Dr.S.Sethupathy

RMMC,

Annamalai university

“A biomarker is a substance used as an indicator of a biologic state.

It is a characteristic

It is objectively measured

It is evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.

Biomarkers

“Cardiac markers are substances released from heart muscle when it is damaged as a result of myocardial infarction.”

Cardiac markers

Objectives

1) CKMB and TI false-positive and false-negative possibilities should be entertained

2) Associations between TI, CKMB and CK in patients with suspected acute coronary syndrome and elevations in non-ACS situations

3) New markers

Cardiac markers

Triad of Chest pain, ECG manifestations and elevations of biomarkers of cardiac injury

Chest Pain: highly variable and subjective

ECG: Objective ST or T-wave changes

Biomarker elevations: Objective data definingACS/AMI

Diagnosis of AMI

Acute coronary syndrome (ACS)- any group of symptoms attributed to obstruction of the coronary arteries.

Common - chest pain, often radiating to the left arm or angle of the jaw, pressure-like in character, with nausea and sweating.

ACS due to one of three problems:

non-ST segment elevation myocardial infarction (NSTEMI) – 25%

ST segment elevation myocardial infarction (STEMI) – 30%,

unstable angina (38%).

ACS

Unstable angina is angina pectoris -disruption of an atherosclerotic plaque with partial thrombosis and embolization or vasospasm.

Occurs at rest or minimal exertion and usually lasts less than 20 minutes

severe flank pain, new onset (i.e., within 1 month)

more severe, prolonged, or increased frequency than before

50% of people with unstable angina -with myocardial necrosis - elevated CK-MB and troponin T or I

non-ST elevation myocardial infarction.

Unstable angina

Natriuretic peptide - Both B-type natriuretic peptide

(BNP) and N-terminal Pro BNP can be applied to predict the risk of death and heart failure following ACS.

Monocyte chemo attractive protein (MCP)-1 -identify patients with a higher risk of adverse outcomes after ACS.

Prognostic markers

Acute Myocardial infarction happens when blood

stops flowing properly to part of the heart and the heart muscle is injured due to hypoxia.

Troponin levels: Normally not found in serum; it is released only when myocardial necrosis occurs.

Creatine kinase (CK) levels: CK-MB levels increase within 3-12 hours of the onset of chest pain, reach peak values within 24 hours, and return to baseline after 48-72 hours

AMI

The ECG is the most important tool in the initial

evaluation and triage of patients in whom an acute coronary syndrome (ACS), such as myocardial infarction, is suspected.

It is confirmatory of the diagnosis in approximately 80% of cases.

Cardiac imaging – in individuals with highly probable or confirmed ACS, a coronary angiogram can be used to definitively diagnose or rule out coronary artery disease.

Electrocardiography

Myoglobin levels: Myoglobin is released more

rapidly from infarcted myocardium than is troponin; urine myoglobin levels rise within 1-4 hours from the onset of chest pain

Complete blood count

Chemistry profile

Lipid profile

C-reactive protein and other inflammation markers

Investigations

Ischemia-Modified Albumin (IMA) - In cases of

Ischemia - Albumin undergoes a conformational change and loses its ability to bind transitional metals (copper or cobalt).

IMA- Alb- N terminus –Cobalt binding –DTT(dithiothreitol) – complexes with unbound –500nm- > 85 U/ml – C.Ishemia

IMA can be used to assess the proportion of modified albumin in ischemia. Its use is limited to ruling out ischemia rather than a diagnostic test for the occurrence of ischemia.

Biomarkers

Myeloperoxidase (MPO) - The levels of circulating

MPO, a leukocyte enzyme, elevate early after ACS and can be used as an early marker for the condition.

Glycogen Phosphorylase Isoenzyme BB-(GPBB) is an early marker of cardiac ischemia and is one of three isoenzyme of Glycogen Phosphorylase.

Troponin is a late cardiac marker of ACS

Biomarkers

Diagnosing AMI/ACS

Detecting myocardial damage

Risk stratification of the patients

Commenting on Prognosis In ACS, pre and post PCI/reperfusion therapy

CHF

Renal Disease

What biomarkers are good for:

CK (CPK)

CK-MB

Troponin-I/T

LD (LDH)

Myoglobin

ALT/AST

Others

Cardiac biomarkers

Creatine kinase (CK/CPK) is an enzyme expressed in a number of tissues

Function: it catalyzes the conversion of creatine to phosphocreatine degrading ATP to ADP

phosphocreatine serves as an energy reservoir for the rapid regeneration of ATP)

The CK enzyme consists of two subunits, B (brain type) or M (muscle type), three different isoenzymes: CK-MM, CK-BB and CK-MB

Creatine Kinase

CK-BB occurs mainly in tissues, rarely of any significance in the bloodstream

Skeletal muscle expresses CK-MM (98%) and low levels of CK-MB (1%)

Sensitive lab tests can pick up these low levels of CK-MB from skeletal muscle

The myocardium has CK-MM at 70% and CK-MB at ~30%

CK therefore, lacks specificity for cardiac damage and needs to be augmented with the MB fraction and Relative Index (RI) to indicate true cardiac damage

CK

Needs >two-fold increase with simultaneous increase in CK-MB

to be diagnostic for MI problematic for use in patients with little muscle mass Increases 4-6 hours after onset of MI Peak activity is at 18 to 24 hoursUsually has returned to baseline levels by 36 hours False positive (for MI) CK elevation can be seen in: Significant skeletal muscle injury Significant CNS damage (Stroke/Trauma) Occasionally from GI, renal, urologic disease

elevations due to non-cardiac causes- shows a flatter curve, rising and disappearing at a slower pace than a cardiac source

CK

High specificity for cardiac tissue

Begins to rise 4-6 hours after onset of infarction

Peaks at about 12 hours

Returns to baseline at 24-36 hours

Can be used to indicate early re-infarction if level normalizes and then increases again

Lab test for mass better

mass assays are more sensitive.

CK-MB

False positive (for MI) CK-MB elevation :

Significant skeletal muscle injury

Cardiac injury - other than MI

Cardioversion, Defibrillation

Blunt chest trauma (Sports injuries)

Cardiac AND non-cardiac surgical procedures

Cocaine abuse (vasospasm, tachycardia, perfusion/demand mismatch)

Severe myocarditis

CK-MB

Troponin - in skeletal as well as cardiac muscle

Troponin has three subunits, TnC, TnT, and TnI

Troponin-C binds to calcium ions

Troponin-T binds to tropomyosin

Troponin-I binds to actin in thin myofilaments to hold the troponin-tropomyosin complex in place

So far no source of Troponin-I outside the heart, but some Troponin-T in skeletal muscle.

Highly specific - Troponin-I

Troponin

Increased level of the cardiac Protein isoform of

troponin circulating in the blood- a biomarker of myocardial infarction.

Raised Troponin levels indicate cardiac muscle cell death as the enzyme is released into the blood upon injury to the heart.

cardiac troponin I and T are very sensitive and specific indicators of damage to myocardium.

To differentiate unstable angina and MI in chest pain or acute coronary syndrome.

Troponin

Laboratory range definition:

Cutoff is set at 99th percentile of a normal reference population

Since troponin levels are undetectable in normal subjects

This 99th percentile corresponds to <0.06

-heparin in sample can result in lowered values

Elevated troponin level within 2-3 hours of emergency department (ED) arrival, versus 6-9 hours or more with CK-MB and other cardiac markers.

More about Troponin

Troponin-I levels begin to rise 2-3 hours after onset of MI and roughly 80% of patients withAMI will have positive values at 3 hours

Elevations in Troponin-I and Troponin-T can persist for up to 10 days after MI

It has good utility for retrospectively diagnosing AMI

CK-MB returns to baseline by 48 hours

Troponin release can also be precipitated by other conditions that cause myocardial damage

Cardiac troponin T and I can be used to monitor drug and toxin-induced cardiomyocyte toxicity.

Troponin Use

Since normal people have virtually nil levels

of troponin in serum, it is thought that detectable levels indicate chronic disease even if not acute myocardial damage

Degree of elevation of Troponin value can give prognostic information

72-96 hour peak TI correlates with infarct size

Not with other biomarkers

Troponin Influence on Prognosis

Used along with aminotransferases to diagnose AMI.

LD is non-specific for cardiac tissue , which contains LD-1.

pancreas, kidney, stomach tissue and red cells also contain LD-1.

In AMI, LD rises at about 10 hours,

peaks at 24-48 hours,

remains elevated for up to 8 days.

AST very non specific – now not used for AMI

LDH

Ubiquitous small-size heme protein released from all

damaged tissues.

Increases often occur more rapidly than TI and CK.

Not utilized often for AMI/cardiac damage assessment because of its very rapid metabolism (short plasma half-life) causing short burst increases that are difficult to assess clinically.

its lack of specificity for cardiac tissue.

Myoglobin

CK (U/L) Normal Range: 0-215

CKMB - < 25 U/L If CK-MB is elevated The ratio of CK-MB to total CK (relative index) is more

than 2.5–3 it is AMI. A high CK with index below this value suggests that

skeletal muscle damage. BNP - <100 pg/ml NO HF > 400 pg/ml HF

Reference range

LESS THAN 0.07 NG/ML: NEGATIVE

0.07 - 0.5 NG/ML: CONSISTENT WITH POSSIBLE CARDIAC DAMAGE AND

POSSIBLE INCREASED CLINICAL RISK.

>0.5 NG/ML: CONSISTENT WITH CARDIAC DAMAGE, INCREASED CLINICAL RISK

AND MYOCARDIAL INFARCTION.

TROPONIN I

Timing Summary

TEST ONSET PEAK DURATION

CK/CK-MB 3-12 hours 18-24 hours 36-48 hours

Troponins 3-12 hours 18-24 hours Up to 10 days

Myoglobin 1-4 hours 6-7 hours 24 hours

LDH 6-12 hours 24-48 hours 6-8 days

“clinical evidence of myocardial ischemia” is

necessary in addition to elevated biochemical markers .

Example : hypoxia due to hypovolemia, GI bleeding,CO,CN poisoning, sepsis, Pul.emb, Pul.H, COPD,atrial fibrillation, myocarditis, myocardial contusion, renal failure , PET and tachycardia

Cardiac troponin T and I can be used to monitor drug and toxin-induced cardiomyocyte toxicity.

Elevated cardiac biomarkers in non-ACS situations

Situations of prolonged mycyte ischemia prolonged/profound hypotension, chronic, pulmonary

hypertension CPR/Cardiac contusion Electrical Cardioversio PE, pericarditis, myocarditis Sepsis ( myocardial oxygen demand-supply mismatch) Apical Ballooning syndrome-- “Takotsubo

Cardiomyopathy” Chemotherapy, e.g. Adriamycin, Herceptin Toxins, cocaine Extreme exertion--Marathons, ultramarathons, Military

basic training LVH--leads to subendocardial ischemia by increased O2

demand from increased mass HF

Elevated cardiac biomarkers in non-ACS sitouations

CAD is highly prevalent in patients with end-stage renal disease and

patients on dialysis.

HTN and DM

ESRD as well as dialysis change homeostatic mechanisms for lipids, calcium and electrolytes

HF patients and ESRD patients have low levels of troponin elevations chronically without evidence of myocardial damage, although the mechanism and significance are not known.

Possible reasons parallel those for HF:

significant LVH, endothelial dysfunction, loss of cardiomyocyte membrane integrity and possibly impaired renal excretion

Biomarkers in Renal Failure

Chronically elevated troponin levels indicate a worse long-

term prognosis for cardiovascular outcomes

False positives- with use of troponin-T in ESRD patients but not as much with troponin-I

CK: plasma concentrations are elevated in 30-70% of dialysis patients at baseline, secondary to skeletal myopathy, intramuscular injections and reduced clearance

CK-MB: 30-50% of dialysis patients exhibit an elevation in the MB fraction >5% without evidence of myocardial ischemia

The most specific marker for suspected AMI in ESRD patients is Troponin-I with an appropriate sequential rise

Biomarkers in Renal Failure

Small elevations in TI are chronically found in patients with heart

failure, without current symptoms of ischemia

The presence of TI remained an independent predictor of death

A positive TI in a hospitalized patient with HF is associated with a higher in-hospital mortality.

The presumed mechanism of cardiac troponin release in HF is from

myocardial strain-volume and pressure overload of both ventricles causing excessive wall tension leading to decreased subendocardial myocyte perfusion.

There is a correlation of elevated BNP and TI release

myocyte death- (sympathetic stimulation, inflammatory cytokines) -progressive myocyte apoptosis and cardiac dysfunction

Biomarkers in Heart Failure

1. Heart-type fatty acid binding protein

2. Kinetically similar to myoglobin but more specific to cardiac tissue which contains a greater percentage of this protein than skeletal muscle

3. May also have role in prediction-prognosis in patients with NSTEMI

Newer markers - H-FABP

H-FABP Protein 15 kdmyoglobin 17 kd

Released 3 hours early marker

Plasma level returns within 24 hours

H-FABP

62 yo male with PMH of HTN x20 years, DM

II x 10 years presents with 2 hours of mid-sternal chest pain radiating to left arm and jaw, with associated SOB and diaphoresis. He was given O2, ASA 325mg and SL NTG en-route by EMS. Upon arrival to ED his CP is 5/10, somewhat relieved by the nitro, His ECG shows TWI in v2-v6. BP 150/100, P115, R18, 96% 2L NC

Case 1

What is your pre-test probability for ACS before you

get cardiac biomarkers in this patient?

Which biomarkers to you think will be positive at this time? In 12 hours?

Will you wait for the biomarker results to start treatment for ACS?

Case 1 Discussion

55 yo female with no significant PMH but

positive FHx for early MI in her brother at 48 years, and her father at 56 years, presents with mid-epigastric pain episodes lasting 1hr each, off and on for the last 24 hours after her labor Day BBQ (1st episode 24hrs ago), and she thinks her right arm is “tingly.” The last episode was 2 hours ago, but the pain is gone now. The ED gave her 1” nitropaste, 81mg asa x4 and Lovenox1mg/kg, as well as Zofran and Morphine. Her ECG shows TWI in lead II. Pulse is 100. Other VS WNL.

Case 2

What is your pre-test probability of ACS in this

patient and how are you going to utilize your blood tests?

Obviously the ED physician felt this was likely to be ACS, do you agree?

If her troponin comes back as 0.07 with a normal CK and CK-MB what will you do?

Case 2 Discussion

73 yo AAM presents to clinic for routine HF check. By office scale he has gained 10# since last visit 2 months ago. He admits to sleeping upright and has1block DOE. He denies angina/chest pain. In-office ECG is notable for strain pattern. He is diagnosed with HF exacerbation and direct admitted. AMI panel is drawn and CK is 250, MB is 8, TI is 1. BNP is 3500. 2nd TI is 1.2 and 3rd is 1.1. He is hypertensive but stable.

Case 3

What is the likely explanation for this patient’s

elevated cardiac biomarkers?

How do you plan to manage this patient from here? Does he need to be in the CICU? Does he need further enzyme studies?

Case 3 Discussion

44 yo AAF with ESRD secondary to HTN on dialysis

(HD x 7 years) presents with chest pain at dialysis. Her end-HD BP was 190/100 and she reports a headache. ECG shows Q-waves in the inferior leads but no acute changes. She got her flu shot at dialysis today. You draw AMI panel and CK is 300, MB 15, RI 4% and TI is 1.13

Case 4

If her serial enzymes stay at the same levels what is her general Cardiovascular prognosis?

Given the story, what other findings do you expect on her ECG?

What is the likely physiological mechanism for her elevated CK? Her TI?

She refuses cath. What is the best, simplest way to attenuate her cardiovascular mortality?

Case 4 Discussion

Thank you