W4: Heart Disease

Question 1

Cardiac biomarkers

Answer 1

substances that are released into the blood when the heart is damaged or stressed.

Question 1

Cardiac biomarkers Important in two areas

Answer 1

Diagnosis and management of Acute Coronary Syndrome.
Diagnosis and risk stratification of Heart Failure.

Question 2

development of new biomarkers revolutionised the diagnosis which heart conditions.

Answer 2

Cardiac Troponins in Acute Coronary Syndrome.
Natriuretic Peptides in Heart Failure

Question 3

Acute Coronary Syndrome (ACS)

Answer 3

spectrum of conditions involving sudden decr in coronary artery blood flow - causes part of heart muscle to die/ stop functioning properly

Need to quickly assess so rapid treatment can be given

Question 4

3 types of ACS

Answer 4

ST-segment Elevation Myocardial Infarction (STEMI)
Non-ST-segment Elevation Myocardial Infarction (NSTEMI)
Unstable angina

Question 5

ACS assess made through

Answer 5

Careful clinical history
12-lead Electrocardiogram (ECG) – representation of heart’s electrical activity captured by electrodes on the body’s surface.
Blood test for cardiac biomarkers

Question 6

Non-ST-segment elevation MI (NSTEMI) and Unstable Angina both involve

Answer 6

involve partial blockage of one of coronary arteries, causing reduced blood flow and ischaemia.

Question 6

ST-segment elevation MI (STEMI): cause, diagnosis, treatment

Answer 6

“Classic” heart attack. Most serious type of ACS

Caused by complete blockage of a coronary artery - usually acute plaque rupture + thrombosis

Diagnosis: ECG changes (ST segment elevation).

Treatment: Reperfusion therapy to unblock artery and restore blood flow:

Angiography followed by Percutaneous Coronary Intervention (PCI) - to unblock artery and restore blood flow with balloon catheter + stent

Thrombolysis (e.g. streptokinase) if PCI not possible - dissolve blood clots.

Coronary Artery Bypass Grafting (CABG) .

Antiplatelet drugs (e.g. aspirin, clopidogrel), anticoagulant drugs (e.g. heparin), painkillers.

Question 7

Non-ST-segment elevation MI (NSTEMI) and Unstable Angina detection

Answer 7

ECG: may see some changes or may be normal.
NSTEMI: acute cardiac cell injury demonstrated by a dynamic rise in cardiac troponin.
Unstable Angina: myocardial ischaemia at rest or on minimal exertion in the absence of acute cardiac cell injury. No dynamic rise in cardiac troponin.

Question 8

Non-ST-segment elevation MI (NSTEMI) and Unstable Angina treatment

Answer 8

Anticoagulant (e.g. heparin), dual antiplatelet drugs (e.g. aspirin and clopidogrel), anti-ischaemic (e.g. beta-blocker).
If higher risk: coronary angiography + revascularisation

Question 9

describe the ideal cardiac biomarker for MI

Answer 9

Sensitive: can detect a small amount of heart damage.

Specific to heart muscle (esp. not elevated in skeletal muscle damage). Not detected in patients with no myocardial damage.

Released rapidly after myocardial injury and persists for long enough to provide a suitable diagnostic window but not so long that a recurrent event would not be detected.

Easy, cheap to measure, rapid turnaround time.

Quantitative and correlates with severity and prognosis of disease, as well as effectiveness of treatment.

Question 10

3 cardiac biomarker no longer used + why

Answer 10

aspartate aminotransferase (AST)
lactate dehydrogenase (LDH)
creatine kinase (CK)

not specific enough

Question 11

Isoenzymes and CK-MB

Answer 11

CK contains two subunits, M and B: 3 isoenzymes.
CK-MM (predominant form in all tissues)
CK-MB (mainly found in heart, accounting for 20% of total CK in heart)
CK-BB (predominant form in brain, GI tract, bladder)

Question 12

CK-MB as a heart biomarker:

Answer 12

Greater specificity for heart than CK BUT also found in skeletal muscle (average 1% but as much as 20% in some muscles).
False positives seen in: rhabdomyolysis, muscular dystrophy and exercise; non-ischaemic cardiac injuries such as pericarditis and myocarditis as well as some malignancies.
Rises after MI at around 4-8h, peaks at 24h but returns to normal within 3 days (a little earlier than for total CK).
Gold standard for many years but has been superseded by better, more specific markers.

Question 13

Myoglobin

Answer 13

Haem protein in cytoplasm of muscle cells used in oxygen transport.
Released rapidly following muscle damage
Increases within 2h and peaks at 6-9h, returning to normal by 24-36h.
Earliest marker for both heart and skeletal muscle damage but may miss late presentations.
Limited value as not cardiac-specific: distributed in all muscles – rises even with minor skeletal muscle damage.
Some studies show may be useful in measuring success of reperfusion therapy and assessing size of infarct.
Not routinely used.

Question 14

Cardiac Troponins

Answer 14

Troponin is a regulatory protein complex involved in muscle contraction in skeletal and cardiac muscle. Found in thin filaments of muscle tissue attached to tropomyosin. Regulates interaction of myosin and actin.
Troponin C – calcium binding component.
Troponin I – “Inhibitory component”. Binds to actin in thin myofilaments and holds actin-tropomyosin complex in place.
Troponin T – Tropomyosin binding component.

Question 15

Cardiac Troponins

Answer 15

C protein only has one form and is distributed throughout all muscles but T and I each have skeletal and cardiac isoforms.
Cardiac T and I have different amino acid sequences compared to skeletal isoforms and are encoded by different genes.
cTnI is not expressed in skeletal muscle at all, so is thought to be completely specific to cardiac tissue.
Small amounts of cTnT can be expressed in diseased skeletal muscle (e.g. muscular dystrophy, polymyositis).
Cardiac troponins increase within 2-3 hours of cardiac cell necrosis, peak at ~24h and persist for 1-2 weeks.
Large diagnostic window.

Question 16

Clinical Utility of Cardiac Troponins

Answer 16

Only cardiac biomarker now recommended due to superior sensitivity and specificity compared to older biomarkers.
Main role is diagnosis of NSTEMI.
Use of cTn has vastly improved our ability to detect and quantify myocardial injury, sometimes “subclinical”.
Early clinical studies comparing various biomarkers found that ~1/3 of patients considered to have MI excluded on the basis of either CK-MB or CK measurement had an elevated cTnT or cTnI.
Paradigm shift in thinking with biomarker results becoming fundamental and central to diagnosis of MI/ACS.
Incorporated into “Universal Definition of Myocardial Infarction” from 2000 version onwards and other guidelines (e.g. NICE).

Question 17

Cardiac troponin assays measured using

Answer 17

immunoassays:
Sandwich immunoassay which uses two antibodies (capture and detection).
One manufacturer (Roche diagnostics) for cTnT
Several different immunoassay platforms for cTnI.

Question 18

Traditional assays

Answer 18

Traditional assays: optimum sensitivity for MI achieved 10-12 hours after onset of symptoms.
Previous NICE Guidelines (2010) recommended measuring troponin on admission and 10-12 hours later.
Patients often needed hospital admission

Question 19

Issues with troponin analysis

Answer 19

TnT and TnI results are not comparable.
Lab-based vs. point of care (POC) assays are not comparable.
Lack of standardisation for TnI assays so each different assay has different 99th percentile cut-offs.

Many possible causes of an elevated cTn level due to myocardial injury not infarction: e.g. severe anaemia, respiratory failure, heart failure, sepsis.

Need proper understanding of significance of elevated result – serial sampling needed to look for dynamic change.

assay interferences = false positives from:
Heterophilic antibodies/HAMA
Macro-troponin
Biotin interference

Question 20

what’s heart failure (HF), 2 types, symptoms

Answer 20

Complex clinical syndrome where the heart does not pump enough blood to meet the needs of the body
acute or chronic.
Symptoms: shortness of breath, fluid retention, fatigue.

Question 21

HF not curable so how is it controlled, QOL, causes

Answer 21

medications:
ACE inhibitors, beta blockers, angiotensin-2 receptor blockers, diuretics.

QOL: 50% of people with HF will die within 5 years of diagnosis

Causes: coronary heart disease (50%), hypertension, cardiomyopathies, heart valve disease.

Question 22

HF diagnosis

Answer 22

No gold standard diagnostic investigation.

Diagnosis = challenging as breathlessness + fluid retention common in other conditions - patient may already have a condition, e.g. COPD, that give similar symptoms.

Key investigation: Echocardiography
ultrasound scan:
Assessment of cardiac chamber size and structure, ventricular function, valve function and calculation of “ejection fraction”.

Question 23

Biomarkers for Heart Failure (3)

Answer 23

Natriuretic Peptides

Atrial natriuretic peptide (ANP) – predominantly synthesised in atria of heart.
B-type natriuretic peptide (BNP) predominantly produced in ventricles of heart.
C-type natriuretic peptide (CNP) – widely expressed, acts locally as a paracrine/ autocrine regulator. Role in vascular homeostasis

Question 24

Function of ANP/BNP + which is better for HF diagnosis

Answer 24

Hormones that help to maintain cardiovascular homeostasis.

Released in response to cardiac wall stretch.
Promote sodium and water excretion and vasodilation, lowering blood volume and blood pressure.

BNP has a longer half-life than ANP so superior for use in the diagnosis of HF

Question 25

what are very useful in ruling out HF

Answer 25

BNP and NT-proBNP

Question 26

Difficulties with BNP/NTproBNP – analytical aspects

Answer 26

Values of BNP and NT-proBNP in the same patient are very different.
Different clinical cut-off points are required for these two biomarkers so not comparable and cannot be interconverted.
Circulating BNP forms are complex and diverse
Most BNP/NT-proBNP immunoassays also cross-react with proBNP
NT-proBNP assay results are more comparable than BNP assays as antibodies and calibrators are from the same manufacturer
Standardisation is lacking across BNP manufacturers.
Analytical interferences: heterophilic Ab/HAMA, biotin, etc.

Question 27

Difficulties with BNP/NTproBNP – clinical aspects

Answer 27

Older age is independently associated with higher NT-proBNP levels, even in absence of HF/CVD.

Strong association with renal function for NT-proBNP