Prof. Dr .R.BALAJI NATHAN MD,

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EVALUATION OF SERUM URIC ACID AS A PREDICTIVE FACTOR OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH

ACUTE ST ELEVATION MYOCARDIAL INFARCTION

A Dissertation Submitted to

THE TAMILNADU DR. M.G.R MEDICAL UNIVERSITY CHENNAI

In Partial Fulfillment of the requirement for the Award of the Degree of M.D. (GENERAL MEDICINE) - BRANCH – I

REGISTRATION NO: 201711707

APRIL 2020

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CERTIFICATE FROM THE DEAN

This is to certify that the dissertation entitled “EVALUATION OF SERUM URIC ACID AS A PREDICTIVE FACTOR OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH ACUTE ST ELEVATION MYOCARDIAL INFARCTION” is the bonafide work of Dr. POOJA.H in partial fulfilment of the University regulations of The Tamilnadu Dr. M.G.R Medical University, Chennai, for the award of degree of Doctor Of Medicine (M.D) Branch- I -General Medicine.

Prof. Dr .R.BALAJI NATHAN MD,

Dean, Kanyakumari Government Medical College

^,

Asaripallam.

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CERTIFICATE FROM THE HOD

This is to certify that the dissertation entitled “EVALUATION OF SERUM URIC ACID AS A PREDICTIVE FACTOR OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH ACUTE ST ELEVATION MYOCARDIAL INFARCTION”is the bonafide work of Dr. POOJA.H in partial fulfilment of the University regulations of The Tamilnadu Dr. M.G.R Medical University, Chennai, for the award of degree of Doctor Of Medicine (M.D) Branch- I -General Medicine.

Prof. Dr. PRINCE SREEKUMAR PIUS, M.D., HEAD OF DEPARTMENT, DEPARTMENT. OF GENERAL MEDICINE, Kanyakumari Government Medical College, Asaripallam.

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CERTIFICATE FROM THE GUIDE

This is to certify that the dissertation entitled “EVALUATION OF SERUM URIC ACID AS A PREDICTIVE FACTOR OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH ACUTE ST ELEVATION MYOCARDIAL INFARCTION” is the bonafide work of Dr.POOJA.H in partial fulfilment of the University regulations of The Tamilnadu Dr. M.G.R Medical University, Chennai, for the award of degree of Doctor Of Medicine (M.D) Branch- I -General Medicine

PROF.Dr. S SANKAR, M.D.,

Department. Of General Medicine,

Kanyakumari Government Medical College,

Asaripallam.

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DECLARATION

I,

Dr. POOJA.H, hereby declare that, I carried out this work entitled

“EVALUATION OF SERUM URIC ACID AS A PREDICTIVE FACTOR OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH ACUTE ST ELEVATION MYOCARDIAL INFARCTION” at

Kanyakumari Government Medical College Hospital, Asaripallam, under the guidance of

Prof. Dr. PRINCE SREEKUMAR PIUS M.D.,

Professor of Medicine, during the period of May 2018-June 2019.I also declare that this bonafide work has not been submitted in part or full by me or any others for any award, degree or diploma to any other University or Board either in India or abroad.

This is submitted to The Tamilnadu Dr. M.G.R Medical University, Chennai, in partial fulfilment of the University rules and regulations for the award of degree of Doctor of Medicine (M.D) Branch- I-General Medicine.

Place: Asaripallam

Date: Dr. POOJA. H

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ACKNOWLEDGEMENTS

I would like to express my sincere gratitude to

Prof. Dr. R. BALAJI NATHAN MD., Dean,Kanyakumari Government Medical College, for having

permitted me conduct this study and to use the hospital facilities at Kanyakumari Government Medical College Hospital, Asaripallam.

I am greatly indebted to my beloved teacher

Prof. Dr. PRINCE SREEKUMAR PIUS, M.D., Professor and Head, Department of Medicine for

allowing me to do this study in the Department of Medicine. I also express my sincere thanks to him for giving me proper guidance, protocol and immense help and encouragement in conducting this study.

I express my gratitude to

Dr.S.SANKAR MD., Associate professor,

Department of Medicine who immensely helped me in conducting this study. I also express my gratitude to DR P. JOHN CHRISTOPHER,MD my unit chief who helped me in conducting the study. I express my gratitude to

Dr Muralidharan, MD, DM Assistant professor,Department of Cardiology for his

guidance throughout the study.

I express my sincere and heartfelt gratitude to

Dr Geetha, Dr John Vinoj, Dr Brindha Davis,Dr Jenu Santhosh, Dr Preethi, Dr Sivaranjini, Dr

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Sofia, Dr Eunice

my Assistant professors in the Department of Medicine for their encouragement, kind guidance, constant support and cooperation in evaluating the patients.

I thank the Members, Secretary and Chairman of the Institutional Ethical committee, Kanyakumari Government College hospital, Asaripallam.

I thank all the paramedical staff and other staff of the Kanyakumari Government Medical College Hospital for all their help and cooperation in conducting this study.

I thank all my colleagues and friends for their constant encouragement and valuable criticism.

I am extremely thankful to all my family members for their continuous support. Above all I thank God Almighty for his immense blessings.

Last, but not least, my profound gratitude to all the patients, to whom I owe

everything because this venture would not have been possible without them.

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Hyperuricemia may precede the onset of type 2 diabetes, hypertension, coronary artery disease and gout in individuals with metabolic syndrome. It has also been observed in patients with congestive cardiac failure. In all the aforementioned conditions activation of xanthine oxidase through the release of free radicals result in leukocyte and endothelial cell adhesion.. Hyperuricemia increases oxidative stress and activate inflammatory cytokines while inducing myocardial apoptosis, thereby promoting myocardial remodelling. Furthermore acute MI may cause tissue hypoxia and hypoperfusion which could enhance the role of xanthine oxidase and oxidative stress subsequently increasing serum uric acid levels. Hence a vicious cycle is formed which further worsens cardiac function. In this study we ought to determine whether serum uric acid levels correlate with clinical scoring systems, echographic evidence of LV dysfunction and mortality in a patient with acute ST elevation MI.

METHODS

A hundred patients with a diagnosis of acute ST elevation myocardial infarction who were admitted in the ICCU and general medicine wards of Kanyakumari Government Medical College from the time period of May 2018 to June 2019 were studied . The patients were clinically allotted to KILLIP Class and TIMI Score. Serum uric acid levels were measured on day 0,3 and 7 from the venous sample. Risk factors like hypertension, diabetes mellitus, smoking and prior CVA were noted. Routine

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investigations including Random blood sugar, HbA1c, total cholesterol. ECG, Echocardiogram and cardiac biomarkers like CPK, CKMB were done.

RESULTS

About 58% subjects had hyperuricemia. Mean serum uric acid among hyperuricemic patients 9.54 + 1.52. Patients with higher serum uric acid levels was found to have higher KILLIP class and TIMI SCORE. Mortality rate was 12% and all these subjects were observed to have hyperuricemia. Of the 14% subjects who had severe LV systolic dysfunction 12% had hyperuricemia. However it was not found to have any association with age, gender and other risk factors like diabetes, hypertension, dyslipidemia , smoking and prior CVA.

CONCLUSION

Serum uric acid levels were found to be elevated in Acute ST elevation myocardial infarction. It was observed that hyperuricemia correlates with KILLIP classification and TIMI Score for STEMI. Elevated serum uric acid levels was also observed to have a correlation with mortality of the patient. Hyperuricemia was also found to have association with LV systolic dysfunction.

Key words : Uric acid ,oxidative stress, xanthine oxidase, hypoxia ,STEMI , KILLIP class, TIMI SCORE, LV systolic dysfunction.

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INTRODUCTION

Myocardial infarction remains one of the major health care problem in the industrialized countries and is also increasing in incidence in developing countries like India.¹ But the overall number of deaths due to STEMI show a decreasing trend compared to yesteryears due to early detection of cases and timely management. This in turn is made possible because of picking up early ECG changes, detection of elevation of cardiac biomarkers and echocardiographic detection of regional wall motion abnormalities. As the appropriate initiation of reperfusion is lifesaving there has been consideration for finding new biomarkers for effective management of the patient as well as prognosis.

Almost all acute coronary syndromes result from coronary atherosclerosis with superimposed coronary thrombosis caused by rupture or erosion of an atherosclerotic plaque.²When the coronary thrombus occludes the vessel completely it results in transmural ischemia and STEMI. Metabolic syndrome, type 2 DM, obesity, inflammation each one of which accelerates the problem of coronary atherosclerosis ³ Mortality is found to be significantly reduced by reperfusion within 12 hours of onset of symptoms. The conventional biomarkers such as troponin, creatinine kinase and myoglobin are widely in use during clinical practice. There has been an upsurge for finding new molecules which could help in assessing the prognosis after a myocardial infarction as well as for predicting the major adverse cardiac events following an MI and mortality. Novel biomarkers include homocysteine, hs CRP, cytokines like IL6 myeloperoxidase, lipoprotein associated phospholipase A2, unbound free fatty acid, co peptin, BNP, lipoprotein A and uric acid.⁴

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Uric acid is the end product of purine metabolism in humans. Howsoever it is by far implicated to rise in a large number of inflammatory conditions due to oxidative stress and has been linked with hypertension, cardiovascular disease, ischemic stroke, renal disease and metabolic syndrome.⁵

Serum uric acid level depends on diet, body mass index, age and gender. Since serum acid is thought to play an important role in the pathogenesis of acute myocardial infarction, this study aims to evaluate the prognostic role of serum uric acid in acute ST elevation MI by comparison with the various established scores of myocardial infarction related morbidity and mortality risk like KILLIP Class⁶, TIMI Score ⁷

As it is a cheap marker it can also be used for identifying the high risk patients and could serve as a guide for timely management thereby reducing cardiovascular morbidity.

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AIMS AND OBJECTIVES

1. To estimate the Serum Uric acid levels in patients with acute ST elevation myocardial infarction.

2.To correlate the levels of serum uric acid with the severity of myocardial infarction as assessed by various scoring systems

3.To determine whether there is any correlation between serum uric acid and echocardiographic evidence of left ventricular dysfunction.

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REVIEW OF LITERATURE History

The history of coronary syndromes and sudden death, goes back to antiquity. From the twentieth century, a heart attack with myocardial infarction was well known to cause death, but it was not yet understood whether a patient could survive from acute coronary syndrome. It was believed that a change in the environmental factors had led to the emergence of this new epidemic

The sudden cardiac death of John Hunter,an eighteenth century surgeon and anatomist was attributed to angina pectoris, and sudden death.⁸ James Herrick, a Chicago internist, observed the clinical and electrocardiographic evolution of the phenomenon and documented his findings by creating coronary occlusion in animals⁹.A classical description of clinical coronary disease was elucidated by René Marie in France in 1896 and George Dock in U.S. the same year reported having made the clinical diagnosis during life in a patient with autopsy proven myocardial infarction¹⁰

The discovery of electrocardiography by Wilhelm Einthoven of Leiden, which measured the electrical activity in the heart beat and its disturbances marked the turning point in a better understanding of coronary artery disease¹¹.In the 1920s Sir Thomas Lewis, made ECG an essential and practical instrument for diagnosing myocardial ischemia and infarction.

Later the cardiac biomarkers were discovered,the first one to be identified being serum glutamic oxaloacetic transaminase (SGOT) in 1954¹²by Ladue JS, Wrŏblewski F et al. Lactate dehydrogenase (LDH) was found to be of utility in diagnosing

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myocardial infarction by Hill and Levi IN 1955¹³.In the 1960s creatine kinase (CK) total enzyme activity was found to have a role. In1972 Roe et al. quantified CK-MB isoenzyme activity.¹⁴The discovery of troponins by Professor Setsuro Ebashi¹⁵ in 1963 was a remarkable achievement for the diagnosis and prognosis of acute myocardial infarction

Even today hs cTn immunoassays is considered as the best biomarker available for the diagnosis of acute coronary syndrome

.

EPIDEMIOLOGY Global burden of IHD

According to 2018 Heart Disease and Stroke Statistics update of the AHA, 16.5 million persons in the United States have CAD with 55% of patients being male . It is estimated thatcardiovascular disease accounted for one-third of all deaths in 2015, and there were an estimated 422 million prevalent cases according to The Global Burden of Disease Study 2015¹⁶

Burden of Cardiovascular Diseases in India

According to current statistics about 1 in 4 deaths in India is due to cardiovascular disease the major causes being ischemic heart disease and stroke.The estimated prevalence of CVD in India is estimated to be about 54.5 million in 2016¹⁷

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ATHEROSCLEROSIS

Atherosclerosis, introduced by Marchand is derived from the greek word, “athero”

which means Gruel. Atheroma isthe subintimal patchy intramural thickening. The clinical events are due to unstable plaque and fibrous plaque which is derived from the initial fatty streak.

Medium sized and large arteries is the most common location. The plaque has a cellular component,fat component and a fibrous component. The cellular component is comprised of inflammatory cells, smooth muscle cells, fibrous component of connective tissue and fat component of lipids.¹⁸Prominent risk factors are hypertension, diabetes, dyslipidemia, obesity, sedentary life style, Family history, smoking.The symptoms are caused by intraplaque rupture, bleeding, thrombosis and stenosis.

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Pathogenesis of atherosclerotic plaque formation¹⁹ Turbulent blood flow leading to endothelial dysfunction

Endothelial injury

inhibition of NO production

production of adhesion molecules

Recruitment of inflammatory cells subendothelial migration of monocytes and T cells

LDL, VLDL bind to endothelial cells and oxidize in the subendothelial space

Monocytes engulf oxidized LDL  foam cells and fatty streak formation

Macrophages release proinflammatory cytokines and smooth muscle cell replication

SUBENDOTHELIAL FIBROUS PLAQUE

(inner core by lipids, outer surface by smooth muscle cells and connective tissue fibers)

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ACUTE CORONARY SYNDROME Includes²⁰

Unstable angina

Non–ST-segment elevation myocardial infarction (NSTEMI) ST-segment elevation myocardial infarction (STEMI)

As the prognosis and treatment of each of these syndromes vary it is necessary to distinguish them on the basis of symptoms, ECG findings and cardiac biomarkers.

UNSTABLE ANGINA

Here cardiac biomarkers are not elevated.

 Rest angina -prolonged (usually > 20 min)

 New-onset angina of at least class 3 severity in the Canadian Cardiovascular Society (CCS) classification

 Increasing angina i.e. previously diagnosed angina that has become distinctly more frequent, more severe, longer in duration, or lower in threshold

 ECG changes such as ST-segment depression, ST-segment elevation, or T- wave inversion are transient.

CK is not elevated but cardiac troponin, particularly when measured using high- sensitivity troponin tests (hs-cTn), may be slightly increased.

Unstable angina is clinically unstable and can lead on to myocardial infarction or arrhythmias or rarely to sudden death.

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NON–ST-SEGMENT ELEVATION MI (NSTEMI)

Myocardial necrosis is present. Cardiac biomarkers troponin I or troponin T and CK are elevated, but there is no acute ST-segment elevation.

ECG changes such as ST-segment depression, T-wave inversion, or both may be present.

ST-SEGMENT ELEVATION MI(STEMI)

Myocardial necrosis with ECG showing ST-segment elevation that is not quickly reversed by nitroglycerin or new left bundle branch block. There is elevation of cardiac biomarkers.

Fourth Universal Definition of Myocardial Infarction²⁰

1.The definition of MI is updated to accommodate the increased use of high- sensitivity cardiac troponin (hs-cTn).

2.Myocardial injury is defined as an elevation of cTn value above the 99th percentile upper reference limit (URL).

3.Type 1 MI - Detection of a rise and/or fall of cTn with at least one value above the 99th percentile and with at least one of the following:

Symptoms of acute myocardial ischemia;

New ischemic electrocardiographic (ECG) changes Development of pathological Q waves;

Imaging evidence of new loss of viable myocardium or new regional wall

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motion abnormality

Identification of a coronary thrombus by angiography

4.Type 2 MI -Detection of a rise and/or fall of cTn with at least one value above the 99th percentile with evidence of imbalance between myocardial oxygen supply and demand unrelated to coronary thrombosis, requiring at least one of

Symptoms of acute myocardial ischemia;

New ischemic electrocardiographic (ECG) changes Development of pathological Q waves;

Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

5.Cardiac procedural myocardial injury- increase of cTn values (>99th percentile URL) in patients with normal baseline or a rise of cTn values >20% of the baseline value when it is above the 99th percentile, but it is stable or falling.

6.Coronary intervention-related MI -elevation of cTn values >5 times the 99th percentile URL in patients with normal baseline values

7.Coronary artery bypass grafting (CABG)-elevation of cTn values >10 times the 99th percentile URL in patients with normal baseline values with

Development of new pathological Q waves;

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Angiographic documented new graft occlusion

Imaging evidence of new loss of viable myocardium or new RWMA

8.Myocardial infarction with non-obstructive coronary arteries (MINOCA)-MI patients with no angiographic obstructive coronary artery disease.

TYPES OF MYOCARDIAL INFARCTIONS

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STEMI (ST-elevation myocardial infarction)

STEMI is one of the leading causes of mortality and morbidity worldwide. Survival after acute STEMI has improved due to increasing symptom recognition, accurate diagnosis and timely reperfusion.

An outline of Coronary circulation²²

Left main and right coronary arteries supply the heart

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 Left main coronary artery (LMCA) supplies the left ventricle and left atrium and divides into

o The left anterior descending artery.

o The circumflex artery branches

 Right coronary artery (RCA) - supplies right ventricle, the right atrium, and the SA (sinoatrial) and AV (atrioventricular) nodes, divides into

o right posterior descending artery

o acute marginal artery.

 Smaller branches of the coronary arteries include: obtuse marginal (OM), septal perforator (SP), and diagonals.

STEMI is defined by ECG ²³features which include

 Persistent ST elevation of ≥ 1mm in 2 contiguous limb leads

 ST elevation of ≥ 2mm in 2 contiguous chest leads

 New LBBB pattern

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Area of infarction ECG Changes Artery involved

Anteroseptal V1-V3 LAD

Anterior V2-V4 LAD

Lateral I,Avl,V5-V6 LAD / left circumflex

Inferior II, III, Avf RCA/

Posterior V7-V9 Posterior descending

Right Ventricle V3R-V6R RCA

ECG can be considered as a poor man’s angiogram as it gives valuable information for finding the culprit vessel.

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FOUR WALLS OF THE LEFT VENTRICLE

Sgarbossa criteria for LBBB

Concordant ST elevation ≥1 mm 5 points ST depression >1mm in V1-V3 3 points Discordant ST elevation≥5mm 2 points

*A score of 3 points for diagnosing myocardial infarction.

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With a clinically suspected acute myocardial infarction and ECG showing LBBB, and if so the patient is hemodynamically unstable or in acute heart failure even if the patient doesn’t fulfil Sgarbossa criteria it is considered as a STEMI equivalent.

BIOCHEMICAL MARKERS OF MYOCARDIAL NECROSIS

Myocardial cell death is demonstrated by presence of different proteins released into the blood from the ischemically injured myocytes: including myoglobin, cardiac troponin T and I, CK, LDH, heart fatty acid binding protein. Myocardial infarction is diagnosed when blood levels of cardiac troponin or CK-MB are elevated in the clinical setting of acute myocardial ischemia. When there is elevated cardiac biomarkers without clinical findings of ischemia we have to search for other causes of cardiac damage like myocarditis.

Creatine kinase and CK-MB isoenzyme

Creatine kinase is a regulator of high-energy phosphate production, utilized in contractile tissues. Cytoplasmic CK is a dimer²³, composed of both M and/or B subunits, that produce CK-MM, CK-MB and CK-BB iso-enzymes. Mitochondrial CK is unstable in human serum, so it is difficult to measure.

CK-MM - striated muscle ( 97% of the total CK) CK-MB - cardiac muscle (15–40% of the total CK ) CK-BB - brain, intestinal and urinary systems

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Following an event of acute myocardial injury, there will be significant increase in both total CK activity and CK MB concentration.CK-MB best predicts AMI in the first 4 hours compared with myoglobin and TnT.

If CK index that is CK-MB divided by total CK is lower than 4%, a non-myocardial etiology of a high CK-MB should be suspected.

Troponin

The troponins are regulatory proteins found in both cardiac and skeletal muscles. They have 3 subunits. Troponin can originate from both skeletal and cardiac muscles, but the specific forms of troponin vary between types of muscle. Smooth muscle does not contain troponin.

Individual subunits play different roles:

Troponin C: binds to calcium ions producing a conformational change in TnI.

Troponin T: binds to tropomyosin, forming a troponin-tropomyosin complex

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Troponin I: binds to actin in thin myofilaments thereby holding the troponin- tropomyosin complex in place.

High-sensitivity troponin (hsTn)²⁴ assays enable lower limits of detection (e.g.,<0.001 ng/mL or <1 pg/mL)

Cardiac troponin T (cTnT)-It is a cardio-specific, highly sensitive marker for myocardial injury. MI can be diagnosed when blood levels of cTnT are above the 99th percentile of the accepted limit along with an evidence of myocardial ischemia. It can be used as an independent prognostic marker which can predict short and long- term outcome of events in patients with acute coronary syndrome (ACS).

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Cardiac troponin I (cTnI)-It is the contractile part present inside the myocardium. It is a part of the troponin complex (I, T, C) that along with the tropomyosin binds to actin within the thin myofibril filament. Increased troponin I levels are also found in unstable angina and congestive cardiac failure. In acute MI serum concentrations of both cTnI and CK-MB show similar increase and decrease patterns. In the cardiac muscles the level of cTnI is 13 times more than that of CK-MB. Troponin I levels reach the peak level at approximately 12–16 h and remain elevated for 4–9 days after acute MI.

Myoglobin²⁵

Low-molecular-weight protein that is present in cardiac and skeletal muscle. It can be detected in the serum as early as two hours after myocardial necrosis and has low cardiac specificity but high sensitivity. It is useful for ruling out myocardial infarction if level is normal in the first 4-8 hours after the onset of symptoms. Myoglobin should be used along with other serum markers, because its level peaks and falls rapidly in patients with ischemia.

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COMPARISON OF TROPONIN,CK MB AND MYOGLOBIN

NOVEL CARDIAC BIOMARKERS

hFABP ( heart type Fatty Acid Binding Protein )

They are 15 kDa proteins involved in intracellular buffering and transport of long fatty-acid chains with a t1/2 of 20 minutes. It also protect cardiac myocytes against long-chain fatty acids present at high concentrations, especially during ischemia within 3 hours of onset of chest pain and returns to normal after 12–24 hours. It is metabolized by the kidneys. An increase in blood hFABP is in favour of MI along with other suspected criteria.²⁶

Glycogen Phosphorylase Isoenzyme BB

GPBB is necessary to create energy for muscle contraction and is released from cardiac myocytes during ischemia rising within the first 1–4 hours of AMI²⁷peaks at6–10 hours, and returns to reference values within 1–2 days.

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Ischemia-modified albumin

A lower metal-binding capacity of albumin with cobalt was observed on the albumin–

cobalt binding test in patients with myocardial ischemia due to a change in the N terminus of albumin. IMA rises within 3 hours after the ACS^28.it is non-specific and is elevated in cancer, infection, brain ischemia, liver disease, and end-stage renal disease.

S100A-It is a 21 kDa protein which is an intracellular calcium-binding protein dimer²⁹.It is highly sensitive in showing myocardial injury but is also elevated in trauma and acute ischemic stroke

Choline-It is released by the hydrolysis of phosphatidylcholine, and its levels increase during early period of AMI, which is attributed to coronary plaque destabilization and stimulation of PLD by macrophages in tissue ischemia.

Copeptin-It is used along with other biomarkers to diagnose suspected MI.

PAPP-A-It is elevated 2–30 hours after the onset of chest pain

HsCRP-It monitors the inflammatory process, coronary artery pathologies, and the course of CAD³⁰.

Cytokines-TNF, IL6, IL18, CD40 ligand, MPO, MMP9,

Procalcitonin-Useful in the diagnosis and prognosis of AMI as it shows significant association with LV dysfunction and Cardiac remodelling.

LpA, ApoA, ApoB,-Is found to have a role in the diagnosis of AMI.

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SCORING SYSTEMS FOR MI KILLIP CLASS

In 1967, Killip and Kimball classified about 250 patients suffering from MI based on their clinical presentation at the time of admission to ICU to assess the clinical

severity and was managed accordingly. This stratification led to a decline in the mortality and morbidity of the patients

GRACE SCORE³¹

Predict death, or MI over an extended 1 year and also death over a 3-year period from the time of hospital admission. The clinical variables include age, heart rate, systolic blood pressure, creatinine, congestive HF, cardiac arrest, ST-segment deviation and elevated enzyme/cardiac biomarkers. It provides the most accurate stratification of risk both on admission and at discharge due to its good discriminative power

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RISK CATEGORY GRACE SCORE FOR STEMI

LOW RISK 27-99

INTERMEDIATE RISK 100-127

HIGH RISK 128-263

TIMI Score

The TIMI score was created and validated in a sample of patients with ST-segment elevation myocardial infarction, and thus, has specific variables for this clinical condition. In brief, this score consists of eight dichotomic variables, with the

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exception of age that adds points in two distinct strata.. The final score range between 0 and 14.

TIMI risk score was originally focused on the 30-day mortality. Subsequently, it was validated for STEMI patients treated by PCI and for prediction of one-year mortality CADILLAC SCORE

The Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) risk score³²is used to predict the one-year mortality.

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PURSUIT SCORE³³

It predicts 30 day risk and is calculated by using variables like age, gender ,CCS angina class, BP,HR ,signs of heart failure and ST depression

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ROLE OF ECHOCARDIOGRAPHY IN STEMI

Echocardiography³⁴ helps in diagnosis of patients with suspected MI and is also necessary in all patients with confirmed acute MI for assessment of ventricular function, to look for mechanical complications and rule out intraventricular thrombosis. It also provides prognostic information. Stress echocardiography is recommended for identifying residual ischemia post MI. When the ECG is nondiagnostic, evaluation of wall motion while a patient has typical chest pain is helpful. As well as when there is severe ischemia RWMA can be picked up within seconds of coronary artery occlusion³⁵

Ejection fraction is assessed by echo, nuclear imaging, ECG-gated myocardial perfusion single-photon emission computed tomography (SPECT) ³⁶

Right ventricular dysfunction is recognised as fractional area shortening of the right ventricle <32% detected 1 year after infarction also useful in predicting mortality and heart failure in the future ³⁷ Contrast-enhanced MRI images can also detect myocardial no-reflow in the subendocardium surrounded by late-enhanced myocardium.³⁸Myocardial viability can be detected by positron emission tomography and SPECT using tracers²⁰¹Thallium, ^99mTechnetium sestamibi, or ^99mTechnetium tetrofosmin.

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TREATMENT OF STEMI

Initial medical therapy during STEMI consists of Oxygen administration,

Antiplatelet therapy (aspirin, thienopyridines and glycoprotein IIb/IIIa inhibitors), Anginal pain relief with nitrates and morphine

Fibrinolysis^39-The choice of reperfusion therapy is between PCI and thrombolysis therapy. PCI is the best available treatment modality if performed promptly.

Thrombolytics such as streptokinase or tissue type plasminogen activator also restore perfusion to ischemic area by clot lysis and reduce infarct size; the greatest benefit obtained when lysis done within 12 hours of symptoms.

Anticoagulation (heparin or bivalirudin), Beta-blockade.

HMG CoA reductase inhibitors.

Contraindications To Thrombolytic Therapy

Absolute- active bleeding, significant closed head or facial trauma, aortic dissection,

prior intracranial haemorrhage, tumour or AVM, ischemic stroke within past 3 months, GI bleed within1 month.

Relative- recent major surgery <3 weeks, active peptic ulcer, prolonged cardiopulmonary resuscitation, advanced liver disease, poorly contolled SHTN (>180/100mm Hg), pregnancy.

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2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction⁴⁰

Medical therapy upon hospital discharge may include antiplatelet drugs, ACE inhibitors, beta blockers, aldosterone antagonists, nitrates and HMG CoA reductase inhibitors.

COMPLICATIONS

The complications following an acute myocardial infarction can be. mechanical, arrhythmic, ischemic, inflammatory and embolic

1.MECHANICAL-LV failure in cardiogenic shock⁴¹ – can be treated by intra aortic balloon pump insertion improves cardiac output, ionotropic and vasopressor agents and temporary left ventricular assist device

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COMPLICATION ARTERY TIME COURSE

CLINICAL FINDINGS

ECHO

RV FAILURE RCA Acute Hypotension,

clear lungs, Kussmaul sign

Hypokinetic RV

Papillary muscle rupture

RCA Acute and within 3-5 days

Acute pulmonary edema, new holosystolic murmur

Severe MR with leaflet flail

Interventricular septal defect

LAD(apica l),RCA(bas al)

Acute within 3-5 days

Shock and chest pain,new

holosystolic murmur

Left to right shunt at the level of rupture

Free wall rupture LAD Within first 5 days to 2 weeks

Shock and chest pain,elevated JVP,distant heart sounds

Pericardial effusion with tamponade.

Ventricular aneurysm

LAD Acute or

chronic

Cardiac

failure,arrhythmi a,embolic

manifestations

Dilated LV with dyskinetic area of thinned myocardium.

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2.Arrhythmia-accelerated idioventricular rhythm, ventricular tachycardia, ventricular fibrillation, sinus tachycardia, atrial flutter, atrial fibrillation and AV block can occur 3.ischemic –Re- infarction

4.Inflammatory-pericarditis which can be early or late

5.Embolic-mural thrombus, limb ischemia and mesenteric ischemia

MACE

Multiple adverse events included in different research as a component of MACE are

 heart failure,

 Non-fatal re-infarction,

 Recurrent angina pain,

 Re-hospitalization for cardiovascular-related illness,

 Repeat percutaneous coronary intervention (PCI), coronary artery bypass grafting and

•MITRAL REGURGITATION

•DRESSLER SYNDROME

•ATRIAL FIBRILLATION

•COMPLETE HEART BLOCK

•HEART FAILURE

•LV

DYSFUNCTION

CARDIOGENIC SHOCK

BRADY AND TACHY ARRHYTHMIA

RUPTURE OF VENTRICAL SEPTUM OR

FREE WALL PERICARDITIS

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 Stroke

 All-cause death and mortality

PROGNOSIS

Reduction in STEMI mortality is due to greater use of percutaneous coronary intervention (PCI), antithrombotic therapy and secondary cardiovascular prevention strategies. Prognosis after STEMI depends on factors such as age, comorbidities (diabetes mellitus, hypertension, previous myocardial infarction and renal failure), multi vessel disease , left ventricular ejection fraction and timely revascularization

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32

URIC ACID.

Uric Acid (2,6,8- tri oxy purine- chemically represented as C5H4N4O3), an organic acid is the final breakdown product of purine metabolism. An intricate balance exists between the generation and excretion of uric acid in human beings so blood levels are maintained in a normal range.

It is synthesised in the liver and mainly excreted by the specialised transporters located in proximal tubular cells of the kidneys, intestinal epithelial cells and vascular smooth muscle cells. ATP, DNA and RNA are broken down into purine nucleotides and bases. These unwanted purine nucleotides are metabolized by the enzyme Xanthine Oxidase into the final products of xanthine and uric acid. In humans uric acid cannot be further metabolised as humans lack the enzyme uricase whereas in other species uric acid is converted into allantoin. which is a soluble metabolic end product and is excreted through kidney. For instance this is the mechanism underlying the use of Rasburicase⁴² which is a recombinant uricase converting urate into allantoin

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33

SYNTHESIS⁴³

De novo purine biosynthesis forms inosine monophosphate (IMP) through multiple steps

TRANSPORT OF URIC ACID

Uric acid transporters are mainly either urate reabsorption transporters and urate excretion transporter. Uric acid crosses through the glomerulus freely, then most is reabsorbed by proximal tubular urate transporters and only a small portion of it is secreted back into the filtrate via the late proximal tubule.

Urate reabsorption transporters- Urate anion transporter 1

URAT1 (SLC22A12 gene), the major urate reabsorption transporter, is found in the apical membrane of proximal tubule epithelial cells and interchanges uric acid in the proximal tubular lumen with Cl− or organic anions in the epithelial cells.

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34

Urate excretion transporters-The organic anion and urate transporters OAT1 (SLC22A6) and OAT3 (SLC22A8) are expressed at the basolateral side of the same cells that express OAT4 and have a great influence on urate excretion as urate/dicarboxylate exchangers

Tubular secretion of uric acid transporters-Urate transporter, first identified in the brush border of rat renal tubular epithelial cells, is a specific secretion of uric acid transporter protein

HYPERURICEMIA⁴⁴

Elevated uric acid can be seen in accelerated purine degradation, in high cell turnover states (hemolysis, rhabdomyolysis, and tumor lysis) and decreased excretion (renal insufficiency and metabolic acidosis). Hyperuricemia can lead to gout and nephrolithiasis. It has also been implicated as an indicator for diseases like metabolic syndrome, diabetes mellitus, cardiovascular disease, and chronic renal disease

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35

Urate Overproduction

 Purine rich diet

 Error of purine metabolism: hypoxanthine phosphoribosyltransferase (HPRT) deficiency, phosphoribosylpyrophosphate (PRPP) synthetase over activity

 Cell breakdown or turnover: lymphoproliferative diseases, myeloproliferative disease, polycythemia vera, Paget disease, psoriasis, tumor lysis, hemolysis, rhabdomyolysis, exercise

Decreased Uric acid Excretion

Acute or chronic kidney disease, acidosis (lactic acidosis, ketoacidosis), hypovolemia, medication/toxin (diuretic, niacin, pyrazinamide, ethambutol, cyclosporin, beryllium,

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36

salicylates, lead, alcohol), sarcoidosis, hyperparathyroidism, hypothyroidism, Bartter syndrome, Down syndrome

DRUGS AND URIC ACID

CAUSING HYPERURICEMIA CAUSING HYPOURICEMIA⁴⁵

Theophylline Allopurinol

Phenothiazines Probenecid

Methyl dopa Mannitol

Ethambutol Corticosteroids

Epinephrine Estrogen

Cisplatin Azathioprine

Aspirin Clofibrate

Alcohol; caffeine Warfarin

Diazoxide Losartan

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37

HYPERURICEMIA AND SYSTEMIC DISEASES

Hyperuricemia is implicated in the development of gouty arthritis, nephrolithiasis, urate nephropathy and uric acid nephropathy. However recent studies imply its role in multiple systemic diseases like diabetes mellitus, hypertension, coronary artery

disease and metabolic syndrome through the following mechanisms.

Hyperuricemia and atherosclerosis⁴⁶

Atherosclerosis is a predisposing factor for cardiovascular diseases and can also trigger renal artery stenosis and correlates with acute or chronic kidney disease.

Oxidized low-density lipoprotein has a pivotal role on the formation of atheromatous plaques. Uric acid can stimulate the up-regulation of C-reactive protein in both vascular smooth muscle cells and endothelial cells, which add to the pro-atherogenic properties of soluble uric acid

HYPERURICEMIA

INFLAMMATION

ENDOTHELIAL DYSFUNCTION

VISCERAL ADIPOSITY AND

INSULIN RESISTANCE INCREASED

OXIDATIVE STRESS

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38

Hyperuricemia and coronary heart disease

Atherosclerotic lesions and vessel narrowing in the coronary arteries decrease blood supply of heart. Hyperuricemia act as a stimulating factor to individuals at risk of CHD related-events. Studies have shown that there is an increased CHD risk ratio of 1.12 in men and 1.22 in women with hyperuricemia.

Inflammation can be considered as a mechanism for hyperuricemia in promoting cardiovascular disease ⁴⁷.Xanthine oxidase activation leads to production of reactive oxygen species which inducing endothelial dysfunction and vascular inflammation Uric acid in turn has a negative effect on vascular function by inducing oxidant damage and decreasing nitric oxide bioavailability. This p explains a link between hyperuricemia and coronary heart disease

Hyperuricemia and diabetes

Studies have shown that a correlation exists between high levels of serum uric acid and high-risk of diabetic nephropathy complications among type I diabetes. So a novel intervention for diabetic nephropathy involves reducing serum uric acid levels, Allopurinol is being considered as a renoprotective medicine in diabetic patients in recent times

Higher serum urate acid concentration has an association with type II diabetes and the metabolic syndrome .Urate crystals deposited in islet β cells of pancreas⁴⁸ causes islet dysfunction, leading to diabetes. Elevated blood glucose level decreases the ability of urate transporter GLUT9, further worsening hyperuricemia, leading to renal

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dysfunction. Also hyperuricemia promotes the development of diabetes through inhibition of nitric oxide synthase

Uric acid and hypertension

Hyperuricemia lead to angiopathy ⁴⁹by

 oxidative stress during uric acid production,

 the urate transporter disorders, and

 hyperuricemia-induced vascular disorders –accelerated arteriosclerosis by deposition of monosodium urate crystals

LITERATURE SUPPORTING THE STUDY 1.The Framingham Heart Study⁵⁰

Among the 6763 participants followed up with serial serum uric acid levels it was observed as

 No causal role for uric acid in the development of coronary heart disease and death from cardiovascular disease

 Any association with these outcomes is most probably due to the association of uric acid level with other risk factors

2. Japanese acute coronary syndrome study ⁵¹

Among the 1124 patients studied a close relationship was observed between serum uric acid levels and KILLIP’s classification. Hence it was concluded that serum uric

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40

acid levels is a good marker for predicting mortality and acute MI related adverse events.

3. Rotterdam study⁵²

In this study 4385 participants, free from stroke and coronary artery disease were studied and were followed up for incident stroke and MI. it was observed that high serum uric acid levels were associated with increased risk of myocardial infarction and stroke.

4.Study conducted in Japan china Friendly hospital, department of cardiology ⁵³ Among the 502 patients with STEMI who were retrospectively studied from the period of January 2005 to December 201 it was observed that

 is a positive correlation between serum uric acid and serum triglyceride values

 Also patients with hyperuricemia in STEMI have a higher rate of left systolic dysfunction and diastolic dysfunction.

 they are alsomore likely to have more in hospital MACE.

5.A hospital base prospective analytical observational study conducted among 102 acute MI patients admitted inDepartments of General Medicine and Cardiology, Gauhati Medical College & Hospital⁵⁴,; showed that

 in acute MI patients with a higher Killip class,signifying severe disease found to have higher serum uric acid level.

 Further patients with higher serum uric acid had longer hospital stay and significantly higher in-hospital mortality.

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41

6.Among the studied 50 patients with acute MI and 50 controls enrolled in Gandhi Hospital (Hyderabad, India) ⁵⁵between August 2011 and August 201it was

concluded that

 Higher level of serum uric acid in patients with acute MI compared with normal individuals.

 patients with hyperuricemia had higher mortality in acute MI.

 Serum uric acid levels correlated with Killip classification

 Serum uric acid level can be used as a marker of short-term mortality in acute MI, and

 hyperuricemia may be an indicator of poor prognosis.

 Serum uric acid levels were also elevated in acute MI patients with systemic hypertension and diabetes mellitus.

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42

METHODOLOGY

Design of study: observational cross sectional study

 Study setting: ICCU and internal medicine wards of KGMCH, Asaripallam

 Sample size : 100 patients

 Duration of study: 12 months Inclusion criteria

 Adult (>18 years) patients

 Diagnosed as a caseof acute MI (STEMI) on the basis of clinical history, examination,ECG, biochemical markers

Exclusion criteria

 Chronic kidney disease

 Gout

 Malignancy

 Hypothyroidism

 Patients on hypo/hyperuricemic medications

 Liver disease

 Systemic or local infection

 Chronic alcoholics

 Patients with prior myocardial infarction

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43

PROCEDURE

About 100 patients of acute STEMI who fulfill the inclusion/exclusion criteria and presented within 24 h onset of symptoms who were admitted in intensive care unit and ,internal medicine department were studied. A detailed history and examination including KILLIP classification and TIMI Score was carried out.

Diagnosis of STEMI was based upon

 New onset chest pain lasting more than 20 minutes

 ECG changes-ST elevation in contiguous leads,new onset LBBB

 Elevation of cardiac biomarkers

Any patient fulfilling 2 out of the 3 criteria was included in the study.

All patients underwent routine investigations including hemoglobin, complete blood count, renal and liver function test, ECG, Echocardiogram, lipid profile and serum uric acid.Uric acid was measured on day 0,3 and 7 of admission of cases by collecting venous blood sample after venepuncture and was measured using autoanalyser.

According to our lab reference values in male subjects uric acid range of 3.5-7mg/dl was considered normal and in females the range is 2.5-6 mg/dl. The cardiac marker used in the study was CPK and CK MB the lab values being for CPK –55-

170U/L(Males) ,30-135U/L(Females) and CK MB 5-24U.Hypertension was classified according to JNC 8 CLASSIFICATION. An RBS value>200mg/dl was considered hyperglycemia according to ADA Criteria. An HbA1c of 5.6-6.4 2was considered normal. Serum total cholesterol level above 200 mg/dl was considered as

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44

dyslipidemia. Any subject who smokes atleast 1 cigarette/day everyday was considered as a smoker

STATISTICAL ANALYSIS

All data collected in the study was analysed using the SPSS structured software(SPSS IBM) version 21.The statistical test used in the study were Chi square test and Pearson correlation.

ETHICAL CONCERNS:

Ethical committee approval was obtained for the study.

FUNDING:

Nil

CONSENT

The subjects were enrolled in the study after obtaining an informed written consent from them.

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45

OBSERVATIONS AND RESULTS

This study was conducted as an observational, cross-sectional, non-interventional study with a study population of 100 subjects

1.AGE DISTRIBUTION

The mean age of the study participants was 59.25 years. About 30% of the patients belonged to the age group of 61-70 years and 26% belonged to the age group between 51-60 years. So the majority of study population belonged to the middle and elderly age groups.

Variable Frequency Percentage

Age in years 30-40

41-50 51-60 61-70

>71

4 24 26 30 16

4 24 26 30 16 Table 1: Profile of the study participants:

Fig 1: Distribution of study participants according to age

0 5 10 15 20 25 30

30-40 41-50 51-60 61-70 >71

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46 2.GENDER DISTRIBUTION

There was a male predominance among the study subjects.Among the 100 patients studied,71 were male subjects.

Gender Male Female

frequency 71 29

Percentage 71 29

Table 2-Gender distribution

Fig 2-Gender distribution

3. SYMPTOM ANALYSIS

All the patients presented with typical retrosternal chest pain. Majority of patient with anterior wall ST elevation myocardial infarction have associated palpitation and inferior wall MI had associated vomiting. A significant proportion of patients had associated breathlessness.All the study subjects had chest pain, 35% had associated palpitation, 23% had dyspnea, 17% had vomiting and 2% had giddiness

71%

29%

Male Female

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47

S no Variable Frequency Percentage

1 Chest pain Yes

No

100 0

100 0 2 Palpitation

Yes No

35 65

35 65 3 Dyspnoea

Yes No

23 77

23 77 4 Vomiting

Yes No

17 83

17 83 5 Giddiness

Yes No

2 98

2 98 Table 3: Distribution of study participants according to the symptoms

Fig 3 : Distribution of study participants according to symptoms

0 20 40 60 80 100 120

chest pain palpitation dyspnea vomiting giddiness

%

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48 4.COMORBIDITIES

Among the study population about 35 subjects were diabetic,31 patients were hypertensive and about 3 patients had a history of cerebrovascular disease. There is a significant increase in prevalence of myocardial infarction among patients who are diabetic or hypertensive.

Table 4: Distribution of study participants according to comorbidities

Fig 4: Distribution of study participants according to comorbidities

DM

SHTN OLD CVA

NORMAL

DM SHTN OLD CVA NORMAL

S no Variable Frequency Percentage

1 Diabetes Yes No

35 65

35 65 2 Hypertension

Yes No

31 69

31 69 3 Old CVA

Yes No

3 97

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49 RISK FACTORS

5.Smoking and myocardial infarction-

Among our study population about 33 subjects were smokers. Smoking adds to the risk of myocardial infarction in young patients.

Smoking

Yes No

frequency 33 67

percentage 33 67 Table 5:Distribution of study subjects based on smoking

Fig 5: Distribution of study subjects based on smoking

Smokers Non smokers

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6.Prevalence of risk factors among subjects

Risk factors 0

1 2 3

34 39 23 4

34 39 23 4 Table 6: Distribution of study participants according to personal history

A major proportion of the study population had at least 1 risk factor. About 34% of the population had no previously identified risk factor. The risk factors studied include DM,HTN,smoking, and history of old CVA

Fig 6: Distribution of study participants according to personal history

% subjects 0

5 10 15 20 25 30 35 40

0 1 2 3

% subjects

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51 7.WINDOW PERIOD

Window period in hours 1-3

3-5 5-7 7-9 9-11

27 28 26 15 4

27 28 26 15 4 Table 7: Distribution of study participants according to window period

81% of the patients reached the hospital within 6 hours and the rest of the patients had a late presentation to the hospital.

Fig 7 : Distribution of study participants according to window period

27 28 26 15

4

0 5 10 15 20 25 30

1-3 HOURS 3-5 HOURS 5-7 HOURS 7-9 HOURS

>9HOURS

no. of subjects

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52 8.SYSTEMIC HTN AND MI

Blood pressure Hypotension Optimal Normal High normal

Grade I Hypertension Grade II Hypertension

Isolated Systolic

Hypertension

Isolated Diastolic Hypertension

19 31 16 12 8 2 10 2

Table 8: Distribution of study participants according to the examination of the participants

About 22% of the study subjects were hypertensive, and about 19 subjects presented with hypotension.

Fig 8: Distribution of study participants according to the examination of the participants

19% 59%

22%

Normotensive Hypotensive Hypertensive

Prof. Dr .R.BALAJI NATHAN MD,

CERTIFICATE FROM THE DEAN

Prof. Dr .R.BALAJI NATHAN MD,

Dean, Kanyakumari Government Medical College

CERTIFICATE FROM THE HOD

Prof. Dr. PRINCE SREEKUMAR PIUS, M.D., HEAD OF DEPARTMENT, DEPARTMENT. OF GENERAL MEDICINE, Kanyakumari Government Medical College, Asaripallam.

CERTIFICATE FROM THE GUIDE

PROF.Dr. S SANKAR, M.D.,

Department. Of General Medicine,

Kanyakumari Government Medical College,

Asaripallam.

DECLARATION

I,

Kanyakumari Government Medical College Hospital, Asaripallam, under the guidance of

Professor of Medicine, during the period of May 2018-June 2019.I also declare that this bonafide work has not been submitted in part or full by me or any others for any award, degree or diploma to any other University or Board either in India or abroad.

This is submitted to The Tamilnadu Dr. M.G.R Medical University, Chennai, in partial fulfilment of the University rules and regulations for the award of degree of Doctor of Medicine (M.D) Branch- I-General Medicine.

Place: Asaripallam

Date: Dr. POOJA. H

ACKNOWLEDGEMENTS

I would like to express my sincere gratitude to

permitted me conduct this study and to use the hospital facilities at Kanyakumari Government Medical College Hospital, Asaripallam.

I am greatly indebted to my beloved teacher

allowing me to do this study in the Department of Medicine. I also express my sincere thanks to him for giving me proper guidance, protocol and immense help and encouragement in conducting this study.

I express my gratitude to

Department of Medicine who immensely helped me in conducting this study. I also express my gratitude to DR P. JOHN CHRISTOPHER,MD my unit chief who helped me in conducting the study. I express my gratitude to

guidance throughout the study.

I express my sincere and heartfelt gratitude to

my Assistant professors in the Department of Medicine for their encouragement, kind guidance, constant support and cooperation in evaluating the patients.

I thank the Members, Secretary and Chairman of the Institutional Ethical committee, Kanyakumari Government College hospital, Asaripallam.

I thank all the paramedical staff and other staff of the Kanyakumari Government Medical College Hospital for all their help and cooperation in conducting this study.

I thank all my colleagues and friends for their constant encouragement and valuable criticism.

I am extremely thankful to all my family members for their continuous support. Above all I thank God Almighty for his immense blessings.

Last, but not least, my profound gratitude to all the patients, to whom I owe

everything because this venture would not have been possible without them.

CONTENTS

.

no. of subjects