1. Biomarkers in cardiac diseases
Szakács Júlia
M.D.
Department of Pathophysiology
Biomarkers in cardiac diseases
FAINELLI Manon
BOGÓ Ákos

2. Numbers… Cardiovascular diseases The most frequent cause of death
7.5 millions of death/ year
Important concerns in developed countries

3. Acute coronary syndrome (ACS)
Cardiac diseases
Ischemic diseases
Stable angina
Acute coronary syndrome (ACS)
Unstable angina
Ischemic heart diseases: hypoxia or anoxia as a result of decrease or arrest of oxygen delivery
ACS: obstruction of coronary arteries by a thrombus
NSTEMI
STEMI
Myocardial
infarction (MI)

4. Cardiovascular risk factors
Age
Genetics
Smoking
Arterial Hypertension
Type II diabetes mellitus
Inflammatory markers : CRP, endothelin…
Protective factors:
HDL-level

5. Atherosclerosis Progressive complex chronic inflammatory disease
accumulation of
oxidized LDL
inflammatory cells
calcifications and of fibrosis
leading to plaque formation
this set modifies the intima of large and medium artery vessels

6. Atherosclerosis
Essentials of Pathophysiology: Concepts of Altered Health State; C. MATTSON PORTH and G.MATFIN

7. Myocardial infarction (MI)
Acute myocardial ischemia leading to myocardial necrosis
Diagnosis
Cardiac biomarker levels
And at least of this items :
Clinical symptoms of ischemia
Modification of ST-segment
Pathological Q waves
Demonstration of loss cardiac
muscle or function
Thrombus into coronary artery
Clinical classification
Type 1: spontaneous MI due to ATS
Type 2: secondary to an ischemic imbalance (e.g. coronary spasm, emboli, anemia)
Type 3: sudden cardiac death when biomarkers value are not available with new ischemic ECG changes or new LBBB
Type 4 and 5: MI related to revascularization procedures
European Heart Journal (2012) 33, 2551–2567
It could also be demonstrated in case of death caused by myocardial ischemia in presence of symptoms or if thrombosis is detected by angiography or autopsy in association with symptoms and changes of biomarkers levels.²

8. Clinical symptoms of MI
chest pain (>20min)
not affected by position changing),
not relieved by nitroglycerine
radiation of pain to the lower jaw or the left-arm, even gastric pain.
Less specific symptoms:
nausea or vomiting,
dyspnea,
asthenia
palpitations,
sweating
fainting
European Heart Journal (2012) 33, 2551–2567

9. Heart failure
abnormality of the structure or the function of myocardium, which prevents enough oxygen delivery to satisfy the metabolic needs of the tissues, at a normal filling blood pressure
2 categories
Heart failure with Preserved Ejection Fraction (HF-PEF)
Heart Failure with Reduced Ejection Fraction (HF-REF)
Different states
Asymptomatic
Acute
Chronic
Compensated/Decompensated
Congestive
Clinical classification: NYHA
European Heart Journal (2012) 33, 1787–1847

10. Clinical symptoms and signs of HF
Breathlessness
Orthopnea
Paroxysmal nocturnal dyspnea
Reduced exercise tolerance
Asthenia
Signs
Elevated jugular venous pressure
Hepatojugular reflux, hepatomegaly
Gallop rhythm (3rd heart sound)
Laterally displaced apical impulse
Cardiac murmur
Peripheral edema
Pulmonary crepitations
„Heart failure in a nutshell”
(From: rickolddoc.wordpress.com)
European Heart Journal (2012) 33, 1787–1847

11. BIOMARKERS Definition:
-measurable and quantifiable biological parameter
-suitable for early diagnosis, prognosis, follow-up and risk stratification
-cardiospecific with enough released concentration levels
-easily measurable
(quick and adapted to emergency
situations)
-accurate
-reproducible
-cost-effective
Chan D, Ng L.L. Biomarkers in acute myocardial infarction. BMC Med. 8:

12. Inflammation CRP Other inflammatory proteins
Peak and return to the base line are too late
Correlation with MI
can help to stratify, to screen ischemic heart disease and seems to be a prognostic factor of acute or chronic HF
But lack of specificity -> prentraxin-3 = treatment
Other inflammatory proteins
IL-6 and TNF-α: asymptomatic HF screening
PaPPA: risk of cardiovascular death and future MI prediction

13. Oxidative stress : indirect markers
Plasmaoxidized low density lipoproteins
8-isoprostane urinary levels correlate with matrix metalloproteinases levels: predicting the risk of ventricular remodeling and more severe HF
Myeloperoxidase: death caused by HF or MI
Uric acids indicates detrimental prognosis in HF

14. Neurohormones Activation of Sympathetic nervous system
Norepinephrin ↑
Renin-angiotensine-aldosterone system
Components ↑
Predictors of mortality
Gerald W. Dorn II Circulation Research. 2011;108:

15. Elevated level post-MI Predictor of death and hospitalization
Big Endothelin-1
Elevated level post-MI
Predictor of death and hospitalization
CTproET1 is in use for measurement
Arginin Vasopressin
Persistently → heart failure / mortality
For measurements: Copeptin
(in combination with cTns)

16. Copeptin is marked on this illustration post-MI
Biomarkers
Copeptin is marked on this illustration post-MI
Kehl DW, Iqbal N, Fard A, Kipper BA, De La Parra Landa A, Maisel AS. Biomarkers in acute myocardial injury. Translational Research. 159:

17. Myocyte injury Severe cardiac disease impairs the heart
Injury of cardiac muscle → release of biomarkers
Biomarkers reach the circulation with delays

18. Following Tissue Ischemia
Biomarkers
Following Tissue Ischemia
Kehl DW, Iqbal N, Fard A, Kipper BA, De La Parra Landa A, Maisel AS. Biomarkers in acute myocardial injury. Translational Research. 159:

19. Choline
Component of cell membrane (not specific)
Ischemia, necrosis, ACS
Predictor of cardiac arrest or death
H-FABP
Cytosolic, low molecular weight protein
Mainly expressed in myocardium
Associated with MI, heart failure and death
Combined with cTnI → higher sensitivity and NPV

20. Ischemia modified albumin (IMA)
Most frequent plasma protein
Ischemia → not able to bind divalent ion
albumin cobalt binding test
Rapid elevation
Contradictory results
Hs-Tn
High sensitivity troponin assays

21. Biomarkers Following necrosis
Kehl DW, Iqbal N, Fard A, Kipper BA, De La Parra Landa A, Maisel AS. Biomarkers in acute myocardial injury. Translational Research. 159:

22. Cardiac troponins (cTns)
Complex of three regulatory proteins
cTnI and cTnT is in use
Specificity!
Widest diagnostic window
Preferred for MI detection and diagnosis
Indicate poor prognosis
The only biomarkers influencing the treatment

23. Creatine kinase (CK-MB)
BM isotype – specific for myocardium
Former „gold standard” in MI diagnostics
Predictor of hospitalization and death
Less sensitive /specific
Myoglobin
Cytoplasmic heme protein
Not specific!
Earlier
Early AMI detection (often in combination with cTns)

24. Induced by myocyte stretch
Biomarkers
Induced by myocyte stretch
Kehl DW, Iqbal N, Fard A, Kipper BA, De La Parra Landa A, Maisel AS. Biomarkers in acute myocardial injury. Translational Research. 159:

25. Myocyte stress N-terminal pro-B-type natriuretic peptide (NT-proBNP)
Inactive by-product of pro-BNP cleavage
MI, heart failure and possibly ACS too
Others
MR-proANP
MR-proAdrenomedullin
ST2 (plus IL-33)

26. Conclusion Nowadays, no perfect biomarker Need more studies
Leads to a multimarker strategies

27. Thank you for your attention !