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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)
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
What are the risk factors for the development of
atherosclerotic disease?
Modifiable
Smoking
*Dyslipidaemia
*Hypertension
*Obesity/T2DM
Lack of exercise
Non-modifiable
Age
Gender
Family history
Ethnicity
Premature
menopause
Other risk factors for atherosclerosis
•Stress/Personality
•Homocysteine
•Lipoprotein (a)
•Fibrinogen
•Socioeconomic
•Geographic
•? Depressive illness
JBS CVD Risk Assessment Chart - Female
JBS CVD Risk Assessment Chart - Male
European CVD Guideline – SCORE CVD Risk Assessment Charts
How is‘obese’ defined?
Body mass index (BMI)=
weight/height2 (kg/m2)
BMI 30
Health
Hazard
overweight
BMI 25
Healthy
weight
Insufficient
weight
BMI 20
Classification of Obesity & Overweight
Time trends in the prevalence of obesity (BMI > 30kg/m2)
25
USA
Germany
20
UK
15
%
10
Netherlands
5
0
1980
1985
1990
1995
1998
Year
WHO MONICA 1997
data , 1997
Central (Visceral) adiposity is associated with a greater
risk of developing metabolic syndrome
Criteria for clinical identification of Metabolic syndrome
Component
Defining value
Abdominal obesity
WC >88cm in females
>102cm in males
> 1.65mmol/L
Elevated fasting Triglyceride
Reduced HDL cholesterol
Elevated BP
Elevated fasting glucose
< 1/3mmol/L in females
<1.0mmol/L in males
SBP ≥ 130mmHg OR
SBP ≥ 85mmHg
6.0mmol/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 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)
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/L
LDLC <3.0mmol/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
CHD-related mortality is in decline over the last 30 years
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
-HAART
-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

1.
2.
3.
4.
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
Corneal Arcus and Xanthelasmata may also be features of FH
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
1. The Simon Broome FH Register
2. Dutch Lipid Clinic Network
3. US MEDPED Program
Simon Broome Register FH Criteria
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
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)
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
-STEMI or NSTEMI
-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
Changes CK, AST and LDH after MI
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
Changes in Troponin I or T and CK-MB post MI
Future Markers for use in diagnosis of ACS
Ischaemia modified albumin
- May fulfil a role as an early sensitive marker of ACS
Biochemical changes in Cardiac Failure
Biochemical abnormality
Hyponatraemia
Hypokalaemia
Renal Failure
Pathophysiology
Diuretics, increased AVP
Diuretics, 2o hyperaldosteronism
Reduced perfusion
Biomarkers in Diagnosis of Cardiac Failure
Natriuretic 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
How can NT-proBNP be used in clinical practice?