What does an indeterminate troponin really mean?...other than another 3am rule out ACS admit

Jamie Navel, MD

September 30th, 2009

Noon Conference

Contra Costa Regional Medical Center

Goals

• Discuss the definition of a troponin leak

• Discuss diagnosis of AMI

• Discuss new classifications of AMI

• Discuss in detail mechanisms of Type 2 AMI and indeterminate troponins

• Clinical significance of elevated troponins

Introduction

• Troponins are a commonly ordered test in the Emergency room

• The appropriate interpretation of a positive or negative troponin is important in determining correct course of intervention (namely Percutaneous Coronary Intervention/anti-thrombotics)

• Clinical correlation is still very important in determining cause of an elevated troponin

What are troponins?

• Regulatory proteins that control the calcium-mediated interaction of actin and myosin

• 3 sub-units Troponin T, Troponin I and Troponin C

• Found in all muscle but our assays test for the cardiac specific troponins of I and T

• Troponin C not clinically significant

Troponin I Range

• Troponin T was the first troponin used but now Troponin I is considered superior and the newer assays are very sensitive (can detect <1g myocardial necrosis)

• <0.05 is normal (At CCRMC our cutoff is <0.07)* >99% of controls

• >0.05 - <0.5 is indeterminate

• 0.5 or greater considered suggestive of acute myocardial ischemia

Troponin costs

• Single test $78

• CARP (not just cool fish) ~$200

• Number of rule out ACS admits because of indeterminate troponins-priceless

Significance of a “positive troponin”

• There are clear standards for the interpretation of positive (>0.5) in setting of high suspicion of coronary artery disease. This leads to a protocalized approach with the common goal being early revascularization

On the other hand there’s the gray area…

• Troponin leak-a common term often

synonymous with indeterminate troponin, or positive troponin secondary to a non coronary artery pathology cause.

Troponin leak

• Not a standardized term

• Typically denotes a non coronary artery disease pathology that does not require cardiac cath or anti-thrombotic agents

• Sounds gentler and is often explained away but does have prognostic importance

• Treatment strategies are varied based on the underlying pathology and goals of care

Indeterminate Troponin

• 0.05 (0.07)-0.49

• Has outpatient clinical significance in providing marker of increased mortality

• Does not rule out concurrent CAD but clinical suspicion and risk factors are very important in guiding initial management

• Cause should be indentified and treatment based on treating underlying pathology

The diagnosis of Acute Myocardial Infarction

• The reason we initially order a troponin

• Myocardial Infarction is cell death secondary to ischemia- evidenced by coagulation necrosis or contraction band necrosis under a microscope

(Interestingly normal apoptosis does not cause measurable troponin levels)

Three Pathologic Phases of AMI

• Acute MI-First 6 hours coagulation necrosis. After 6 hours there is PMN invasion

• Healing MI-can take up to 5-6 weeks with mononuclear and fibroblast invasion

• Healed MI-scar tissue with no cellular infiltration

Clinical Classification of AMI

• Type 1-spontaneous AMI secondary to primary coronary event

• Type 2-MI secondary to ischemia from increased oxygen demand or decreased supply

Clinical Classification of AMI cont.

• Type 3- sudden cardiac death with evidence of ischemia but no biomarkers

• Type 4a- PCI

• Type 4b- Stent thrombosis

• Type 5- CABG

Diagnosis of AMI

• High clinical suspicion

• EKG changes

• Elevated biomarkers (troponin >0.5)

Symptoms of Acute MI

• 25% have no symptoms

• Classic crescendo crushing chest pain

• Discomfort in upper back, neck, jaw, teeth

• Diaphoresis, SOB, nausea, vomiting or syncope

Signs of AMI

• Pale and diaphoretic

• Cool extremities

• Soft heart sounds

• S3 or S4

• Tachy or bradycardia

• Hyper and hypotension

EKG findings

• STEMI-new ST elevation at the J point in two contiguous leads

>0.1mV in two contiguous anatomic leads

New LBBB*inferior leads >0.05 acceptable if high suspicion

• NSTEMI-new horizontal or down-sloping ST depression

0.05mV in two contiguous leads and/or T

wave inversion >0.1mV in two contiguous

leads with prominent R wave

EKG limitations/pitfalls

• Meaning of Q waves (acute or prior MI)

• Posterior MI

look for ST↓ V1-V2 and ST↑ lateral leads

• Right Ventricular Infarction

V4R ST ↑, ST↑ in lateral leads

• J point elevation

Echocardiography

• Outcome data still being studied

• Very helpful in early MI when troponins aren’t elevated yet

• Large wall motion abnormality helps guide decision for immediate cardiac cath

• Not always immediately available and requires further training of personnel

Use of troponins in initial evaluation of AMI

• When the pretest probability of Acute Myocardial infarction secondary to coronary artery occlusion (Type 1) is high a positive troponin is very helpful and part of the diagnostic criteria

• When pretest probability is low this can lead to unnecessary cardiac evaluation including cardiac cath (i.e. Type 2 AMI)

Nonthrombus Ischemia/Type 2 AMI

Increased Myocardial Oxygen DemandTachycardia

Changes in cardiac loading conditions

Increased cardiac output

Myocardial depression

Decreased Oxygen SupplyReduced coronary perfusion

Decreased systemic oxygenation

CAD in setting of Type 2 AMI

• Type 2 AMI can be caused by increased demand in the setting of stable coronary artery disease (won’t necessarily be immediately improved by PCI/anticoagulation)

• Often cause of Type 2 AMI might be contraindication to PCI or anti-coagulation but worth discussing risks/benefits

Does negative cardiac cath rule out coronary artery disease?

• New studies showing evidence of AMI on cardiac MRI despite negative cardiac cath

• Cardiac Syndrome X-patients with symptoms of angina but normal coronary arteries

• Microvascular occlusion can cause angina, EKG changes and cell death with normal coronary arteries

Cardiac Syndrome X

• Endothelial Cell Dysfunction-reduced vasodilator or enhanced vasoconstrictor response to medications or exercise

• Autonomic Dysfunction-increased sympathetic tone

• Occult coronary artery disease-diagnosed by intravascular ultrasound

• Enhanced pain sensitivity

What causes troponin release?

• Cell death- When myocytes are irreversibly damaged the cell membrane degrades releases the contents. Some believe this is always the cause regardless of evidence of coronary artery disease

• Increased membrane permeability coupled with myocardial depressive factors-Degradation to smaller fragments that “leak” out-not completely understood

Non-thrombotic causes of elevated troponins

Demand Ischemia• Tachy or bradyarrhythmias• Critically ill patients • Hypotension• Hypovolemia• LVH• HCM• Burns (>25%)

Nonthrombotic Myocardial Ischemia• Coronary vasospasm• Acute Stroke• Ingestion of Sympathomimetics• Aortic dissection• Aortic valve disease

• Apical ballooning syndrome

Myocardial Strain• CHF• Pulmonary embolism• Extreme exertion• Aortic valve disease

Direct Myocardial Damage• Infiltrative diseases• Inflammatory diseases including

myocarditis• Drug toxicity• Rhabdomyolysis• Cardiac Trauma including surgery• Defibrillation

Multi-factorial • Renal disease

Troponins in CKD

• Troponin I is still the most helpful in distinguishing AMI

• Troponin T is more often elevated in asymptomatic patients

• Elevated troponin associated with poorer prognosis at same GFR

Diagnosis of AMI in CKD

• Difficult because many ESRD/CKD patients have co-morbid CAD

• Troponin I more specific as both myoglobin and CK-MB can be falsely elevated with elevated GFR

• Many dialysis patients have elevated CK but generally less than 3x normal

• Trend is very important in CKD patients for determining presence of new ischemia

Mechanism of Elevated Troponin in CKD

• LVH

• Endothelial dysfunction

• Loss of membrane integrity

• Impaired renal excretion

• Stretch mediated troponin release

Pounce demonstrating stretching

Left Ventricular Hypertrophy

• Degree of troponin elevation increases as degree of LVH increases.

• Occult subendocardial ischemia from increased oxygen demand from increased muscle mass

• Decreased flow reserve due remodeled coronary microcirculation

Heart Failure

• Troponin release via strain and cell death

• Close correlation between BNP and troponin

• Wall stress leads to subendocardial ischemia

• Cell death secondary to RAS, sympathetic stimulation, inflammatory mediators

• Elevations associated with advanced heart failure

Pulmonary Embolism

• Secondary to acute right heart strain

• Usually resolves in 40 hours (more quickly then with ischemic heart disease)

Pulmonary Hypertension

• Tachycardia

• Lower mixed venous oxygen saturation

• Higher BNP elevation

• Independently COPD exacerbations with elevated troponins have higher in hospital mortality

Sepsis

• Myocardial depression secondary to circulating factors (TNF-a, IL-6, CRP)

• Hypoperfusion

• LV dysfunction generally reversible and can be exacerbated by norepinephrine

Burns

• Related to extent of burns rather than age or co-existing conditions

• Generally seen when greater than 25-30% surface area is affected

Stroke

• Imbalance of autonomic nervous system

• Increased sympathetic activity and cathecholamine release

• Difficult to interpret secondary to high degree of co-existing CAD

Stress induced cardiomyopathy

• Otherwise known as Takotsobu’s or Broken Heart Syndrome

• Classic apical ballooning seen on Echo

• Increased levels of circulating catecholamines

Direct myocardial Damage

• Cardiac contusion• ICD shock• Infiltrative disorders (amyloidosis via

compression of myocytes)• High dose chemo• Myocarditis or Myopericarditis• Immune response after cardiac

transplantation

Conclusion

• The cause of a positive troponin must be immediately classified for appropriate intervention

• An indeterminate troponin is not normal

• There are many causes of an indeterminate troponin.

• Still give an ASA if any suspicion

• Regardless of the cause of elevation there is

increased mortality/poor prognosis

Resources

Chaudhary, Imran. ”Cardiac Syndrome X”. UTDOL updated 10/16/08

Gibson MD MS, C Michael. “Serum Cardiac Enzymes in patients with Renal Failure” UTDOL updated 6/13/08

Henrich MD MACP, William L. “Serum cardiac enzymes in patients with renal failure” UTDOL updated 6/19/09

Jaffe MD, Allan S. “Troponins and creatinine kinase as biomarkers of cardiac injury” UTDOL updated 6/19/09

Jeremias MD, Allen. “Narrative review:Alternative cause for elevated cardiac troponin levels when Acute Coronary Syndrome are excluded. Annals of Internal Medicine. Vol 142. No 9. Pg786-791

Senter MD MS, Shaun. “A new, precise definition of acute myocardial infarction” Cleveland Clinic Journal of Medicine. Volume 76. Number 3. March 2009. pg 159-166

Questions?