This document discusses several novel biomarkers for acute coronary syndrome (ACS). It describes C-reactive protein (CRP) as a marker of extensive vascular inflammation. High-sensitivity CRP levels above 10 mg/L are more predictive of outcomes in ACS patients. Soluble CD40 ligand and myoglobin are also discussed as inflammation markers. Microalbuminuria is related to endothelial dysfunction and an increased risk of cardiovascular disease. Cystatin C and metalloproteinases are associated with arterial stiffness and plaque degradation. Several microRNAs such as miR-1, miR-133 and miR-208 are described as potential biomarkers for myocardial infarction, cardiac hypertrophy, and arrhythmias.

1. Novel Biomarkers in ACS
Dr.Praveen Nagula

2. Markers of Inflammation
 CRP
 Myoglobin
 CD 40 ligand

3. C Reactive Protein
 Acute phase protein.
 Homopentameric structure.
 Ca binding specificity for phosphocholine.
 It is a mediator >>> marker of atherogenesis.
 It is a marker of extensive vascular inflammation,hyper
responsiveness of the inflammatory system.

4.  In Unstable angina pts – CRP levels were useful in prediction of the
long term prognosis, while troponin T levels were useful in prediction
of inhospital prognosis.
- Tanaka et al.
 CAPTURE trial - Troponin T – predictive of cardiac risk < 72 hrs
but not CRP .
 Hs CRP >3mg/l - predictor of outcomes in stable CAD.
 >10 mg/l – more predictive in patients with ACS.

7. CD 40 ligand
 Elevation of soluble CD 40 Ligand – high risk of
Unstable angina/ACS.
 Role in proinflammatory, prothrombotic milieu for
aggravating atheroscleorsis, plaque instability.
 Elevated levels after one month after PCI predicts
angiographic restenosis.
 No prognostic value as per Morrow et al,2008.

9. Myoglobin
 Ubiquitous heme protein.
 Small size – rapidly released.
 T1/2 – approx 9 min.
 TIMI 11 B
 TACTICS TIMI 28
Serum Myoglobin above MI detection threshold
>110 ug/l increased risk of 6 month mortality
independent of other factors

11. Microalbuminuria
 20-200ug/min.
 Related to dysfunctional endothelium in non diabetes.
 Imp.risk factor for CVD.
 Early CV mortality in patients with +/- HTN,DM
Crerstein et al 2001,Wachtell et al 2003.
 HOPE trial (2001) – “microalbuminuria is assosciated with an
increased relative risk of the primary aggregate
point,MI,stroke,CV death in +/- diabetic patients.”
 LIFE trial
 PREVEND study – for each doubling of urine albumin excretion
increased RR of CV mortality of 1.53.

12.  In hypertensives,increased levels of microalbuminuria in
tandem with decreased levels of adiponectin -
assosciated with aortic stiffness -
Tsiouffis et al ,2007.

15. Cystatin C
 Member of cysteine protease inhibitor.
 Filtered at glomerulus.
 Not reabsorbed.
 Metabolised in tubules.
 Not used for measuring clearance.
 Unaffected by gender,age,muscle mass.
 Affected by hyperthyroidism,hypothyroidism.
 Increased risk of CV mortality – Toft et al,2012

16.  Cystatin C  cardio ankle vascular index.
 Responsible for arterial stiffness in chronic renal
insufficiency.
Nakamura et al,2009.

17. Metalloproteinases
 Causes degradation of ECM.
 Zinc metallo endopeptidases.
 Increased activity in atheromatous plaque.
 Involved in all stages of atherosclerosis.
 MMP2.,MMP9 – repsonsible for degradation of fibrous
cap of vulnerable plaque.
 Statin therapy – decreased macrophage infiltration –
inhibition of PG synthesis - decreased MMP –
decreased thin cap – stabilization.
Moreau et al ,2009

18. BNP
 32 AA peptide.
 Released from ventricular myocardium in response to
ventricular dilation, pressure overload.
 Functions – balanced vasodilation.
 Natriuresis.
 Inhibits SNS.
 Inhibits RAAS.
 Higher plasma BNP – increased risk of new or recurrent
MI.,new or worsening HF.
“Presently still not approved for risk stratification in ACS
patients”.

19. Pregnancy assosciated plasma
protein A
 Metalloproteinase.
 Prenatal screening test for detection of trisomy 21 in
first trimester.
 Heterotetrameric complex.
 Dependent on IGF.
 Biomarker of plaque rupture.
 Local proliferative process.
 Independent predictor of death or non fatal MI even
in patients with normal Serum Trop T in patients with
chest pain.

20. http://dx.doi.org/10.1093/eurheartj/ehi433

21. Micro RNAs
 22 nucleotide non coding RNAs.
 Function is – differentiation,proliferation,apoptosis.
 Role in CVD – atheroslcerosis, plaque rupture, HF,
cardiac arrhythmias,hypertrophy.
• Primary long
RNA s
(Pri mRNAs)
RNAase III
enzyme DROSHA
• PRE mi RNAs
Cytoplasm
• mi RNAs

24. Biological aspects
 Binds to complementary sequences located on the 3ft
UTR of target genes.
 Regulate gene expression.
 Organized in clusters.
 They have common transcriptional region,located both
in introns and exons of coding as well as noncoding
genes.
 Dicer enzyme – essential for maturation.

25.  First miRNA to be discovered is Lin -4.
 > 700 human miRNAs have been registered.
 miR1
 miR133
 Let 7
 miR 126 -3p
 All are expressed in cardiac muscle.

26. Role in CVS
 miR 1 – regulates the balance between proliferation and
differentiation during cardiogenesis.
 miR 21 – anti apoptopic,proproliferative properties on VSMCs .
 Circulating miRNAs are stable – protected from RNAase
dependent degradation – secreted in microvesicles,exosomes.
 Overexpression of miR1 – thickens ventricle wall – premature
differentiation,early withdrawal of cardiac cells from cell cycle.

27.  miR21 – NOS – attenuates endothelial apoptosis.
 miR221,miR222 – decreased eNOS- increases
apoptosis.

28.  VSMC – miR 143,miR145 – decreased proliferation.
 PDGF – causes VSMC migration – attenuates
miR143,miR145 expression –stimulates
miR221,miR222 –proliferation,neointimal formation.


29.  Mutation of dicer - supresses angiogenesis.
 miR130
 miR27b
 miR378
 miR92a
 Let 7F
 miR210 – enhanced by VEGF – inhibits hypoxia induced
angiogenesis.
 miR221/miR222 – attenuates angiogenesis,decreases NO
bioavailability.
Angiogenic properties

30. Inflammation
 miR126 – inhibits VCAM 1 – leucocyte adherence to
endothelium.
 miR155 – inhibits T cell adhesion to ECs – decreased migration.
 miR155 – reduced in atherosclerosis patients.
 miR221/222- upregulated in atherosclerosis pts.
 miR125a/b – causes downregulation of ET1,IL6,IL2,TNF.
 miR31,miR17-3p – ANTIINFLAMMATORY properties.

31. Role in MI
 mi208 - related to Troponin I.
 Detectable in circulation after MI.
 Reflects its extent of MI.
 Superior to cardiac troponins in diagnosing MI in patients
with renal dysfunction - Xu et al,2012.
 Antagomir miR92a – vessel growth,recovery of damaged
tissue. – “therapuetic agent for ischemic disease”.
 miR1 – biomarker for MI,First 6 hrs – 3 days.

32.  miR1
 miR133a
 miR133b
 miR499
 miR1 – inversely related to cardiac hypertrophy.
 miR21 – directly related to cardiac hypertrophy.
 miR1,miR133 – attenuated in HCM,dilated atria.
 Normalizes on treatment with LVAD by 70%.
MI

33.  miR133 – arrhythmogenesis.
 miR1
 miR133 – downregulation – increased HCN2,HCN4 –
arrhythmia.

34. 10.1111/jcmm.12148