clinical biochemistry aspects of cardiovascular disease dr vivion crowley mrcpath frcpi
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Clinical Biochemistry Aspects of Cardiovascular Disease Dr Vivion Crowley MRCPath FRCPI Consultant Chemical Pathologist Biochemistry Department St James’s Hospital. Atherosclerosis is a major cause of morbidity and mortality. Clinically manifests as Coronary Heart Disease (CHD) - PowerPoint PPT PresentationTRANSCRIPT
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Clinical Biochemistry Aspects of Cardiovascular Disease
Dr Vivion Crowley MRCPath FRCPIConsultant Chemical PathologistBiochemistry DepartmentSt James’s Hospital
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Atherosclerosis is a major cause of morbidity and mortality
Clinically manifests as
• Coronary Heart Disease (CHD) angina 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?
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
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Other risk factors for atherosclerosis
•Stress/Personality
•Homocysteine
•Lipoprotein (a)
•Fibrinogen
•Socioeconomic
•Geographic
•? Depressive illness
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JBS CVD Risk Assessment Chart - Female
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JBS CVD Risk Assessment Chart - Male
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European CVD Guideline – SCORE CVD Risk Assessment Charts
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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
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Classification of Obesity & Overweight
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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
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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
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
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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 hyepretensive)
Prevalence
- 33% White males
- 38% Black males
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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
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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
Very low density lipoprotein (VLDL)VLDL remnant (IDL)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)•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
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LDL cholesterol is calculated using the Friedewald formula
Treatment targets for Plasma lipids
TC <5.0mmol/LLDLC <3.0mmol/L (primary prevention) <2.5mmol/L (secondary prevention)HDL >1.0mmol/L in males >1.3mmol/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
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CHD-related mortality is in decline over the last 30 years
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WHO Classification of Dyslipidaemia is now outdated
Adopted by WHO in 1970
Based on laboratory parameters
- Lipoprotein analysis - Lipoprotein electrophoresis- Serum/plasma appearance
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Most practical classification takes account of aetiology and Plasma Lipid pattern
Primary (Inherited)
Secondary (Acquired)
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Secondary Dyslipidaemias have multiple causes
LFTs, U/E, TFTs, BMI, WC, Glycaemic status, medications and dietary habits need to be adequately assessed in the context of dyslipidaemia
Diabetes mellitusObesityAlochol abuseHypothyroidism*Nephrotic syndrome*Chronic Renal failure*Cholestasis*PCOSDrugs-Retinoic acid-Diuretics-Steroids-OCP-HAART-Cyclosporin
* Predominant Hypercholesterolamia
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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 implications1. CHD risk2. Clinical management3. Family screening4. Genetic counselling
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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
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Monogenic Hypercholesterolaemias
All known defective genes causing monogenic hyeprcholesteroloaemiaare involved in the receptor mediated uptake of LDL by LDL Receptor (LDLR)
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Familial Hypercholesterolaemia (FH) is the most prevalentautosomal 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
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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)
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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
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Corneal Arcus and Xanthelasmata may also be features of FH
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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
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•Due to atheromatous involvement of the aortic root •Usually present by puberty
•In Heterozygotes, aortic valve involvement is not characteristic
Haemodynamically significant Aortic stenosis is a major cause of morbidity in Homozygous FH
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How do you diagnose FH?
Three established sets of diagnostic criteria
1. The Simon Broome FH Register
2. Dutch Lipid Clinic Network
3. US MEDPED Program
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Simon Broome Register FH Criteria
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Differential diagnosis of FHDifferential diagnosis of FH
• Polygenic HypercholesetrolaemiaPolygenic Hypercholesetrolaemia
• Familial Combined HyperlipidaemiaFamilial Combined Hyperlipidaemia
• Other monogenic Other monogenic HypercholesterolaemiaHypercholesterolaemia
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Screening for FHUniversal 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
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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
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Dysbetalipoproteinaemia •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)
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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 100However Type III HPLA prevalence is 1 in 5000-10000Further environmental “stresses” required to manifest this pheontypee.g. T2DM, alcohol, hypothyroidism, obesityExample of a gene-environment interaction
Other Mutations in ApoE e.g. R147W-can cause an autosomal dominant form 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 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
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Changes CK, AST and LDH after MI
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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 >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
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Changes in Troponin I or T and CK-MB post MI
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Future Markers for use in diagnosis of ACS
Ischaemia modified albumin
- May fulfil a role as an early sensitive marker of ACS
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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
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Biomarkers in Diagnosis of Cardiac FailureNatriuretic peptides
•Atrial Natriuretic peptide
•B-type Natriuretic peptide
-Both are normally produced in atrium-Induce natriuresis (Na loss in urine)
BNP - produced in ventricle 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
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How can NT-proBNP be used in clinical practice?