clinical biochemistry aspects of cardiovascular disease dr vivion crowley mrcpath consultant...
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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