A dissertation on
“A STUDY ON SERUM URIC ACID LEVEL IN PREDICTING EARLY HOSPITAL OUTCOME IN PATIENTS WITH ACUTE CORONARY
SYNDROME”
Submitted in partial fulfilment of requirements for
M.D. DEGREE IN GENERAL MEDICINE BRANCH-I
OF
THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSITY CHENNAI, INDIA.
INSTITUTE OF INTERNAL MEDICINE MADRAS MEDICAL COLLEGE
CHENNAI – 600 003
MAY 2020
CERTIFICATE
This is to certify that this dissertation entitled “A STUDY ON SERUM URIC ACID LEVEL IN PREDICTING EARLY HOSPITAL OUTCOME IN PATIENTS WITH ACUTE CORONARY SYNDROME” submitted by Dr. M. SENTHIL KUMAR
appearing for M.D. Branch I – General Medicine Degree examination in MAY – 2019 is a bonafide record of work done by him under my direct guidance and supervision in partial fulfillment of regulations of the TamilNadu Dr. M. G. R. Medical University, Chennai. I forward this to the TamilNadu Dr. M. G. R. Medical University, Chennai, Tamil Nadu, India.
Prof.Dr.S.USHALAKSHMI,M.D.,FMMC, Prof.Dr.S.RAGUNANTHANAN .M.D Professor of Medicine, Director I/C and Professor,
Guide and Research Supervisor, Institute of Internal Medicine, Institute of Internal medicine, MMC & RGGGH,
MMC & RGGGH, Chennai- 600 003.
Chennai- 600 003.
Prof. Dr. R.JAYANTHI, M.D.,FRCP, The Dean,
MMC & RGGGH Chennai-600 003.
DECLARATION
I solemnly declare that the dissertation titled “A STUDY ON SERUM URIC ACID LEVEL IN PREDICTING EARLY HOSPITAL OUTCOME IN PATIENTS WITH ACUTE CORONARY SYNDROME” is done by me at Madras Medical College & Rajiv Gandhi Govt. General Hospital, Chennai during 2019 under the guidance and supervision of Prof. Dr. S. USHALAKSHMI, M.D., FMMC. The dissertation is submitted to The TamilNadu Dr. M. G. R. Medical University towards the partial fulfillment of requirements for the award of M. D.
Degree (Branch I) in General Medicine.
DR. M. SENTHIL KUMAR, Place: M.D.General Medicine, Date: Postgraduate student,
Institute of Internal Medicine, Madras Medical College, Chennai - 600003.
ACKNOWLEDGEMENT
I would like to thank our beloved Dean, Madras Medical College, Prof.Dr.R.JAYANTHI, M.D.,FRCP, for her kind permission to use the hospital resources for this study.
I would like to express my sincere gratitude to my beloved Professor and Director I/C, Institute of Internal Medicine Prof.Dr.S.RAGHUNANTHAN, M.D., for his guidance and encouragement.
With extreme gratitude, I express my indebtedness to my beloved Chief and teacher Prof.Dr.S.USHALAKSHMI, M.D.,FMMC, for her motivation, advice and valuable criticism, which enabled me to complete this work.
I am extremely thankful to Assistant Professors of Medicine Dr.M.SHARMILA,M.D., and Dr.S.APARNA, M.D., for their co-operation and guidance. I thank all Professors, Assistant Professors, and Post- graduates of Institute of Biochemistry and cardiology for their valuable support in the analysis.
I am immensely grateful to the generosity shown by the patients who participated in this study.
ABBREVIATIONS
ACC American College of Cardiology ACS Acute Coronary Syndrome AMI Acute Myocardial Infarction CAD Coronary Artery Disease
CABG Coronary Artery Bypass Grafting CCS Canadian Cardiovascular Society CHD Coronary Heart Disease
CHF Congestive Heart Failure
CK Creatine Kinase
CRP C – Reactive Protein cTnI Cardiac Troponin I cTnT Cardiac Troponin T CVD Cardiovascular diseases
DM Diabetes Mellitus
ECG Electrocardiogram
ESC European Society of Cardiology hs - cTn High sensitivity Cardiac Troponin
HTN Hypertension
IHD Ischemic Heart Disease LBBB Left Bundle Branch Block LDL Low - density Lipoprotein LVH Left Ventricular Hypertrophy MI Myocardial Infarction
MR Mitral Regurgitation
NSTE-ACS Non ST-segment Elevation Acute Coronary Syndrome NSTEMI Non ST-segment Elevation Myocardial Infarction PCI Percutaneous Coronary Intervention
STEMI ST-segment Elevation Myocardial Infarction
SUA Serum Uric Acid
UA Unstable Angina
URL Upper Reference Limit WHO World Health Organisation
XO Xanthine Oxidase
CONTENTS
SERIAL TITLE PAGE
No. NO.
1. INTRODUCTION 1
2. AIMS AND OBJECTIVES 3
3. REVIEW OF LITERATURE 4
4. MATERIALS AND METHODS 36
5. OBSERVATION AND RESULTS 39
6. DISCUSSION 56
7. CONCLUSION 59
8. LIMITATIONS 60
9. BIBLIOGRAPHY 61
10. ANNEXURES 81-94
PROFORMA
ETHICS COMMITTEE APPROVAL INFORMATION SHEET
PATIENT CONSENT FORM PLAGIARISM SCREENSHOT PLAGIARISM CERTIFICATE MASTER CHART
1
INTRODUCTION
Cardiovascular disease is responsible for 30% of all deaths in the world.
Although the mortality for this condition has gradually declined over the last decades in western countries, it still causes about one-third of all deaths in people older than 35 years. About 80% of the global burden of cardiovascular disease occurs in low and middle-income countries. In India cardiovascular diseases (CVD) have become the leading cause of mortality. CVD affects Indians at least a decade earlier and in their most productive midlife years when compared to the people of European ancestry.
In addition, case fatality attributable to CVD in low-income countries including India appears to be much higher than in middle and high-income countries.
Until now various bio-markers have been studied in patients of acute coronary syndrome (ACS). However, no single marker gives definite prognostic information during the course of the disease. While there is no doubt that multiple factors play different roles in the development of acute coronary syndrome, recent studies have revealed the potential role of hyperuricemia as a novel prognostic marker. Epidemiological studies have recently shown that uric acid may be a risk
2
factor for cardiovascular diseases and a prognostic marker for mortality in subjects with heart failure and coronary artery disease.
3
AIMS AND OBJECTIVES
• To implicate the elevation of Serum Uric acid in Acute Coronary Syndrome.
• To assess the prognostic significance of Serum Uric acid in patients with Acute Coronary Syndrome.
4
REVIEW OF LITERATURE
The term ACUTE CORONARY SYNDROME (ACS) forms a part of the continuum of disease pathologies that falls under CORONARY HEART DISEASE (CHD). CHD, a worldwide health epidemic, includes chronic CHD, acute coronary syndromes and sudden death. Acute coronary syndrome (ACS) is a unifying term which represents the common end result, acute myocardial ischemia. Acute ischemia is usually, but not always, the result of atherosclerotic plaque rupture, fissuring, erosion, or a combination of these with superimposed intracoronary thrombosis and is mostly associated with an increased risk of cardiac death and myonecrosis.¹Patients with acute coronary syndrome (ACS) commonly are generally classified into two groups to aid largely in the evaluation and management, namely patients with acute myocardial infarction with ST-segment elevation (STEMI) on their presenting electrocardiogram (ECG) and patients with non- ST-segment elevation acute coronary syndrome (NSTE-ACS). NSTE-ACS includes patients with non-ST-segment elevation myocardial infarction (NSTEMI), when the injury is sufficiently severe to cause myocyte necrosis that results in the release of a biomarker of myocardial necrosis into the circulation (cardiac-specific troponins T or I, or muscle and brain fraction of creatine kinase [CK-MB]), and those with unstable angina (UA), when there is absence of biochemical evidence of
5
myocardial necrosis in the bloodstream hours after the initial onset of ischemic chest pain. Unstable angina and NSTEMI can be viewed as very closely related clinical conditions: their pathophysiologic origins and clinical presentations are similar, but they differ in severity. The relative incidence of NSTEMI is rising as a result of the increasing burden of diabetes and chronic kidney disease in aging population, while that of STEMI is declining as a result of the greater use of aspirin, statins, and less smoking. Among patients with NSTE-ACS, the proportion with NSTEMI is increasing while that with UA is decreasing because of the wider use of troponin assays with higher sensitivity to detect myocyte necrosis, leading to reclassifying patients with UA as NSTEMI.
DEFINITION OF UNSTABLE ANGINA
Unstable angina is usually secondary to reduced myocardial perfusion which results from coronary artery atherothrombosis. In this event, however, the nonocclusive thrombus that has developed on a disrupted atherosclerotic plaque does not result in any biochemical evidence of myocardial necrosis. Due to the lack of objective data associated with the condition, unstable angina can only be diagnosed from careful history taking and hence, is the most subjective of the ACS diagnoses.
6
Three principal presentations of unstable angina are noted which are as follows:
(1) Rest angina or angina occurring with minimal exertion that lasts at least 20 minutes;
(2) new-onset severe angina, generally defined as occurring within the last month;
and
(3) Crescendo pattern angina, described as a previously diagnosed angina that has become significantly more frequent, longer in duration, more severe in nature or any combination of these factors.2
Braunwald developed a useful classification of unstable angina, by assessing risk, that helps clinicians with the heterogenous nature of the patients who fall under these loose definitions.3 This classification takes into account the severity and clinical circumstances surrounding the presentation of unstable angina. In terms of severity, class I unstable angina includes new onset or accelerated angina but without rest pain. Class II includes presentation with rest angina within the last month but not within the last 48 hours. Class III angina includes presentation at rest and within the last 48 hours of initial evaluation.
7
Table 1. Braunwald’s classification of Unstable Angina
NON–ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION
Patients who present with NSTEMI carry an intermediate risk of acute complications as compared to those with unstable angina (who carry a lower risk) and STEMI (higher risk), with an estimated 30-day mortality rate of approximately 5%.4 Interestingly, at 6 months, patients who present with NSTEMI have actually been reported to have a higher mortality rate than those with STEMI.4
As evidence of myonecrosis is required, the diagnosis of NSTEMI is less subject to error when compared with unstable angina and requires more careful monitoring and aggressive therapy. In fact, the main purpose of differentiating a true unstable angina from NSTEMI is in the management strategy during the early
8
hospitalization period.5-7 Cardiac troponins have been established as the biochemical marker of choice in the evaluation of myonecrosis and the diagnosis of NSTEMI. The greater sensitivity and specificity of troponins for cardiac muscle damage, in addition to the proven prognostic value, have established their current clinical position.8, 9
ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION
STEMI represents the most lethal form of ACS, where a completely occlusive thrombus leads to total cessation of coronary blood flow within the territory of the occluded artery and the resultant ST-segment elevation on the ECG.
Typically, new Q waves develop as a result of full or nearly full-thickness necrosis of the ventricular wall supplied by the culprit vessel. As this might only occur in up to 70% of patients and because a minority of patients who do not have ST- segment elevation can eventually develop new Q waves, the nomenclature has changed from Q-wave MI to STEMI.10, 11
The actual diagnosis of an acute MI does not rely entirely on the ECG itself, as the name might imply. The World Health Organization criteria for an acute MI requires atleast two of the following three elements: (1) a history that suggests coronary ischemia for a prolonged period of time (>30 minutes), (2) evolutionary changes on serial ECGs that suggests myocardial infarction, and (3) a rise and fall
9
in serum cardiac biomarkers consistent with myonecrosis. Only two of the three criteria are required as there exists a wide variability in the pattern of presentation of a patient with acute MI. It has been estimated that atleast one-third of patients with STEMI might not describe classic chest pain.12 The accurate diagnosis of STEMI is of paramount importance as it mandates immediate consideration for reperfusion therapy.
UNIVERSAL DEFINITION OF MYOCARDIAL INFARCTION
With the availability of more sensitive cardiac biomarkers, the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) collaborated to redefine MI using both the biochemical and the clinical approach in the most recent Fourth Universal Definition of MI which states that the clinical definition of MI denotes the presence of acute myocardial injury as detected by abnormal cardiac biomarkers in the setting of acute myocardial ischemia.13
Detection of an elevated cTn value above the 99th percentile upper reference limit (URL) is defined as myocardial injury. The injury is considered acute if there is a rise and/or fall of cTn values. Cardiac troponin I (cTnI) and T (cTnT) are the preferred biomarkers for detecting the myocardial injury.14,15 and high-sensitivity (hs)–cTn assays have been recommended for routine clinical use.15
10
Table 2. Universal Definition of Myocardial Injury and Infarction
11
PATHOPHYSIOLOGY OF ACS
INITIATION OF ATHEROSCLEROSIS: ROLE OF THE ENDOTHELIUM
Atherosclerosis is an ongoing process of plaque formation where the intima of large- and medium-sized arteries are involved primarily. The condition progresses relentlessly throughout one’s lifetime, before being manifested as an acute ischemic event. Many risk factors have been identified to influence this process, including hypercholesterolemia, hypertension, diabetes, and smoking.16, 17 These risk factors are postulated to damage the endothelium of the blood vessel resulting in endothelial dysfunction, which plays a key role in the initiation of the atherosclerotic process. Endothelial dysfunction is characterized by decreased availabilityof nitric oxide and increased production of endothelin 1, impairing the vascular hemostasis; higher expression of adhesion molecules; and increased thrombogenicity of blood as a result of secretion of several locally active substances.18, 19
12
PROGRESSION OF ATHEROSCLEROTIC PLAQUE:
ROLE OF INFLAMMATION
Once the endothelium has sustained damage, the inflammatory cells, especially the monocytes, migrate into the subendothelial space through the endothelial adhesion molecules whose expression has been increased; once in the subendothelium, they undergo differentiation and activation, becoming macrophages. Macrophages endocytose oxidized low-density lipoprotein (LDL) which has also penetrated the arterial wall. Following this the macrophages transform into foam cells and resulting in the formation of fatty streaks. The activated macrophages also release several chemoattractant proteins and cytokines (eg, monocyte chemoattractant protein 1, tumor necrosis factor α, and interleukins) that accentuates the process as they result in recruiting of additional macrophages and vascular smooth muscle cells (which synthesize extracellular matrix components) to the site of the plaque. In addition, macrophages also elaborate matrix metalloproteinases, the enzymes that digest the extracellular matrix which might contribute to plaque disruption.20
The ratio between vascular smooth muscle cells and macrophages plays a key role in plaque vulnerability and the propensity for plaque rupture. Although plaque rupture may result in ACS, more often, as in 99% of cases, it is clinically
13
silent.21 The rate of progression of these atherosclerotic lesions is highly variable, nonlinear, and unpredictable.22
Figure 1. Clinical determinants of myocardial infarction injury
14
STABILITY OF PLAQUES AND TENDENCY FOR RUPTURE
As mentioned earlier,the stability of atherosclerotic plaques varies. The so- called high-risk or vulnerable plaques are characterized by a large lipid core, thin fibrous cap, a high density of macrophages and T cells,23, 24 a relative paucity of smooth muscle cells,25 locally increased levels of matrix metalloproteinases which degrade collagen, eccentric outward remodeling,26, 27 and increase in neovascularisation of plaque and intraplaque hemorrhage.28 The composition of atherosclerotic plaques in humans is markedly heterogeneous, even within the same person. Inflammation, that which determines the “vulnerability” of plaques, is marked by an increased activity of macrophages at the site of plaque, leading to the enlargement of the lipid core and thinning of the plaque cap. Elevated levels of C-reactive protein (CRP) have been reported to correlate positively with the number of plaque ruptures29 and might indicate the activity of these macrophages.
PLAQUE DISRUPTION, THROMBOSIS, AND ACS
As explained earlier, the pathogenesis of ACS involves a complex interplay among the endothelium, the inflammatory cells, and the thrombogenicity of the blood.30,31 Angiographically identified noncritical coronary lesions (<50% stenosis in the diameter of the vessel) might undergo an abrupt progression to severe or total occlusion and eventually account for as many as two-thirds of cases of
15
ACS.32,33 The lipid content of the plaque, the severity of the plaque rupture, the degree of inflammation at the rupture site, and the antithrombotic and prothrombotic balance of the pateint are some of the important factors that play role in determining the degree of thrombus formation which in turn determines whether a given plaque rupture will result in ACS.34 -36 Studies employing intravascular ultrasonography have reported that at least 80% of patients with ACS actually harbor multiple plaque ruptures distinct from the culprit lesion.37
It has been shown by autopsy studies that plaque rupture accounts for approximately 75% of fatal MIs, whereas superficial endothelial erosion are the culprit lesions in the remaining 25%.38 Following either a plaque rupture or an endothelial erosion, the subendothelial matrix, rich in tissue factor (a potent procoagulant), is exposed to the circulating blood; this exposure results in platelet adhesion followed by platelet activation and aggregation and eventually thrombus formation. There are two types of thrombi that can form: a platelet rich clot (referred to as a white clot) which is formed in areas of high shear stress and are only partially occluding, or a fibrin-rich clot (referred to as a Red clot) that occurs as the result of an activated coagulation cascade and decreased flow in the artery.
More frequently the red clots are found superimposed on white clots and this accounts for total occlusion of the artery. There exist several evidences to support the key role of thrombosis in the pathogenesis of ACS.39 - 41
16
CLINICAL PRESENTATION
HISTORY AND PHYSICAL EXAMINATION FINDINGS
A very careful and focused history taking and physical examination are the key to both assessing the likelihood that the presenting illness is ACS and determining the risk of an adverse outcome.
Possible ischemic symptoms include many different combinations of chest, upper extremity, mandibular, or epigastric discomfort during exertion or at rest, or any of the ischemic equivalents such as dyspnea or fatigue. By far, chest pain is the most common initial symptom that brings the patients to the emergency department. It is so much helpful to frame the initial diagnostic assessment and triage of patients with acute chest discomfort around the following three categories:
(1) myocardial ischemia;
(2) other cardiopulmonary causes (pericardial disease, aortic emergencies, and pulmonary conditions); and
(3) non-cardiopulmonary causes.
17
The primary aim is to assess the likelihood of the chest discomfort having its origin from an ischemic myocardium. Guidelines have been published by the Agency for Health Care Policy and Research listing features that signify the likelihood of signs and symptoms suggestive of an ACS likely caused by CHD, 42 listed in the table below.
Table 3. Likelihood That Signs and Symptoms Indicate an ACS Secondary to CAD
18
Figure 2. Assessment of patients with suspected Acute Coronary syndrome
Although patients generally describe a stable angina as deep, poorly localized chest or arm discomfort that which gets exacerbated by activity or emotional stress and relieved following rest, nitroglycerin intake, or both, the discomfort associated with UA is much more severe, occurs at rest, and is usually described as frank pain. Often located in the retrosternal region (sometimes the epigastric area), the pain or discomfort may radiate to the neck, jaw, left shoulder, and left arm. The clinical characteristics of angina pectoris, often referred to simply as “angina,” are very much similar whether the ischemic discomfort is a manifestation of stable ischemic heart disease, unstable angina, or MI.
19
To aid placing the patient’s symptom under the most likely of these categories, a decision of vital importance as it determines the emergent management of the patient and thus the outcome, the Canadian Cardiovascular Society (CCS) has developed a classification system to grade anginal symptoms.43 In this grading, Class I angina is the least symptomatic denoting that ordinary physical activity does not bring out anginal symptoms. Class II implies to anginal symptoms that slightly impair ordinary activities like walking >2 blocks or climbing >1 flight of stairs. Class III angina is the one where the symptoms markedly limit ordinary physical activity such as walking for less than a block or climbing less than a flight of stairs. Finally, Class IV angina is defined as symptoms that occur at rest or that causes an inability to carry out any physical activity without discomfort. Thus, by using this classification, crescendo angina can be defined as symptoms that lead to at least 1 CCS class increase or to at least CCS class III severity as shown below in table 4.44
20
Table 4. Grading of Angina Pectoris According to Canadian Cardiovascular Society Classification
It is important to distinguish chest discomfort that represents angina from those due to the vast number of other causes as enlisted in table 5.
21
Table 5. Typical Clinical Features of Major Causes of Acute Chest Discomfort
22
Also it is important to differentiate angina that arises out of ACS from that of a stable chronic IHD. Pain that is sharp, stabbing or pleuritic, or being reproducible with palpation or with movement or able to be localized by the tip of one finger is usually not ischemic. Chest pain that resolves with the administration of sublingual nitroglycerin in the emergency setting is not predictive of ACS.
It is quite common for patients to present with symptoms other than chest discomfort; such symptoms, referred to as “angina – equivalents” include dyspnea (most common), nausea and vomiting, diaphoresis, and unexplained fatigue.45 Rarely, syncope may even be the presenting symptom of ACS.
Patients with ACS may even present with “atypical” symptoms, such as acute dyspnea, indigestion, unusual locations of pain, altered mental status, and profound weakness. Such atypical presentations are more commonly seen in women, elderly individuals, and patients with long-standing diabetes mellitus. It has been found that such presentations are associated with higher risk for death and major complications.46 In addition, UA/ NSTEMI may even be present without any evident clinical symptoms, especially among patients in the perioperative state and those with comorbidities such as diabetes.
The five most important history-related factors that aid in identifying ischemia due to CAD, ranked in order of importance, are the nature of the anginal
23
symptom, a history of CAD, male sex, older age, and the number of risk factors present.47, 48 The traditionally associated cardiac risk factors such hypertension, hypercholesterolemia, cigarette smoking, diabetes, and family history of premature CAD have actually been reported to be weak predictors of the likelihood of acute ischemia,49 although their presence correlates with poorer outcomes for patients with established ACS.
EARLY ASSESSMENT
Recognizing a patient with ACS is of utmost important because the diagnosis triggers both triage and management. Because of the life-threatening nature of an ACS, it is only prudent to have a low threshold in suspecting a patient with acute chest pain as potentially having an ACS.
Those suspected to have an acute coronary syndrome in the emergency department should be triaged immediately to an area with continuous electrocardiographic monitoring and defibrillation capability. Any patient with symptoms suggestive of ACS should have an ECG performed and accurately interpreted within 10 minutes.
The most important purpose of the early ECG is to identify patients with STEMI who become candidates for immediate reperfusion therapy. Each patient should be given a provisional diagnosis of one of the following: (1) definite ACS,
24
which in turn, should further be classified as STEMI, NSTEMI, or UA; (2) possible ACS; (3) a non-ACS cardiac condition such as chronic stable angina or heart failure; or (4) a noncardiac diagnosis, which should be as much specific as possible. If a patient gets assigned a provisional diagnosis of ACS , the next step is to perform a risk assessment to determine the probability of major cardiac complications.50 Such risk assessment is important not only among patients with definite ACS; among patients with possible ACS, such risk assessment should be used to determine the probability of an adverse cardiac event if the diagnosis of ACS is confirmed because this information will in turn guide appropriate triaging, medical therapy, and timing of subsequent evaluation, including the use of invasive procedures.
ELECTROCARDIOGRAPHY
The ECG is an integral part of the diagnostic workup of patients with suspected MI, and as mentioned earlier, the ACC/AHA guidelines state that an experienced emergency physician should review the results of 12-lead ECG within no more than 10 minutes from the arrival of a patient with chest discomfort or other symptoms suggestive of ACS.51 The ECG aids in two ways: to support a clinical diagnosis of ACS and to aid in risk stratification. Prehospital ECGs can reduce the time to diagnosis and treatment, and can facilitate the triage of patients with STEMI to hospitals with PCI capability if within the recommended
25
window period (120 minutes from STEMI diagnosis).52,53 Acute myocardial ischemia is usually associated with dynamic changes in ECG waveform and thus serial ECG acquisition can provide critical information, especially when the ECG at initial presentation is nondiagnostic. Recording several standard ECGs at 15–30 minute intervals for the initial 1–2 hours, or the use of continuous computer- assisted 12-lead ECG recording when available, to detect dynamic ECG changes, is recommended for patients who have persistent or recurrent symptoms or those with an initial nondiagnostic ECG.54
Findings on ECG that are associated with UA include ST-segment depression, transient ST-segment elevation, T-wave inversion, or any combination of these factors; depending on the severity at the time of clinical presentation, these findings may be present in 30% to 50% of patients.55,56,57
A new ST-segment deviation, even of only 0.05 mV, is still an important and specific measure of ischemia and prognosis.56-58 T-wave inversion is a sensitive indicator of ischemia but is generally considered less specific, unless it is marked (≥0.3 mV).59 In general, a ST-segment elevation of 0.1 mV or more, when present in 2 or more contiguous leads, indicates an acute MI in 90% of patients, as confirmed by serial measurements of cardiac biomarkers.60 It is of vital importance to compare current and previous findings on ECG because studies have reported
26
that patients without ECG changes are at a lower risk of complications than those with ECG changes.61
Table 6. ECG manifestations of acute myocardial ischemia
It should always be remembered that ST deviation may also be observed in several other conditions, such as acute pericarditis, LV hypertrophy (LVH), left bundle branch block (LBBB), Brugada syndrome, and early repolarization patterns.62 Reciprocal changes in ECG can help in differentiating STEMI from pericarditis or early repolarization changes. A prolonged new convex ST-segment elevation, particularly when associated with a reciprocal ST-segment depression, usually indicates an acute coronary occlusion. Another finding of significance is an increased hyperacute T wave amplitude, with prominent symmetrical T waves
27
found in at least 2 contiguous leads, as this is an early sign which might precede the elevation of the ST-segment.
ECG recordings, however, has several limitations. For example, the posterior, lateral, and apical walls of the left ventricle are not adequately represented by the standard 12 lead ECG recording. Additionally, normal findings in an ECG recording do not exclude the possibility of ACS.
CARDIAC BIOMARKERS OF NECROSIS
Cardiac biomarkers must be measured for every patient who presents with chest discomfort or other symptoms suggestive of ACS. Measurements of the cardiac-specific troponins T and I provide us with highly accurate, sensitive, and specific determination of myocardial injury in the context of ischemic symptoms;
these troponins have largely replaced CK-MB as the preferred biomarker for the detection of myocardial necrosis.
However, troponin measurements have some limitations. Troponin levels usually do not increase until at least 6 hours from the onset of symptoms; therefore, a negative result obtained within this period should not validate excluding a patient from ACS workup and prompt repetition of the assay after 8 to 12 hours from the onset of symptoms is suggested. Also of note is that the troponin levels remain
28
elevated for a prolonged period of 5 to 14 days after myocardial necrosis which makes their usefulness in detecting recurrent myocardial damage limited.
Cardiac troponin I (cTnI) and T (cTnT) are essential components of the contractile apparatus of myocardial cells and are expressed almost exclusively in the heart.14,15 Increased cTnI values have not been reported to occur following injury to noncardiac tissues. Biochemical data indicate that injured skeletal muscle may express proteins that are detected by the cTnT assay, resulting in some situations where elevations of cTnT could arise from skeletal muscle.63-67 Despite this, cTnI and cTnT are the preferred biomarkers for the evaluation of myocardial injury, and high-sensitivity (hs)–cTn assays are recommended for routine clinical use.15
An acute myocardial injury, when associated with a rising and/or falling pattern of cTn values with at least 1 value above the 99th percentile URL and caused by myocardial ischemia, is defined as an acute MI.14,15,68 Because CK-MB has a shorter half-life, the levels of this isoenzyme can be used for diagnosing infarct extension (reinfarction) and periprocedural MI.
29
Figure 3. Illustration of early cardiac troponin kinetics in patients after acute myocardial injury including acute myocardial infarction.
RISK STRATIFICATION
Post-MI risk stratification that has been derived from several clinical trials is important to set the appropriate treatment and prognosis. The ACC/AHA guidelines recommend that risk stratification be carried out for all patients as it is an integral prerequisite to decision-making.51 The outcomes of patients deemed with a diagnosis of ACS span the entire risk spectrum: data from a global registry
30
has indicated that the 30-day mortality rate ranges from 1.7% for patients with UA to 7.4% for patients with NSTEMI to 11.1% for those with STEMI.69
Early risk stratification can be useful for selecting the site of care (coronary care unit or monitored step-down unit), selecting the initial therapy (such as glycoprotein [GP] IIb/IIIa inhibitors70,71 and early invasive strategy72), and estimating prognosis.
HIGH-RISK CLINICAL SUBGROUPS
Certain clinical characteristics have been found to be associated with a substantial increase in adverse outcomes for patients with ACS and listed below are some of the important high risk clinical subgroups
1. Older age,56,73
2. Diabetes (diabetic patients with UA/NSTEMI are at an approximately 50%
higher risk of adverse outcomes than nondiabetic patients),74,75 3. Extracardiac vascular disease,76
4. Evidence of congestive heart failure (CHF; Killip class II or higher),73,77 and 5. Presentation with ACS despite long-term aspirin therapy.78
31
Risk assessment is needed to guide triage and key management decisions in any patient with a diagnosis of ACS. For decades scientists are trying to create ideal scores for predicting risk which is simple, fast, and applicable to everyday practice. Although number of risk scores have been developed to predict short and long term outcomes in patients with ACS, Killip classification is the most popular way of assessing risk at presentation clinically and recommended by contemporary guidelines.
KILLIP CLASSIFICATION
The Killip classification was developed for simple risk stratification of myocardial infarction in 1967. Killip class 4 (cardiogenic shock) is well known to be the strongest predictor of hospital mortality in ACS patients. The Killip classification was based on the evaluation of 250 patients admitted with an MI in a coronary care unit.79 The “pigeonholing” of patients to classes I to IV (no heart failure, some evidence of such a complication, pulmonary edema, and cardiogenic shock, respectively) was based on routine physical examination-derived parameters. The proportion of patients in class IV was 19% in the original study.80 This approach was based on clinically derived information (physical examination and chest radiography) and thus this system carries the imprimatur of simplicity, and intuitively makes sense, which explains its popularity and relative longevity.
32
In January 1965, a study of specialized care for myocardial infarction was begun at The New York Hospital-Cornell Medical Center, following which was the details of a two year experience with 250 patients with objectively proved acute myocardial infarction treated in a specially designed, equipped and staffed coronary care unit in a voluntary teaching hospital was communicated in the most popular article by THOMAS KILLIP III, M.D., F.A.C.C. and JOHN T.
KIMBALL, M.D.80
In this study, to provide a clinical estimate of the severity of the myocardial derangement, each patient was classified into one of the following groups:
I. NO heart failure. No clinical signs of cardiac decompensation.
II. Heart failure. Diagnostic criteria include rales, S3 gallop and venous hypertension.
III. Severe heart failure. Frank acute pulmonary edema.
IV. Cardiogenic shock. Signs include hypotension (systolic pressure of 90 mm Hg or less) and evidence of peripheral vasoconstriction such as oliguria, cyanosis and altered mental status. Heart failure, often with pulmonary edema, has also been present in the majority of these patients.80
33
It has been well established that prognosis in myocardial infarction will be influenced by the degree of altered myocardial mechanical performance. Utilizing the presence of heart failure, pulmonary edema, or shock as rough clinical guides to myocardial function, this study has demonstrated a good correlation with mortality.80 Patients without evidence of heart failure have had a low mortality.
Patients with pulmonary edema and especially shock, have had a high mortality.
Still today, the Killip classification first described in 1967, continues to be a simple and valid tool to risk-stratify patients with STEMI as well as with NSTE- ACS with a steady increase of mortality in clinical practice with increasing Killip class.81
Patients with higher Killip class were found to have more severe angiographic coronary artery disease, higher incidence of ventricular dysfunction, and larger myocardial infarctions.
Furthermore, it has also been reported that the risk associated with high Killip class was independent of the ventricular function.82-84
SERUM URIC ACID AND CAD
Uric acid (urate), an organic compound of carbon, nitrogen, oxygen and hydrogen, is the final oxidation product of purine metabolism and and excretion of UA occurs mainly through the kidneys.85,86
34
An increase in its concentration may reflect increased xanthine oxidase (XO) pathway activity, as well as decreased elimination by the kidneys. The XO pathway is an important source of oxygen-free radicals, with several detrimental processes.87
For decades it has been hypothesised that the oxidant properties of uric acid might be protective against ageing, oxidative stress and oxidative cell injury.
However, recent epidemiological and clinical evidences suggest that hyperuricaemia might be a risk factor for cardiovascular disease where enhanced oxidative stress play an important pathophysiological role.88
Hyperuricemia is present frequently in patients with symptomatic heart failure, acute coronary syndromes, arterial hypertension, and atrial fibrillation.89-91 It has been postulated that serum uric acid plays a pivotal role in the pathogenesis of cardiovascular diseases affecting xanthine oxidase pathway that contributes to the production of reactive oxygen species with deterioration of cell membranes.92 Reactive oxygen species contribute to vascular oxidative stress and endothelial dysfunction, which are associated with the risk of atherosclerosis, damages of both cardiomyocytes and vascular endothelium inducing disturbances of myocardial contractility and vasoconstriction.93The increase in serum uric acid in patients with cardiovascular disease may reflect a compensatory mechanism to counter the oxidative stress that occurs with tissue hypoxia, thus, the higher levels of uric acid
35
corresponding to high risk may reflect response to tissue injury, whereas the higher risk at lower levels of uric acid levels may be the result of decreased antioxidant capacity.
36
MATERIALS AND METHODS
SETTING
This study was conducted at the Institute of Internal Medicine, Rajiv Gandhi Government General Hospital (RGGGH), Madras Medical College, Chennai.
ETHICS COMMITTEE APPROVAL Obtained.
STUDY DURATION
The study was conducted over a period of six months.
STUDY POPULATION
Patients with acute decline in renal function admitted in the medical and toxicology wards at the Institute of Internal Medicine.
SAMPLE SIZE 100 patients.
37
TYPE OF STUDY
Observational prospective study.
INCLUSION CRITERIA
• Any patient >18 years admitted to the General Medicine and Cardiology Departments with the diagnosis of Acute Coronary Syndrome as per WHO criteria which require at least two of the following three elements to be present:
1. A history of ischemic-type of chest pain.
2. Evolutionary change on serially obtained ECG tracings.
3. A rise and fall in cardiac markers.
EXCLUSION CRITERIA
• Chronic kidney disease
• Gout
• Malignancy
• Hypothyroidism
• Patients on hypo/hyperuricemic medications
• Chronic alcoholics
• Recurrent Myocardial infarction.
38
DATA COLLECTION AND METHODS
On patients who have been admitted in the medical and cardiology wards, Rajiv Gandhi Government General Hospital, Chennai with symptoms suggestive of Acute Coronary Syndrome, an observational study was conducted for a period of 6 months. Patients were selected as per the Inclusion and Exclusion criteria.
Detailed history taking and clinical examination were done. ECG recording as per ACC guidelines and serum levels of cardiac biomarkers were estimated. Killips Class of all the patients were estimated both on the day of admission and on day 5 following admission. Serum levels of Uric acid were estimated on the day of admission and on day 5 following admission for these patients.
All the data obtained were entered in the proforma. Data were analysed using SPSS package and by Chi square and Independency tests.
39
OBSERVATION AND RESULTS
Age distribution
There were 17 cases in the age group of 41-50 years and 19 controls falling under the same age group. Among the age group of 51-60, there were 24 cases and 22 controls. There were 8 in each in the age group of 61-70 and 1 in each of the age group of 71-80 years.
The major representation of cases was seen in the age group of 51-60 years about 48% and least represented by the group between 71 and 80 years.
(Table 7 and Figure 4).
Table 7. Age distribution among cases and controls
GROUP Total
Case Control
AGEGROUP
41-50 Years Count 17 19 36
% within GROUP 34.0% 38.0% 36.0%
51-60 Years Count 24 22 46
% within GROUP 48.0% 44.0% 46.0%
61-70 Years Count 8 8 16
% within GROUP 16.0% 16.0% 16.0%
71-80 Years Count 1 1 2
% within GROUP 2.0% 2.0% 2.0%
Total Count 50 50 100
% within GROUP 100.0% 100.0% 100.0%
Pearson Chi-Square=0.198 p=0.978
40
Figure 4. Age distribution among cases and controls
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
41-50 Years 51-60 Years 61-70 Years 71-80 Years 34%
48%
16%
2%
38%
44%
16%
2%
Case Control
41
Sex distribution
Both cases and controls contained equal representation of male and female genders. (Table 8 and Figure 5)
Table 8.
GROUP Total
Case Control
SEX
FEMALE Count 25 25 50
% within GROUP 50.0% 50.0% 50.0%
MALE Count 25 25 50
% within GROUP 50.0% 50.0% 50.0%
Total Count 50 50 100
% within GROUP 100.0% 100.0% 100.0%
Pearson Chi-Square=0.0 p=1.0
42
Figure 5
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Female Male
50% 50%
50% 50%
Case Control
43
Profile of hypertensive and diabetic status among cases and controls
There were 27 individuals who were hypertensives among cases and 29 among controls. (Table 9 and Figure 6)
Table 9. Hypertensive status among cases and controls
GROUP Total
Case Control
HTN
NO Count 23 21 44
% within GROUP 46.0% 42.0% 44.0%
YES Count 27 29 56
% within GROUP 54.0% 58.0% 56.0%
Total Count 50 50 100
% within GROUP 100.0% 100.0% 100.0%
Pearson Chi-Square=0.162 p=0.687
44
Figure 6. Hypertensive status among cases and controls
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Case Control
46%
42%
54%
58%
No Yes
45
Among cases, 31 individuals were diabetics, about 62% and among controls, 29 were diabetics. (Table 10 and Figure 7)
Table 10. Diabetic status among cases and controls
GROUP Total
Case Control
DM
NO Count 19 21 40
% within GROUP 38.0% 42.0% 40.0%
YES Count 31 29 60
% within GROUP 62.0% 58.0% 60.0%
Total Count 50 50 100
% within GROUP 100.0% 100.0% 100.0%
Pearson Chi-Square=0.167 p=0.683
46
Figure 7. Diabetic status among cases and controls
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Case Control
38% 42%
62% 58%
No Yes
47
Comparison of mean serum Uric acid levels among cases and controls
The mean serum Uric acid level among cases was found to be 6.8 ± 2.6 and that among controls was found to be 4.8 ± 0.7. (Table 11 and Figure 8)
Table 11. comparison of Serum uric acid values on the day of admission among cases and controls
GROUP N Mean Std.
Deviation
Std. Error Mean
t value P value
SUA DAY 0
Case 50 6.8182 2.68382 .37955 4.916** p<0.001 Control 50 4.8840 .73356 .10374
48
Figure 8. comparison of Serum uric acid values among controls and cases on the day of admission.
0 1 2 3 4 5 6 7
Case Control
6.82
4.88
Serum Uric Acid
49
Table 12. Assessment of correlation between the SUA levels and Killips class on the day of admission and on day 5 following among cases
Correlations
SUA DAY 0
SUA DAY 5
KILLIPS DAY 0
KILLIPS DAY 5
SUA DAY 0
Pearson
Correlation 1 .905** .819** .394**
Sig. (2-tailed) .000 .000 .006
N 100 47 50 47
SUA DAY 5
Pearson
Correlation .905** 1 .559** .619**
Sig. (2-tailed) .000 .000 .000
N 47 47 47 47
KILLIPS DAY 0
Pearson
Correlation .819** .559** 1 .081
Sig. (2-tailed) .000 .000 .588
N 50 47 50 47
KILLIPS DAY 5
Pearson
Correlation .394** .619** .081 1
Sig. (2-tailed) .006 .000 .588
N 47 47 47 47
**. Correlation is significant at the 0.01 level (2-tailed).
50
Comparison of Serum Uric Acid levels with Killips class on the day of admission among cases
Among the cases, the mean of serum uric acid values on the day of admission was found to be 6.8 ± 2.68. There were 23 patients who were of Killips class 1 on the day of admission while it was 14 under Killips class 2, 8 under Killips class 3 and 5 patients under Killips class 4. The mean serum uric acid value of patients under Killips class 1 was found to be 5.16 ± 1.3. Patients under Killips class 2 had a mean serum uric acid value of 6.5 ± 1.4, those under Killips class 3 had a value of 8.5 ± 1.8 and those under Killips class 4 had a value of 12.58 ± 1.5.
Majority of the patients belonged to Killips class 1 and the least were represented under Killips class 4. The highest value of serum uric acid level among the cases was 14.5 with the individual falling under Killips class 4. (Table 13 and Figure 9)
51
Table 13. Comparison of Serum Uric Acid levels with Killips class on the day of admission among cases
KILLIPS DAY0
Descriptives N Mean Std.
Deviation Std.
Error
95% Confidence Interval for Mean
Minimum Maximum
Lower Bound
Upper Bound
F VALUE P
VALUE
SUA DAY 0
1.00 23 5.1613 1.33068 .27747 4.5859 5.7367 3.50 9.20 39.029** P<0.001 2.00 14 6.5143 1.41957 .37939 5.6947 7.3339 4.90 10.60
3.00 8 8.5125 1.87954 .66452 6.9412 10.0838 6.70 11.10 4.00 5 12.5800 1.55467 .69527 10.6496 14.5104 10.90 14.70 Total 50 6.8182 2.68382 .37955 6.0555 7.5809 3.50 14.70
52
Figure 9. Comparison of Serum Uric Acid levels with Killips class on the day of admission among cases
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00
Class 1 Class 2 Class 3 Class 4
5.16
6.51
8.51
12.58
Serum Uric Acid on day 0
53
Comparison of Serum Uric Acid levels with Killips class on the day 5 following admission among cases
There were 30 patients under Killips class 1 on day 5, 11 patients under class 2, 6 patients under class 3 and 3 cases had deceased. The mean serum uric acid level on day 5 among individuals under Killips class 1 was 5.6 ± 1.2 while that for individuals under Killips class 2 was 6.3 ± 1.9 and for individuals under class 3 was 9.2 ± 1.1.
The highest value of serum uric acid on day 5 was found to be 10.37 and the individual belonged to Killips class 3. There were a total of 47 cases on day 5 and the mean serum uric acid level on day 5 among the cases was 6.2 ± 1.8. (Table 14 and Figure 10).
54
Table 14. Comparison of Serum Uric Acid levels with Killips class on the day 5 following admission among cases
N Mean Std.
Deviation
Std.
Error
95% Confidence Interval for Mean
Minimum Maximum
Lower Bound
Upper Bound
F VALUE P
VALUE
SUA DAY 5
1.00 30 5.6000 1.19971 .21904 5.1520 6.0480 4.00 9.90 17.060** P<0.001 2.00 11 6.3364 1.89118 .57021 5.0659 7.6069 3.90 10.00
3.00 6 9.2000 1.11893 .45680 8.0258 10.3742 7.40 10.00 Total 47 6.2319 1.79808 .26228 5.7040 6.7599 3.90 10.00
55
Figure 10. Comparison of Serum Uric Acid levels with Killips class on the day 5 following admission among cases
0 1 2 3 4 5 6 7 8 9 10
Class 1 Class 2 Class 3
5.6
6.3364
9.2
Serum Uric Acid on day 5
56
DISCUSSION
Elevated serum UA levels have been associated with an increased risk for cardio-vascular disease. The potential mechanisms by which serum UA may directly cause cardiovascular risk include enhanced platelet aggregation and inflammatory activation of the endothelium.94 Previous studies have shown that serum uric acid increases in cardiac failure.95 In a study done in Japan in 2005 by Kojima et al96 it was shown that serum uric acid levels correlated with Killip classification. Combination of Killip class and serum uric acid level after AMI is a good predictor of mortality in patients who have AMI.
Present study was conducted on 50 patients of ACS, 25 male and 25 female patients, who presented to Rajiv Gandhi Government General Hospital, Chennai with symptoms suggesting Acute Coronary Syndrome. All the patients with acute STEMI were thrombolysed in our study. Fifty age and sex matched healthy controls were also evaluated for comparison of uric acid levels. There was no significant difference with regard to age, status of systemic hypertension and diabetes mellitus in patients with acute coronary syndrome and healthy controls.
The majority of the patients belonged to the age group of 51 – 60 years, who contributed 24% and so was the case with the control group having 22% in the age group of 51 – 60 years. Majority of the participants in each group were
57
hypertensives, 27% of cases and 29% of controls. Diabetics constituted 31% of cases and 29% of controls.
Patients with acute coronary syndrome had statistically significant higher serum uric acid levels on the day of admission compared with healthy controls (P<
0.01). The mean serum uric acid level on the day of admission was 6.8 ± 2.6 among cases as compared to 4.8 ± 0.7 among controls.
On the day of admission, the majority (46%) of patients belonged to Killips class 1, 28% to killips class 2, 16% to killips class 3 and only 10% to Killips class 4. In the present study, 15 patients had a SUA level above 7, of which 4 were in killips class 4, 9 were in killips class 3 and the remaining in Killips class 2. The mean serum uric acid levels were higher among cases who belonged to higher killips class on the day of admission. During the hospital stay, a shift in the Killips Class of the patients was observed.
On day 5 following admission, the majority (63%) of patients belonged to Killips class 1, 23% to killips class 2, 12% to killips class 3 and none belonged to Killips class 4. The mean serum uric acid levels was higher among cases who belonged to higher killips class on day 5 following admission.
58
It was also observed that patient with a higher SUA level (10.6) and killips class 2 on clinical evaluation on day of admission had exhibited clinical worsening to killips class 3 on day 5 with a SUA level of 10.79.
It was also noted that there was a significant relationship between SUA levels and mortality. Three patients who were in killips class 4 on the day of admission had deceased following ACS. All patients who died had a SUA level of
> 10 mg/ dL. Thus, there was a significant association between SUA level and mortality. Sinisa Car et al found that higher SUA on admission was associated with higher in-hospital and 30- day mortality, and poorer long term survival after acute MI. Thus, SUA may rise following an ACS and the converse also holds good;
elevated SUA may be associated with coronary artery disease. Nadkar and Jain concluded that SUA levels were higher in patients with higher killips class among patients of acute MI. Kojima et al noted that hyperuricemia after acute MI was associated with the development of heart failure.
In the present study, a positive correlation was found between SUA concentration and killip classification, both on the day of admission and 5 days later, suggestive of left ventricular failure. Higher SUA levels on admission were strongly associated with adverse outcomes in patients with acute coronary syndrome.
59
CONCLUSION
It is concluded from the present study that serum uric acid levels were higher in patients of ACS as compared to healthy controls. Patients with elevated serum uric acid levels belonged to higher Killip’s classification and had higher mortality.
It can be inferred from this study that serum uric acid can be regarded as an inexpensive independent risk factor and prognostic marker for assessing short term adverse outcomes in patients with ACS.
60
LIMITATIONS
• Although, conducting this study in a sole institution with paucity of time and resource highlighted the role of serum uric acid in influencing the course of ACS, a more elaborate multi centric study would have been desirable to precisely establish the role of serum uric acid in ACS.
• The details of the treatment modalities such as thrombolysis and PCI, which could potentially alter the clinical outcome of patients with ACS has not been included under this study.
61
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