LITHUANIAN UNIVERSITY OF HEALTH SCIENCES
Faculty of medicine
Uric acid as a potential marker for the risk of
heart failure in hypertension
ABSTRACT
Uric acid as a final purine metabolism is a risk factor for cardiovascular disease when hyperureceamia appears which is above 6mg/dl for women and above 7 mg/dl for men . hyperureceamia is been a single effective factor in cardiovascular disease for many years ,yet the exact mechanism hasn't noticed. many studies suggested how uric acid provoking inflammatory factors can affect and damage endothelial cell and thus acute coronary artery diseases.
finally, it is essential to find out hypertension and increased uric acid in early stages in order to provide preventive treatment .
Keywords: Uric acid, Inflammatory factor, Heart failure risk, Hypertension، xanthine oxidase, hyperuricemia,
raktiniai žodžiai: Šlapimo rūgštis, uždegiminis faktorius, širdies nepakankamumo rizika, hipertenzija, ksantino oksidazė, hiperurikemija,
CHAPTER ONE:... 9
INTRODUCTION AND GENERALITIES ... 9
1. Introduction ... 10 1-2-research method... 12 1-3-research aim ... 12
CHAPTER TWO: ... 13
RESEARCH LITERATURE ... 13
2-1- Chronic Diseases ... 142-2-The concept of heart failure ... 14
2-2-1- Signs and symptoms ... 14
2-2-2-Treatment... 15
2-3- Advanced renal failure ... 15
2-4-1-increase in uric acid ... 17
2-4-2-Causes of hyperuricemia ... 17
2-4-3-Prevention of hyperuricemia ... 18
2-5- Hypertension ... 23
2-5-1- Blood pressure levels ... 24
CHAPTER THREE: ... 25
MATERIAL AND METHODS ... 25
3-1- Search strategy and study selection ... 25
CHAPTER FOUR: ... 26
RESEARCH FINDINGS ... 26
4-1 Research Findings ... 27
4-2 Relationship between uric acid and various diseases ... 28
4-3 Hypertension and hyperuricemia ... 29
4-4 Uric acid, metabolic syndrome and diabetes ... 31
4-5 uric acid and chronic kidney disease ... 31
4-6 Other diseases associated with hyperuricemia ... 32
CHAPTER FIVE: ... 33
DISCUSSION AND CONCLUSION ... 33
5-1- Discussion on the findings ... 33
5-2- Summary... 36
List of Pictures
Title
Page
picture 1: Uric acid formation...21 picture
2: Uric acid cycle ...22 picture 3:
Uric acid metabolism ...23 picture 4: Uric
acid excretion from the body ...24 picture 5: Urates
formation from the purine free diet ...24
ACKNOWLEDGEMENTS
I would like to thank my dear DR.jolanta laukaitiene for all her support, patience and unlimited help in such a difficult time during pandemic.
CONFLICT OF INTEREST
ABBREVIATIONS LIST
UA Uric acid HNT hypertension
SUA Serum uric acid NHANES National center for
health and nutrition research
CHF Congestive heart failure CAD Coronary artery
disease
CRP C-reactive protein GFR Glomerular filtration
rate
NAD+ Nicotinamide adenine dinucleotide
XO Xanthine oxide
CDC Center of disease control and prevention
ESRD End stage renal disease
CHAPTER ONE:
1. Introduction
Nowadays cardiovascular disease is one of the most common diseases all around the world. Salient increase of these diseases and their effects and complications and the costs they incur on society have led the medical community to seek programs for further investigation, prevention, early detection and effective treatment. Heart failure often means chronic heart failure and it occurs when the heart is unable to pump and cannot supply enough blood to the organs of the body. Heart failure in other words congestive heart failure (CHF)(1). Common causes of heart failure include coronary artery disease such as heart attack (stroke), high blood flow, atrial fibrillation, heart valve failure, alcohol abuse, cardiomyopathy, etc.(2).
As from previous century was found many connections between hypertension and other disease such as gout disease, renal disease, diabetes and cardiovascular diseases. Cardiac researchers have suggested that uric acid may be a cause of high blood pressure and kidney disease. In 1897, Dr. Davis wrote in a report to the American Medical Society: "High arterial pressure in gout is due in part to uric acid or other toxic substances in the blood that increase the tone of the arteries (kidneys)." Because uric acid-lowering drugs were not available during Dr. Davis' time, there was no study showing that uric acid played a causal role in the development of these diseases ...(3).
The relation between uric acid and cardiovascular disease was largely ignored until the mid1950s and early 1960s. Up to now, some epidemiological studies have reported an association between serum uric acid levels and a wide range of cardiovascular diseases, including hypertension, metabolic syndrome, coronary artery disease, cerebrovascular disease, vascular dementia, preeclampsia, and kidney disease. The relationship between uric acid and cardiovascular disease is seen not only in hyperuricemia (defined as uric acid levels above 6 mg/ dl in women and above 7 mg/ dl in men) but also in normal to high uric acid levels (Above mg/ dl 5.5-2.5)(4, 5).
endothelial cell proliferation and migration and stimulate the production of reactive protein (CRPC)(6). UA activates mitogens and proliferates VSMC cells through the membrane ion transport system, which is important in the onset of atherosclerosis(7). As a result, uric acid is produced in the human body by the breakdown of purines that 75% of which is excreted by the kidneys. Uric acid is a reducing compound, it oxidizes and releases electrons. The conversion of proteins to uric acid is catalyzed by an enzyme called xanthine oxidoreductase. The enzyme oxidoreductase has two different isoforms. The xanthine dehydrogenase isoform operates under physiological conditions and uses the nicotinamide adenine dinucleotide (NAD +) as the electron acceptor. In ischemic conditions, along with the breakdown of ATP into adenine and xanthine and the consequent increase in uric acid, the second isoform of the enzyme xanthine oxidase is activated. This form of xanthine oxidase enzyme, which uses oxygen as an electron acceptor, leads to the formation of superoxide anions(8). Superoxide anion directly inhibits nitric oxide. Nitric oxide acts as a vasodilator. Nitric oxide also inhibits the accumulation of leukocytes and platelets. Then with reduction of nitric oxide, which occurs in the presence of an increase in free radicals, it causes endothelial dysfunction(9).
The relative importance of these diseases remains controversial. Some experts, such as the Framingham Heart Research Group, have suggested that uric acid is not a risk factor for cardiovascular disease, and physicians only should rely on classical risk factors in assessing the patient. Serum uric acid levels have not been considered as a cardiovascular risk factor by non-of the major specialist associations(10).
Reactive oxygen species by xanthine oxidase can suppress the exciting and contractility process of cardiomyocytes through decrease in calcium load. These radicals from xanthine oxidase interfere with cell permeability as well as cell modulation of cell apoptosis (74,75).
The mechanism in which uric acid can lead to hypertension can be explained as following steps: 1. Increased in uric acid leading to 2. Activation of renin angiotensin aldosterone system and directly activating angiotensin two that causes 3. Increase in inflammatory factors, vasoconstriction, and reactive oxygen species results 4. Lipid peroxidase and inflammation to finally hypertension and atherosclerosis (74,75).
Uric acid is the final natural product of the breakdown of body tissues and food, especially protein. Uric acid is usually excreted by the kidneys, and excreted in the urine(12). If uric acid is overproduced, or the kidneys are unable to remove it from the blood, its level will increase in blood (called Hyperuricemia). The relationship between hyperuricemia and hypertension has been known since the 19th century(13).
Hypertension is one of the most common diseases and the main reasons of disability and mortality in the world. However, control of the disease is still difficult(14). Inhibition of various predisposing factors of hypertension can lead to better control of this disease(15). Hyperuricemia is known as a factor involved in the development of hypertension. Uric acid seems to be a potential marker for the risk of heart failure in hypertension, so it was investigated in this study.
1-2-research method
This study was done according to the main purpose of the study in a literature review method.
1-3-research aim
To conduct a literature review of available studies and researchers on uric acid risk in heart failure on patients with hypertension, epidemiology, prognosis, relation with other disease, treatment and clinical features.
AIMS AND OBJECTIVES:
AIM:
To conduct a literature review of available studies and researchers on uric acid risk in heart failure on patients with hypertension, epidemiology, prognosis, relation with other disease, treatment and clinical features
1.serum uric acid (SUA) and xanthine oxide (XO) activity, metabolism and their impacts on endothelial cells.
2.prognosis significant of uric acid in heart failure and adverse outcomes.
3.novel treatment requirements and their aims.
2-1- Chronic Diseases
Chronic diseases are the most common cause of death in the world today. Mortality from these infectious diseases has decreased since the beginning of the twentieth century due to immunization and the promotion of health care, but at the same time the achieved progress has caused the illnesses that were lethal in the past decades, led to be as chronic disease now(20). The population aging and the improvement of health care and especially the poor way of life are reasons for the increasing prevalence of chronic diseases in the world. At present, these diseases lead to the death of 38 million people annually(21). It is expected to cause as much as 80% of deaths in low- and middleincome countries by 2020(22). Some researchers also estimate that the number of people with chronic diseases by 2050 is more than 167 million(23). Statistics of the United States show that half of the population suffers from at least one type of chronic disease(24).
According to the definition of the World Health Organization, chronic diseases, including those physical or mental illnesses that have a slow trend and lasting more than a year, cause limitations in the patient's daily functions and require constant control and treatment(25).
The CDC report on chronic diseases indicates that the cost of treating these diseases is 20 to 30 times of acute diseases, so that $ 5,300 is spent annually on various aspects for person with a type of chronic disease recover, and in general these diseases lead to the loss of 75% of the total health budget of the United States. In addition to significant economic losses, chronic diseases also affect the quality of life of patients and labor productivity, so the control and management of these diseases play an important role in reducing these losses and other problems such as the need for readmission and finally, improve the quality of patient's life(26).
2-2-The concept of heart failure
Heart failure often means chronic heart failure and occurs when the heart is unable to pump and supply enough blood to the organs. Heart failure is also called congestive heart failure (CHF). Congestion means the accumulation of fluid in the body due to the reduced ability of the heart to pump blood. Symptoms of heart failure develop over weeks and months as the heart becomes weaker and less able to pump blood according to the body's needs. Heart failure often leads to cardiomegaly (left ventricle)(27).
2-2-1- Signs and symptoms
dyspnea usually gets worse with exercise, lying down, and sleeping at night. There is often a limit to exercise for sufferers, even if they are well treated(28).
Common causes of heart failure include coronary heart disease such as heart attack, high blood flow, atrial fibrillation, heart valve failure, alcohol abuse, and cardiomyopathy. These can cause heart failure by altering the structure or function of the heart. There are generally two types of heart failure: left ventricle dysfunction and heart failure with a normal ejection fraction, depending on how much left ventricle function is affected to contract or how the heart is able to rest. The severity of the disease is usually measured by the amount of a person's ability to exercise. Heart failure is not like a myocardial infarction (in which part of the heart muscle fails) or cardiac arrest (in which blood flow is completely cut off). Other conditions that have symptoms similar to those of heart failure include obesity, kidney failure, liver problems, anemia, and thyroid disease.
The condition is diagnosed based on symptoms and physical examination, as well as echocardiographic confirmation. Blood tests, ECGs, and chest radiographs may also be appropriate to determine underlying factors(29).
2-2-2-Treatment
Treatment depends on the severity and cause of the disease. In people with chronic illnesses who are currently in a stable condition, treatment includes some lifestyle precautions such as smoking cessation, physical activity, dietary changes, and medication. In those with heart failure due to left ventricular dysfunction, the use of angiotensin-converting enzyme inhibitors and betablockers is recommended. For those with severe disease, aldosterone antagonists, angiotensin receptor blockers, or hydralazine may be used in combination with nitrate. If there is a normal mutant fraction, health problems should be treated. Diuretics are recommended for preventing fluid retention. Sometimes, depending on the cause of the disease, implants such as a pacemaker or implantable cardioverter defibrillator can be used. A ventricular assist device or, in some cases, heart transplants can also be recommended in severe cases instead of all other measures(30).
Allopurinol inhibits xanthine oxidase and thus decrease in uric acid to improve endothelial function. Atorvastatin can be effective in hyperuricemia caused endothelial malfunction (75).
2-3- Advanced renal failure
meters of body surface. Which lasts more than three months. Controlling patients with this disease requires a long time and heavy financial costs, and instead early diagnosis and proper management can play an important role in reducing treatment costs and preventing the disease from progressing to end-stage renal disease (ESRD)(32). The prevalence of this disease in the world is estimated at about 242 cases per one million population (19 bulbs)(33, 34). The important point is that the annual growth rate of this disease in the world is estimated at about 8% per year. The existence of this upward trend, in addition to the high economic burden that ESRD patients impose on society, has led health managers to view the disease as a significant health concern and threat(35, 36).
Chronic kidney failure includes the following 5 stages: G1: GFR equal to and above 90% of normal
G2: At this stage the GFR is 60 to 89% of normal
G3: At this stage the GFR is between 30 and 59% of normal
G4: At this stage the GFR is 15-30% of normal
G5: GFR less than 15% of normal, called the final stage, or ESRD, which is due to accumulation of toxins, fluids, and electrolytes that are naturally excreted from the organ, causing a syndrome called uremic syndrome. Failure to treat these patients with alternative kidney therapies, such as dialysis and kidney transplantation, can lead to the patient's death in a short time(37). To validate of it, Amirkhani also acknowledges that in order to survive patients with ESRD, need to use treatments such as kidney transplantation (48.5%) and dialysis (hemodialysis, 48.5%, peritoneal dialysis, 3.2%)(36).
2-4-Introduction of uric acid (picture
1
: Uric acid formation)Uric acid is the final natural product of the breakdown of body tissues and food, especially protein(38). To formation of uric acid:
1. An amine group is removed from AMP to produce IMP, or an amino group is removed
2. IMP and GMP are converted to their nucleosides, adenosine and guanosine, by the enzyme 5 nucleosidase.
3- Purine nucleoside phosphorylase converts inosine and guanosine to purine bases such
as hypoxanthine and guanine.
4- Guanin is deaminated and xanthine is formed.
5. Hypoxanthine is oxidized to xanthine-by-xanthine oxidase. Xanthine oxidase is then further oxidized to uric acid. Uric acid is the final product of purine breakdown in humans. Uric acid is excreted in the urine(38). (Picture 2 uric acid cycle)
2-4-1-increase in uric acid
too much uric acid in the blood lead high levels of uric acid or hyperuricemia. Uric acid is produced by the breakdown of purine (a substance found in many foods). Uric acid enters the blood after production and is excreted in the urine after passing through the kidneys. High levels of uric acid can cause gout attacks, however, not everyone with high uric acid has gout, and not everyone with gout has high uric acid. Purines are found in animal foods such as red meat and legumes. Because of this, uric acid levels are low in people on vegetarians. Lack of proper diet, obesity, inactivity and metabolic syndrome, means high blood sugar, fat and blood pressure can be factors in high blood uric acid.
Most of the uric acid made by the body is dissolved in the blood and excreted through the kidneys into the urine. But sometimes your body either produces a lot of uric acid or excretes a small amount of it. Consumption of alcohol and foods that are high in purines, and foods such as red meat, fish, shrimp, internal organs such as offal, liver, lamb, poultry eggs, and foods that are moderately purine-rich, such as asparagus, cauliflower, and spinach. Rhubarb, beans, mushrooms and lentils greatly increase uric acid levels.
2-4-2-Causes of hyperuricemia
High uric acid levels can be due to the production of too much uric acid by body slow elimination of uric acid by kidneys.
heart disease or chronic kidney disease. However, it is not clear whether this is a direct cause or just an early warning sign. (Picture 4: uric acid excretion from urine)
Factors that increase the level of uric acid in the blood include the following:
• Diuretics
• Drink too much alcohol •Genetics Hypothyroidism • Immunosuppressive drugs • Niacin or vitamin B-3 • Obesity • Psoriasis
• Purine-rich diet: meat, gypsy fish, herring fish, sauces, dried beans, dried peas, mushrooms and other foods
Kidney failure: The inability of the kidneys to filter waste
Tumor lysis syndrome: The rapid release of cells into the blood by certain cancers or chemotherapy
2-4-3-Prevention of hyperuricemia
To prevent hyperuricemia, the following can be mentioned to reduce the risk of developing this complication as much as possible:
Control body weight and lose weight slowly.
Daily consumption of fresh fruits, vegetables, grains and legumes and also daily consumption of low-fat dairy products.
Avoid eating canned fish such as sardines in oil.
Do not consume more than 100 grams of meat, sausages, fish and poultry per day.
Avoid alcohol.
Use low fat foods.
Drink low-calorie fluids such as water, tea and natural juices daily.
Treatment
High uric acid does not cause symptoms in many people, however the level of uric acid in the blood test is slightly high.
picture 2: Uric acid formation
picture 3: Uric acid cycle
picture 4: Uric acid metabolism
picture 5: Uric acid excretion from the body
picture 6: Urates formation from the purine free diet
2-5- Hypertension
Committee on the Diagnosis, Evaluation and Treatment of Hypertension in 2003, the last classification for hypertension was presented and a new class called hypertension was introduced. It emphasizes that minor levels above normal blood pressure increases the risk of cardiovascular disease. From a blood pressure of 115.75 mm Hg, with each increase of 20.10 mm Hg, the risk of cardiovascular disease doubles. Admittedly, this new JNC classification has expanded the target population to control blood pressure(23, 24).
Blood pressure is a global problem. The relationship between the risk of cardiovascular disease and blood pressure has been a stable and continuous relationship(25) and therefore, the prevention of prehypertension and hypertension and the control of blood pressure are the crucial goals of public health.
It seems that one of the most important steps in controlling blood pressure is to increase the motivation of people that it can be demonstrate, by raising their awareness of the importance of timely diagnosis and follow-up of high blood pressure treatment by mobile medical staff and mobile devices. Also is necessary that physicians and health groups be aware of the new definition of hypertension.
2-5-1- Blood pressure levels
According to the JNC-7 definition, individuals are in different studies three different groups:
1- Normal: systolic pressure less than 120 and diastolic pressure less than 80 mm Hg
2- Prehypertension: systolic pressure 139-120 or diastolic pressure 80-89 mm Hg
3- Hypertension: systolic pressure ≥ 140 mm Hg or diastolic pressure ≥ 90 mm Hg, which
includes the following two categories:
4- Stage 1: with systolic pressure 159-140 or diastolic pressure 99-90 mm Hg
CHAPTER THREE:
MATERIAL AND METHODS
3-1- Search strategy and study selection
PRISMA guidelines were followed in conducting this literature review and meta-analysis(11). Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 29 December 2020 using the following keywords: uric-acid-lowering therapy, Hypertension, blood pressure, literature review, BP. References lists of relevant studies were also examined for additional studies which might meet the inclusion criteria. Searches were conducted by two independent reviewers and a third reviewer was consulted for resolutions of any disagreements.
CHAPTER FOUR:
RESEARCH FINDINGS
4-1 Research Findings
This review summarizes studies on uric acid and their possible association with hypertension in patients at risk of heart failure. Although such evidence is conclusive, it does not support the general treatment of asymptomatic hyperuricemia to reduce cardiovascular risk. Nevertheless, there seems to be sufficient evidence to support clinical trials to determine whether reducing uric acid levels is clinically useful in preventing or treating cardiovascular and renal disease.
● Cause or effect
One problem in determining whether or not uric acid should be considered a cardiovascular risk factor in itself is that elevated uric acid levels are often associated with proven cardiovascular risk factors. For example, uric acid levels are higher in many high-risk cardiovascular groups, such as postmenopausal women, blacks, and people with high blood pressure, metabolic syndrome, or kidney disease(19). The increased risk of cardiovascular disease seen in Westerners, immigrants to Western countries, and migrants from rural to urban communities is also associated with increased uric acid levels. In addition, the sharp rise in hypertension, obesity, diabetes, and kidney disease in the United States over the past 100 years has been associated with a progressive rise in serum uric acid levels. Average uric acid levels in men gradually increased from 3.5 mg/ dl in the 1920s to 6-5 mg/ dl in the 1970s. Women have lower uric acid levels than men (0.5-1 mg/ dl), which may be due to the uricosuric effect of estrogens(39).
There has been a similar debate about the association between elevated uric acid levels and chronic kidney disease. Before the availability of medicine that reduce uric acid levels, more than 50 gout patients had some degree of kidney failure and nearly 100 had autopsy of kidney disease. Kidney mass in gout patients with advanced arteriosclerosis, Glomerulosclerosis, and interstitial fibrosis are often characterized by the presence of urate crystals in the external medulla. The presence of these urate deposits causes the disease to be called "gouty nephropathy". However, the hypothesis that kidney damage is caused by the deposition of urate crystals seems distorted or incomplete, because the deposition of the crystals is local and thus unlikely to justify the diffuse nature of the disease. Crystals in normal kidneys can also be found in the absence of inflammation(40). In addition, the most significant findings of advanced arteriosclerosis and glomerulosclerosis, are indistinguishable from those found in prolonged hypertension or agerelated glomerulosclerosis, and may reflect the fact that most gout patients are hypertensive and elderly. Finally, over the past 30 years, there has been widespread belief that uric acid is unlikely to be a risk factor for kidney disease(41). (Picture 5: Urates formation from the purine free diet)
4-2 Relationship between uric acid and various diseases
"gouty nephropathy". However, the hypothesis that kidney damage is caused by the deposition of urate crystals seems distorted or incomplete, because the deposition of the crystals is local and thus the diffuse nature of the disease is unlikely and crystals in normal kidneys can also be found in the absence of inflammation. In addition, the most significant findings of advanced arteriosclerosis and glomerulosclerosis, are indistinguishable from those observed in prolonged hypertension or agerelated glomerulosclerosis, and may reflect the fact that most gout patients develop hypertension and They are elderly. Finally, over the past 30 years there has been a widespread belief that uric acid is unlikely to be a risk factor for kidney disease(42, 43).
Some studies that have been controlled for multiple risk factors suggest that uric acid may be an independent risk factor for both cardiovascular and renal disease. Other studies have suggested that elevated uric acid levels may cause high blood pressure, obesity, kidney disease and diabetes(44-46). Studies in animal models and cell cultures have identified mechanisms by which uric acid may cause cardiovascular and renal disease, and there have been reports of cardiovascular and renal benefits from reduced uric acid levels in early and new clinical trials(47, 48).
Do we have to accept the assumption that a "causal" factor must be independent of other risk factors? In practice, this hypothesis has been challenged by reports that elevated uric acid levels should be both a direct and an indirect cause of kidney and cardiovascular disease. For example, Zhang et al. reported that kidney disease occurred in 40% of gout patients, but argued that uric acid was not likely to cause the disease because hypertension (a much more likely cause of kidney disease) was also present(49). The Framingham Heart Study reported that uric acid was not a causal risk factor for cardiovascular events because uric acid was not independent of hypertension. However, if uric acid causes high blood pressure and high blood pressure causes kidney and heart disease, then uric acid may not be independent of high blood pressure if it is considered as a risk factor for kidney or heart disease(50).
4-3 Hypertension and hyperuricemia
New empirical and clinical evidence support that elevated uric acid levels may lead to hypertension. Numerous studies have reported that hyperuricemia increases the relative risk of developing hypertension within 5 years, independent of other independent risk factors. Studies of uric acid levels and hypertension have generally been consistent and similar(51, 52).
is not a result of hypertension by itself. Only one study showed that uric acid did not predict hypertension. This study included samples in which hypertension developed after the age of 60. Hyperuricemia is also more common in primary hypertension than secondary hypertension (at least in adolescents). In one study, elevated uric acid levels (more than 5.5 mg/ dl) were seen in nearly 90 adolescents with essential hypertension, whereas uric acid levels were clearly seen less in control group and adolescents with secondary hypertension. Finding that showed uric acid levels did not increase in secondary hypertension, reduced the possibility of hyperuricemia due to hypertension. The relationship between uric acid level and hypertension is different in people with proven hypertension. In some studies, hyperuricemia was present in 40-60% of people with treated hypertension, while other studies reported a lower prevalence(39). Part of this variability may be due to the inclusion of patients with secondary hypertension in various reports. In addition, the relationship between uric acid levels and hypertension decreases with age increasing and duration of hypertension which suggests uric acid may be more important in younger people with new hypertension. The development of a model of mild hyperuricemia in animals provided the first direct evidence that increased uric acid may lead to hypertension. In this regard, it is noteworthy that humans and monkeys have higher levels of uric acid than other mammals because they lack the liver enzyme uricase, which breaks down uric acid into allantoin(39). Only one uricase inhibitor was used to hyperuricemia the mice (which is essential for their use as an animal model). In this model, hypertension developed weeks after elevated uric acid levels. In such animals, blood pressure is directly related to serum uric acid levels and decreases when uric acid is reduced with a xanthine oxidase inhibitor or a uricosuric drug. In the model was shown that hypertension due to renal vascular stenosis is because of uric acid, which occurs due to a decrease in endothelial nitric oxide levels and activation of the renin-angiotensin system. According to these observations, increased uric acid levels in humans are also associated with endothelial dysfunction and increased plasma renin activity(53).
uric acid levels through angiotensin II infusion or inhibition of nitric oxide synthesis. When these lesions develop, hypertension becomes salt-sensitive and it remains even when angiotensin II infusion is stopped or the blockade of nitric oxide synthesis is removed(53, 54). In another study in mice with hyperuricemia, when uricase inhibitors were discontinued after renal microvascular disease and interstitial inflammation, blood pressure improved only when the mice were kept on a low-salt diet. Both experimental and human studies have provided a possible explanation for how uric acid causes hypertension in humans. In addition, experimental studies have provided a rationale that why uric acid may be associated with newly diagnosed or newly initiated hypertension, since samples with long-term hypertension may already have the disease that may be primarily responsible for their current hypertension(55, 56).
4-4 Uric acid, metabolic syndrome and diabetes
Evidence show that uric acid may play a role in the development of metabolic syndrome. Traditionally, the increase in uric acid levels seen in metabolic syndrome has been attributed to hyperinsulinemia because insulin reduces renal uric acid excretion. However, hyperuricemia often occurs before developing hyperinsulinemia, obesity, and diabetes. Hyperuricemia may also be present in the metabolic syndrome in people who are not overweight or obese. In one study, only 5.9% of people with normal BMI and uric acid levels below 6 mg/ dl 6, versus 59% of people with high BMI and uric acid levels above 10 mg/ dl, had metabolic syndrome(10).
4-5 uric acid and chronic kidney disease
Both experimental and clinical studies indicate the possibility that elevated uric acid levels in turn can lead to kidney disease without uric acid crystal deposition. Experimental studies in mice have shown that elevated uric acid levels can lead to kidney disease as well as accelerate previous kidney disease(57).
independent predictor of microalbuminuria and renal impairment in individuals with normal renal function and are associated with glomerular secretion disorders in patients with type 1 diabetes who do not have proteinuria. In contrast, uric acid levels do not predict the progression of previous chronic kidney disease, indicating that in pre-existing diseases, microvascular and glomerular structural lesions are already present, leading to the development of disease independent of uric acid levels(60).
4-6 Other diseases associated with hyperuricemia
Hyperuricemia is strongly associated with peripheral vascular, carotid, and coronary heart disease, as well as stroke, preeclampsia, and vascular dementia. The association between uric acid and cardiovascular events is particularly strong, especially in patients at high risk for heart disease, as well as in women. Some of the cardiovascular benefits of losartan and atorvastatin have also been attributed to the ability of these drugs to reduce uric acid levels. Whether uric acid is causally associated with these diseases still needs to be investigated(61).
CHAPTER FIVE:
DISCUSSION AND CONCLUSION
5-1- Discussion on the findings
Hypertension is one of the most common diseases in the world. Blood pressure measurements are the main reason for patients to visit a doctor and antihypertensive drugs are the most common prescriptions written by physicians(41). According to the National Center for Health and Nutrition Research (NHANES), about 29-31 percent of US adults, or about 65-56 million people, and about 1 billion people worldwide have high blood pressure(51).
Chronic renal failure is a progressive and often irreversible disease that causes kidney damage over time(63). Acute renal failure or sudden decline in renal function that causes an increase in the amount of kidney toxins in the blood is called acute renal failure(64, 65).
All systems of the body are damaged due to chronic renal failure and complications from various parts of the body show their clinical symptoms. These include high blood pressure and elevated uric acid. Some kidney diseases can cause high blood pressure, but high blood pressure mainly causes kidney failure. In addition, high blood pressure increases the rate of kidney failure in cases of kidney disease(66, 67). Chronic renal failure can progress to advanced kidney disease, which can be fatal without dialysis or kidney transplantation.
Drug adverse effects and insufficient time to educate patients, poor access to health care and medication in some areas, and patients not cooperating to receive long-term treatment for hypertension, which is often asymptomatic, make it difficult to control. When patients have to take multiple medications, these medications interfere with their quality of life and they abandon treatment because the short-term benefits of controlling blood pressure are not obvious to them(68).
The asymptomatic nature of the disease delays its diagnosis, and effective treatment requires continued care by a qualified physician and frequent visits, which are often less common in men and low-income groups(68). On the other hand, despite national and global guidelines for the treatment of hypertension, physicians sometimes resist or shorten the time to start the drug or change its type or increase the number or amount of its use. thus, proper control of blood pressure is seen in only about one-third of patients with the disease(19, 42).
disease, which stimulates uric acid reabsorption. In addition, hypertension can lead to damage to the microvascular system and result in local tissue ischemia, and by producing lactate inhibits the secretion of uric acid in the proximal tube of the kidney, and by activating xanthine oxidase, increases its production(57).
Jelic et al. measured uric acid levels in men and women (356) with CAD (more than 50% clogging) compared with 350 in the control group (clogging less than 50%). They found that in women there was a significant difference between serum UA levels in the CAD group compared to the control group (5.3 mg / dl and 4.1 mg / dl, respectively) but no significant difference was observed in men(26). Devesi et al. assessed the association between ocular acid levels in 1,012 patients with the severity of coronary artery occlusion. The data are divided according to the severity of clogging as follows: 31.6% of the 1VD group, 32.5% of the 2D group and 34.9% of the 3VD group. In this study, the distribution of subjects (83 patients) in terms of severity of congestion was 1VD (24%) and Multi VD (50%), respectively. Devesi also showed that the increase in uric acid in both sexes (male and female) was correlated with the severity of CAD (p <001)(31).
Reyhan pour et al., who studied the effect of uric acid on pulmonary hypertension, showed that the mean serum uric acid level was significantly higher in the group with high pulmonary hypertension (p <0.05)(69). In the study of Ganj et al., which examined the relationship between serum calcium and uric acid levels with gestational hypertension and pregnancy outcomes, it was observed that serum uric acid levels were 0.24 ± 5.36 mg/ dl in the hypertensive group and normal blood pressure in the group 0.28 ± 3.99 mg/dl, which is statistically significant (P <0.01)(37).
In animal models, hyperuricemia was caused by an increase in renin and a decrease in nitric oxide production, followed by hypertension over several weeks. Epidemiological studies in humans also show a relationship between high serum uric acid and high blood pressure. This connection is stronger in young people(70). On the other hand, an increase in uric acid is associated with an increased risk of cardiovascular disease in the general population as well as an increased risk of stroke in diabetics and healthy individuals and can even predict the incidence of Hypertension and kidney disease in the general population(71, 72).
Both pregnant and non-pregnant groups receiving two weeks fraction showed higher uric acid than the control group. They concluded that according to the dose of R10 fraction used in this study, which was higher than the doses affecting the immune system, has an increasing effect on blood pressure and serum uric acid, and since the observed changes were to induce preeclampsia, they suggested caution consuming high amounts of garlic and R10 fraction during pregnancy and further studies in animal and human models(73). Also, the results on serum uric acid are significant. Both pregnant and non-pregnant mice by receiving a two-week fraction, show a higher serum level of uric acid than the control group. This difference is noticeable not only in both groups but also in mice. Non-pregnant also has a remarkable fraction compared to the group receiving one week of fractionation. Numerous studies confirm the association between elevated serum uric acid and hypertension(32, 33). Researchers have studied the mechanism of action of uric acid on hypertension in many studies and the most important factors that can be stimulated cell proliferation of vascular smooth muscle(35) and decreased concentration of endothelial nitric oxide(41);
5-2- Summary
Author: shadi fallahzadeh
Scientific supervisor: Dr.jolanta laukaitiene
Research title: Uric acid as a potential marker for the risk of heart failure in hypertension Aim: To conduct a literature review of available studies and researchers on uric acid risk in heart failure on patients with hypertension, epidemiology, prognosis, relation with other disease, treatment and clinical features.
Objectives:
1.serum uric acid (SUA) and xanthine oxide (XO) activity, metabolism and their impacts on endothelial cells.
2.prognosis significant of uric acid in heart failure and adverse outcomes.
3.novel treatment requirements and their aims.
Method: This study was done according to the main purpose of the study in a literature review method.
Uric acid, the end product of purine metabolism, has been suggested as a risk factor for cardiovascular disease. Numerous studies have shown that uric acid is an independent risk factor for cardiovascular disease in the general population. However, the role and mechanism of this factor is not well understood. Most studies have shown the role of uric acid as an inflammatory factor in coronary artery injury in acute coronary syndrome, but their role in patients at risk for heart failure, which includes a wide range of heart patients, is unclear. Epidemiological studies in humans also show a relationship between high serum uric acid and high blood pressure, and this relation is stronger in young people. Since the diagnosis and correction of risk factors in patients is very important to prevent the progression to the acute stages, so studying them, including uric acid, can provide important solutions in the prevention and treatment programs of these patients.
