CHAPTER ONE

INTRODUCTION AND LITERATURE REVIEW

1.1       Introduction

Hypertension also is known as high blood pressure is one of the most common non-communicable disease afflicting the adult population in the world especially in African countries. It is an important public health problem causing morbidity, mortality and cost to society. Globally, hypertension prevalence among adults aged 18 years and older were reported to affect about one billion people with an annual death of approximately 7.1 million people. Africa records the highest prevalence at 29.6% (Ajonina et al., 2018). According to Kearney et al, 75% of death in sub-Saharan Africa (SSA) by 2020 will be attributed to hypertension. The average global prevalence of hypertension has declined slightly during the past two decades; meanwhile there is an increasing trend in the middle and low-income countries. However, about two-thirds of patients with hypertension are now living in developing countries. In Cameroon, the prevalence of hypertension spans from 5.7% in rural settings (Tabi et al., 2016) through 21.9% in semiurban (Atashili et al., 2010) to 47.5% in urban milieu (Dzudie et al., 2012) with a national average survey of 31.0% (Kingue et al., 2015). Hypertension is a well-known risk factor for various cardiovascular, peripheral vascular and renal events in our body. The cause of essential hypertension is multifactorial; genetic factors also a part of it (Watt et al., 1992). Genetic factors are responsible for about 30-60% of the familial aggregation of blood pressure and the transmission of cultural factors being responsible for the remaining (stress, diet, physical activity) (Ward, 1990). Elevated blood pressure (BP) is a precursor to excessive morbidity and premature mortality. Blood pressure is mainly regulated by Renin-angiotensin system (RAS) which also acts as a key regulator of electrolyte balance. The angiotensin-converting enzyme (ACE) gene is the key gene in RAS. ACE insertion/deletion (ACE I/D) polymorphism is one of the well-described polymorphism of the RAS. The ACE genotypes include the presence (I allele) or absence (D allele) of a 287 bp Alu repeat sequence in intron 16, resulting in 3 genotypes (D/D and I/I homozygote, and I/D heterozygote). Studies have demonstrated that ACE Insertion (I)/Deletion (D) polymorphism are associated with common diseases like hypertension, diabetic nephropathy, coronary heart disease and tuberculosis (Mulder et al., 2003). There are very limited studies available in Cameroonian, subjects regarding the association of ACE polymorphism with hypertension. The present study therefore aimed at exploring the association of ACE polymorphism with hypertensive patients in Buea municipality.

1.2 Literature review

1.2.1 Types of Hypertension

There are different types of hypertension include; Primary (essential or idiopathic) hypertension is systemic hypertension of unknown cause that results from dysregulation of normal homeostatic control mechanisms of blood pressure in the absence of detectable known secondary causes. Primary hypertension (97-98%) appears to be the result of an interplay of complex genetic and environmental factors. (Kaplan, 2002).  Several pathophysiological mechanisms contribute to the development of primary hypertension. The factors include genetics, high salt intake, low physical activity, obesity, insulin resistance, renin-angiotensin system, sympathetic nervous system, intrauterine nutrition and low birth weight. Secondary hypertension is systemic hypertension due to an underlying disorder and mechanism usually involving the kidneys or endocrine system. It accounts for <5% of cases of hypertension (Kaplan, 2002). The causes are unusual but are important because the cause may be curable. Endocrine causes: Cushing‟s syndrome, Conn‟s syndrome, phaeochromocytoma, hyper/hypothyroidism, acromegaly,hyperparathyroidism, exogenous hormones, e.g. contraceptive pills, glucocorticoids. Renal causes: glomerulonephritis, diabetic nephropathy, polycystic kidney disease, renal artery stenosis. Other causes include; coarctation of the aorta, Pregnancy-associated hypertension, alcohol, acute stress.

1.2.2 Epidemiology of Hypertension

As per the World Health Statistics 2012, of the estimated 57 million global deaths in 2008, 36 million (63%) were due to non-communicable diseases (NCDs). The largest proportion of NCD deaths is caused by cardiovascular diseases (48%). In terms of attributable deaths, raised blood pressure is one of the leading behavioural and physiological risk factor to which 13% of global deaths are attributed. Hypertension (HTN) is reported to be the fourth contributor to premature death in developed countries and the seventh in developing countries. Recent reports indicate that nearly 1 billion adults (more than a quarter of the world’s population) had hypertension in 2000, and this is predicted to increase to 1.56 billion by 2025. Earlier reports also suggest that the prevalence of hypertension is rapidly increasing in developing countries and is one of the leading causes of death and disability. While mean blood pressure has decreased in nearly all high-income countries, it has been stable or increasing in most African countries. Today, mean blood pressure remains very high in many African and some European countries. The prevalence of raised blood pressure in 2008 was highest in the WHO African Region at 36.8% (34.0–39.7). The Global Burden of Diseases; Chronic Disease Risk Factors Collaborating Group has reported 35-year (1980-2005) trends in mean levels of body mass index (BMI), systolic BP and cholesterol in 199 high-income, middle-income and low-income countries. Mean systolic BP declined in high and middle-income countries but increased in low-income countries and is now more than in high-income countries. India specific data are similar to the overall trends in low-income countries. HTN in Sub-Saharan Africa (SSA) has also been on the rise with reports indicating higher values in urban settings compared to rural settings (Malhotra et al., 2008). The prevalence of HTN in SSA ranges between 14.5% in rural Eritrea, 32.9% in semi-urban Ghana, and 40.1% in urban South Africa (Tabi et al., 2016). Likewise, adequate blood pressure (BP) control has been on the decline, ranging between 1.7% in rural Ghana 4% in urban slum dwellers in Nigeria and 21.5% in urban Kenya (Tabi et al., 2016). In Cameroon, the prevalence of hypertension spans from 5.7% in rural settings (Tabi et al., 2016) through 21.9% in semiurban (Atashili et al., 2010) to 47.5% in urban milieu (Dzudie et al., 2012) with a national average survey of 31.0% (Kingue et al., 2015). Despite the relatively better BP control in urban over rural settings, levels of adequate BP control as low as 2% (Kamadjeu et al., 2006) to 27.5% (in men) and 38.7% (in women) (Dzudie et al., 2012) have been reported in urban settings. Even though much has been done so far to reduce the incidence of hypertension in urban areas, this has not been the same in rural areas, with public health policies aimed at controlling hypertension mainly directed towards the large cities

1.2.3 Clinical Manifestations of Hypertension

Frequently asymptomatic until severe and target organ disease has occurred fatigue, reduced activity tolerance, dizziness, palpitations, angina Dyspnea. Complications are primarily related to the development of atherosclerosis (“hardening of arteries”), or fatty deposits that harden with age. The common complications are target organ diseases occurring in the heart, brain, kidney and eyes.

1.2.4 Diagnosis of Hypertension

Uncomplicated hypertension is usually asymptomatic and many of the symptoms often attributed to hypertension such as headache, tinnitus, dizziness and fainting are probably psychogenic in origin. They may reflect hyperventilation, induced by anxiety over the diagnosis of a lifelong disease that threatens well-being and survival. However recent data indicate that, surprisingly, a person’s general sense of well-being often improves during the initiation of medical treatment of hypertension. These new data suggest that hypertension may not be as asymptomatic as was previously assumed. Even if not totally asymptomatic, hypertension can go unrecognized for years because overt symptoms and signs generally coincide with the onset of target organ damage. Therefore, proper technique of blood pressure measurement is the cornerstone of hypertension detection. This can be achieved with the help of the following guidelines (O’Brien et al., 2003).

 Home (self) blood pressure measurements

Home readings of blood pressure tend to be better correlated with both the extent of target organ damage and the risk of future mortality than are readings taken in the physician’s office. They are also helpful in evaluating symptoms of hypotension particularly if they are intermittent and infrequent (Sakuma et al 1997). Many machines are now available for the purpose that is convenient, inexpensive and relatively accurate. Home readings are on average 12/7 mmHg less than office measurements, even in normotensive subjects. However, many factors that contribute to blood pressure variability including circadian variation, food and alcohol ingestion, exercise and stress are more difficult to control in the home environment (O’Brien et al., 2003).

Equipment

Cuff size

The bladder size (six sizes are available) encircle at least 80% of the arm circumference and cover two-thirds of the arm length; if not, place the bladder over the brachial artery. If the bladder is too small, spuriously high readings may result. The lower edge of the bladder is within 2.5 cm of the antecubital fossa.

Manometer

Mercury, aneroid or electronic devices used in measurement of blood pressure is calibrated frequently and routinely against standards (typically every 6 months) to assure accuracy. The equipment used is in working order: clean, calibrated, filled with non-leaking tubing and has a properly sized cuff.

Ultrasonic

For infants use ultrasonic equipment e.g. Doppler method.

1.2.5 Risk factors of hypertension

Common hereditary and physical risk factors for high blood pressure include:

Age: The older you are, the more likely you are to get high blood pressure. As we age, our blood vessels gradually lose some of their elastic quality, which can contribute to increased blood pressure. However, children can also develop high blood pressure.

Gender: Until age 64, men are more likely to get high blood pressure than women are. At 65 and older, women are more likely to get high blood pressure.

Race: African-Americans tend to develop high blood pressure more often than people of any other racial background in the United States. It also tends to be more severe in African Americans, and some medications are less effective in treating HBP in blacks.

Chronic kidney disease (CKD) HBP may occur as a result of kidney disease. And, having HBP may also cause further kidney damage.

Family history: If your parents or other close blood relatives have high blood pressure, there’s an increased chance that you’ll get it, too.

Modifiable risk factors

These are the risk factors you can change to help prevent and manage high blood pressure, including:

Lack of physical activity: Not getting enough physical activity as part of your lifestyle increases your risk of getting high blood pressure. Physical activity is great for your heart and circulatory system in general, and blood pressure is no exception.

An unhealthy diet, especially one high in sodium: Good nutrition from a variety of sources is critical for your health. A diet that is too high in salt consumption, as well as calories, saturated and trans fat and sugar, carries an additional risk of high blood pressure. On the other hand, making healthy food choices can actually help lower blood pressure.

Being overweight or obese: Carrying too much weight puts an extra strain on your heart and circulatory system that can cause serious health problems. It also increases your risk of cardiovascular disease, diabetes and high blood pressure.

Drinking too much alcohol: Regular, heavy use of alcohol can cause many health problems, including heart failure, stroke and an irregular heartbeat (arrhythmia). It can cause your blood pressure to increase dramatically and can also increase your risk of cancer, obesity, alcoholism, suicide and accidents.

Smoking and tobacco use: Using tobacco can cause your blood pressure to temporarily increase and can contribute to damaged arteries. Secondhand smoke, exposure to other people’s smoke, also increases the risk of heart disease for nonsmokers.

1.2.6 Treatment and Management of Hypertension

The ultimate goal in the treatment of the hypertensive patient is to achieve the maximum reduction in the long-term total risk of cardiovascular morbidity and mortality (Chobanian et al., 2003 and American Diabetes Association, 2003). This requires:

• Treatment of all reversible risk factors identified including smoking, dyslipidaemia and diabetes mellitus;
• Appropriate management of associated clinical conditions such as congestive heart failure, coronary artery disease, peripheral vascular disease and transient ischaemic attacks;
• Achieving office blood pressure values <130/80 mmHg for patients with diabetes mellitus or chronic renal disease. When a home or ambulatory pressure measurements are used to evaluate the efficacy of treatment, daytime values around 10–15 mmHg lower for systolic blood pressure and 5–10 mmHg lower for diastolic blood pressure are the goal values. Treating systolic and diastolic blood pressure to target is associated with a decrease in cardiovascular complications. This includes 35%–40% mean reduction in stroke incidence, 20%–25% mean reduction in myocardial infarction and >50% mean reduction in heart failure. There are several strategies for achieving therapeutic goals: lifestyle modifications, pharmacological modifications and general strategies for hypertensive therapy

Lifestyle modifications

Adoption of healthy lifestyles by all individuals is critical in the prevention of high blood pressure and an indispensable part of the management of those with hypertension. Lifestyle modifications decrease blood pressure, enhance antihypertensive drug efficacy and decrease cardiovascular risk. Patients with prehypertension and no compelling indication (including heart failure, prior myocardial infarction or stroke, high coronary risk status, diabetes mellitus, chronic renal disease) respond well to lifestyle modifications and usually do not need drug therapy. For all other abnormal blood pressure categories, drug therapy is indicated if goal blood pressure is not achieved by lifestyle modification alone.

Cessation of smoking

This is probably the single most powerful lifestyle measure for the prevention of non-cardiovascular and cardiovascular diseases, including stroke and coronary heart disease. (Primatesta et al., 2001). Smoking may interfere with the beneficial effects of some antihypertensive agents such as β-adrenergic blockers. When necessary, nicotine replacement or buspirone therapies should be considered since they appear to be safe in hypertension and to facilitate smoking cessation (Omvik, 1996).

Weight reduction and physical exercise

Weight reduction reduces blood pressure in overweight patients and has beneficial effects on associated risk factors such as insulin resistance, diabetes, hyperlipidaemia and LVH (Pubbey et al., 1992). Blood pressure is lowered by 1.6/1.1 mmHg for every kilogram of weight loss. Many hypertensive patients have much more than 10 kg of excess adiposity and many of them would no longer be hypertensive if they lost even this amount of body fat. (Whelton PK et al.1998) The blood pressure-lowering effect of weight reduction may be enhanced by a simultaneous increase in physical exercise. Thus, sedentary patients should be advised to take up modest levels of aerobic exercise on a regular basis such as brisk walking for at least 30 minutes per day, most days of the week.

Reduction of salt intake and other dietary changes

Reducing dietary sodium intake to no more than 100 mEq/L (2.4 g sodium or 6 g sodium chloride) reduces the blood pressure by an average of 4–6 mmHg. Patients should be advised to avoid added salt, to avoid obviously salted food (particularly processed foods) and to eat more meals cooked directly from natural ingredients containing more potassium (law, 1997). Hypertensive patients should also be advised to eat more fruit and vegetables, to eat more fish and to reduce their intake of saturated fat and cholesterol (Cutler et al., 1997). This is well achieved by adoption of the Dietary Approach to Stop Hypertension (DASH) eating plan. The DASH diet is rich in fruits, vegetables and low-fat dairy foods including whole grains, poultry, fish and nuts, and is reduced in fats, red meat, sweets and sugar-containing beverages (Margetts et al., 1986).

Cessation of alcohol consumption

There is a linear relationship between alcohol consumption, blood pressure levels and prevalence of hypertension in populations (Wannamethee, 1996). High levels of alcohol consumption are associated with a high risk of stroke, particularly so for binge drinking. Additionally, alcohol attenuates the effects of antihypertensive drug therapy. Heavy drinkers may also experience a rise in blood pressure after acute alcohol withdrawal. Hypertensive patients who drink alcohol should be advised to stop drinking (Puddey, 1987). If they insist on continuing to drink they should be advised, in any case, not to consume more than 30 ml of ethanol (the equivalent of two drinks per day) in men and no more than 15 ml of ethanol (one drink per day) in women and lighter-weight persons. (One drink is 360 ml of beer, 150 ml of wine and 45 ml of 80%-proof liquor).

Pharmacological therapy

Initial drug therapy is determined by the presence or absence of compelling indications. (Sica, 2002). In patients without compelling indications, drug therapy is usually initiated by a thiazide-type diuretic. Diuretics have been virtually unsurpassed in preventing the cardiovascular complications of hypertension. They enhance the antihypertensive efficacy of multidrug regimens and are more affordable than other antihypertensive agents. In patients with compelling medications, initial drug selection is based on favourable outcome data (from clinical trials) for specific antihypertensive drugs in the treatment of special patient groups.

1.2.6 Effect of ACE gene Polymorphism

The cause of essential hypertension is multifactorial; genetic factors also a part of it (Watt et al., 1992). Genetic factors are responsible for about 30-60% of the familial aggregation of blood pressure and the transmission of cultural factors being responsible for the remaining (stress, diet, physical activity) (Ward, 1990). Elevated blood pressure (BP) is a precursor to excessive morbidity and premature mortality. Although systemic hypertension is a risk factor for disease burden, the risk is uneven, heterogeneous, and unpredictable. This clinical scenario, therefore, raises the possibility of genetics in the development of hypertension and/or related complications. Blood pressure is mainly regulated by Renin-angiotensin system (RAS) which also acts as a key regulator of electrolyte balance. The RAS regulates long term blood pressure and extracellular volume of the body by the action of Angiotensin II, a potent vasoconstrictor. This system has been implicated in the pathological changes of organ damage through modulation of gene expression, proliferation, fibrosis and inflammatory response. Genetic polymorphism of RAS has been thoroughly studied to elucidate the genetic susceptibility to Hypertension (Zhu, 2003). The angiotensin-converting enzyme (ACE) gene is the key gene in RAS. ACE has two functions: one is to cut the two amino acids of the C-terminal of angiotensin I to generate angiotensin II, an octapeptide that is a potent vasoconstrictor. The other function is to inactivate bradykinin. The imbalance between forces of vasoconstriction over forces of vasodilation elevates vascular tone and leads to systemic elevation of blood pressure. ACE consists of 1306 amino acids sequence (Soubrier et al., 1998). Angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism is one of the well-described polymorphism of the RAAS. The ACE genotypes include the presence (I allele) or absence (D allele) of a 287 bp Alu repeat sequence in intron 16, resulting in 3 genotypes (D/D and I/I homozygote, and I/D heterozygote). An I/D polymorphism of ACE gene at this region correlates with circulating ACE plasma activity (Ipsita et al., 2012). An I/D (region in intron 16) polymorphism of ACE gene correlates with circulating ACE plasma activity. Studies have demonstrated that ACE Insertion (I)/Deletion (D) polymorphism are associated with common diseases like hypertension, diabetic nephropathy, coronary heart disease and tuberculosis (Mulder et al., 2003).

1.3 Rationale

Hypertension is a major health problem with a high prevalence in Africa and a leading cause of morbidity and mortality. The angiotensin-converting enzyme (ACE) gene, the key gene in Renin-angiotensin-aldosterone system (RAAS) which is mainly regulated by blood pressure and also acts as a key regulator of electrolyte balance is said to control the manifestation of hypertension. Studies have demonstrated that ACE Insertion (I)/Deletion (D) polymorphism is associated with hypertension while other studies show that it is not associated with the disease. This, therefore, implies that the association of this gene with hypertension is based on geographical location and ethnic groups. This study, therefore, sought to assess the association of ACE gene polymorphism with Hypertension in Buea Municipality, South West Cameroon.

1.4 Hypothesis

Angiotensin-converting enzymes polymorphism is associated with hypertension in individuals from the Buea Regional Hospital.

1.5 Objectives

1.5.1 General objective

To investigate the prevalence association of Angiotensin-converting enzyme gene polymorphism in individuals from the Buea Regional Hospital.

1.5.2 Specific objectives

1. To genotype individuals in individuals from the Buea Regional Hospital
2. To identify the genotypes of Angiotensin-converting enzymes responsible for Hypertension in individuals from the Buea Regional Hospital.