interleukin-6 (IL-6), and Interleukin-10 (IL-10),

early satiety from congestive hepatomegaly, abdominal fullness, reduced absorption of

nutrients due to congestion of the intestinal veins and anorexia108.

The height and body mass index were not statistically significant. The mean BMI in patients

in this study is in conformity with a finding obtained in an African study7. A study on obesity

paradox in Nigerians revealed HF patients with higher BMI had less severe presentation of

HF compared to patients with normal BMI109.

5.02.02 BIOCHEMICAL PARAMETERS:

The PCV was slightly lower in the patients with HHF compared with the control subjects,

although there was no statistically significant difference between the two groups (P =0.051).

This observation conforms with previous findings on the impact of anaemia on HF110,111.

Familoni and colleagues reported anaemia as one of the contributory factors to poor outcome

in Nigerian patients with advanced heart failure109. This was collaborated by Ogah and

colleagues who reported a low PCV in the registry obtained among HHF patients110. Anaemia

in Heart failure might be attributed to the effect of malnutrition as a result of chronic nature of

the illness110.

Serum creatinine was significantly elevated and eGFR lower in patients with HHF compared

with the control counterparts, the difference was statistically significant (P<0.001). Mild renal

impairment is a common finding in HF and also confers increased mortality risk112.Impairment

xciv

in renal function in HF occurs as a result of chronic hypoperfusion of the kidneys leading to

renal ischaemia and a reduction of GFR113. The concentration of serum sodium and potassium

were lower in the HHF group compared with the control counterparts. However, this difference

did not attain statistical significance at (P=0.020) and (p=0.018) respectively. The lower

sodium level has been shown to increase mortality in the heart failure population 114-116.

Hyponatremia in heart failure is due to inappropriate vasopressin activity despite

hypoosmolality and volume overload as well as use of diuretic treatment. Hyponatraemia has

been shown to be contributory to intra-hospital mortality among CHF patients117.

The total cholesterol and LDL were significantly higher among the HHF group compared with

the control group while the HDL and TG were lower in the HHF group. The difference was

statistically significant (P <0.001). The high cholesterol in this study is comparable to findings

obtained in other works among Nigerian patients with HHF16,110.111.

5.03 PULSE RATE, BLOOD PRESSURE, PULSE PRESSURE AND CARDIAC

OUTPUT: In the study, the pulse rate, systolic blood pressure, diastolic blood pressure and

pulse pressure were elevated more in the HHF group compared to the control group. This

increase was statistically significant (p<0.001). The significantly elevated pulse rate and BP

measurements in the HHF patients compares favourably to previous studies10,12,35,111. The

average heart rate among the HHF patients was 96.65±12.54 bpm, SBP was 141.22±24.07

mmHg and DBP was 88.35±14.81mmHg which is comparable with findings reported by Ogah

and colleagues. These findings also collaborated with the study by Ojji and colleagues in a

HHF registry16.

5.04 2-D AND 2-D DERIVED M-MODE ECHOCARDIOGRAPHIC PARAMETERS:

This study found a significantly higher LAD, LVIDD, LVIDS, IVSD and LVPWD among the

HHF patients compared with the controls. These findings compared favourably with reports

xcv

from the Heart Failure Registry in Abeokuta where 320 patients admitted with CHF were

consecutively studied110. The study revealed a significant difference in the 2-D and M-mode

echocardiographic parameters among HHF patients and their apparently healthy controls111. In

this study, LVM and LVMi were significantly increased in the HHF patients than their

apparently healthy controls.

The geometry of the HHF patients showed left ventricular eccentric hypertrophy was present

in 69.1% cases. Patients who had left ventricular concentric hypertrophy were 24.5% while

6.4% had left ventricular eccentric hypertrophy. This observation compares well with other

previous studies110,111,118.

5.05 SERUM Hs-CRP AND URIC ACID LEVELS OF THE STUDY POPULATION.

In this study the levels of both Hs-CRP and SUA in HHF patients were significantly elevated

compared with the control subjects. The increase in both Hs-CRP and uric acid levels can be

associated with increased degree of inflammation in CHF. This finding compares favourably

with previous studies 53,54,118. The increase in baseline measurement of Hs-CRP and serum uric

acid in this study showed that both biomarkers are associated with myocardial dysfunction in

patients with heart failure. In ASCEND-HF trial, elevation in baseline measurement of Hs-

CRP were associated with worsening progression of HF119. The Framingham Heart Study

demonstrated that participants with CRP serum levels of ≥5 mg/L experienced a significantly

increased risk of heart failure120. Limitation in that study was by the use of a low-sensitivity

CRP assay. Finally, in the Health ABC study, high levels of CRP independently predicted the

incidence of events of heart failure121. Leyva and colleagues reported in a study that increased

mean serum uric acid level was strongly related to severity of HF123. Elevated uric acid causes

increased xanthine oxidase activity in response to inflammation that contribute to the severity

of CHF56, 58.

xcvi

5.06 RELATIONSHIP BETWEEN BIOMARKERS AND THE NYHA FUNCTIONAL

CLASS

The study showed a significant relationship between the Hs-CRP and uric acid levels on the

one hand and the NYHC functional classification of the study population (p<0.001). In this

study, the levels of the biomarkers (Hs-CRP and uric acid) increased proportionately as the

NYHA functional classification worsened from class II to class IV. This can be due to the

higher degree of inflammation with the increased severity of CHF. The observation in this

study is comparable with similar studies on relationship between NYHA functional

classifications and each of the biomarkers (Hs-CRP 118,122,123and uric acid 56,57) done separately.

Hs-CRP has many pathophysiologic roles in the inflammatory process. It can amplify the

inflammatory response through complement activation, which may cause myocardial cell

apoptosis and thus ventricular damage or dysfunction. Also, at concentrations known to predict

adverse vascular events, it directly quenches the production of nitric oxide, which, in turn,

inhibits angiogenesis, an important compensatory mechanism in chronic ischemia. In doing so,

Hs-CRP may facilitate the development and worsening of CHF. Other proinflammatory effects

of Hs-CRP include the induction of inflammatory cytokines and tissue factor in monocytes and

a direct proinflammatory effect on human endothelial cells118. Karaye and colleagues reported

that increased morbidity and mortality in HF patients were observed more in those with higher

NYHA functional classifications12. This was similarly observed in the study by Ahmed and

colleagues where HF patients with NYHA class III and IV presented with increased disease

severity124.

Relationship in between the NYHA functional classes and the two biomarkers also showed

significant relationship (p<0.001). The biomarkers are significantly elevated in each of the

NYHA functional classification and tend to worsen as the class increases. The observation is

xcvii

similar to other previous works on biomarkers in HF 56, 124. The levels of the biomarkers are

more significantly elevated as the NYHA functional class increase. This increase is related to

increased inflammatory changes as the myocardial dysfunction worsened.

This study showed a positive correlation between Hs-CRP and uric acid and the NYHA

functional class among HHF patients. This finding compares favourably with previous studies

54,56,119. Anker and colleagues demonstrated that SUA positively correlated with HF and was

associated with increased myocardial dysfunction124. Alonso-Martinez and colleagues also

observed that Hs-CRP levels were significantly increased with the severity of CHF and were

correlating with NYHA functional class and that higher levels were associated with an

increased disease severity54.

5.07 RELATIONSHIP BETWEEN BIOMARKERS AND THE EJECTION FRACTION

In this study HHF patients with HFrEF were 66.4% at presentation. HHF patients who had

HFmrEF were 8.2% while those with HFpEF were 25.5%. The predominance of HFrEF in this

study is comparable to previous works obtained in other centers in Nigeria3,12,16,110. The

predominance of HFrEF may be related to hypertension as a cause of heart failure which the

study is centered upon. Also, the finding corroborates epidemiologically with research works

obtained in other centers within the country3,12,16.

This study also showed a progressive decrease in the ejection fraction with increasing

biomarkers values which relate to worsening disease severity. It reveals an inverse relationship

between the two biomarkers (Hs-CRP and uric acid) and LVEF. The levels of the biomarkers

were significantly elevated in patients with HFrEF when compared with HFmrEF and HFpEF.

This observation is in conformity with similar studies in the United States of America, Europe

and Asia where Hs-CRP and SUA were found to be significant in HF patients who had LVEF

less than 40% 54,123,125,126. HFrEF have been shown to contribute poorly to disease severity in

xcviii

HHF 12,16,111. The increase in the biomarkers at reduced LVEF in HF is associated with

worsening inflammatory process. Karaye and colleagues found that among factors which

contributed poorly to the outcome of CHF patients was the identification of low ejection less

than 40%12.

There was a negative correlation between the biomarkers and the ejection fraction of the

patients with the HHF in this study. This observation is comparable with similar research works

on Hs-CRP and SUA54,56,58,119. Alonso-Martinez and colleagues reported a significant

relationship between Hs-CRP and LVEF58. This was corroborated by Hirochi and colleagues

who showed a negative correlation between serum uric acid and LVEF58. The

pathophysiological process of serum uric acid to increase disease severity in HF is related to

the increase xanthine oxidase activity. This contributes to more oxidative stress and

inflammation58.

xcix

CHAPTER SIX

CONCLUSIONS

1. Hs-CRP and serum uric acid are elevated in patients with hypertensive heart failure.

2. There is a proportionate increase in the biomarkers as the NYHA functional

classifications of the HHF patients worsen.

3. There is a significant relationship between the biomarkers and left ventricular ejection

fraction of the HHF patients.

RECOMMENDATION

The recommendations are as follow.

1. Routine request of Hs-CRP and serum uric acid to provide further insight into the role

of inflammation among patients with HHF.

2. A larger prospective trial would be needed to assess the impact of elevated Hs-CRP

and serum uric acid in predicting the disease severity in HHF patients.

LIMITATIONS

A higher sample size of each study group may have brought out more statistically relevant

relationship among the parameters that were otherwise not significant.

REFERENCES

c

1. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al.

ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur

Heart J. 2012; 33:1787-847.

2. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Caots AJ, et al. 2016

European Society of Cardiology Guideline for the diagnosis and treatment of acute and

chronic heart failure. Eur Heart J. 2016; 37(27):2129-2200.

3. Adebayo AK, Adebiyi AA, Oladapo OO, Ogah OS, Aje A, Ojji DB, et al.

Characterisation of heart failure with normal ejection fraction in a tertiary hospital in

Nigeria. BMC Cardiovascular Disorders. 2009; 9: 52-57.

4. Zile MR, Gaasch WH, Carroll JD, Feldman MD, Aurigemma GP, Schaer GL et al.

Heart failure with a normal ejection fraction: is measurement of diastolic function

necessary to make the diagnosis of diastolic heart failure? Circulation. 2001;104-110.

5. Roger VL. Epidemiology of heart failure. Circulation Research. 2013; 113: 646–659.

6. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure.

Nature Reviews. Cardiol,2011; 8(1): 30–41.

7. Damasceno A, Mayosi BM, Sani M. The Causes, Treatment, and Outcome of Acute

Heart Failure in 1006 Africans From 9 Countries: Results of the Sub-Saharan Africa

Survey of Heart Failure. Arch Intern Med. 2012:1–9.

8. Obasohan AO, Ajuyah CO. How common is heart failure due to systemic hypertension

alone in hospitalised Nigeria. J Hum Hypertens. 1996; 10(12): 801-804.

9. Adedoyin RA, Adesoye A. Incidence and pattern of cardiovascular disease in a

Nigerian teaching hospital. Trop Doct. 2005; 35:104–106.

10. Ogah OS, Stewart S, Falase AO, Akinyemi JO, Adegbite GD, Alabi AA et al.

Contemporary profile of acute heart failure in Southern Nigeria: Data from the

Abeokuta heart failure clinical registry. JACC: Heart Failure 2014; 2(3): 250–259.

ci

11. Oyati IA, Danbauchi SS, Al Hassan MA, Isa MS. Diastolic dysfunction in persons with

hypertensive heart failure. J Natl Med Assoc. 2004; 96(7): 968-973.

12. Karaye KM, Sani MU; Factors associated with poor prognosis among patients admitted

heart failure in a Nigerian tertiary medical centre: a cross sectional study. BMC

Cardiovasc Disord. 2008;8:16-24.

13. Strömberg A, Mårtensson J. "Gender differences in patients with heart failure". Eur. J.

Cardiovasc. Nurs. 2003; 2 (1): 7–18.

14. Ladipo GO, Froude JR, Parry EH. Pattern of heart disease in adults of the Nigerian

Savanna: a prospective clinical study. Afr J Med Sci.1977;6:185-192.

15. Kingue S, Dzudie A, Menanga A, Akono M, Ouankou M, Muna W, et al. ‘A new look

at adult chronic heart failure in Africa in the age of the Doppler echocardiography’:

experience of the medicine department at Yaounde General Hospital. Ann Cardiol

Angeiol. 2005; 54: 276-283.

16. Ojji D, Stewart S, Ajayi S. A predominance of hypertensive heart failure in the Abuja

Heart Study cohort of urban Nigerians: A prospective clinical registry of 1515 de novo

cases. Eur. J. Heart Failure, 2013;15(8): 835–842.

17. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, et al. "Heart disease

and stroke statistics: a report from the American Heart Association Statistics

Committee and Stroke Statistics Subcommittee". Circulation.2008;117 (4): 25–146.

18. Krumholz HM, Chen YT, Wang Y, Vaccarino V, Radford MJ, Horwitz RI. "Predictors

of readmission among elderly survivors of admission with heart failure". Am. Heart

J.2000; 139: 72–77.

19. Krumholz HM1, Parent EM, Tu N, Vaccarino V, Wang Y, Radford MJ et al.

Readmission after hospitalization for congestive heart failure among Medicare

beneficiaries. Arch Intern Med. 1997;5: 157:99-104.

cii

20. Solomon SD, Dobson J, Pocock S, Skali H, McMurray JJ, Granger CB, et al. Influence

of nonfatal hospitalization for heart failure on subsequent mortality in patients with

chronic heart failure. Circulation. 2007; 116:1482-1490.

21. Baker DW, Einstadter D, Thomas C, Cebul RD. Mortality trends for 23,505 Medicare

patients hospitalized with heart failure in Northeast Ohio, 1991 to 1997. Am Heart J.

2003; 146:258-264.

22. Eleuteri E, Di Stefano A. Biomarkers in heart failure. Minerva Cardio angiologica.

2012; 5(4): 589-599.

23. Anand IS, Latini R, Florea VG, Kuskowski MA, Rector T, Masson S, et al. C-reactive

protein in heart failure: prognostic value and the effect of valsartan. Circulation.

2005;112: 1428-1434.

24. Kittleson MM, St John ME, Bead V, Champion HC, Kasper EK, Russell SD, et al.

Increased levels of uric acid predict haemodynamic compromise in patients with heart

failure independently of B-type natriuretic peptide levels. Heart. 2007;93:365-367.

25. Ofori SN, Odia OJ. Serum uric acid and target organ damage in essential hypertension.

Vascular Health and Risk Management. J. Hum. Hypertens.2014;10: 253–261.

26. Glezeva N, Gallagher J, Ledwidge M, O’Donoghue J, McDonald K, Chipolombwe J,

et al. Heart failure in sub-Saharan Africa: Review of aetiology of heart failure and the

role of point-of-care biomarker diagnostics. J Tropical Med. 2015; 10: 581-588.

27. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH. 2013 ACCF/AHA

guideline for the management of heart failure: A report of the American College of

Cardiology foundation/American Heart Association task force on practice guidelines.

Circulation. 2013; 16:128-135.

ciii

28. The Seventh Report of the Joint National Committee on Prevention, Detection,

Evaluation, and Treatment of High Blood Pressure (The JNC 7 Report). J Am Med

Assoc. 2003;289(19):2560–2572.

29. Kelly DT, Dudley P. White International Lecture. Our future society: a global

challenge. Circulation. 1997; 95(11):2459-2464.

30. Zile MR, Baicu CF, Gaasch WH. Diastolic Heart failure: abnormalities in active

relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004; 350-356.

31. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al.

ACC/AHA 2005 Guideline update for the diagnosis and management of chronic heart

failure in the adult: a report of the American College of Cardiology/American Heart

Association Task Force. Circulation. 2005; 112:154-235.

32. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Heart

disease and stroke statistics: a report from the American Heart Association. Circulation.

2010; 121:46-54.

33. Adewuya AO, Ola BA, Ajayi OE, Oyedeji AO, Balogun MO, Mosaku SK. Prevalence

and correlates of major depressive disorder in Nigerian outpatients with heart failure. J

Psychosomatic Research. 2006; 47:479–485.

34. Ogah SO. Hypertension in Sub-Saharan populations: The burden of hypertension in

Nigeria. Letter to the editor. Ethn Dis. 2006; 16:765-772.

35. Unachukwu CN, Agomuoh DI, Alasia DD. Pattern of non-communicable diseases

among medical admissions in Port Harcourt, Nigeria. Nigerian J Clin Practice.2008;

11(1): 14–17.

36. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003; 348:2007–2018.

civ

37. Dokainish H, Teo K, Zhu J, Roy A, Alhabib KF, Elsayed A, et al. Heart failure in

Africa, Asia, The Middle East and South America: The INTER-CHF study. J Cardiol.

2016;204: 133-141.

38. Amoah AG, Kallen C. Aetiology of heart failure as seen from a National Cardiac

Referral Centre in Africa. Cardiology. 2000; 93:11–18.

39. Kannel WB, Ho K, Thom T. Changing epidemiological features of cardiac failure. Br

Heart J. 1994; 72:S3-S9.

40. Sliwa K, Damasceno A, Mayosi BM. Epidemiology and aetiology of cardiomyopathy

in Africa. Circulation. 2005; 112:3577-3583.

41. Mensah GA. Global burden of cardiovascular disease. Ischaemic heart disease in

Africa. Heart. 2008; 94:836–843.

42. Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human

heart: myocyte loss and reactive hypertrophy. Circ Res. 1991; 68: 1560-1568.

43. Kemp CD, Conte JV. The pathophysiology of heart failure. Cardiovasc.

Pathology.2012; 21(5): 365-371.

44. Verdu JM, Comin-Colet J, Domingo M, Lupon J, Fuentes S, Mena A. Usefulness of

Framingham clinical criteria, ECG and NT-proBNP in patients with suspected heart

failure in a primary health care center. Eur. Heart J.2011; 10: S234–S235.

45. Davie AP, Francis CM, Love MP, Caruana L, Starkey IR, Shaw TR, et al. Value of the

electrocardiogramin identifying heart failure due to left ventricular systolic

dysfunction. Br Med J. 1996; 312(7025):222-223.

46. Adebayo RA, Bamikole OJ, Balogun MO, Akintomide AO, Adeyeye VO, Bisiriyu LA,

et al. Echocardiographic assessment of left ventricular geometric patterns in

hypertensive patients in Nigeria. Clinical Medicine Insights: Cardiol. 2013; 7: 161–

167.

cv

47. Teichholz LE, Kreulen T, Herman MV, Gorlin R: Problems in echocardiographic

volume determinations: echocardiographic-angiographic correlations in the presence of

absence of asynergy. Am J Cardiol. 1976; 37:7-11.

48. Schirmer H, Lunde P, Rasmussen K: Mitral flow derived Doppler indices of left

ventricular diastolic function in a general population; the Tromso study. Eur Heart J.

2000, 21:1376-1386.

49. Hobbs R. E. Using BNP to diagnose, manage, and treat heart failure. Cleveland Clinic

J Med: 2003; 70(4): 333–336.

50. Raymond RJ, Dehmer GJ, Theoharides TC, Deliargyris EN. Elevated interleukin-6

levels in patients with asymptomatic left ventricular systolic dysfunction. Am Heart J.

2001; 141: 435–438.

51. Vasan RS, Sullivan LM, Roubenoff R, Dinarello CA, Harris T, Benjamin EJ, et al..

Inflammatory markers and risk of heart failure in elderly subjects without prior

myocardial infarction: the Framingham Heart Study. Circulation. 2003; 107:1486-

1491.

52. Baba M.M, Kolawole B.A., Balogun M.O., Akintomide A.O., Ikem R.T., Arogundade

F.A., et al. C reactive protein in healthy Nigerians. Nig Quarterly J Hosp Med. 2012;

22(4) 288-299.

53. Idemudia J, Ugwuja E, Afonja O, Idogun E, Ugwu N. C-reactive proteins and

Cardiovascular Risk indices in Hypertensive Nigerians. The Internet J Cardiovasc

Research. 2009; 6(2): 351-360.

54. Alonso-Martinez JL, LLorente-Diez B, Echegaray-Agara, Olaz-Preciado , Urbreta-

Echezarrete M and Arencibic G. C-reactive as predictor of improvement and re-

admission in Heart Failure. Eur heart J. 2002;4(3): 331-336.

cvi

55. Anand JS, Latini R, Florea VG, Kuskowski MA, Rector T, Masson S et al. C-reative

Protein in Heart Failure: Prognostic value and the effect of Valsartan. Circulation.

2005; 112:1428-1434.

56. Leyva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ et al.Peptide in

the emergency diagnosis of heart failure with reduced or preserved ejection fraction.

Results from the Breathing Not Properly Multinational Study. J Am Coll Cardiol. 2003;

41(11):2010–2017.

57. Amin, A., Vakilian, F. and Maleki, M. Serum uric acid levels correlate with filling

pressures in systolic heart failure. Congestive Heart Fail J,2011; 17(2): 80–84.

58. Hioshi S, Takayashi T, Talashi T, Toshinari T, Chitose I and Minoru H. Uric acid as

Prognostic Markers in Congestive Heart Failure. Cir J. 2006; 70: 1006-1011.

59. Anker SD, Ponikowski P, Varney S. Wasting as an independent risk factor for mortality

in chronic heart failure. Lancet. 1997; 349:1050–1053.

60. Michalsen A, Konig G, Thimme W. Preventable causative factors leading to hospital

admission with decompensated heart failure. Heart. 1998; 80:437–441.

61. Maeder MT, Kaye DM. Heart failure with normal left ventricular ejection fraction. J

Am Coll Cardiol.2009;53(11): 1531-1540.

62. Pflugfelder PW, Baird MG, Tonkon MJ. Clinical consequences of angiotensin-

converting-enzyme inhibitor withdrawal in chronic heart failure: a double- blind

placebo-controlled study of quinapril. J Am Coll Cardiol. 1993; 22:1557–63.

63. Pitt B, Segal R, Martinez FA. Randomised trial of losartan versus captopril in patients

over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet.

1997; 349:747–752.

64. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of

spironolactone on morbidity and mortality in patients with severe heart failure.

cvii

Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341:709–

717.

65. Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW. Effects of digoxin

on morbidity and mortality in diastolic heart failure: The ancillary digitalis

investigation group trial. Circulation. 2006; 114(5): 397–403.

66. Butler J, Young JB, Abraham WT, Bourge RC, Adams KF, Clare B. Beta-Blocker Use

and Outcomes Among Hospitalized Heart Failure Patients. J Am Coll Cardiol.2006;

47(12):2462–2469.

67. Chatterjee K, Wolfe CL, and DeMarco T. Nonglycoside in congestive heart failure: are

they beneficial or harmful? Cardiol Clin. 1994; 12(1):63–72.

68. John J.V., McMurray, Packer M., Akshay S. D., Jianjian G., Martin P. Lefkowitz M.P.

et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure.

PARADIGM-HF Investigators and Committees. N Engl J Med. 2014; 371:993-1004.

69. Pitt B, Anker SD, Böhm M, Gheorghiade M, Køber L, Krum H, et al. Rationale and

design of Mineralocorticoid Receptor antagonist Tolerability Study-Heart Failure

(ARTS-HF): a randomized study of finerenone vs. eplerenone in patients who have

worsening chronic heart failure with diabetes and/or chronic kidney disease. Eur J

Heart Fail. 2015;17(2):224-232.

70. Piotr P., Dirk J.V., Josep C., Georg E., Michel K., Viacheslav M., et al. Beneficial

effects of long-term intravenous iron therapy with ferric carboxymaltose in patients

with symptomatic heart failure and iron deficiency. Eur Heart J. 2015; 36:657-668.

71. Teerlink J.R., Cotter G., Davison B.A., Felker G.M., Filippatos G., Greenberg B.H. et

al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure

(RELAX-AHF): a randomised, placebo-controlled trial. Lancet. 2013; 381:29-39.

cviii

72. Boren SA, Wakefield BJ, Gunlock TL, Wakefield DS. Heart failure self-management

education: a systematic review of the evidence. Int J Evid Based Healthc. 2009; 7:159-

168.

73. Alchanatis M1, Tourkohoriti G, Kosmas EN, Panoutsopoulos G, Kakouros S,

Papadima K. et al. Evidence for left ventricular dysfunction in patients with obstructive

sleep apnoea syndrome. Eur Resp J. 2002; 20:1239–1245.

74. Xie A, Skatrud JB, Barczi SR, Reichmuth K, Morgan BJ, Mont S. et al. Apnoea-

hypopnea threshold for CO2 in patients with congestive heart failure. Am J Respir Crit

Care Med. 2002; 165:1245–1250.

75. Krum H, Gilbert RE. Demographics and concomitant disorders in heart failure. Lancet.

2003; 362:147–158.

76. Dries D.L., Exner D.V., Domansky M.J. et al. The prognostic implications of renal

insufficiency in asymptomatic and symptomatic patients with left ventricular systolic

dysfunction. J Am Col Cardiol. 2000; 35(3):681–689.

77. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart

failure in elderly patients: an under-recognized public health problem. Arch Intern Med.

2000; 160(6):777–784.

78. Jong P, Vowinckel E, Liu PP, Gong Y, Tu JV. Prognosis and determinants of survival

in patients newly hospitalized for heart failure: a population-based study. Arch Intern

Med. 2002; 162:1689-1694.

79. Frazier CG, Alexander KP, Newby LK, Anderson S, Iverson E, Packer M.et al.

Associations of gender and aetiology with outcomes in heart failure with systolic

dysfunction: a pooled analysis of 5 randomized control trials. J Am Coll Cardiol. 2007;

49:1450-1456.

cix

80. Dries DL, Strong MH, Cooper RS, Drazner MH. Efficacy of angiotensin-converting

enzyme inhibition in reducing progression from asymptomatic left ventricular

dysfunction to symptomatic heart failure in black and white patients. J Am Coll

Cardiol. 2002; 40:311-318.

81. Araoye M. Research methodology with statistics for health and social sciences:

Nathadex Publishers. 2003; 115-120.

82. Guidelines subcommittee: 1999 WHO/ISH guidelines for the management of

hypertension. J Hypertens. 1999; 17: 151-183.

83. World Health Organization: Prevention and managing the global epidemic of obesity.

Report of the World Health Organization consultation on obesity WHO, Geneva 1997.

84. Aziz N, Fahey JL, Roger D. Analytical performance of a highly sensitive C-reactive

protein based immunoassay and the effects of laboratory variables on levels of protein

in blood. Clin Diagn Lab Immunn. 2003;10(11):651-657.

85. Myers GL, Rifai N, Tracy RP, Roberts WL, Alexander RW, Biasucc LM et al. Centers

for Disease Control and Prevention/American Heart Association workshop on markers

inflammation and cardiovascular disease. Circulation. 2004; 110:545-549.

86. Halcox PJ, Roy C, Tubach F, Banegas JR, Dallongeville J, De Backer G. et al. C-

Reactive Protein levels in patients at Cardiovascular risk. EURIKA Study. Br Med

cardiovasc Disorders. 2014, 14;25-26.

87. American Diabetic Association: Diagnosis and classification of diabetes mellitus.

Diabetes care. 2010; 33(1): 562-563.

88. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in

Adults: National Cholesterol Education Programme: Report of the Expert Panel on

Detection, Evaluation, and Treatment of High Blood Cholesterol (Adult Treatment

Panel III). JAMA. 2001, 29: 395-409.

cx

89. Nkado R, Onwubere B, Ikeh V, Anisiuba B. Correlation of Electrocardiogram with

Echocardiographic left ventricular mass in adult Nigerians with systemic hypertension.

West Afr J Med. West African College of Physicians and the West African College of

Surgeons; 2004 Mar 24;22(3):246–249.

90. Kligfield P, Gettes L, Bailey JJ. Recommendation for the standardization and

interpretation of the electrocardiogram: Part 1: The electrocardiogram and its

technology: A scientific statement from the American Heart Association

Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology, the

American College of Cardiology Foundation, and the Heart Rhythm Society: endorsed

by the International Society for Computerized Electrocardiology. Circulation.2007;

115:1325-1332.

91. Devereux RB, Casale PN, Eisenberg RR, Miller DH, Kligfield P. Electrocardiographic

detection of left ventricular hypertrophy using echocardiographic determination of left

ventricular mass as the reference standard. J Am Coll Cardiol. 1984;3(1):82–87.

92. Gubner R. Elecrocardiographic Criteria of Left Ventricular Hypertrophy. American

Medical Association. Arch Intern Med. 1943;72(2):196-202.

93. Araoye M. Left ventricular hypertrophy by electrocardiography: A code system

applicable to Negroes. Nig Postgr Med J. 1996; 3:92-97.

94. Okin PM, Roman MJ, Devereux RB, Kligfield P. Electrocardiographic identification

of increased left ventricular mass by simple voltage-duration products. J Am Coll

Cardiol. 1995 Feb 1;25(2):417–423.

95. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al.

Recommendations for Quantitation of the Left Ventricle by Two-Dimensional

Echocardiography. J Am Soc Echocardiogr. 1989 Sep 10;2(5):358–367.

cxi

96. Feigenbaum H, Armstrong WF, Ryan T, editors. Feigenbaum’s Echocardiography. 6th

ed.New York: Lippincott,William & Wilkins. 2005; 6: 148-154.

97. Savage DD, Garrison RJ, Kannel WB, Levy D, Anderson SJ, Stokes J 3rd, et al. The

spectrum of left ventricular hypertrophy in a general population: the Framingham study.

Circulation. 1987; 75: 126-133.

98. .Monsteller RD. Simplified calculation of body surface area. N Engl J Med. 1987;

317(17): 1098-1099.

99. Teicholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic

volume determinations: echocardiographic-angiographic correlations in the presence or

absence of synergy. Am J Cardiol. 1976; 37:7-8.

100. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et

al. Recommendations for chamber quantification. Eur J Echocardiogr. 2006;7(1):79–

108.

101. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et

al: Recommendations for Chamber Quantification: A Report from the American

Society of Echocardiography's Guidelines and Standards Committee and the Chamber

Quantification Writing Group, Developed in Conjuction with the European Association

of Echocardiography, a Branch of European Society of Cardiology. J Am Soc

Echocardiogr. 2005; 18: 1440-1463.

102. Ommen S.R., Nishimura R.A., Appleton C.P., Miller F.A., Oh J.K., Redfield

M.M., et al. Clinical Utility of Doppler Echocardiography and Tissue Doppler Imaging

in the Estimation of Left Ventricular Filling Pressures: A Comparative Simultaneous

Doppler-Catheterization Study. Circulation. 2000; 102: 1788-1794.

cxii

103. Oh JK, Hatle L, Tajik AJ, Little WC. Diastolic heart failure can be diagnosed

by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol.

2006; 47: 500-506.

104. Oh JK, Park S, Nagueh SF. Advances in cardiovascular imaging: Established

and novel clinical applications of diastolic function assessment by echocardiography.

Circulation: Cardiovascular imaging. 2011; 4:444-445.

105. Yasuhiko S, Hiroaki S. Epidemiology of Heart Failure in Asia. Circ J. 2013;

77:2209-2217.

106. Niemine MS, Brustaert D Dickstain K, Drerler H, Follath F, Harjola VP et al.

EuroHeart Survey Investigators Heart Association, European Society of Cardiology

EuroHeart failure Survey II (EHFS II): A survey on hospitalized acute heart failure

patients: Description of population. Euro Heart J. 2006; 27:2725-2736.

107. Fonarow GC, Abraham WT, Albert NM, Stough WG, Gheorghiade M,

Greenberg BH et al. Admission and clinical outcome for patients hospitalized for heart

failure. Finding from the organized program to imitate lifesaving treatment in

hospitalized patients with heart failure (optimize-HF). circ heart fail. 2008;1:50-57.

108. Desiual A, Peterson NJ, Feldman AM, Yoing JB, White BG, Mam DL

Cytokines and cytokine receptors in advanced heart failure: Analysis of the database

from the vesnarinone trial (vest). Circ heart fail. 2001; 103:2055-2059.

109. Oyedeji AT, Balogun MO, Akintomide AO, Sunmonu TA, Adebayo RA, Ajayi

OE. The Obesity Paradox in Nigerians with heart failure. Annals Med. 2012; 4(11):212-

216.

110. Familoni OB, Olunuga TO and Olufemi BW. A clinical study of pattern and

factors affecting outcome in Nigerian patients with advanced heart failure. Cardiovasc

J Afr. 2007. 18(5); 308-311.

cxiii

111. Ogah OS, Karen S, Akinyemi JO. Hypertensive Heart Failure in Nigerian

Africans. Insight from the Abeokuta Heart Failure Registry. J Clin Hypertens. 2015;17:

263-272.

112. Oyedeji AT, Balogun MO, Akintomide AA. The significance of mild renal

dysfunction in chronic heart failure. West Afr J Med. 2011;30(6):442–446.

113. Obasohan AO, Ajuyali CO. Heart failure in Nigeria Hypertensive patients. The

role of renal dysfunction. Int J cardiol. 1995; 52 (3): 251-255.

114. Sica DA. Sodium and water retention in heart failure and diuretic therapy: basic

mechanisms. Cleveland Clinic J Med. 2006; 73(2):30-33.

115. Goldberg A, Hammerman H, Petcherski S, Nassar M, Zdorovyak A, Yalonetsky

S et al. Hyponatremia and long-term mortality in survivors of acute ST-elevation

myocardial infarction. Archives of Internal Medicine. 2006; 166(7): 781-786.

116. De Luca L, Klein L, Udelson JE, Orlandi C, Sardella G, Fedele F et al.

Hyponatremia in patients with heart failure. Am J Cardiol. 2005; 96(12): 19-23.

117. Ajuluchukwu JN, Mbakwern AC, Daniel FA. Dilated cardiomyopathy: the

effect of clinical and biochemical parameters in the survival of patients with congestive

heart failure hospitalized in a Sub-Saharan tertiary facility. World cardiology congress

2003. Abstract 19.

118. Kardys I, Knetsch AM, Bleumink GS, Deckers JW, Hofman A, Stricker BHet

al. C-reactive protein and risk of Heart Failure. The Rotherdam Study. Am Heart J.

2006; 152(3): 514-520.

119. Kalogeropoulos AP, Tang WH, Hsu A, Felker GM, Hernandez AF, Troughton

RW et al. High-Sensitivity C-Reactive Protein in Acute Heart Failure: Insights From

the ASCEND-HF Trial. J Card fail. 2014; 20(5): 319-326.

cxiv

120. Vasan RS, Sullivan LM, Roubenoff R. Inflammatory markers and risk of heart

failure in elderly subjects without prior myocardial infarction: the Framingham Heart

Study. Circulation. 2003; 107:1486-1491.

121. Cesari M, Penninx BW, Newman AB. Inflammatory markers and onset of

cardiovascular events: results from the Health ABC study. Circulation. 2003;

108:2317-2322.

122. Leyva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox W, et al.Uric

acid in Chronic Heart Failure: A marker of in inflammation. Eur Heart J. 1998; 19:

1814-1822.

123. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for

cardiovascular disease and death: The Framingham Heart Study. Ann Intern Med.

1999; 131: 7–13.

124. Ahmed A, Aronow WS, Fleg JL. Higher New York Heart Association Classes

and increased mortality and hospitalization in heart failure patients with preserved left

ventricular function. Am Heart J. 2006;15(2):444–450.

125. Huang WP, Yin WH, Jen HL, Chiang MC, Feng AN and Young MS. C-reactive

protein levels in Chronic Congestive Heart Failure. Acta Cardiol Sin. 2004; 20:7-14.

126. Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, et al.

Uric acid and survival in chronic heart failure. Circulation. 2003; 107: 1991– 1997.

APPENDIX I

cxv

INFORMATION SHEET

THE CORRELATION BETWEEN HIGH SENSITIVE C-REACTIVE PROTEINS AND

SERUM URIC ACID LEVELS IN HYPERTENSIVE HEART FAILURE PATIENTS IN

OBAFEMI AWOLOWO UNIVERSITY TEACHING HOSPITALS COMPLEX.

WHAT IS THE STUDY ABOUT?

The study is aimed at assessing the serum levels of high sensitive C - reactive protein and uric

acid and correlate them with the severity of hypertensive heart failure.

WHAT IS EXPECTED IF I AGREE TO PARTICIPATE?

You will be expected to provide answers to some questions like, your age, marital status,

occupation, address, telephone number as well as contact details of your next of kin.

Information about your health and your medications shall also be obtained.

You will undergo a thorough physical examination, which will include measurements of your

weight, height and blood pressure. You will also undergo an Echocardiography – a painless

test and have about 10mls of your blood collected for laboratory investigations.

CONFIDENTIALITY

The Information collected from you will be handled in absolute confidence. No information,

in part or whole shall be divulged to anybody except with your permission.

BENEFIT TO PARTICIPANTS

By enrolling into this study, you will have the benefit of knowing how well your heart is

functioning. If you have had an Echo done before, you will know if there is any improvement

in function as compared to the previous one.

RISKS

There is no risk except for the discomfort of a needle prick when the blood sample is collected.

REFUSAL

Refusal to participate in the study will not deny you access to continuity of care.

NAME OF RESEARCHER: DR AGOKE ADEKUNLE

PHONE NUMBERS OF RESEARCHER: 08033658146

ADDRESS OF RESEARCHER: DEPARTMENT OF MEDICINE, OBAFEMI AWOLOWO

UNIVERSITY TEACHING HOSPITAL COMPLEX, ILE-IFE.

EMAIL OF RESEARCHER: drkaygoks02@gmail.com

APPENDIX II

cxvi

APPENDIX III

cxvii

INFORMED CONSENT FORM Initials: ……………………………….......................

In order to participate in this research study, it is necessary that you give informed consent.

By signing this form, you are indicating that you understand the nature of the research study

and your role in the research, and that you agree to participate in the research.

Please consider the following points before signing:

• I understand that I am participating in a research;

• I understand that my participation will be anonymous (that is, my name will not be

linked with my data) and that all information I provide will remain confidential;

• I understand that I will be provided with an explanation of the research in which I am

participating

• I understand that my participation in this research is voluntary, and that I may refuse to

participate further at any time without having to offer an explanation.

By signing this form I am stating that I am 18 years or older, and that I understand the above

information and consent to participate in this study.

…………………………….. ……………………………..

Signature of participant/ Date Signature of Investigator/ Date

APPENDIX 1V

cxviii

PROFORMA

Tick (√ ) or circle as appropriate

DERMOGRAPHIC DATA

Serial No. …………… Date ......./ ……. / ……..

1. Initials ……………..

2. Age at last birthday (years)

3. Sex: 1. Male ( ) 2. Female ( )

4. Occupation: 1. Unemployed ( )

2. Civil servant ( )

3. Business ( )

4. Others ( )

(Specify)

5. Marital status: 1. Married ( )

2. Single ( )

3. Separated ( )

4. Divorced ( )

7. Religion: 1. Christianity ( )

2. Islam ( )

3. Traditional ( )

4. Others ( )

(Specify)

8. Ethnicity: 1. Hausa ( )

cxix

2. Ibo ( )

3. Yoruba ( )

4. Others ( )

(Specify)

9. Educational status: 1. Primary ( )

2. Secondary ( )

3. Tertiary ( )

4. Others ( )

(Specify)

10. Phone number ……………………

HISTORY OF HEART DISEASE

1) Do you usually have difficulty in breathing ………

2) If yes, how often ………

3) Does it occur at rest ( ) or during moment of activity ( )

4) Do you usually have difficulty in breathing while lying down on bed unsupported by

pillow ………

5) If yes, how often ………

6) Do you usually have difficulty in breathing that may awake you at night ………

7) If yes, since when ……..

8) Do you usually cough ………

9) If yes, since when ……

10) Is the cough productive of sputum Yes ( ) No ( )

11) What is the colour of the sputum Whitish ( ), Reddish ( ), others ( )

12) Have you noticed leg swelling ………

13) If yes, since when ………

14) Do you usually have palpitation ………

15) If yes, how often ………

16) Do you usually have chest pain ………

17) If yes, how often ………

cxx

18) Have you ever been told to have high blood pressure …………

19) If yes, when ………

20) Family history of hypertension/who ……………

CO-MORBID CONDITIONS

Diabetes Yes/No

Renal disease Yes/No

Height: Weight: BMI:

Waist circumference: Hip circumference:

SMOKING, ALCOHOL AND SALT CONSUMPTION

Do you smoke cigarettes? Yes/No

If yes, how many stick per day……………..

For how long

Do you take alcohol? Yes/No

If yes, what type, how much- how many bottles per day/week, how often?

Occasionally………………………

At least weekly……………………

Daily………………………………..

New York Heart Association Functional class…………………………..

Clinical outcome on follow-up

Re-admission Yes/No

Death Yes/No

CARDIOVASCULAR EXAMINATION

Pulse rate (beat/min): Volume: Rhythm:

Blood pressure (mmHg):

Jugular Venous Pulsation: Elevated/Not elevated

cxxi

Apex beat: Left parasternal heave:

Palpable sounds/Thrills: Heart sounds:

CHEST: Bilateral basal crepitations

ABDOMEN: Tender hepatomegaly Ascites

LABORATORY RESULTS

Urinalysis

Protein Yes/No

Glucose Yes/No

Ketones Yes/No

Urine microscopy findings:

Fasting Blood Glucose: ------------- (mmol/L)

2-Hour Post Prandial :------------------(mmol/L)

Fasting Serum Lipid.

• Total cholesterol :-------------( mmol/L)

• HDL cholesterol :--------------( mmol/L)

• LDL cholesterol :--------------( mmol/L)

• Triglycerides :-------------------( mmol/L)

PCV (Packed Cell Volume)… WBC (White blood cell)…

Electrolyte, Urea and Creatinine

• Sodium: ---------------(mmol/L) Potassium: -------------(mmol/L)

• Bicarbonate: ------------- (mmol/L) Urea: ----------------(mmol/L)

• Creatinine: --------------(Umol/L)

BIOMARKERS

Hs C-reactive protein …………… mg/L

Uric acid …………. Mg/dl

IMAGING

ELECTROCARDIOGRAPHY:

cxxii

HR: RHYTHM:

PR INTERVAL: QRS DURATION:

QT/QTC INTERVAL: P WAVE DURATION/MORPHOLOGY:

LVH/RVH: T AND S CHANGES:

ARRYTHMIAS:

ECHOCARDIOGRAPHY:

2D/M-MODE

LAD…………. (cm) AOD…………. (cm) ACS…………. (cm)

IVSD…………. (cm) IVSS…………. (cm) LVIDd…………. (cm)

LVIDs…………. (cm) LVPWd…………. (cm) LVPWs…………. (cm)

EDV…………. (ml) ESV…………. (ml) SV…………. (ml)

EF…………. (%) FS…………. (%) RVDd…………. (cm)

LAarea (apical 4 chamber) ..…. (cm2) LAlength (apical 4 chamber) …….(cm)

LAarea (apical 2 chamber) …….(cm2) LAlength (apical 2 chamber) …….(cm)

DOPPLER

PULMONARY VALVE

PVVmax………….(ms-1) PVVmean………….(ms-1)

PVPGmax………….(mmHg) PVPGmean………….(mmHg)

PVVTI………….(ms) PVET………….(ms)

PVPEP………….(ms) HR………….(min-1)

MITRAL VALVE

E VEL ………….(ms-1) A VEL………….(ms-1) E/A…………

Dec T………….(ms) IVRT………….(ms) IVCT………….(ms)

MVVmax………….(ms-1) MVVmean………….(ms-1)

MVPGmax…………. (mmHg) MVPGmean………….(mmHg)

MVVTI………….(ms) MVPHT………….(ms)

Aduration………….(ms) Eduration………….(ms)

cxxiii

TDI

E1………….(ms-1) A1………….(ms-1) S1………….(ms-1)

AORTIC VALVE

AVVmax………….(ms-1) AVVmean………….(ms-1) AVPGmax………….(mmHg)

AVPGmean………….(mmHg) AVVTI………….(ms) HR………….(min-1)

LVET………….(ms) LVPEP………….(ms)

PULMONARY VEIN

PvS………….(ms-1) PvD………….(ms-1) S/D………….

Arev………….(ms-1) Adur………….(ms)

TRICUSPID VALVE

Evelocity………….(ms-1) Avelocity………….(ms-1)

E/A………….

FRAMINGHAM HEART FAILURE DIAGNOSTIC CRITERIA

Criteria: Major (Heart Failure diagnosis requires 1 or more criteria positive)

A. Acute pulmonary oedema Yes/No

B. Cardiomegaly Yes/No

C. Hepatojugular reflex Yes/No

D. Neck vein distention Yes/No

E. Paroxysmal nocturnal Dyspnoea or Orthopnoea Yes/No

F. Pulmonary rales Yes/No

G. Third Heart Sound (S3 Gallup Rhythm) Yes/No

Criteria: Minor (Heart Failure diagnosis requires 2 or more criteria positive)

A. Ankle oedema Yes/No

B. Dyspnoea on exertion Yes/No

C. Hepatomegaly Yes/No

D. Nocturnal cough Yes/No

E. Pleural Effusion Yes/No

F. Tachycardia (Heart Rate >120 beats per minute) Yes/No

cxxiv

APPENDIX V

Immunoplate well before analysis

cxxv

APPENDIX VI

Immunoplate wells showing colour change

cxxvi

APPENDIX VII

Data analysing on Hs-CRP

APPENDIX VIII

cxxvii

Transthoracic M-mode echocardiography of a 57yr old hypertensive heart failure patient.

KEY: LAD=left atrial diameter; AOD=Aortic root diameter, AV Cusp= Aortic valve

cusp.

APPENDIX IX

cxxviii

The investingator in an echo session.

APPENDIX X

cxxix

ECG tracing of a 59 year woman with low limb voltage and left ventricular hypertrophy

(Cornel’s criterion).