Clinical Biochemistry aspects of Cardiovascular Disease

Dr Vivion Crowley MRCPathConsultant Chemical PathologistBiochemistry DepartmentSt James’s Hospital

Recommended Reading

Lecture Notes in Clinical Biochmesitry 7th EditionG Beckett, S Walker, P Rae, P Ashby (Blackwell publishing)

Clinical Chemistry 5th EditionW J Marshall, S K Bangert (Pubslished by Mosby)

An illustrated Colour text - Clinical Biochmeistry 3rd editionAlan Gaw et al (Churchill Livingston)

Handbook of Clinical biochmeistry 1st EditionR Swaminathan (Oxford University Press)

Clinical Chemistry in diagnosis and treatmentPhilip Mayne (Edward Arnold)

A Guide to Diagnostic Clinical Chemistry 3rd EditionWalmsely & White (Blackwell)

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

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

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

ModifiableModifiable Non-Non-modifiablemodifiable

SmokingSmoking AgeAge

*Dyslipidaemia*Dyslipidaemia GenderGender

*Hypertension*Hypertension Family historyFamily history

*Obesity/T2DM*Obesity/T2DM EthnicityEthnicity

Lack of Lack of exerciseexercise

Premature Premature menopausemenopause

Other risk factors for atherosclerosis

•Stress/Personality

•Homocysteine

•Lipoprotein (a)

•Fibrinogen

•Socioeconomic

•Geographic

•? Depressive illness

How is‘obese’ defined?How is‘obese’ defined?

Body mass index (BMI)= weight/height2 (kg/m2)

Healthy weight

Healthy weight

BMI 20

BMI 25

BMI 30

HealthHazard

HealthHazard

overweightoverweight

Insufficientweight

Insufficientweight

Classification of Obesity & Overweight

0

5

10

15

20

25

1980 1985 1990 1995 1998

Year

USA Germany

UK

Netherlands

data , 1997

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

%

WHO MONICA 1997

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

Criteria for clinical identification of Metabolic syndrome

ComponentComponent Defining valueDefining value

Abdominal obesityAbdominal obesity WC >88cm in femalesWC >88cm in females

>102cm in males>102cm in males

Elevated fasting TriglycerideElevated fasting Triglyceride > 1.65mmol/L> 1.65mmol/L

Reduced HDL cholesterolReduced HDL cholesterol < 1/3mmol/L in females< 1/3mmol/L in females

<1.0mmol/L in males<1.0mmol/L in males

Elevated BPElevated BP SBP ≥ 130mmHg ORSBP ≥ 130mmHg OR

SBP ≥ 85mmHgSBP ≥ 85mmHg

Elevated fasting glucoseElevated fasting glucose 6.0mmol/L6.0mmol/L

Waist circumference is a clinically useful measure of central adiposity

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

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

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 remnantLow density lipoprotein (LDL)High density lipoprotein (HDL)

Outline of normal lipoprotein metabolism

LDL accumulates in the atherosclerotic plaque

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

LDL cholesterol is calculated using the Friedewald formula

Treatment targets for Plasma lipids

TC <5.0mmol/LLDLC <3.2mmol/L (primary prevention) <2.5mmol/L (secondary prevention)HDL >1.0mmol/L in males >1.3mmol/L in females

Elevated Plasma Cholesterol levels are associated with increased CHD mortality

Plasma Total Cholesterol levels vary with age and gender

Female

Male

CHD-related mortality is in decline over the last 30 years

Related to recognition and treatment of dyslipidaemia

Classification of Hyperlipidaemia

Primary

Secondary

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

Secondary Hyperlipidaemia

Diabetes mellitusObesityAlochol abuseHypothyroidism*Nephrotic syndrome*Chronic Renal failure*Cholestasis*PCOSDrugs-Retinoic acid-Diurestics-Steroids-OCP-HAART-Cyclosporin

* Predominant Hypercholesterolamia

Familial Hypercholesterolaemia

1 in 500 Heterozygote1 in 1,000,000 HomozygoteAutosomal DominantHeterozygotes – Plasma Cholesterol 6-12mmol/LHomozygotes – Plasma Cholesterol 10-20mmol/LMutations in-LDL receptor -ApoB-PCSK9

Clinical aspects of FH

Family Hx of hyperlipidaemia

Family Hx of premature CHD- <55yr in Male- <65yr in Female

Specific Clinical manifestationsXanthomata e.g. on extensor tendons of hands, achilles tendonXanthelasmaCorneal arcus (particularly if age under 45yr)

Diagnosis of FH•History – family hx

•Examination

•Lipid profile

•Mutation detection

Simon Broome Register Criteria for FH DiagnosisDefinite 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)

Lipaemia retinalis occurs in association with severe hypertriglyceridaemia

Palmar xamthomata are a feature 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 -STEMI or NSTEMI-Q waves appear later

Clinical Biochemistry

“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

MB

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

MB

Biochemical changes in Cardiac Failure

Biochemical abnormalityBiochemical abnormality PathophysiologyPathophysiology

HyponatraemiaHyponatraemia Diuretics, increased AVPDiuretics, increased AVP

HypokalaemiaHypokalaemia Diuretics, 2Diuretics, 2oo hyperaldosteronism hyperaldosteronism

Renal FailureRenal Failure Reduced perfusionReduced perfusion

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

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 ofFamilial Hypercholesterolaemia

To understand the clinical biochemistry changes associated with acute coronary syndrome

To understand how biochemical tests may be used to facilitate diagnosis ofHeart failure