ORAL MANIFESTATIONS OF HYPERTENSION

AND RHEUMATIC HEART DISEASE:

A CROSS SECTIONAL STUDY IN ELDERLY PATIENTS

Untuk Memenuhi Tugas :

Journal Review Departemen Ilmu Penyakit Mulut

Disusun oleh:
Abigail Chang Tian Ai 160112162516
Nur Emalina Akhma Binti Mohamad Shafree 160112172501

Pembimbing :
drg. Wahyu Hidayat, Sp. PM

FAKULTAS KEDOKTERAN GIGI

UNIVERSITAS PADJADJARAN
BANDUNG
2018
TITLE : ORAL MANIFESTATIONS OF HYPERTENSION AND
RHEUMATIC HEART DISEASE: A CROSS SECTIONAL
STUDY IN ELDERLY PATIENTS

AUTHOR : ABIGAIL CHANG TIAN AI

160112162516
NUR EMALINA AKHMA BINTI MOHAMAD SHAFREE
160112172501

Bandung, May, 2018

Approved by,

Supervisor:

____________________________
drg. Wahyu Hidayat, Sp. PM
197911082006041003
 TABLE OF CONTENT

TABLE OF CONTENT ........................................................................................... i

CHAPTER 1 ........................................................................................................... 1
CHAPTER 2 ........................................................................................................... 3
2.1 Aim............................................................................................................ 3
2.2. Ethical statement ...................................................................................... 3
2.3 Participants ................................................................................................ 3
2.4 Evaluations ................................................................................................ 4
2.5 Statistical Analysis .................................................................................... 4
2.6 Results ....................................................................................................... 4
2.7 Conclusion ................................................................................................ 6
CHAPTER 3 ........................................................................................................... 7
3.1 Cardiovascular System .................................................................................. 7
3.1.1 Anatomy ................................................................................................. 7
3.1.2 Physiology .............................................................................................. 9
3.2 Cardiovascular Disease (CVD) ................................................................... 12
3.2.1 Definition ............................................................................................. 12
3.2.2 Classification ........................................................................................ 12
3.2.3 Epidemiology ....................................................................................... 15
3.2.4 Risk Factors .......................................................................................... 16
3.2.5 Pathophysiology ................................................................................... 19
3.2.6 Oral Manifestation and clinical features .............................................. 21
3.2.7 Diagnosis of cardiovascular diseases ................................................... 24
3.2.8 Treatment ............................................................................................. 38
3.2.9 Oral Manifestation of Cardiovascular Drugs ....................................... 42
CHAPTER 4 ......................................................................................................... 55
CHAPTER 5 ......................................................................................................... 57
REFERENCES...................................................................................................... 58

i
 CHAPTER 1

INTRODUCTION

Cardiovascular disease (CVD) encompasses diseases affecting the heart and/or

blood vessels and include coronary heart disease, cerebrovascular disease,

rheumatic heart disease and other conditions, many of which are related to a process

called atherosclerosis. (Nguyen et al., 2015). According to the World Health

Organization (WHO), cardiovascular diseases are projected to continue to be the

single leading cause of death in men and women around the world (Mendis, Puska

and Norrving, 2011)

Two of the most common CVDs are Hypertension (HT) and Rheumatic Heart

disease (RHD). HT is a chronic medical condition in which the blood pressure in

the arteries is elevated. This induces harder work to the heart to circulate blood

through the blood vessels (Alipour and Goldust, 2016). In RHD, this organ is

involved in Acute Rheumatic Fever (ARF) and causes permanent damage to the

The effect of oral health upon general health has been investigated by several

studies. The pathogenesis and related risk factors for both oral diseases and CVDs

are well studied. A recent but controversial possible relationship between oral

infections and CVD is inflammation due to infectious agents(Wang et al., 2011).

Also, oral bacteria-related systemic inflammation is an important mechanism in the

oral related pathogenesis aspect of CVD (Kholy, Genco and Van Dyke, 2015).

There have been reports that poor oral hygiene, specifically periodontal disease, is

1
 2

associated with an increased risk for cardiovascular disease (Genco, Offenbacher

and Beck, 2002) probably by adding to the inflammatory burden of individuals. The

meta-analyses demonstrated poor oral hygiene with periodontal disease had an

overall increased risk of 24% to 35% for coronary heart disease and a higher risk

for stroke ranging from 1.2% to 3.0% (Genco, Offenbacher and Beck, 2002).

Despite such relations, there are few reports regarding the oral manifestation of

patients with CVD especially from Iran as a developing country in Asia. Most of

previous studies are epidemiological based reports and performing well- conducted

clinical studies are highly needed to explore these oral manifestations of CVD..

This article, is a case report of a cross sectional study of the oral manifestations

in hypertension and rheumatic heart disease among elderly patients attending

Cardiovascular Department of Imam Reza Subspecialized Clinic, Shiraz, Iran.

 CHAPTER 2

CASE REPORT

Cardiovascular diseases and oral disorders share common risk factors. A cross

sectional study was performed from September 2015 to December 2015 among

patients attended to Cardiovascular Department, Imam Reza Subspecialized Clinic

affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. After receiving

medical history from each patient, the oral cavity was examined by an oral medicine

specialist using proper light, dental mirror and explorer.

2.1 Aim

The aim of this study was to evaluate the involvement of oral cavity in patients

with cardiovascular diseases.

2.2. Ethical statement

Shiraz Dentistry School Review Board approved the protocol of this study and

the written consent was obtained from all patients who agreed for participation in

the study.

2.3 Participants

In a cross sectional study from September 2015 to December 2015, 77 patients

with HT and 73 patients with RHD were included from patients who were admitted

to Cardiovascular Department, Imam Reza Subspecialized Clinic affiliated to

Shiraz University of Medical Sciences. The participants were residents in various

3
 4

locations of the Southern of Iran. Among them, 9 patients were edentulous with

complete dentures (6%), 12 patients were using partial dentures (8%), 21 patients

had crown and bridge (14%) and 108 cases had their own dentition (72%). Also, 6

patients (7.8%) had Diabetes Mellitus (DM) in the HT group. Patients with

dementia were excluded because of concerns about the reliability of self-reported

oral health information.

2.4 Evaluations

A medical history was obtained from the patients and all medications used by

the patients were recorded. The oral cavity was examined by an oral medicine

specialist using proper light, mirror and explorer. The lips, cheek, tongue, palatal

mucosa, floor of the mouth, mucous membrane, gingiva, pharyngeal fauces,

dentures, teeth and occlusion were completely checked. Several symptoms such as

burning sensation, xerostomia and neurologic disorders were also recorded.

2.5 Statistical Analysis

Data were presented as mean or percentage and analyzed using SPSS software

version 18.0 (SPSS Inc., Chicago, IL, USA) with the significance level set at

P<0.05. A comparison between the groups was performed using the independent

sample t test. Any relationships between qualitative variables were analyzed using

the Chi- square test

2.6 Results

The study consisted of 150 participants with mean age 62.2 ± 7.6 years (Range:

47-77 years) and 78 (52%) of them were male. Among them, 77 patients had HT

and 73 patients had RHD. The frequency and percentage of diagnosed oral disorders
 5

and lesions are presented in table 1. As shown, the most diagnosed lesion in our

patients was Xerostomia. The patients with DM showed more oral symptoms such

as burning sensation, angular chelitis, xerostomia and Median Rhomboid Glossitis

(MRG).

A variety of medications were used by the patients such as Ca2+ channel

blockers, β-blockers, diuretics, anti-platelet aggregation and anti-dysrhythmia such

as captopril, amlodipine atenolol, propranolol, aspirin, clopidogrel bisulfate,

losartan, furosemide, hydrochlorothiazide, and digoxin. Statistical analysis did not

show a significant correlation between the type of the drug and presence of oral

lesions (P=0.999). Oral lesions were significantly more common in dentate HT

patients than RHD (P=0.047). All patients were age and sex matched and statistical

analysis did not show significant relations between age, sex and presence of oral

lesions in both groups (P>0.05).

Table 1
Frequency and percentage of diagnosed oral disorders and lesions in patients with
hypertension or rheumatic heart disease who were enrolled in this study

Disorder and lesions Frequency Percentage (%)

Xerostomia 21 14
Denture stomatitis, median 12 8
rhomboid glossitis (MRG) and
angular chelitis
Lichen planus and lichenoid 8 5.3
reaction
Oral stomatitis and aphtous ulcers 7 4.7
 6

2.7 Conclusion

The current research showed that a wide variety of oral manifestations could be

seen in patients with CVDs. Many of used medications can induce oral

manifestations as xerostomia, lichenoid reactions, burning mouth sensation, and

stomatitis. Candidia associated lesions could also be seen in dentate and edentulous

elderly patients. However, further studies are needed to confirm our findings in fatal

and non-fatal CVD among larger sample of patients.

 CHAPTER 3

LITERATURE REVIEW

3.1 Cardiovascular System

The cardiovascular system consists of three interrelated components: blood, the

heart, and blood vessels.

3.1.1 Anatomy

Blood contributes to homeostasis by transporting oxygen, carbon dioxide,

nutrients, and hormones to and from cells. It helps regulate body pH and

temperature, and provides protection against disease through phagocytosis and the

production of antibodies (Tortora and Derrickson, 2013).

Blood vessels contribute to homeostasis by providing the structures for the flow

of blood to and from the heart and the exchange of nutrients and wastes in tissues.

They also play an important role in adjusting the velocity and volume of blood flow.

The five main types of blood vessels are arteries, arterioles, capillaries, venules, and

veins. The wall of a blood vessel consists of three layers (figure 3.1), an epithelial

inner lining (tunica interna,) a middle layer consisting of a smooth muscle and

elastic connective tissue (tunica media), and a connective tissue outer covering

(tunica externa)(Tortora and Derrickson, 2013; Khonsary, 2017).

7
 8

Figure 3. 1 Comparative structure of blood vessels (Tortora and Derrickson, 2013)

The heart has four chambers as seen in figure 3.2. The two superior receiving

chambers are the atria (entry halls or chambers), and the two inferior pumping

chambers are the ventricles It is composed of three major types of cardiac muscle:

atrial muscle, ventricular muscle, and specialized excitatory and conductive muscle

fibers (Tortora and Derrickson, 2013).

The atrial and ventricular types of muscle contract in much the same way as

skeletal muscle, except that the duration of contraction is much longer. The

specialized excitatory and conductive fibers, however, contract only feebly because

they contain few contractile fibrils; instead, they exhibit either automatic rhythmical

electrical discharge in the form of action potentials or conduction of the action

potentials through the heart, providing an excitatory system that controls the

rhythmical beating of the heart (Agur and Dalley, 2013; Khonsary, 2017).
 9

Figure 3. 2 Anterior view of frontal section showing internal anatomy

(Tortora and Derrickson, 2013)

3.1.2 Physiology

Arteries are thick-walled, high pressure vessels which conduct the blood from

the heart to the tissues, while veins are thin-walled, low pressure vessels returning

blood to the heart (Greenwood, Seymour and Meechan, 2009). To complete a full

circuit from the left ventricle, oxygenated blood must pass via the systemic arteries

to a tissue capillary bed where oxygen is taken up by the tissues. Deoxygenated

blood returns via the systemic veins to the right side of the heart, and thence through

the pulmonary artery to the pulmonary capillaries, where it is reoxygenated. The

pulmonary veins return the blood to the left side of the heart. Figure 3.3 represents

a schematic view of the heart and circulation (Tortora and Derrickson, 2013)
 10

Figure 3.3 Systemic and pulmonary circulations (Tortora and Derrickson, 2013)

The heart comprises four chambers that pump the blood, with four valves to

prevent retrograde flow. The left side of the heart receives oxygenated blood from

the lungs, via the pulmonary veins, into the left atrium. Blood flows from here,

through the mitral valve, filling the left ventricle, aided by atrial systole (contraction

of the left atrium). Ventricular systole ejects blood from the left ventricle through

the aortic valve into the aorta, and thence the systemic arterial circulation and

capillaries. During ventricular systole, the mitral valve closes to prevent blood
 11

flowing backwards into the left atrium, and the aortic valve opens to allow forward

flow from the left ventricle(Greenwood, Seymour and Meechan, 2009).

The right atrium receives deoxygenated blood from the systemic veins via the

inferior and superior venae cavae. The blood passes through the tricuspid valve into

the right ventricle. Right ventricular systole closes the tricuspid valve and propels

the blood through the pulmonary valve into the pulmonary artery, which divides

and takes blood to both lungs. During diastole, the heart muscle relaxes and the

mitral and tricuspid valves open to allow ventricular filling, while the aortic and

pulmonary valves close to prevent retrograde fl ow from the aorta and pulmonary

artery into the ventricles (Greenwood, Seymour and Meechan, 2009)

Contraction and relaxation of the cardiac muscle is coordinated by specialised

electrical tissues. The sino-atrial node, situated in the right atrium, acts as the

pacemaker, which stimulates atrial contraction. This occurs in a wave, with the

electrical activity and consequent contraction spreading across both atria towards

the atrioventricular (A-V) node. The A-V node detects the atrial depolarisation and

conducts it, after a short pause, via the bundle of His and the Purkinje fibres to both

ventricles (Greenwood, Seymour and Meechan, 2009; Tortora and Derrickson,

2013). These then depolarise and contract together to eject the blood. A diagram of

the cardiac conduction system is given in Figure 3.4

 12

Figure 3.4 The conduction system of the heart (Tortora and Derrickson, 2013)

3.2 Cardiovascular Disease (CVD)

3.2.1 Definition

CVD refers to a class of diseases that involve the heart and/or blood vesssels. It

is commonly related to atherosclerosis, a process whereby plaques (fatty deposit)

form in arteries.

3.2.2 Classification

The different types of CVDs are listed below.(Mendis, Puska and Norrving, 2011):

1. CVDs due to atherosclerosis,( the underlying disease process in the blood

vessels that results in coronary heart disease and cerebrovascular disease)

a) Ischaemic heart disease or Coronary artery disease (e.g. heart attack)

Coronary heart disease (CHD), is the end result of the accumulation of

atheromatous plaques within the walls of the arteries that supply the

myocardium (Greenwood, Seymour and Meechan, 2009)

b) Cerebrovascular disease (e.g. stroke)

 13

Cerebrovascular disease includes a variety of medical conditions that affect

the blood vessels of the brain and the cerebral circulation. Arteries

supplying oxygen and nutrients to the brain are often damaged or deformed

in these disorders. The most common presentation of cerebrovascular

disease is an ischemic stroke (Mendis, Puska and Norrving, 2011).

c) Hypertension

Hypertension is defined as systolic blood pressure greater than 140 mm Hg

or diastolic blood pressure greater than 90 mm Hg. It is one of the most

common and potentially dangerous medical conditions among the elderly,

affecting approximately two-thirds of men and three-quarters of women 75

years and older (Tavares, Lindefjeld Calabi and San Martin, 2014).

d) Peripheral vascular disease.

Peripheral artery disease refers to the obstruction of large arteries (outside

the heart and brain) from atherosclerosis. As a result of the inflammatory

process, stenosis, thrombus, or embolism can develop (Greenwood,

Seymour and Meechan, 2009).

2. Other CVDs

a) congenital heart disease

Malformations of heart structures present at birth are known as congenital

heart defects. They may be caused by: (i) a close blood relation between

parents; (ii) maternal infections (e.g. rubella); (iii) maternal use of alcohol

and drugs (e.g. warfarin); and (iv) poor maternal nutrition (e.g. deficiency

of folic acid). Examples of congenital heart disease include holes in the

 14

septum of the heart, abnormal valves and abnormalities in heart chambers

(Burket et al., 2008).

b) rheumatic heart disease

Rheumatic heart disease is caused by damage to the heart muscle and heart

valves from rheumatic fever, following a streptococcal pharyngitis/

tonsillitis (Nason, 2007) .

c) cardiomyopathies

Cardiomyopathy is a progressive disease of the myocardium, or heart

muscle, which affects the ability of the heart muscle to pump effectively.

There are different types of cardiomyopathy such as Dilated, Hypertrophic,

Restrictive and Arrhythmogenic Right Ventricular Cardiomyopathy

(Mendis, Puska and Norrving, 2011)

d) cardiac arrhythmias

Abnormalities of cardiac rhythm can be broadly defined as any deviation

from the normal cardiac pacemaker and conduction mechanism.

Tachyarrhythmias, when the heart rate is >100 bpm, occur as a result of

increased automaticity of cardiac pacemaker cells or due to a reentrant

mechanism where the electrical impulse circulates rapidly in certain areas

of the heart. Bradyarrhythmias occur as a result of sinoatrial node

dysfunction or conduction block at any level of the conduction system,

including the AV node, His-Purkinje system, or distal branches of the left

and right bundles. Bradyarrhythmias are associated with heart rates of <60

bpm (Burket et al., 2008)

 15

3.2.3 Epidemiology

CVD deaths account for one third of all deaths (50% attributed to coronary

deaths). In developed countries there is are decreasing tendencies (e.g, USA,

Sweden), attributed to: improvement of lifestyle factors, decrease of tobacco use,

higher level of health consciousness, better diagnostic and therapeutic procedures.

While in developing countries it shows an increasing tendencies due to increasing

longevity, urbanization and limited resources (Andersson and Vasan, 2018).

Early lesions of blood vessel, atherosclerotic plaques may be detected as early as

around 20 years of age. Adult lifestyle patterns usually start in childhood and youth

(tobacco use, dietary habits, sporting behavior, etc.) have an effect in the prevalence

of CVD premature death (<64 years). There is an increase in CVD morbidity and

mortality with increasing age however: in the elderly population it is more difficult

to interpret death rate due to multiple ill health (Institute of Medicine, 2010)

CVD mortality are more common among men. However, CVD affect nearly as

many women as men, but at an older age, women: have a higher risk (tobacco use,

high triglyceride levels). Higher prevalence of certain risk factors in women

(diabetes mellitus, depression) Gender-specific risk factors (risks for women only:

use of oral contraceptives, hormone replacement therapy, polycystic ovary

syndrome, etc. In a study done in the US, showed increased CVD deaths among

African-American and South-Asian populations in comparison with Caucasians

(Andersson and Vasan, 2018).

 16

3.2.4 Risk Factors

As CVD is such a complex collection of diseases, unsurprisingly there are a

number of risk factors involved. There is also the added complication that many of

the risk factors for CVD interact with one another.

Smoking

Smoking increases the risk of developing coronary heart disease is by 2–4 times.

Smoking is a powerful independent risk factor for sudden cardiac death in patients

with coronary heart disease; where smokers have about twice the risk of non-

smokers. For non-smokers; the British Heart Foundation estimates that regular

exposure to second hand smoke can increase the risk of CHD by up to 25%.23 The

main risk is in the increased tendency towards thrombosis, which can lead to

myocardial infarction. Other mechanisms include increased atherosclerosis, blood

pressure, heart rate, cardiac output and coronary blood flow. Smoking also

increases the levels of carbon monoxide in the body, which binds to haemoglobin,

reducing the amount of oxygen reaching body tissues (Andersson and Vasan, 2018).

Obesity

Obesity, particularly in those with excess fat around the waist, increases the

chance of developing CHD. Excess weight increases strain on the heart, raises

blood pressure and blood cholesterol and triglyceride levels, and lowers HDL

cholesterol levels. All of these factors can increase the risk of atherosclerosis and

thrombolytic embolism. It also increases the risk of developing type II diabetes,

another risk factor for CVD (Tavares, Lindefjeld Calabi and San Martin, 2014).
 17

Diabetes

Diabetes is a disease that affects an individual’s ability to maintain an

appropriate blood glucose level. The disease has two forms, Type I and Type II

diabetes. Type I diabetes is also known as insulin dependent diabetes and is caused

by the body not producing any insulin. Type II diabetes is the more common form

of the disease, and occurs when the body either does not produce enough insulin or

cells do not process the insulin properly. Both of these forms can lead to an

increased risk of CVD via increased cholesterol levels, hypertension and

atherosclerosis. Insulin resistance is also related to CHD (Andersson and Vasan,

2018).

High blood pressure

High blood pressure (hypertension) is strongly linked to both cardiac diseases

and those of the vascular system. High blood pressure affects the heart by causing

it to thicken and stiffen as it has to work harder to pump blood; this can lead to heart

attacks. The effect on the vascular system is one of pressure on vasculature walls,

leading to aneurisms and stroke. High blood pressure is a very common problem

in developed countries, with one in four adults in the USA diagnosed with

hypertension (Institute of Medicine, 2010).

High LDL cholesterol

The basic method by which LDL cholesterol (low density lipoprotein

cholesterol) increases the risk of CVD is by increasing the fatty deposits in blood

vessels, leading to atherosclerosis. Recently, research has suggested that LDL

 18

cholesterol actually activates endothelial cells to express adhesion molecules that

speed the process of atherosclerosis (Mendis, Puska and Norrving, 2011).

Socio-economic risks

CVD deaths are associated with low socio-economic standing. For example, in

developing countries such as Ukraine and India, the levels of CVD are up to 6 times

higher than developed countries such as Canada, Australia and Britain. This risk is

inextricably tied in with several other risk factors such as diet, physical activity and

levels of obesity. Even smoking is correlated with lower socio-economic status in

south Asian populations (Andersson and Vasan, 2018).

Physical inactivity

Physical inactivity is an important contributor to cardiovascular risk across all

continents and age groups. Physical activity can reduce cholesterol levels, decrease

obesity and cause the heart and muscles to work harder in pumping blood around

the body (Institute of Medicine, 2010).

Alcohol intake

Alcohol intake is complex since low levels of alcohol can reduce the risk of heart

disease (through antioxidant polyphenols inhibiting the oxidation of LDL

cholesterol) but high levels of alcohol intake actually increase the risk of CHD and

stroke (by increasing blood pressure) (Arunkumar et al., 2013).

Poor Diet

Another key risk factor often cited is nutrition, with poor diet having a direct effect

on fat concentrations in the body (increasing the risk of high cholesterol and

obesity), sugar levels in the blood (increasing the risk of developing type II
 19

diabetes) and salt levels in the blood (increasing blood pressure and the risk of

stroke)(Arunkumar et al., 2013).

3.2.5 Pathophysiology

Atherosclerosis

Atherosclerosis is the most common vascular disease and affects only arteries.

It is important in the pathogenesis of both coronary heart disease and cerebral

vascular disease. Atherosclerosis affects medium and large calibre arteries and

develops through three morphological stages: 1. Fatty streak, 2. Fibrolipid plaque

and 3. Complicated plaque (Greenwood, Seymour and Meechan, 2009).

The fatty streak is an accumulation of lipid in the intima of the artery wall, just

below the endothelial lining of the vessel. The lipid lies free and is also contained

within foamy macrophages. The fibrolipid plaque shows significant narrowing of

the arterial lumen, characterised by the deposition of collagen and progressive

fibrosis. The lesion has a fibrous cap that bulges into the lumen of the vessel.

Beneath the cap there are pools of lipid that contain cholesterol clefts and numerous

foamy macrophages. The internal elastic lamina fragments and smooth muscle cells

from the tunica media migrate into the lesion and lymphocytes also start to

accumulate (Greenwood, Seymour and Meechan, 2009).

In the complicated plaque, the fibrous cap becomes unstable and develops

surface defects, referred to as ulcers or intraplaque fissures. This exposes the fl

owing blood to plaque contents and consequently thrombosis develops over the

plaque. The thrombus may partially or completely occlude the vessel lumen. The

damaged artery may also show progressive calcification. In some cases, damage to
 20

the elastic tissue and smooth muscle of the vessel, as a consequence of

inflammation, results in gradual permanent dilation of the artery, forming an

aneurysm (Nason, 2007).

Some of the molecular changes that are associated with the development of

atherosclerosis have been elucidated. For example, cell adhesion molecules

(ICAM-1 and E-selectin) are important in recruiting macrophages into the fatty

streak and early fibrolipid plaque. Plateletderived growth factor (PDGF) is thought

to be pivotal in the progression of the lesion, as it stimulates the proliferation of

smooth muscle cells and fi broblasts and increases the deposition of collagen, elastin

and other matrix proteins within the lesion (Tavares, Lindefjeld Calabi and San

Martin, 2014).

Valvular heart disease

The two most important diseases affecting the heart valves are rheumatic fever

and infective endocarditis. These two diseases are characterised by permanent

damage to heart valves, which is associated with long-term risk of developing

recurrent disease and further damage to the heart. Damage to heart valves caused

by rheumatic fever increases the risk of developing infective endocarditis. In some

instances, the infective agent is an oral pathogen (Burket et al., 2008).

Rheumatic fever is a systemic disease that occurs 2–3 weeks after a streptococcal

upper respiratory tract infection; typically a pharyngitis caused by Lancefield group

A, β-haemolytic Streptococcus. The disease is characterised by inflammation at

multiple sites including the heart, arteries, joints and skin. The heart becomes
 21

generally inflamed and shows signs of endocarditis, myocarditis and pericarditisn

(Khonsary, 2017).

The damaging effects of endocarditis are long-lasting, whereas the effects of

myocarditis and pericarditis are transient. Endocarditis at the heart valves initially

produces small irregularities on the cusps of the valve called vegetations, which are

composed of platelets and fibrin. Recurrent infections cause valvular fibrosis, fusion

of valve leaflets and calcification. The mitral valve is most frequently affected,

although the aortic valve may also be involved. Over time the function of the valves

deteriorates and there is valvular stenosis and incompetence. An episode of

rheumatic fever increases the risk of developing infective endocarditis (Greenwood,

Seymour and Meechan, 2009).

3.2.6 Oral Manifestation and clinical features

Oral health is an imperative part of overall human health. Oral disorders are

often unreported, but are highly troublesome to human health in a long-standing

situation. The oral cavity is a mirror that reflects many of the human body’s internal

secrets. Poor periodontal health has been positively correlated with cardiovascular

disease (CVD) in numerous observational studies

3.2.6.1 Periodontal disease

Recent research indicates that periodontitis may be associated with the

development of cardiovascular disease. Periodontitis has been defined as ‘’an

infectious disease resulting in inflammation within the supporting tissues of the

teeth progressive attachment loss, and bone loss (Carranza et al., 2012).

Periodontitis is a chronic inflammatory disease of the tooth supporting tissues and

 22

is caused by oral bacteria, primarily anaerobic Gram-negative rods and spirochetes,

organized in protective biofilms on the surface of the teeth and extending into the

periodontal pockets (Hansen et al., 2016).

Figure 3.1 Periodontitis (Ubertalli, 2017).

Two biological mechanism that explain the relationship between cardiovascular

disease and periodontal disease are the bacteria from periodontal disease may enter

the circulation and contribute directly to the atheromatous or thrombotic processes

and the systemic factors alter the immune inflammatory process involved in both

periodontal and cardiovascular diseases (Figure 3.2). These may result in a systemic

inflammatory response and in combination with the predisposing condition

gingivitis, it is the most commonly occurring chronic infection in humans (Yahya,

2015).
 23

Figure 3.2 Two biological mechanism that explain the relationship between
cardiovascular disease and periodontal disease (Yahya, 2015).

Periodontitis and atherosclerosis are highly prevalent chronic inflammatory

diseases and it has been suggested that periodontitis is an independent risk factor of

cardiovascular disease (CVD) and that a causal link may exist between the two

diseases. Though no causal relation has been firmly established, there is mounting

evidence of an association between periodontitis and cardiovascular disease (CVD).

 24

Research has indicated that periodontal disease increases the risk of heart disease.

Scientists believe that inflammation caused by periodontal disease may be

responsible for the association. Periodontal disease can also exacerbate existing

heart conditions. Periodontitis and CVD share important common risk factors such

as smoking, diabetes mellitus and low socioeconomic status (Yahya, 2015).

3.2.7 Diagnosis of cardiovascular diseases

3.2.7.1 Hypertension

Hypertension is defined as having systolic blood pressure (SBP) ≥ 140 mm Hg

or diastolic blood pressure (DBP) ≥ 90 mm Hg or as having to use antihypertensive

medications. Hypertension is classified as primary (or essential) and secondary. For

most adults, there's no identifiable cause of high blood pressure. This type of high

blood pressure, called primary (essential) hypertension, tends to develop gradually

over many years (Greenberg and Glick, 2006).

Some people have high blood pressure caused by an underlying condition. This

type of high blood pressure, called secondary hypertension, tends to appear

suddenly and cause higher blood pressure than does primary hypertension. These

includes renal disorders such as renal parenchymal disease, renovascular disease,

renin-producing tumors, and primary sodium retention. Endocrinologic disturbace

that may result in hypertension include thyroid disease, adrenal disorders, carcinoid,

and exogenous hormones. Remaining causes include aortic coarctation,

complications of pregnancy (such as pre-eclampsia), neurlogic causes, acute stress,

 25

alcohol ingestion, nicotine use, increased intravascular volume, and the use of drugs

such as cyclosporine or tacrolimus (Greenberg and Glick, 2006).

Hypertension is usually asympromatic for many years, many patients are

undiagnosed, and many hypertensive patients present with only mild elevation in

blood pressure (BP) readings. The diagnosis of hypertension is made only after an

elevated BP has been recorded on multiple BP readings. Figure 3.3 shows the

classification of blood pressure in adults (Fraser et al., 2007).

Figure 3.3 Classification of Blood Pressure in Adults (Fraser et al., 2007).

3.2.7.2 Coronary Artery Disease

Coronary artery disease develops when the major blood vessels that supply the

heart with blood, oxygen and nutrients (coronary arteries) become damaged or

diseased. Cholesterol-containing deposits (plaque) in the arteries and inflammation

are usually to blame for coronary artery disease. When plaque builds up, they

narrow the coronary arteries, decreasing blood flow to the heart. Eventually, the

decreased blood flow may cause chest pain (angina), shortness of breath, or other

coronary artery disease signs and symptoms. A complete blockage can cause a heart

attack (Greenberg and Glick, 2006).

 26

Coronary artery disease is thought to begin with damage or injury to the inner

layer of a coronary artery, sometimes as early as childhood. The damage may be

caused by various factors, including smoking, high blood pressure, high cholesterol,

diabetes or insulin resistance and sedentary lifestyle. Once the inner wall of an

artery is damaged, fatty deposits (plaque) made of cholesterol and other cellular

waste products tend to accumulate at the site of injury in a process called

atherosclerosis. If the surface of the plaque breaks or ruptures, blood cells called

platelets will clump at the site to try to repair the artery. This clump can block the

artery, leading to a heart attack (Figure 3.4) (Mayoclinic, 2017).

Figure 3.4 Development of antherosclerosis (Mayoclinic, 2017).

If the coronary arteries narrow, they can't supply enough oxygen-rich blood to

the heart especially when it's beating hard, such as during exercise. At first, the

decreased blood flow may not cause any coronary artery disease symptoms. As

plaque continues to build up in the coronary arteries, however, you may develop

coronary artery disease signs and symptoms, including:

 27

1) Chest pain (angina). May feel pressure or tightness in the chest, as if someone

were standing on the chest. This pain, referred to as angina, usually occurs on

the middle or left side of the chest. Angina is generally triggered by physical or

emotional stress. The pain usually goes away within minutes after stopping the

stressful activity. In some people, especially women, this pain may be fleeting

or sharp and felt in the neck, arm or back.

2) Shortness of breath. If the heart can't pump enough blood to meet the body's

needs, you may develop shortness of breath or extreme fatigue with exertion.

3) Heart attack. A completely blocked coronary artery may cause a heart attack.

The classic signs and symptoms of a heart attack include crushing pressure in

the chest and pain in the shoulder or arm, sometimes with shortness of breath

and sweating.

3.2.7.3 Valvular Heart Disease

Heart valve disease is defined as when one or more of the valves in the heart

doesn't work properly. The heart has four valves that keep blood flowing in the

correct direction. In some cases, one or more of the valves don't open or close

properly. This can cause the blood flow through the heart to the body to be

disrupted. Patients with heart valve disease might not experience symptoms for

many years. Signs and symptoms of heart valve disease may include:

1) Abnormal sound (heart murmur) when a doctor is listening to the heart beating

with a stethoscope

2) Fatigue
 28

3) Shortness of breath, particularly when you have been very active or when you

lie down

4) Swelling of the ankles and feet

5) Dizziness

6) Fainting

7) Irregular heartbeat

Figure 3.5 Chambers and valves of the heart

 29

Figure 3.6 A normal heart and heart valve problems

The heart has four valves that keep blood flowing in the correct direction. These

valves include the mitral valve, tricuspid valve, pulmonary valve and aortic valve.

Each valve has flaps (leaflets or cusps) that open and close once during each

heartbeat. Sometimes, the valves don't open or close properly, disrupting the blood

flow through the heart to the body. Heart valve disease may be present at birth

(congenital). It can also occur in adults due to many causes and conditions, such as

infections and other heart conditions. Heart valve problems may include:

1) Regurgitation. In this condition, the valve flaps don't close properly, causing

blood to leak backward in the heart. This commonly occurs due to valve flaps

bulging back, a condition called prolapse.

 30

2) Stenosis. In valve stenosis, the valve flaps become thick or stiff, and they may

fuse together. This results in a narrowed valve opening and reduced blood flow

through the valve.

3) Atresia. In this condition, the valve isn't formed, and a solid sheet of tissue

blocks the blood flow between the heart chambers.

Several factors can increase the risk of heart valve disease, including older age,

history of certain infections that can affect the heart,history of certain forms of heart

disease or heart attack,high blood pressure, high cholesterol, diabetes and other

heart disease risk factors and heart conditions present at birth (congenital heart

disease). Heart valve disease can cause many complications, including heart failure,

stroke, blood clots, heart rhythm abnormalities and death (Greenberg and Glick,

2006).

3.2.7.4 Rheumatic Heart Disease

Patients with rheumatic heart disease will have or recently had a strep infection.

A throat culture or blood test may be used to check for strep. They may have a

murmur or rub that may be heard during a routine physical exam. The murmur is

caused by the blood leaking around the damages valve. The rub is caused when the

inflamed heart tissues move or rub against each other. Along with a complete

medical history and physical exam, tests used to diagnose rheumatic heart disease

may include:

1) Echocardiogram (echo). This test uses sound waves to check the heart's

chambers and valves. The echo sound waves create a picture on a screen as
 31

an ultrasound transducer is passed over the skin overlying the heart. Echo

can show damage to the valve flaps, backflow of blood through a leaky

valve, fluid around the heart, and heart enlargement. It’s the most useful test

for diagnosing heart valve problems.

2) Electrocardiogram (ECG). This test records the strength and timing of the

electrical activity of the heart. It shows abnormal rhythms (arrhythmias or

dysrhythmias) and can sometimes detect heart muscle damage. Small

sensors are taped to patient’s skin to pick up the electrical activity.

3) Chest X-ray. An X-ray may be done to check patient’s lungs and see if

patient’s heart is enlarged.

4) Cardiac MRI. This is an imaging test that takes detailed pictures of the

heart. It may be used to get a more precise look at the heart valves and heart

muscle.

5) Blood tests. Certain blood tests may be used to look for infection and

inflammation (Hopkins, 2018).

3.2.7.5 Heart failure

Heart failure, sometimes known as congestive heart failure, occurs when the

heart muscle doesn't pump blood as well as it should. Certain conditions, such as

narrowed arteries in the heart (coronary artery disease) or high blood pressure,

gradually leave the heart too weak or stiff to fill and pump efficiently. Not all

conditions that lead to heart failure can be reversed, but treatments can improve the

signs and symptoms of heart failure and help patients live longer. Lifestyle changes

such as exercising, reducing sodium in the diet, managing stress and losing weight
 32

can improve the quality of life. One way to prevent heart failure is to prevent and

control conditions that cause heart failure, such as coronary artery disease, high

blood pressure, diabetes or obesity (Mayoclinic, 2017).

Figure 3.7 Heart failure (Mayoclinic, 2017).

Heart failure can be ongoing (chronic), or the condition may start suddenly

(acute). Heart failure signs and symptoms may include:

1) Shortness of breath (dyspnea) when exert theself or when lie down

2) Fatigue and weakness

3) Swelling (edema) in the legs, ankles and feet

4) Rapid or irregular heartbeat

5) Reduced ability to exercise

6) Persistent cough or wheezing with white or pink blood-tinged phlegm

7) Increased need to urinate at night

8) Swelling of the abdomen (ascites)

 33

9) Very rapid weight gain from fluid retention

10) Lack of appetite and nausea

11) Difficulty concentrating or decreased alertness

12) Sudden, severe shortness of breath and coughing up pink, foamy mucus

13) Chest pain if the heart failure is caused by a heart attack

Figure 3.8 Enlarged heart, in heart failure (Mayoclinic, 2017).

Heart failure often develops after other conditions have damaged or weakened

the heart. However, the heart doesn't need to be weakened to cause heart failure. It

can also occur if the heart becomes too stiff. In heart failure, the main pumping

chambers of the heart (the ventricles) may become stiff and not fill properly

between beats. In some cases of heart failure, the heart muscle may become

damaged and weakened, and the ventricles stretch (dilate) to the point that the heart

can't pump blood efficiently throughout the body. Over time, the heart can no longer

keep up with the normal demands placed on it to pump blood to the rest of the body

(Mayoclinic, 2017).
 34

Heart failure can involve the left side (left ventricle), right side (right ventricle)

or both sides of the heart. Generally, heart failure begins with the left side,

specifically the left ventricle the heart's main pumping chamber.

Type of heart failure Description

Left-sided heart failure Fluid may back up in the lungs,

causing shortness of breath.

Right-sided heart failure Fluid may back up into the

abdomen, legs and feet, causing

swelling.

Systolic heart failure The left ventricle can't contract

vigorously, indicating a pumping

problem.

Diastolic heart failure The left ventricle can't relax or fill

(also called heart failure with fully, indicating a filling problem.

preserved ejection fraction)

Table 3.1 Type of Heart Failure (Greenberg and Glick, 2006).

Any of the following conditions can damage or weaken the heart and can cause

heart failure. Some of these can be present without the knowing it:

1) Coronary artery disease and heart attack. Coronary artery disease is the

most common form of heart disease and the most common cause of heart failure.
 35

The disease results from the build-up of fatty deposits (plaque) in the arteries,

which reduce blood flow and can lead to heart attack.

2) High blood pressure (hypertension). If the blood pressure is high, the heart

has to work harder than it should to circulate blood throughout the body. Over

time, this extra exertion can make the heart muscle too stiff or too weak to

effectively pump blood.

3) Faulty heart valves. The valves of the heart keep blood flowing in the proper

direction through the heart. A damaged valve — due to a heart defect, coronary

artery disease or heart infection — forces the heart to work harder, which can

weaken it over time.

4) Damage to the heart muscle (cardiomyopathy). Heart muscle damage

(cardiomyopathy) can have many causes, including several diseases, infections,

alcohol abuse and the toxic effect of drugs, such as cocaine or some drugs used

for chemotherapy. Genetic factors also can play a role.

5) Myocarditis. Myocarditis is an inflammation of the heart muscle. Its most

commonly caused by a virus and can lead to left-sided heart failure.

6) Heart defects you're born with (congenital heart defects). If the heart and its

chambers or valves haven't formed correctly, the healthy parts of the heart have

to work harder to pump blood through the heart, which, in turn, may lead to

heart failure.

7) Abnormal heart rhythms (heart arrhythmias). Abnormal heart rhythms may

cause the heart to beat too fast, creating extra work for the heart. A slow

heartbeat also may lead to heart failure.

 36

3.2.7.6 Arrhythmia

Heart rhythm problems (heart arrhythmias) occur when the electrical impulses

that coordinate the heartbeats don't work properly, causing the heart to beat too fast,

too slow or irregularly. Heart arrhythmias may feel like a fluttering or racing heart

and may be harmless. However, some heart arrhythmias may cause bothersome

sometimes even life-threatening signs and symptoms (Mayoclinic, 2017).

Arrhythmias may not cause any signs or symptoms. However, noticeable

arrhythmia symptoms may include:

1) A fluttering in the chest

2) A racing heartbeat (tachycardia)

3) A slow heartbeat (bradycardia)

4) Chest pain

5) Shortness of breath

6) Light-headedness or dizziness

7) Sweating

8) Fainting (syncope) or near fainting

 37

Figure 3.9 Normal heartbeat

Arrhythmias is classified not only by where they originate (atria or ventricles)

but also by the speed of heart rate they cause:

1) Tachycardia. This refers to a fast heartbeat, a resting heart rate greater than 100

beats a minute.

2) Bradycardia.This refers to a slow heartbeat, a resting heart rate less than 60

beats a minute.

However, not all tachycardias or bradycardias mean you have heart disease. For

example, during exercise it's normal to develop a fast heartbeat as the heart speeds

up to provide the tissues with more oxygen-rich blood. During sleep or times of

deep relaxation, it's not unusual for the heartbeat to be slower (Greenberg and Glick,

2006).
 38

3.2.8 Treatment

3.2.8.1 Hypertension

A large number of drug agents exist, including diuretics, β-blockers, calcium

channel blockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin

II receptor blockers, direct vasodilators, and centrally acting agents. Each of the

antihypertensive agents is roughly equally effective, producing a good

antihypertensive response in 40% to 60% of the cases. Thus, the choice among the

different antihypertensive drugs is not generally made on the basis of efficacy.

There is, however wide interpatient variability as many patients will respond well

to one drug but not to another. The identification of the particular drug class to

which a patient is more likely to respond is therefore one major criterion used in the

choice of an antihypertensive agent. Lifestyle modification is also important in

order to manage hypertension (Table 3.2) (Greenberg and Glick, 2006).

Table 3.2 Lifestyle Modifications to Prevent and Manage Hypertension

(Greenberg and Glick, 2006).
 39

3.2.8.2 Coronary Artery Disease (CAD)

The management of chronic, stable CAD depends on a number of clinical

factors, including the extent and severity of ischemia, exercise capacity, prognosis

based on exercise testing, overall left ventricle function, and associated

comorbidities, such as diabetes mellitus. Patients with a small ischemic burden,

normal exercise tolerance, and normal left ventricle function may be safely treated

with pharmacologic therapy. The front line of modern medical therapy includes the

selected use of aspirin, β-blockers, ACEIs, and HMG CoA reductase inhibitors.

These agents have been shown to reduce the incidence of subsequent myocardial

infarction and death. Nitrates and calcium channel blockers may be added to the

primary agents to relieve angina in selected patients (Greenberg and Glick, 2006).

3.2.8.3 Valvular Heart Disease

Heart valve disease treatment depends on how severe is the condition. Mange

the disease by monitoring the condition and regular follow-up appointments,

making healthy lifestyle changes and taking medications to treat symptoms. Heart

surgery may be needed eventually to repair or replace the diseased heart valve.

Surgery options include heart valve repair. When possible, heart valve repair is

recommended, as it preserves the heart valve and may preserve heart function. To

repair a valve, surgeons may separate valve flaps (leaflets or cusps) that have fused,

replace the cords that support the valve, remove excess valve tissue so that the

leaflets or cusps can close tightly or patch holes in a valve. Surgeons may often

tighten or reinforce the ring around a valve (annulus) by implanting an artificial

 40

ring. Surgeons may conduct a procedure using a long, thin tube (catheter) to repair

a valve with a narrowed opening. In this procedure, a doctor inserts a catheter with

a balloon on the tip into an artery in your arm or groin and guides it to the valve. A

doctor then inflates the balloon, which expands the opening of the valve. The

balloon is then deflated, and the catheter and balloon are removed. However,

additional procedures may be needed to treat the narrowed valve over time.

Another surgery option is heart valve replacement. In some cases, the valve can't

be repaired, and surgeons may perform heart valve replacement. In heart valve

replacement, the surgeon removes the damaged valve and replaces it with a

mechanical valve or a valve made from cow, pig or human heart tissue (biological

tissue valve). Biological tissue valves degenerate over time, and often eventually

need to be replaced. People with mechanical valves will need to take blood-thinning

medications for life to prevent blood clots.

Figure 3.10 Mechanical Valve Replacement

 41

Figure 3.11 Biological Valve Replacement

3.2.8.4 Heart failure

The treatment of heart failure must be individualized to the etiology of the heart

failure and to the patient. Patients with coronary artery disease and heart failure

should be evaluated for ischemia as well as viable but hibernating myocardium that

would improve systolic and diastolic performance with revascularization. Patients

with alcoholic cardiomyopathy should be advised to abstain from alcohol, in

addition to the usual therapeutic options, as this often leads to an improvement in

left ventricle performance. Hypertension should be aggressively treated with

pharmacologic intervention and dietary measures. The initial treatment in

decompensated heart failure is with intravenous or oral diuretics (Greenberg and

Glick, 2006).
 42

Intravenous vasodilators such as Nitroglycerin may also be used. The majority

of patients with symptomatic heart failure will need to stay on oral diuretic therapy.

The dose of the diuretic must always be individualized. For patients with systolic

heart failure, ACEIs are one of the mainstays of chronic drug therapy. These agents

have clearly been shown to decrease mortality and to prolong survival. They also

delay onset and reduce the symptoms of heart failure in patients with Left ventricle

systolic dysfunction. When ACEIs cannot be tolerated, angiotensin receptor

antagonists or the combination of hydralazine and nitrate derivatives may be

substituted. Digoxin is effective in reducing morbidity and hospitalizations but has

little effect on overall mortality (Mayoclinic, 2017).

3.2.8.5 Arrhythmia

A wide variety of strategies have been used in the attempt to restore and maintain

normal sinus rhythm, including β-blocker drugs, antiarrhythmic therapy, and

electrical cardioversion. Historically, chemical or electrical cardioversion has been

performed after at least 3 to 4 weeks of anticoagulation with warfarin as this has

been shown to reduce the risk of thromboembolism (Greenberg and Glick, 2006).

3.2.9 Oral Manifestation of Cardiovascular Drugs

A strong association exists between cardiovascular drugs and oral adverse

effects. Indeed, several cardiovascular drugs employed clinically have been

reported to cause oral adverse effects such as xerostomia, oral lichen planus,

angioedema, aphthae, dysgeusia, gingival enlargement, scalded mouth syndrome,

cheilitis, glossitis and so forth. Oral complications might in turn worsen the
 43

cardiovascular disease condition as some reports suggest an adverse correlation

between periodontal oral disease pathogenesis and cardiovascular disease.

3.2.9.1 Xerostomia: dry mouth

Xerostomia is not a disease, but is the subjective sensation of dry mouth, which

occurs as a result of reduced secretion and flow of saliva. Salivary gland secretion

is regulated by autonomic nervous system where the fluid component is generally

produced by parasympathetic stimulation while the protein component is released

in response to sympathetic stimulation. Despite the fact that dry mouth has a variety

of possible causes, use of medications possibly those with anticholinergic activity

against M3 muscarinic receptors is one of the common causes of reduced salivation

(Greenberg and Glick, 2006).

An antihypertensive drug, clonidine, a centrally acting alpha-2 adrenergic

agonist and imidazoline receptor agonist, is well-known to cause dry mouth as a

common adverse effect. Other centrally acting antihypertensives such as guanfacine

and alpha methyldopa induce peripheral sympathetic inhibition as a result of alpha-

2 adrenoceptor stimulation in the brain stem, and both drugs have a tendency of
 44

causing dry mouth as an adverse effect. Since this adverse effect is mainly mediated

through alpha 2 adrenergic receptor stimulation, it has been suggested that it would

fundamentally be impossible to detach the adverse effect from the desired centrally-

mediated blood pressure-lowering effects of centrally acting antihypertensives.

Diuretics are the commonly used class of drugs for the management of

hypertension and congestive heart failure. The use of diuretics is associated with an

induction of dry mouth. Treatment with thiazide diuretic, bendroflumethiazide in a

low-dose was noted to significantly reduce the stimulated whole salivary flow rate

and total sodium, indicating the involvement of an additional mechanism

accompanying to diuretics-associated dry mouth. It is worth mentioning that

diuretics significantly reduce salivary flow rates and alter salivary composition,

which might have an impact on the incidence of dental caries, periodontal diseases

and mucosal lesion formation (Siegel, 2000).

Calcium Channel Blockers (CCBs) are employed for the management of

hypertension, cardiac arrhythmia and stable angina. Nifedipine, verapamil and

diltiazem can cause dry mouth by inhibiting salivary secretion. Hattori and Wang,

suggested that non-selective cation and voltage-dependent Ca2+ channels are

involved in the resting salivation while CCBs can depress H2O secretion by

blocking Ca2+ channels and by this means can cause dry mouth (Balakumar,

Kavitha and Nanditha, 2015).

 45

3.2.9.2 Oral lichen planus

Oral lichen planus (OLP) is a chronic inflammatory disease in which the oral

mucosa is affected. The etiology of the disease is not clear. The clinical

manifestations of OLP are represented by rarely symptomatic bilaterally located

white papules that form either a reticular, annular or plaque-like pattern. In addition,

OLP can manifest with erythematous, erosive and ulcerative lesions.

The pathogenesis of b-blocker-induced Lichen Planus-Like Drug Eruption

(LDE) is unclear but it may involve the blockade of b-adrenoreceptors. The b2

subclass of receptors is present on epidermal keratinocytes, Langerhans cells, and

dendritic cells. These cells also possess pattern recognition receptors (PRR), whose

role is to detect pathogen-associated molecular patterns (PAMP). Rises in

inflammatory cytokines and antigen-specific plasmacytoid dendritic cells necessary

for the pathologic cascade of lichenoid tissue reactions occur when skin is exposed

to a non-selective b-blocker and a peptidogylcan (a PAMP). This suggests that the

dermal adrenergic system may have a role in controlling the T helper-1 response of

pathogens that is recognized by the PRRs and thus its blockade with a b-blocker

may potentially lead to a T helper-1-sustained skin inflammatory process such as a

lichenoid tissue reaction (Fessa et al., 2012).

 46

3.2.9.3 Aphthous ulcers

Aphthous ulcers are characterized by multiple, recurrent, small and round ulcers

with circumscribed margins and erythematous haloes present in different size.

Aphthous mouth ulcers recur from time to time while the ulcers might usually heal

without treatments in 10-14 days. The etiology of aphthous ulcers is not precisely

known. Few cardiovascular medicines might cause aphthous as an adverse effect

(Siegel, 2000).

ACE inhibitor, Captopril is metabolized by a polymorphic Cytochrome P450

(CYP) enzyme, implying that abnormal drug metabolism could be a risk factor for

oral ulceration. Non-polymorphic variation (CYP3A4) in metabolism phenotype or

interaction by substrate competition/inhibition (CYP3A4) is a candidate risk factor

in the ulceration pathogenesis. Accumulation of drug metabolites or their impaired

detoxification products might account for the delay in clinical presentation of the

reactions (Balakumar et al., 2015).

 47

3.2.9.4 Gingival enlargement

Gingival enlargement or gingival overgrowth is a preferred term for initially

employed terms such as gingival hyperplasia (refers to an increased number of

cells) or gingival hypertrophy (refers to an increase in the size of individual cells).

Phenytoin and a variety of CCBs are known to produce gingival overgrowth as an

adverse effect (Siegel, 2000).

Phenytoin is a sodium channel blocker and a class-I anti-arrhythmic drug. In

phenytoin-induced gingival overgrowth, the fundamental disturbance occurs in the

gingival fibroblast where phenytoin and its metabolites have a direct action leading

to a subsequent increase in collagen production. Metabolism of phenytoin by

CYP2C9 is the major route of elimination of this drug, and phenotyping studies

have identified individuals with impaired capacity to metabolize the substrate are

at a higher risk of gingival over growth (Kalmar, 2016).

Gingival enlargement is also a common adverse effect of some CCBs,

characterized by an increase in the gingival mass and volume ranging from mild to

severe. The pathogenesis of CCB-induced gingival overgrowth remains unclear.

Genetic predisposition and pharmacokinetic variables are among the factors

implicated in its pathogenesis. Alternatively, reactive drug metabolites (RDMs)

may be produced as the CYP3A4 gene catalyzes the formation of such metabolites
 48

in both healthy and hyperplastic gingival tissues from patients receiving

cyclosporine and nifedipine therapy. Overall, the pathogenesis of drug-induced

gingival enlargement has not been precisely understood although some putative

mechanisms exist in the literature (Balakumar et al., 2015).

3.2.9.5 Angioedema

Angioedema is an extreme temporary swelling of a localized body area

involving skin, mucosa and subcutaneous tissues. Areas that are commonly affected

by angioedema include face, lips, tongue and pharynx (Amar and Khan, 2011).

ACE inhibitors are known to cause angioedema. In case of ACE inhibitors-

induced angioedema, the tongue and the mucous membranes of oropharynx and

perioral regions are the most common sites of involvement. ACE inhibitors-induced

angioedema is unaccompanied by hives, and is caused by bradykinin accumulation

because of the inhibition of enzymatic degradation of tissue bradykinin. In addition,

cardiovascular drugs-induced angioedema (Table 1) could occur with the use of

ARBs, renin inhibitor, beta-blockers, CCBs and diuretics. Among these

cardiovascular pharmacological interventions, ACE inhibitors are the most

frequently reported class of drugs causing angioedema (Fig. 1) (Balakumar et al.,

2015).
 49

Table 1 List of Cardiovascular Drugs and associated

Angioedema occurs in 0.1–0.5% of patients taking ACE inhibitors like

Captopril, Enalapril, Lisinopril, etc. The reason behind why a few individuals, but

not all, on ACE inhibitor therapy develop angioedema is not precisely understood.

It was suggested that patients developing angioedema during ACE inhibitor therapy

might be those with a congenital or acquired impairment in the activity of kininase

I, which degrades bradykinin, resulting in significant accumulation of bradykinin

once ACE (also called as kininase II) activity is blocked. ACE inhibitors-induced

angioedema usually appears during the first week of treatment. It was however

suggested that angioedema might occur at any time during the long-term use of

ACE inhibitor like Enalapril. Of note, continuing the use of ACE inhibitors in spite

of angioedema incidence could result in a markedly increased rate of angioedema

recurrence with serious morbidity. Therefore, ACE inhibitors therapy should be

stopped if angioedema develops, while alternative therapy might be considered

(Balakumar et al., 2015).

 50

ARBs have previously been proposed to be an alternative class of drugs for

hypertension management in those patients having a past history of angioedema

incidence with ACE inhibitors. This is because of a theoretical advantage of ARBs

having no direct action on bradykinin accumulation (Balakumar et al., 2015).

3.2.9.5 Taste disturbance-dysgeusia

Taste perception significantly contributes to sense of well-being and satisfactory

life of a person, while dysgeusia (a distortion of the sense of taste) is a kind of

uneasiness and discomfort during food intake. Taste disturbance could therefore

hamper the life quality of a person by influencing appetite, body weight and

psychological well-being that might require discontinuation of drug administration.

Drug-induced taste disorders might involve different mechanisms, including

dysfunction of taste buds or neurons involving the ion channels. Few cardiovascular

drugs are known to cause taste disturbance as one of adverse reactions (Table 2);

however, the precise mechanism involved in it is obscure (Balakumar et al., 2015).

Table 2 List of Cardiovascular Drugs causing dysgeusia and gingival enlargement

 51

It has been previously suggested that 36% of antihypertensive and

antihyperlipidemic drugs produce untoward changes in chemosensory perception,

which could adversely affect the quality of life. The clinical use of ACE inhibitors

like captopril is associated with taste disturbance. This may not be a class effect

since taste disturbance was rarely observed with other ACE inhibitors such as

Lisinopril and Benazepril. Captopril is the one among ACE inhibitors that has been

well-reported to cause taste disturbance. Taste impairment due to Captopril has

been suggested to be reversible and usually self-limited to 2–3months, while weight

loss might be associated with the loss of taste. Although the precise mechanism

involved is unknown, it was proposed that the inhibition of ACE by the drug might

affect the zinc of the ACE protein in salivary gland cells, which might subsequently

cause taste alteration. Like captopril, ARBs also cause taste disturbance (Balakumar

et al., 2015).

Losartan was reported to be associated with reversible dysgeusia. Likewise,

there is an evidence of incidence of dysgeusia and burning mouth syndrome

induced by Eprosartan. Candesartan, an ARB, subclinically reduced the taste

sensitivity after a repeated dosing in healthy subjects. The authors suggested, since

similar events were reported for Losartan and Valsartan in case reports, taste

disturbance might be a class effect of ARBs. The taste disturbance-induced by

Candesartan was potentially similar to that of Valsartan. The mechanism involved

in ARBs-induced taste disturbance remains to be elucidated (Balakumar et al.,

2015).
 52

3.2.9.6 Scalded mouth syndrome

Scalded mouth syndrome may be associated with a burning pain of oral soft

tissues. A few case reports of scalded mouth syndrome have been reported with

ACE Inhibitors such as Captopril, Enalapril and Lisinopril (antihypertensives). This

condition however was suggested to be a rare adverse effect of ACE inhibitors. A

scalded sensation of the oral mucosa during the treatment with Captopril or

Enalapril was initially reported. Hence, a case study reported that a hypertensive

patient treated with Lisinopril developed a burning sensation in lips and buccal

mucosa while the symptoms were noted to be similar to that of scalded mouth

syndrome associated with the use of ACE inhibitors like Captopril and Enalapril as

previously reported. This reaction to ACE inhibitors appeared dose-related whereas

the reaction was reported to be subsided with a decreased dosage or drug

discontinuation. The possible mechanism involved in ACE inhibitors-associated

scalded mouth syndrome is not known. Considering that antihypertensive drugs

which act upon the renin-angiotensin system have been associated with BMS-like

symptoms, and in view of the heterogeneity of the described cases of BMS, the

underlying etiology in some situations may involve an anomaly of the

 53

reninangiotensin system that blocks angiotensin II activity and causes burning

sensation of the oral mucosa.(Balakumar et al., 2015).

3.2.9.7 Cheilitis and glossitis

Cheilitis is an inflammation of the lips that can be manifested as dryness, itching,

burning, erythema, fissuring and edema. The inflammation might occur in the

perioral skin around the mouth and the vermilion border. Simvastatin, a cholesterol-

lowering agent, has been reported to possibly induce cheilitis (Table 3) in patients

with hyperlipidemia. Of note, the rash resolved after drug discontinuation and

subsequent treatment with topical moisturizers and topical corticosteroids.

Unpublished evidence indicates that phenytoin might also cause cheilitis. Not much

clinical data however is available to highlight the association of cardiovascular

drugs and cheilitis (Balakumar et al., 2015).

Glossitis is an inflammation and soreness of tongue that may be associated with

depapillation of the dorsal surface of tongue. Few evidences support the correlation

of glossitis with cardiovascular drugs (Table 3). There have been reports of tongue

ulceration and glossitis associated with the use of nicorandil. Glossitis associated

with upper respiratory tract infection has also been reported with the use of enalapril

(Balakumar et al., 2015).

 54

Table 3 List of Cardiovascular Drugs and associated Oral Adverse Effects.

 CHAPTER 4

DISCUSSION

Adverse correlation between oral diseases and cardiovascular diseases. Several

studies have shown the adverse association between oral disease conditions and

cardiovascular diseases like atherosclerosis and coronary heart disease. Oral

infection and inflammatory condition like periodontitis are considered a risk factor

for vascular endothelial dysfunction in patients with coronary artery disease.

Periodontitis is an oral infection characterized by gradual destruction of tooth

supporting tissues. It was suggested that those with periodontitis had 25% increased

risk of coronary heart disease as compared to those with minimal periodontal

disease. In addition, poor oral hygiene has also been associated with an increased

incidence of coronary heart disease. A recent study demonstrated that pathological

periodontal pockets were related with raised diastolic blood pressure in obese

adolescents. These evidences strongly support the adverse correlation between

periodontal oral diseases and cardiovascular diseases.

Cardiovascular drugs are indeed not reported to directly cause periodontitis.

However, cardiovascular drugs-induced xerostomia might develop a burning or

scalded sensation and poor oral hygiene, make the patients prone to have dental

caries, oral infections and periodontal disease. Xerostomia may therefore be linked

with gum disease and tooth loss. Xerostomia is also adversely associated with

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dysgeusia, cheilitis, inflammation of the tongue and buccal mucosa, oral candidiasis

enough high fiber fruits and vegetables daily. This causes accumulation and

salivary gland infection. Xerostomia could cause a decrease in normal salivary

cleansing mechanisms and buffering capacity of saliva. Medications-induced

xerostomia might be associated with compromised chewing, speaking and tasting,

and increased risk for caries and periodontal disease. An increase in inflammatory

gingival diseases, dental caries and rapid tooth destruction might partially be a

consequence of xerostomia. Adding to this, a recent study suggested that diuretics-

associated xerostomia and altered salivary composition might have an impact on

the incidence of dental caries, periodontal diseases and mucosal lesion formation.

Taken together, cardiovascular drugs-associated oral complications could adversely

affect their cardiovascular therapeutic outcomes. It is therefore indispensable to

have awareness of incidence of oral adverse reactions during cardiovascular

therapies, and healthcare professionals must find an alternate therapy if such

reactions occur in patients in order to have optimal cardiovascular therapeutic

outcomes.
 CHAPTER 5

CONCLUSION

Good oral health is foreseeable to get away from secondary cardiovascular

complications since available evidences correlate oral disease like periodontitis

with cardiovascular diseases. A plethora of evidences support the fact that many

cardiovascular drugs could cause oral adverse reactions such as xerostomia, lichen

planus, aphthous ulcers, angioedema, dysgeusia, gingival enlargement, scalded

mouth syndrome, cheilitis, glossitis and pemphigus, affecting the oral physiology

and health. It is therefore expected that cardiovascular drugs-associated oral adverse

effects could unfavorably affect their cardiovascular therapeutic outcomes. The

physician must therefore be well aware of such oral complications induced by

cardiovascular drugs, and counsel patients to notify if such complications are

experienced by them during the cardiovascular therapy. This could certainly ensure

the physician to timely recommend an alternate cardiovascular medication in order

to have better cardiovascular therapeutic outcomes

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 REFERENCES

Agur, A. and Dalley, A. (2013) ‘Grant’s altas of anatomy’, in Lippincott Williams

& Wilkins. 12th edn, pp. 1689–1699. doi:
10.1017/CBO9781107415324.004.
Alipour, H. and Goldust, M. (2016) ‘The association between blood pressure
components and cognitive functions and cognitive reserve’, Clinical and
Experimental Hypertension, 38(1), pp. 95–99. doi:
10.3109/10641963.2015.1047946.
Andersson, C. and Vasan, R. S. (2018) ‘Epidemiology of cardiovascular disease in
young individuals’, Nature Reviews Cardiology. Nature Publishing Group,
15(4), pp. 230–240. doi: 10.1038/nrcardio.2017.154.
Arunkumar, S. et al. (2013) ‘Adverse Oral Manifestations of Cardiovascular
Drugs’, IOSR Journal of Dental and Medical Sciences, 7(5), pp. 64–71.
Balakumar, P., Kavitha, M. and Nanditha, S. (2015) ‘Cardiovascular drugs-induced
oral toxicities: A murky area to be revisited and illuminated’,
Pharmacological Research. Elsevier Ltd, 102, pp. 81–89. doi:
10.1016/j.phrs.2015.09.007.
Burket, L. W. et al. (2008) ‘Burket’s Oral Medicine’, in, pp. 86–100. doi:
10.1002/1521-3773(20010316)40:6<9823::AID-ANIE9823>3.3.CO;2-C.
Fessa, C. et al. (2012) ‘Lichen planus-like drug eruptions due to beta-blockers: a
case report and literature review’, Am J Clin Dermatol, 13(6), pp. 417–421.
doi: 10.2165/11634590-000000000-00000.
Genco, R., Offenbacher, S. and Beck, J. (2002) ‘Periodontal disease and
cardiovascular disease’, The Journal of the American Dental Association.
American Dental Association, 133(June), p. 14S–22S. doi:
10.14219/jada.archive.2002.0375.
Greenwood, M., Seymour, R. A. and Meechan, J. G. (2009) ‘Textbook of human
disease in dentistry’, in Wiley-Blackwell Publishing Ltd, pp. 340–340. doi:
10.1038/sj.bdj.2009.895.
Institute of Medicine (2010) Promoting cardiovascular health in the developing
world: A critical challenge to achieve global health, The National
Academies Press. doi: 10.1097/01.hjr.0000125758.79536.c2.
Kholy, K. E., Genco, R. J. and Van Dyke, T. E. (2015) ‘Oral infections and
cardiovascular disease’, Trends in Endocrinology and Metabolism, 26(6),
pp. 315–321. doi: 10.1016/j.tem.2015.03.001.
Khonsary, S. (2017) ‘Guyton and Hall: Textbook of Medical Physiology’, Surgical
Neurology International, 8(1), p. 275. doi: 10.4103/sni.sni_327_17.
Mendis, S., Puska, P. and Norrving, B. (2011) ‘Global Atlas on Cardiovascular
disease prevention and control’, World Health Organization, 1(1), p. 155.
doi: NLM classification: WG 120.
Nason, E. (2007) ‘An overview of cardiovascular disease and research’,
International consortium of cardiovascular disease, 1, pp. 1–10.

58
Nguyen, C. M. et al. (2015) ‘Periodontal associations in cardiovascular diseases:
The latest evidence and understanding’, Journal of Oral Biology and
Craniofacial Research. Craniofacial Research Foundation, 5(3), pp. 203–
206. doi: 10.1016/j.jobcr.2015.06.008.
Tavares, M., Lindefjeld Calabi, K. A. and San Martin, L. (2014) ‘Systemic diseases
and oral health’, Dental Clinics of North America, 58(4), pp. 797–814. doi:
10.1016/j.cden.2014.07.005.
Tortora, G. J. and Derrickson, B. (2013) ‘Principles of Anatomy and Physiology’,
in John Wiley & Sons,Inc. 12th edn, pp. 602–610. doi:
10.1017/CBO9781107415324.004.
Wang, Z. et al. (2011) ‘Gut flora metabolism of phosphatidylcholine promotes
cardiovascular disease’, Nature, 472(7341), pp. 57–65. doi:
10.1038/nature09922.

59