BIOMARKERS IN ACS

Novel Biomarkers in ACSDr.Praveen Nagula

Markers of Inflammation CRP Myoglobin CD 40 ligand

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.

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.

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.

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

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.

In hypertensives,increased levels of microalbuminuria in

tandem with decreased levels of adiponectin -

assosciated with aortic stiffness -

Tsiouffis et al ,2007.

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

Cystatin C cardio ankle vascular index.

Responsible for arterial stiffness in chronic renal insufficiency.

Nakamura et al,2009.

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

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”.

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.

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

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

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.

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.

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.

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

apoptosis.

VSMC – miR 143,miR145 – decreased proliferation.

PDGF – causes VSMC migration – attenuates

miR143,miR145 expression –stimulates

miR221,miR222 –proliferation,neointimal formation.

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

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.

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.

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

miR133 – arrhythmogenesis. miR1 miR133 – downregulation – increased HCN2,HCN4 –

arrhythmia.

 10.1111/jcmm.12148