CHAPTER ONE

1.0 INTRODUCTION

1.1 BACKGROUND

Aldosterone is a hormone produced within the Zona glomerulosa of the adrenal glands.

Aldosterone’s major role is to regulate water and electrolytes balance by maintaining blood

pressure homeostasis. The hormone has a significant impact on metabolic pathways and its

implication in pathogenesis of cardiovascular diseases is supported by vast body of evidence

based experimental and clinical studies. For instance increased mortality in patients with chronic

heart failures has been associated with elevated levels of aldosterone and increased levels of

circulating plasma aldosterone could result in myocardial infarction and hypertension. (Krug &

Ehrhart-Bornstein, 2008).

Pathogenesis of hypertension is implicated by mineralocorticoids based on clinical studies.

Evidenced based medical research has suggested that Primary aldosteronism is the most common

form of endocrine hypertension. Other than this, the importance of aldosterone in the incidence

of hypertension is also supported by clinical sub-analyses where plasma aldosterone levels

within the physiological range predispose toward the development of arterial hypertension{Krug,

2008 #3}. The aldosterone- renin ratio was shown to be a heritable trait influenced by clinical

and genetic factors. other than this vital discussion the crucial importance of aldosterone in the

incidence of arterial hypertension has been also supported by a follow-up sub-analyses from the

Framingham Offspring study where serum aldosterone levels were significantly associated with

an elevation of blood pressure in 1688 normotensives participants implying that increased

plasma aldosterone levels within the physiological range predisposes towards the development of

arterial hypertension{Krug, 2008 #3}.

 Aldosterone is connected to multiple cardiovascular diseases which includes endothelial

disfunction, thromboses and myocardial infarction as well as vascular fibrosis through alterations

in the activity of lipid metabolism (Hannich et al., 2018).

Several studies suggested that there may be an association between the concentrations of

aldosterone and certain components of lipid metabolism (Hannich et al., 2018). An interaction

between fat tissue and the aldosterone- sensitive organs might account for the numerous effects

observed in patients predisposed with cardiovascular diseases such as in obese patients.

Numerous findings stated that higher levels of renin and aldosterone are observed with higher

insulinemic effects of salt restriction in subjects with cardiovascular risk factors. Further research

confirmed the interaction between fat tissue and adrenal gland in humans and this occurs in two

pathways: first being the human adipose tissue aids in producing many components of the Renin-

Angiotensin-aldosterone system (RAAS) mainly adipose tissue derived angiotensinogen, and

secondly elevated levels of fatty acids in plasma of obese patients specifically non-esterified

fatty acids stimulates aldosterone production in the adrenal glands (Bruno Vogt, 2007).

The alterations of the lipid metabolic pathway can be determined by assessing the levels of total

cholesterol, HDL-C, LDL-C, VLDL. These parameters can be determined by lipid profile

technique.

A negative link between aldosterone and HDL-C and a positive correlation between aldosterone

and triglycerides was found in a study. Also, several other researches have stated the interaction

between aldosterone and metabolic syndrome, where high HDL-C and triglyceride levels in the

blood could be as a result of lower or higher levels of aldosterone. High levels of low-density

lipoprotein (LDL-C) and low levels of high-density lipoprotein (HDL-C) are risk factors for

cardiovascular diseases. According to the findings of various cross-sectional and longitudinal

investigations reveals that increased plasma aldosterone is linked to an altered lipid metabolism

(Hannich et al., 2018).

Also, aldosterone is thought to affect glucose homeostasis, as recent research has found that

patients with primary aldosteronism had a higher prevalence of type 2 diabetes, another cause for

increased mortality is dyslipidemia. Impaired glucose tolerance or hyperglycemia is an additional

factor balancing the alterations in lipids (Adolf et al., 2016).

Fatty acids and cholesterol are the end product of lipids metabolism. Fatty acids play a major

role in the clinical diagnoses of some certain conditions. Serum free fatty acids can be used to

hyperinsulinemia hypoglycemia. In effects, higher levels of this lipids could lead to deposition in

blood vessels of the cardiovascular system which would in turn cause blockage of the vessel

hence causing cardiac diseases.

1.2 PROBLEM STATEMENT

Alteration in lipid metabolism serves as the underlying factors that may cause the development

of certain diseases within our bodies. However current studies have it that the underlying

mechanism that positively corelates between circulating aldosterone and lipid concentration is

not well understood, also there has not been any study in Ghana regarding the association

between aldosterone and alterations in lipid metabolism.

In accordance with detailed investigations which suggest a direct correlation between

aldosterone and the major components of lipid metabolism in category of patience. The data

from the general population regarding this association is sparse. In summary, some studies

suggest a possible correlation between Plasma Aldosterone and certain lipid metabolic disorders

such as Metabolic syndrome, hypertension, cardiovascular disorders but there hasn’t been any
well-established evidence between whether high or lower levels of aldosterone has a positive

influence on the depletions on the various end products of lipids metabolisms. However, there

could be a possible positive correlation if more intensive research is done to determine the

association between this aldosterone and the alterations in lipids metabolism as stated earlier

1.3 AIM/SPECIFIC OBJECTIVES

1.3.1 AIMs; The aim of this study is to investigate the levels of aldosterone and lipid metabolism

to establish positive correlation between the two parameters among the general population within

the tamale metropolis

1.3.2 SPECIFIC OBJECTIVES

To assess the association between aldosterone levels and lipid profile

To assess the association between aldosterone levels and HbA1c

1.4 RESEARCH HYPOTHESIS

HO: there is no possible correlation between aldosterone and alterations in lipid metabolism.

HA: there is a possible correlation between aldosterone and alterations in lipid metabolism.
 CHAPTER TWO (2)

2.0 LITERATURE REVIEW

2.1 CARDIOVASCULAR DISEASES

Cardiovascular diseases (CVDs) comprise diseases of the heart or blood vessels which are

stroke, coronary artery disease (CAD), peripheral artery disease and aortic disease. This tally

expropriated considerable impressiveness in the intercontinental world-wide health arena. CVDs

are at the moment considered globally, the fundamental cause of death and are proposed to

maintain so for many years to come (1). An estimation of 17.5 million individuals died from

CVDs in 2012, comprising 31% of the global deaths (2). It is estimated that around 7.4 million of

these deaths had to be due to the CAD and 6.7 million, stroke (1). The World Health

Organization (WHO) auspicate that there will be closely 20 million CVD-related deaths globally

in 2015 (3). Interestingly, approximately 80% of CVD-related deaths extremely as 87% of CVD-

related disablements cosmopolitan are recognized to eventualize in little and middle-income

nations (4).

In sub-Saharan Africa, the region is considered to form the youngest population in the world, and

the pattern of CVD-related morbidity and mortality has been somewhat interesting (5). Between

1990 and 2013, Sub-Saharan Africa remained the one region in the world where CVD-related

deaths accrued (6). In other areas of the world, the report has decreased regularly. CVD deaths

are the main cause of death in people over 45 in almost 9.2% of all African deaths and regions

(7). Cardiovascular diseases also represent approximately 7 to 10% of all adult medical

hospitalization for hospitals in Africa, indicating around 3 to 7% of heart failure (8). Africa has

the lowest CAD mortality rate, but the mortality rate by vascular accident of the brain (AVC) is

similar to that of the Western High-income countries (9). Stroke was the main CVD cause of
death and mortality in 2010 in Africa. About half a million of deaths due to stroke occurred in

sub-Saharan Africa only in 2012 and it exemplified 4.4% of all deaths in Africa (10).

The occurrence of rheumatic heart disease in Africa is the most significant form of acquired

CVD in children and adolescents and it stays as the highest globally (15-20 per 1,000 population)

(11). Greater than 50% 0f CVD-related deaths eventualize among individuals between the ages

30-69 years of age in Africa but it is 10 years or more below the equivalent group in the well

developed countries (12). The burden of CVDs will continue to rise in Africa, forecasts show the

doubling of the burden found in 1990 by 2020 (13). The increase in the load of CVD and related

conditions or risk factors on the African continent is partly due to the trendy mega, such as

globalization which leads to epidemiological metastases. Globalization, which has increased the

interconnection and interdependence of people and the state, has reduced the world to the world

village. It is generally a question of understanding two elements of interrelation, the opening of

an international border for the rapid flow of goods, services, finance, people and ideas and the

changes in national and international institutions and policies that promote or facilitate such

trends (14).

In 2008, CVDs were the practically preponderant customer to mortality in Ghana enclosed by

each NCDs extraordinarily as the considerable considerateness of institutional deaths accounting

for 14 .5% of reported deaths in the country compared to 13 .4% deaths from malaria (15). The

WHO approximates that for Ghana, the distinguishable possibility (%) of expiring from CVD,

cancer, diabetes, or long-standing respiratory consideration between magnitude of 30 and 70

years is 20 percent (16). In Ghana’s Capital, Accra, CVD was respectively the seventh and the

10th cause of death in 1953 and 1966 but escalated to be the leading cause of death in 1991 and

2001 (17). In the case of cities in the eastern part of Ghana, the CVDs was rated as a cause major
death in 2014 (18). According to the second largest city in Kumasi, 17.9% of acute medical

hospitalization, caused by CVD causes, including heart failure and stroke (19). In 2011, strokes

and CADs were the main causes of death in Ghana 3rd and 5th, occupying 7.34% and 6.97% of

deaths respectively (20). It has also been confirmed that the second largest Ghana’s tertiary

hospitals also built 9.1% of total medical hospitalization and 13.2% of all deaths by medical

adults due to the examination of total medical care (21). The mortality rate per stroke was 5.7%

in 24 hours, 32.7% in the 7th and 43.2% per 28th. The department of pathology of the Korle-Bu

Teaching Hospital (KBTH), Ghana’s premier health facility conducted a 5-year autopsy reviews

of cases and from the review, with 19,289 completed, CVD deaths took about one-fifth of the

deaths (22.5%) (22). Overall, it is far-reaching to highlight those collections on CVD

unwholesomeness and death rate in Ghana has been hampered by the deprivation of a nationally

characteristic population-based collections on annihilation and occasions of deaths. intrinsically,

several studies on occasions of annihilation chalk up typically been supported on wellness

effortlessness writes down outstanding to the down-and-out reporting of the Civil Registration

and vital Statistics system (23).

2.1.1 RISK FACTORS

CVD epidemiology has been studied in depth and the related risk factors have been well

documented. This includes age, hypertension (high blood pressure), smoking, blood cholesterol,

diabetes, overweight or obesity, lack of exercise and heart disease (24). Almost 13%, 9%, 6%

and 5% of the deaths linked to the CVD are due to hypertension, diabetes, bodily inactivity and

overweight and obesity (25). Most of the CVD risk factors have been reported to be related to

each other, for example, inactivity leads to overweight which is a risk factor for developing

hypertension. Modifiable risk factor is a type of CVD risk factor that are capable of being altered
and the other type that cannot be altered is called non-modifiable risk factor. Non modifiable risk

factors include age, sex, family history and ethnicity and all these can affect cardiovascular

disease. Old age is identified by World Health Organization as the most powerful risk factor for

CVD, with the chance of developing stroke doubling after every decade once the person reaches

the age of 55 years. There are other significant risk factors involved with men having higher

rates of coronary heart disease than women (26).

According to a study between patients reported in the Ghana tertiary center, the prevalence of

lipid abnormalities to be 65% for high total cholesterol, 32% for high triglycerides, 17% for low

high-density lipoprotein (HDL) and 61% for high low-density lipoprotein (LDL) (27). Recent

estimate shows the prevalence of smoking around 10% with increased rates in men (14%) than in

women (7%) and the rate of smoking in men currently is higher than in 2008 (8%) (28).

Individuals especially men with first degree blood relative that has suffered an incidence of CVD

before 55 years of age and similarly for women with a first-degree blood relative suffering CVD

before age 65 have an increased risk of CVD. Also, some ethnic groups exhibit higher rates of

cardiovascular disease than others (26)

The modifiable type of risk factors has notable outcome on CVD occurrence in the community.

The impact of the disease and the damage on the people in Australia 2003, listed 12 risk factors

connected to CVD which if brought together would result answers to 69% of these impact (29).

High cholesterol and high blood pressure are known to be the highest contributors to CVD. Lack

of physical activity, high body mass, tobacco use and low consumption of fruits and vegetables

are all risk factors. (30)

2.2 ALDOSTERONE BIOSYNTHESIS AND REGULATION

Aldosterone is the paramount human mineralocorticoid that is produced in the zona glomerulosa

of the adrenal gland. The endocrinal is the aftermath of a circularize of biosynthetic reactions. In

aldosterone synthesis, the last key steps include, sequential 11- hydroxylation, 18-hydroxylation

and 18-oxidation of the precursor steroid deoxycorticosterone (DOC) in the zona glomerulosa.

Aldosterone synthase is an enzyme encoded by the gene CYP11B2 and this enzyme performs all

the steps leading to the production of aldosterone, but a highly homologous enzyme which is like

aldosterone synthase named 11- beta- hydroxylase (which is also encoded by gene CYP11B1)

works analogously in the zona fasciculata to convert 11- deoxycortisol to cortisol. The two genes

lie in tandem on chromosome 8 in humans and are equivalent; the protein products are very alike

and they share about 95% identity of primary sequence (31)

The primary regulators of aldosterone production are plasma potassium and angiotensin II (Ang

II; regulated by the renin- angiotensin system). Aldosterone secretion is induced by angiotensin

II when there is sodium depletion and reduced extracellular fluid volume (32), however little

increase in plasma potassium act as powerful stimulus for the production of aldosterone (33).

Some other factors such as adrenocorticotrophin (ACTH) also influence aldosterone production,

even though its impact in the long- term regulation of aldosterone is not clear.

2.2.1 PHYSIOLOGIC ACTIONS OF ALDOSTERONE

Aldosterone links to the receptor of mineral corticosteroids (MR), an internal cellular receiver

belonging to steroids / thyroids / retinoid / super family orphans (35). Once a combined ligand /

receiver complex is unloaded in the nucleus and acts as a transcription factor by direct

interaction with the classic genomic effect of the DNA regulatory element (the classical genomic

effect of aldosterone) (36). Since MR has a similar affinity against aldosterone and cortisol, the
steroid system dehydrogenase 11 -Beta -Hydroxy acts as a guard to prevent activation by a much

higher level of cortisol (37). The type 2 isoform of the enzyme is seen in the renal distal nephron

and convert cortisol to its inactive metabolite, cortisone.

Traditionally, the main organ for aldosterone has been known to be the kidney; MR are seen in

the in increased concentration in the renal distal nephron and other epithelial cells like the colon

and ducts of the sweat and salivary glands, MR have been located also in non-epithelial sites like

the heart, brain, vascular smooth muscle, liver, and peripheral blood leukocytes (38). The most

characterized physiological effect of aldosterone is causing the increment of the reabsorption of

sodium in the kidneys and other secretory epithelial sites at the expense of potassium and

hydrogen ions (39).

The main parts of aldosterone- induced sodium and potassium transport are the luminal cells of

the cortical collecting tubes and the distal convoluted tubule. The product of the gene (s) due to

the interaction of the aldosterone / MR complexes which linking to the regulatory elements of

DNA is called Aldosterone Induced Proteins (AIP). The AIP may have influence on the apical

membrane, cellular energy production, and the basolateral Na/K-ATPase pump, leading to

increased sodium reabsorption and potassium and hydrogen ion excretion (40). Aldosterone is

likely to affect the control of BP by mechanisms other than the expansion of the volume of

simple plasma and increases relevant heart production due to the action of sodium homeostasis.

A similar action in peripheral blood vessels can cause reshaping, which can increase the BP. This

is supported by evidence that aldosterone levels are inversely proportional to arterial compliance

in essential hypertension (41).

2.3 HYPERTENSION

Hypertension, furthermore recognized as high blood pressure is a non-communicable disease

(NCD) which is related with increased mortality and morbidity. Hypertension is a disease that is

a silent threat to the health of people globally (42), affecting up to one third of the world

population (43). 7 million deaths occurred globally in 2010 was due to hypertension (44), high

blood pressure doubles the chance of getting cardiovascular diseases (such as coronary heart

diseases (CHD), stroke, peripheral arterial diseases, and congestive heart failure) and renal

failure (45). In Ghana, where the disease has contributed to the incredible prevalence of the heart

failure and renal insufficiency, the situation is not different (46), precursor of clinical

hypertension is prehypertension and also of cardiovascular disease (47)

If there are no appropriate control measures, the prevalence of hypertension in certain African

countries has increased significantly to more than 30% (48). Over the past 60 years, several

epidemiological studies have been carried out in Ghana. According to a survey carried out in a

village around 60 miles from Accra in 1950, 5.5% of the 255 villagers have cardiovascular

disease (49). Also, almost one fourth of deaths that occurred in Mamprobi, Accra in 1975-1980

was due to cardiovascular diseases (50). In 1981, the Ghana health assessment team estimated

that 7% of total healthy lives were lost and it was due to cerebrovascular disease and

hypertensive heart disease (51), the number of new hypertension cases reported in Ghana

outpatient public health establishments has increased more than 10 times, going from 49,087 in

1988 to 505,180 in 2007 (52). Hypertension on total ambulatory diseases reported during the

same period increased from 1.7% to 4.0% in all age groups. In most areas, hypertension is

classified as the most common cause of ambulatory patients. Stroke and hypertension are one of
the main causes of hospitalization and death. Hypertension is an important cause of heart and

renal failure in Ghana and it is ranked the fifth commonest cause of morbidity (53).

Heart disease and stroke are the first and third leading cause of deaths among adults in the

United States, whereas hypertension is a major controllable risk factor for these diseases,

coronary heart disease, stroke, congestive heart failure, renal diseases and peripheral vascular

disease progressively increase as blood pressure rises, this make the prevention and treatment of

hypertension essential (54). Far- reaching predictors of cardiovascular risk include systolic,

diastolic and pulse pressure (55), Blood pressure, in particular systolic blood pressure, increases

as you age. However, among the old hypertension, the risk of cardiovascular risk is closer to

systolic pressure than diastolic pressure (56). About 50 million adult Americans, almost a quarter

of the population, suffer from hypertension (57).

One third of blacks is assumed to have hypertension (58), as a whole, African-Americans

represent approximately 13% of the American population (59). The impact on the renal,

cardiovascular and central nervous system, high blood pressure makes a high price at a similar

cost to annual death and breast cancer of around 45,000 (60), Significantly, affected blacks are

unbalanced. In addition, hypertension is one of the most common reasons to find medical

services with more than 35 million visitors in the past year (61). The very high reimbursement

rate and mortality associated with high blood pressure between blacks are attributed to the

severity of complications related to the disease, such as initial development and cerebral vascular

accidents, acute myocardial infarction and disease renal to the final level (62). In addition, the

possibility of complications increases the prevalence of certain risk factors such as obesity,

stress, alcohol consumption and physical activity (63).

2.3.1 RISK FACTORS OF HYPERTENSION

The risk factors for hypertension that lead to hypertension can help explain why some people are

more likely to develop hypertension than other populations. Risk factors can be genetic,

behavioral or environmental origin or the result of medical disorders. They can be associated

with reversible, irreversible disorders or other influence (panel) (64). High blood pressure is

mainly linked to environmental and lifestyle factors, rather than genetically rejecting racial

differences. After adjusting socioeconomic status, the prevalence of hypertension in Africa and

Europe is considerably reduced. (65). By adding biological social factors such as weight gain,

high salt consumption, anxiety, psychological social stress and excessive alcohol consumption

necessary to cause disease, genetic and social factors can be authorized, and not decisive (66).

The genetic factors seem to play an important role in the common sensitivity to salt in blacks.

Unique genetic mutations promote salt retention by defects in manipulation of the sodium kidney

(67), many common variations linked to blood pressure must be found.

2.3.2 OBESITY

Two clinical factors, obesity and insulin resistance are considered a real contribution to the

variation of blood pressure, in the study of the heart of Framingham, a simple link between

obesity and hypertension is well documented, which indicates that if the weight increases by

10%, the SBP can cause an increase of about 6.5 mmHg (68). Likewise, there is a simple link

between the high body mass index (BMI) and hypertension, which is probably the result of the

increase of blood volume and cardiac output. This link is also supported by discovering that

blood pressure decreases when weight loss occurs (69). The single body mass index was the

most powerful predictor of hypertension in the health nurses Study II (70), a report on a stable
linear relation between adiposity and blood pressure is documented, independent of age and

body- fat distribution across developed and developing countries (71).

2.3.2 URBANISATION AND SOCIOECONOMIC STATUS

Urbanization is closely linked to an increase in the prevalence of hypertension (72), and the

movements from rural areas to urban areas are also associated with an increase in blood pressure.

Mass migration likely result in the increase prevalence of hypertension in black Africans living

in urban areas. Movement of people to settle in new places affect their food consumption, with

increased consumption of fat, oils and animal food, the change in food consumption can increase

weight, which is an independent risk factor for hypertension development. However, it was

argued that this factor was due to socioeconomic status, which is inversely proportional to the

prevalence of hypertension and mortality (73).

2.3.3 DIET AND EXCESS SALT INTAKE

The debate surrounding salt consumption on blood pressure stirred up by the publication of

significant and conflicting reports (74), regardless of this controversy, regulating organizations

like the European Union and the US Institute of Medicine agreed to reduce salt consumption.

The scope of salt consumption and the main source of salt consumption are hard to assess

precisely and changes in the developing countries where assessment were possible. The reactions

of blood pressure to changes in sodium intake (salt sensitivity) are absorbed by genetic, age,

body mass, related diseases and ethnic factors (75).

The high contribution in fructose and the relationship between systolic blood pressure is

evaluated (76), Sugar consumption has actually increased by 30-40 kg / year per person in

developing countries of the Middle East (77). Nutrition of many developing countries quickly

changed between the 1970s and the late 1990s (78). The bringing up of food processing and the
fast food industry has caused a lot of changes in the make-up of diet, most diets have become

richer in salt, sugar calories and fat and this have led to the rise in the prevalence of

hypertension, obesity and metabolic syndrome in developing countries.

2.4 BLOOD PRESSURE

Several constituents have been related with blood pressure levels in epidemiological surveys,

they include age, sex race socioeconomic status, starting level of blood pressure, early life

experiences, nutrition, alcohol intake, physical activity and exposure to several environmental

agents. In the western countries, the average values for systolic and diastolic blood pressure at

birth are around 70 and 50mm Hg, respectively (79). Systolic blood pressure rise progressively

during childhood, adolescence, and adulthood and get to an average value of about 140mm Hg

by the seventh or eighth decade, whereas diastolic blood pressure also increases with age but

with less steep rate than the systolic pressure and the average value stays flat or decline after the

fifth decade. With increasing age, pulse pressure extend and individual systolic pressure become

more common.

Most studies present evidence for an important role of common lifestyle- related exposures in the

beginning of high blood pressure and hypertension (80), they are high body weight and central

obesity, high sodium consumption, excessive alcohol consumption and physical inactivity. In

total, this exposure can probably explain most of the hypertension found in the general

population and is an important emphasis on the treatment and prevention of hypertension. Other

factors, including stress and general environmental exposure, can also play an important drilling

role, but evidence is not enough to guarantee strong recommendations for treatment or

prevention (81). Optimal blood pressure is defined as a systolic blood pressure less than 120 mm

Hg and diastolic blood pressure less than 80 mm Hg. Systolic reading value between 130 and
139-mm Hg or the reading value of diastolic between 85 and 89-mm Hg is designated as high

blood pressure. Hypertension is diagnosed when there is high systolic pressure (140 mm Hg) or

diastolic pressure (90mm Hg) and it is confirmed at two or more visit and measurement in a

health facility (81).

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