Clinical Biochemistry aspects of Cardiovascular Disease Dr Vivion Crowley MRCPath Consultant Chemical Pathologist Bioch

1. Clinical Biochemistry aspects of Cardiovascular Disease Dr Vivion Crowley MRCPath Consultant Chemical Pathologist Biochemistry Department St James’s Hospital

2. 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)

4. 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

5. Atherosclerotic plaque is the key pathological lesion Underlying the morbidity and mortality associated with atherosclerosis

6. What are the risk factors for the development of atherosclerotic disease?

7. Other risk factors for atherosclerosis • Stress/Personality • Homocysteine • Lipoprotein (a) • Fibrinogen • Socioeconomic • Geographic • ? Depressive illness

10. How is‘obese’ defined? Body mass index (BMI)= weight/height2 (kg/m2) BMI 30 Health Hazard BMI 25 Healthy weight BMI 20 overweight Insufficient weight

11. Classification of Obesity & Overweight

12. 25 USA Germany 20 UK 15 Netherlands 10 5 0 1980 1985 1990 1995 1998 Year Time trends in the prevalence of obesity (BMI > 30kg/m2) % WHO MONICA 1997 data , 1997

13. Central (Visceral) adiposity is associated with a greater risk of developing metabolic syndrome

14. Criteria for clinical identification of Metabolic syndrome

15. Waist circumference is a clinically useful measure of central adiposity

16. 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

17. 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 (Conn’s syndrome) • Cushing’s Syndrome • Phaeochromocytoma • Renal tubular genetic defects • Liddle’s syndrome • Drugs • Steroids • OCP

18. 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)

19. Outline of normal lipoprotein metabolism

20. LDL accumulates in the atherosclerotic plaque

21. 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) • TC:HDLC • 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

22. LDL cholesterol is calculated using the Friedewald formula Treatment targets for Plasma lipids TC <5.0mmol/L LDLC <3.2mmol/L (primary prevention) <2.5mmol/L (secondary prevention) HDL >1.0mmol/L in males >1.3mmol/L in females

23. Elevated Plasma Cholesterol levels are associated with increased CHD mortality

24. Plasma Total Cholesterol levels vary with age and gender Female Male

25. CHD-related mortality is in decline over the last 30 years Related to recognition and treatment of dyslipidaemia

26. Classification of Hyperlipidaemia • Primary • Secondary

27. 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

29. 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

30. 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

31. Clinical aspects of FH • Family Hx of hyperlipidaemia • Family Hx of premature CHD • <55yr in Male • <65yr in Female • Specific Clinical manifestations • Xanthomata e.g. on extensor tendons of hands, achilles tendon • Xanthelasma • Corneal arcus (particularly if age under 45yr)

32. Diagnosis of FH • History – family hx • Examination • Lipid profile • Mutation detection • Simon Broome Register Criteria for FH Diagnosis • Definite FH • Total Cholesterol >7.5mmol/L (LDL > 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 >7.5mmol/L (LDL > 4.9mmol/L) • Plus one of the following • -Family hx of MI<50 yr in first degree relative (<60yr in 2o relative) • -Family hx of raised Cholesterol (>7.5mmol/L)

41. Lipaemia retinalis occurs in association with severe hypertriglyceridaemia

42. Palmar xamthomata are a feature of Type III HPLA

43. 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

44. Diagnosis of Acute Coronary Syndrome (ACS) • Clinical history • ECG • -STEMI or NSTEMI • -Q waves appear later • Clinical Biochemistry

46. “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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48. 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 myocardial origin (Fractionated) • CK-MB mass > 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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50. Biochemical changes in Cardiac Failure