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Recommended Reading. Lecture Notes in Clinical Biochmesitry 7 th Edition G Beckett, S Walker, P Rae, P Ashby (Blackwell publishing) Clinical Chemistry 6 th Edition W J Marshall, S K Bangert (Pubslished by Mosby) An illustrated Colour text - Clinical Biochmeistry 3 rd edition

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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 6th 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

Martin Crooke (Edward Arnold)

A Guide to Diagnostic Clinical Chemistry 3rd Edition

Walmsely & White (Blackwell)


Clinical Biochemistry Aspects of

Cardiovascular Disease

Dr Vivion Crowley FRCPath FRCPI

Consultant Chemical Pathologist

Biochemistry Department

St James’s Hospital


Atherosclerosis is a major cause of morbidity and


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

Atherosclerotic plaque is the key pathological lesion

Underlying the morbidity and mortality associated

with atherosclerosis


Other risk factors for atherosclerosis

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

How is‘obese’ defined?

Body mass index (BMI)=

weight/height2 (kg/m2)

BMI 30



BMI 25



BMI 20





















Time trends in the prevalence of obesity (BMI > 30kg/m2)



data , 1997


Central (Visceral) adiposity is associated with a greater

risk of developing metabolic syndrome



  • Defined as SBP ≥ 140 and/or DBP ≥ 90 mm Hg
  • Associated with stroke, CHD, Cardiac Failure, renal failure
  • Aetiology
  • Essential (primary HT) – polygenic disorder
  • Secondary HT (consider in younger hyepretensive)
  • Prevalence
  • - 33% White males
  • - 38% Black males

Secondary Hypertension

  • Renal disease
  • Renovascular disease (Renal artery stenosis)
  • Atheroma in older subjects
  • Fibromuscular dyspalsia in younger subjects
  • Coarctation of Aorta
  • Endocrine causes
  • Primary hyperaldosteronism (Conn’s syndrome)
  • Cushing’s Syndrome
  • Phaeochromocytoma
  • Renal tubular genetic defects
  • Liddle’s syndrome
  • Drugs
  • Streoids
  • OCP

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
  • Very low density lipoprotein (VLDL)
  • VLDL remnant (IDL)
  • Low density lipoprotein (LDL)
  • High density lipoprotein (HDL)

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)
  • 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 < 1.0mmol/L, F <1.3mmol/L)
  • Raised Triglyceride levels are independently associated with CHD

LDL cholesterol is calculated using the Friedewald formula

Treatment targets for Plasma lipids

TC <5.0mmol/L

LDLC <3.0mmol/L (primary prevention)

<2.5mmol/L (secondary prevention)

HDL >1.0mmol/L in males

>1.3mmol/L in females


WHO Classification of Dyslipidaemia is now outdated

  • Adopted by WHO in 1970
  • Based on laboratory parameters
  • Lipoprotein analysis
  • Lipoprotein electrophoresis
  • Serum/plasma appearance

Most practical classification takes account of

aetiology and Plasma Lipid pattern

Primary (Inherited)

Secondary (Acquired)


Secondary Dyslipidaemias have multiple causes

  • Diabetes mellitus
  • Obesity
  • Alochol abuse
  • Hypothyroidism*
  • Nephrotic syndrome*
  • Chronic Renal failure*
  • Cholestasis*
  • PCOS
  • Drugs
  • Retinoic acid
  • Diuretics
  • Steroids
  • OCP
  • Cyclosporin

* Predominant Hypercholesterolamia

LFTs, U/E, TFTs, BMI, WC, Glycaemic status, medications and dietary habits

need to be adequately assessed in the context of dyslipidaemia


Primary Dyslipidaemia should be considered

in specific circumstances

  • Abnormal lipid profile without obvious secondary cause
  • Premature CVD
  • Family hx of Premature CVD
  • Family hx of dyslipidaemia
  • Identification of primary dyslipidaemia may have implications
  • CHD risk
  • Clinical management
  • Family screening
  • Genetic counselling

Primary dyslipidaemias can be sub-classified

  • Predominantly elevated plasma cholesterol
  • Polygenic hypercholesterolaemia
  • Monogenic hypercholesterolaemias e.g. FH, FDB
  • Predominantly elevated plasma triglyceride
  • Lipoprotein lipase (LPL) deficiency
  • ApoC-II deficiency
  • Familial hypertriglyceridaemia
  • Mixed (Combined elevated plasma Cholesterol and Trigs)
  • Familial combined hyperlipidaemia (FCH)
  • Dybetalipoproteinamia (Type III HPLA)
  • Very rare dylipidaemias
  • Low LDL syndromes e.g. abeta-, hypobeta-lipoproteinaemia
  • Low HDL syndromes
  • ApoA-I mutations
  • Tangier disease
  • LCAT deficiency
  • Miscellaneous – Lp(a), Hyperalphalipoproteinamia

Monogenic Hypercholesterolaemias

  • All known defective genes causing monogenic hyeprcholesteroloaemia
  • are involved in the receptor mediated uptake of LDL by LDL Receptor (LDLR)

Familial Hypercholesterolaemia (FH) is the most prevalent

autosomal dominant inherited disorder

Caused by mutation in the LDLR (Goldstein and Brown)

High genetic heterogeneity (implications for genetic screening of populations)

> 700 mutations

  • Heterozygous 1 in 500
  • Homozygous/Compound Het 1 in 1,000,000

Biochemical Characteristics of FH

  • Pathogenesis
  • Reduction in functioning LDLR decreases plasma LDL catabolism
  • Also some degree of LDL overproduction
  • - ? increased IDL conversion or direct liver LDL overproduction
  • Lipid profile
  • Increased plasma Total Cholesterol 8-14mmol/L
  • Increased plasma LDL Cholesterol 6-11mmol/L
  • Normal or decreased plasma HDL Cholesterol
  • Normal plasma triglycerides
  • Lp(a) – may also be increased ( ? Role in increased CHD risk)

Clinical Characteristics of FH

  • Tendon Xanthomata are a pathognomic feature of FH
  • -Usual sites are extensor tendons on hands, Achilles tendon, pretibial tuberosity
  • Present in 70% Heterozgotes by 4th decade of life
  • Present in Homozygotes by age 5 years
  • Homozygotes also have cutaneous planar xanthomas
  • e.g. inter-digital spaces, buttocks, knees, hands

FH is associated with markedly increased risk

of CHD and premature death

  • Heterozygotes
  • Mean age of onset of CHD is 43yrs (males) 53yrs (females)
  • Relative Risk (RR) was 8 pre-introduction of statins for Rx FH
  • RR in statin era is 3-4
  • Homozygotes
  • Symptomatic CHD may be evident before age 10 years
  • Usually present by 20 yrs
  • Mean age of death from CHD is 26 yrs

Haemodynamically significant Aortic stenosis is a

major cause of morbidity in Homozygous FH

  • Due to atheromatous involvement of the aortic root
  • Usually present by puberty
  • In Heterozygotes, aortic valve involvement is not characteristic

How do you diagnose FH?

  • Three established sets of diagnostic criteria
  • The Simon Broome FH Register
  • Dutch Lipid Clinic Network
  • US MEDPED Program
differential diagnosis of fh
Differential diagnosis of FH
  • Polygenic Hypercholesetrolaemia
  • Familial Combined Hyperlipidaemia
  • Other monogenic Hypercholesterolaemia

Screening for FH

  • Universal Population screening – impractical, not cost effective
  • Screening within the clinical setting (Opportunistic screening)
  • Hyperchol, premature CHD, Fam Hx of CHD or dyslipidaemia
  • Cascade screening of FH relatives
  • Use diagnostic criteria (limited sensitivity)
  • Genetic approach

-52-76% of patient who meet criteria are LDLR Mutation positive


Management of FH

  • Heterozygotes:
  • Effective lowering of LDL Chol can significantly reduce morbidity and mortality
  • Use of high dose Statins is the first line treatment
  • Statin may not adequately reduce LDL levels
  • Consider combination with Ezetimibe (18% further reduction), Resin or Fibrate
  • If lack of response consider LDL-apheresis + statin (rarely required now)
  • In females consider contraception if commencing statins or other lipid-lowering drugs
  • Regular non-invasive testing for silent ischemia (every 1-2 years depending on risk)
  • e.g. stress ECGs, thallium scans
  • Family screening is mandatory in FH


  • Type III HPLA
  • Remnant particle disease
  • Pathophysiology:
  • Absence of ApoE R mediated removal of chylomicron and VLDL remnants
  • Mixed HPLA where plasma Cholesterol and Trigs are elevated to the similar levels
  • Mean untreated levels of P Chol and Trigs is 8-10mmol/L
  • Clinical features: Palmar xanthomatosis, tubero-euptive xanthomata
  • Associated with increased risk of premature CHD and PVD (approx 50%)
  • Excellent repsonse to Fibrates (± statin)

Genetics of Dysbetalipoproteinaemia

There are several different genetically determined isoforms of ApoE

  • ApoE2/E2 is present in > 90% Type III HPLA
  • E2/E2 genotype frequency of 1 in 100
  • However Type III HPLA prevalence is 1 in 5000-10000
  • Further environmental “stresses” required to manifest this pheontype
  • e.g. T2DM, alcohol, hypothyroidism, obesity
  • Example of a gene-environment interaction
  • Other Mutations in ApoE e.g. R147W
  • -can cause an autosomal dominant form of Type III HPLA

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

Diagnosis of Acute Coronary Syndrome (ACS)

  • Clinical history
  • ECG
  • -Q waves appear later
  • Clinical Biochemistry

“Older” Cardiac Biomarkers for Diagnosis of MI

  • 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

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 >6%of total CK indicates myocradial origin (Fractionated)
  • CK-MB mass >5
  • 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

Future Markers for use in diagnosis of ACS

Ischaemia modified albumin

- May fulfil a role as an early sensitive marker of ACS


Heart Failure

  • Heart Failure
  • State of reduced myocardial performance
  • Mainly affects the left ventricle
  • Aetiology
  • Coronary Heart disease
  • Hypertension
  • Valvular defects
  • Cardiomyopathies
  • Often classified as
  • Systolic HF – reduced systolic ejection
  • Diastolic HF – impaired diastolic filling of the L ventricle

Systemic consequences and symptoms of HF

  • Mainly caused by H2O and Na retention
  • Activation of the renin-aldosterone pathway
  • Also AVP (ADH) release due
  • Due to reduced effective circulating volume
  • Left HF
  • Pulmonary oedema – PND
  • Right HF
  • -Peripheral oedema – Lower limbs, sacral oedema

Biomarkers in Diagnosis of Cardiac Failure

  • Natriuretic peptides
  • Atrial Natriuretic peptide – produced in atrium
  • B-type Natriuretic peptide – produced in ventricle
  • -Release related to cardiac wall stretch
  • -Induce natriuresis (Na loss in urine)
  • BNP - produced in excess in cardiac failure
  • Measurement of BNP or its cleavage product NT-proBNP
  • Can facilitate the diagnosis of LVF in acute dyspnoeic patient
  • Also can assist in identifying patinets with early LVF for echocardiogram