Clinical Biochemistry aspects of

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Clinical Biochemistry aspects of Cardiovascular
Disease Dr Vivion Crowley MRCPath Consultant
Chemical Pathologist Biochemistry Department St
Jamess Hospital
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Recommended Reading
Lecture Notes in Clinical Biochmesitry 7th
Edition G Beckett, S Walker, P Rae, P Ashby
(Blackwell publishing) Clinical Chemistry 5th
Edition W J Marshall, S K Bangert (Pubslished by
Mosby) An illustrated Colour text - Clinical
Biochmeistry 3rd edition Alan Gaw et al
(Churchill Livingston) Handbook of Clinical
biochmeistry 1st Edition R Swaminathan (Oxford
University Press) Clinical Chemistry in
diagnosis and treatment Philip Mayne (Edward
Arnold) A Guide to Diagnostic Clinical Chemistry
3rd Edition Walmsely White (Blackwell)
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Atherosclerosis is a major cause of morbidity and
mortality

• Clinically manifests as
• Coronary Heart Disease (CHD)
• angina acute coronary syndrome
  (ACS) / MI
• Peripheral vascular disease (PVD)
• Intermittent claudication limb
  amputation
• Cerebrovascular disease
• TIA Stroke

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Atherosclerotic plaque is the key pathological
lesion Underlying the morbidity and mortality
associated with atherosclerosis
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What are the risk factors for the development of
atherosclerotic disease?
Modifiable Non-modifiable
Smoking Age
Dyslipidaemia Gender
Hypertension Family history
Obesity/T2DM Ethnicity
Lack of exercise Premature menopause
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Other risk factors for atherosclerosis

• Stress/Personality
• Homocysteine
• Lipoprotein (a)
• Fibrinogen
• Socioeconomic
• Geographic
• ? Depressive illness

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How isobese defined?
Body mass index (BMI) weight/height2 (kg/m2)
BMI 30
Health Hazard
BMI 25
Healthy weight
BMI 20
overweight
Insufficient weight
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Classification of Obesity Overweight
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Time trends in the prevalence of obesity (BMI gt
30kg/m2)

WHO MONICA 1997
data , 1997
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Central (Visceral) adiposity is associated with a
greater risk of developing metabolic
syndrome
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Criteria for clinical identification of Metabolic
syndrome
Component Defining value
Abdominal obesity WC gt88cm in females gt102cm in males
Elevated fasting Triglyceride gt 1.65mmol/L
Reduced HDL cholesterol lt 1/3mmol/L in females lt1.0mmol/L in males
Elevated BP SBP 130mmHg OR SBP 85mmHg
Elevated fasting glucose 6.0mmol/L
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Waist circumference is a clinically useful
measure of central
adiposity
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Hypertension

• Defined as BP 140/90
• Associated with stroke, CHD, Cardiac Failure,
  renal failure
• Aetiology
• Essential (primary HT) polygenic disorder
• Secondary HT (consider in younger hypertensive)
• Prevalence
• - 33 White males
• - 38 Black males

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Secondary Hypertension

• Chronic Renal disease
• Renovascular disease (Renal artery stenosis)
• Atheroma in older subjects
• Fibromuscular dysplasia in younger subjects
• Coarctation of Aorta
• Endocrine causes
• Primary hyperaldosteronism (Conns syndrome)
• Cushings Syndrome
• Phaeochromocytoma
• Renal tubular genetic defects
• Liddles syndrome
• Drugs
• Steroids
• OCP

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Dyslipidaemia is a major risk factor for
atherosclerosis

• Dyslipidaemia refers to any perturbation in
  lipoprotein metabolism
• -Hyperlipidaemia e.g. hypercholesterolaemia
• Hypolipidaemia e.g. hypoalphalipoproteinaemia
  (low HDL)
• The major lipoprotein particles circulating in
  the fasted state
• Very low density lipoprotein (VLDL)
• VLDL remnant
• Low density lipoprotein (LDL)
• High density lipoprotein (HDL)

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Outline of normal lipoprotein metabolism
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LDL accumulates in the atherosclerotic plaque
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What is the relationship of plasma lipids and CHD?

• The plasma lipid profile consists of
• Total Cholesterol (TC)
• HDL Cholesterol (HDLC)
• LDL Cholesterol (LDLC)
• Triglycerides (TG)
• TCHDLC
• Raised TC and LDLC levels are positively
  associated with CHD
• HDLC levels are inversely associated with CHD
• High level implies lower risk
• Low level implies higher risk (M lt 1.0mmol/L, F
  lt1.3mmol/L)
• Raised Triglyceride levels are independently
  associated with CHD

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LDL cholesterol is calculated using the
Friedewald formula
Treatment targets for Plasma lipids TC
lt5.0mmol/L LDLC lt3.2mmol/L (primary prevention)
lt2.5mmol/L (secondary prevention) HDL
gt1.0mmol/L in males gt1.3mmol/L in
females
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Elevated Plasma Cholesterol levels are associated
with increased CHD mortality
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Plasma Total Cholesterol levels vary with age and
gender
Female
Male
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CHD-related mortality is in decline over the last
30 years
Related to recognition and treatment of
dyslipidaemia
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Classification of Hyperlipidaemia

• Primary
• Secondary

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Primary Hyperlipidaemia

• Hypercholesterolamia (high LDL)
• Polygenic
• Familial Hypercholesterolaemia (FH) (Type IIa)
• Sometimes Familial Combined Hyperlipidaemia (FCH)
• Mixed Hyperlipidaemia
• FCH (high LDL VLDL) (Type IIb)
• Type III (dysbetalipoproteinameia or remnant
  hypelipidameia)
• (abnormal ApoE genotype)
• Hypertriglyceridaemia
• - Lipoprotein lipase (LPL) deficiency high
  Chylomicrons
• - Familial Hypetriglyceridaemia (Type IV) high
  VLDL
• - Familial Hypertriglyceridaemia (Type V) high
  VLDL Chylos

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Secondary Hyperlipidaemia

• Diabetes mellitus
• Obesity
• Alochol abuse
• Hypothyroidism
• Nephrotic syndrome
• Chronic Renal failure
• Cholestasis
• PCOS
• Drugs
• Retinoic acid
• Diurestics
• Steroids
• OCP
• HAART
• Cyclosporin
• Predominant Hypercholesterolamia

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Familial Hypercholesterolaemia

• 1 in 500 Heterozygote
• 1 in 1,000,000 Homozygote
• Autosomal Dominant
• Heterozygotes Plasma Cholesterol 6-12mmol/L
• Homozygotes Plasma Cholesterol 10-20mmol/L
• Mutations in
• -LDL receptor
• ApoB
• PCSK9

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Clinical aspects of FH

• Family Hx of hyperlipidaemia
• Family Hx of premature CHD
• lt55yr in Male
• lt65yr in Female
• Specific Clinical manifestations
• Xanthomata e.g. on extensor tendons of hands,
  achilles tendon
• Xanthelasma
• Corneal arcus (particularly if age under 45yr)

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Diagnosis of FH

• History family hx
• Examination
• Lipid profile
• Mutation detection
• Simon Broome Register Criteria for FH Diagnosis
• Definite FH
• Total Cholesterol gt7.5mmol/L (LDL gt 4.9mmol/L)
• Plus one of the following
• Tendon xanthomata in patient or first degree
  relative
• Molecular genetic diagnosis of LDL-receptor
  mutation
• Possible FH
• -Total Cholesterol gt7.5mmol/L (LDL gt 4.9mmol/L)
• Plus one of the following
• -Family hx of MIlt50 yr in first degree relative
  (lt60yr in 2o relative)

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Lipaemia retinalis occurs in association with
severe hypertriglyceridaemia
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Palmar xamthomata are a feature of Type III HPLA
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CHD clinical aspects

• Spectrum of clinical presentation
• Angina
• Acute Coronary Syndrome (ACS)
• Unstable angina MI
• Symptoms of ACS
• Severe crushing central chest pain
• Dyspnoea
• Cold sweat
• Pallor
• Nausea

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Diagnosis of Acute Coronary Syndrome (ACS)

• Clinical history
• ECG
• -STEMI or NSTEMI
• -Q waves appear later
• Clinical Biochemistry

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Older Cardiac Biomarkers for ACS Diagnosis

• Creatine Kinase (CK)
• muscle enzyme
• Nonspecific in that it may originate from
  skeletal or cardiac muscle
• start to increase at 3-8h
• Peak level 18-24h
• Returns to normal 3-4 days
• Aspartate transaminase (AST)
• Found in Liver and muscle (an dother tissues)
• Nonsepcific
• Incraese 6-10h
• Paek level 24h
• Return to normal 3-5 days
• Lactate dehydrogenase (LDH)
• Nonspecific (LDH 1 isoform is more
  cardiospecific)
• Peak at 72hrs
• Return to normal 8-14 days

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MB
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New Cardiac Biomarkers for ACS Diagnosis

• CK-MB
• Myocardium has higher concentration of CK-MB,
  more specific for heart
• In ACS similar kinetics to total CK
• CK-MB gt6of total CK indicates myocardial origin
  (Fractionated)
• CK-MB mass gt 5 ( interpret with caution if total
  CK elevated)
• Troponins
• Regulatory complex in muscle consisting of 3
  protein T, C, I
• Increases in Troponin T or I are very specific
  for cardiac muscle damage
• In ACS increase at 3-6 hr
• Peak 18-24 hr
• Can remain elevated for 7-10 days
• A Troponin T or I taken at 12 hrs post onset of
  chest pain is very sensitive

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MB
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Biochemical changes in Cardiac Failure
Biochemical abnormality Pathophysiology
Hyponatraemia Diuretics, increased AVP
Hypokalaemia Diuretics, 2o hyperaldosteronism
Renal Failure Reduced perfusion
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Biomarkers in Diagnosis of Cardiac Failure

• Natriuretic peptides
• Atrial Natriuretic peptide
• B-type Natriuretic peptide (BNP)
• -Both are normally produced in atrium
• -Induce natriuresis (Na loss in urine)
• BNP - produced in ventricle in cardiac failure
• Measurement of BNP or its precleavage product
  NT-proBNP
• Can facilitate the diagnosis of LVF in acute
  dyspnoeic patient
• Also can assist in identifying patinets with
  early LVF for echocardiograhy

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Basic Learning Objectives
To understand the risk factors for developing
atherosclerosis To know how to clinically
classify hypertension To understand the basic
concepts underpinning lipoprotein metabolism To
know what the components of a measured lipid
profile are To understand the classification and
aetiology of Dyslipidaemia To understand the
aetiology, clinical manifestation and diagnosis
of Familial Hypercholesterolaemia To understand
the clinical biochemistry changes associated with
acute coronary syndrome To understand how
biochemical tests may be used to facilitate
diagnosis of Heart failure