Cardiac biomarkers objectives

Read this first:

The first five cards answer the objectives, the rest are for your info only.

to sum the last question up...

Markers that rise first: Myoglobin, *CK-MB isoform ratio, Troponins (cTnI) and cardiac TnT (cTnT)* and *CK-MB*: *Rises in 2-4hours* Markers that stay elevated longer: *Cardiac TnI (cTnI) and cardiac TnT (cTnT)* Which are more specific: Cardiac Specific troponin T *(cTnT)* Cardiac Specific troponin I *(cTnI)* *CK-MB*

Natriuretic Peptides Beneficial effects on endothelial dysfunction

⟹ effects on endothelial dysfunction secondary to atherosclerosis -Blunting of shear stress -Regulation of coagulation and fibrinolysis -Inhibition of platelet activation -*responds to endothelin*

Neutral Endopeptidase (NEP)

-Circulating enzyme that *degrades natriuretic peptides* -*Inhibition of this enzyme potentiates the effects of ANP/BNP*

List biochemical markers associated with myocardial injury

*BNP and NT-proBNP* -Diagnosis of heart failure -Stratification of CHF *ANP* -diagnosis of *acute overload or hemodynamic changes* but generally lacks sensitivity and specificity of BNP -*Troponins highly specific for MI* Cardiac Specific troponin T *(cTnT)* also available HS Cardiac Specific troponin I *(cTnI)* aslo available HS -*Enzymes* *Creatine kinase (CK)*: next best to troponin *Creatine kinase from heart (CK-MB)(CK-MB2)* -Archaic and nonspecific tests(Do NOT ORDER!)- Myoglobin Lactate dehydrogenase isoenzyme 1:2 ratio; LD1 = more heart than LD2 so if LD1 >LD2 possible MI

Troponins

-Contractile protein complex -Located along the thin filaments of myofibrils -Troponin I (*inhibitory* component) -Troponin T (*Tropomyosin binding* component) -Troponin C (*Calcium binding* protein) -*TnI and TnT in the myocardium are coded by different genes than that in the skeletal muscle (i.e. cardiac troponins)* -*Troponin I and T are cardiac specific cTnI / cTnT* -*cTnl -DO NOT rise after skeletal muscle injury* -Levels that rise >1 times (and esp. >3) admission levels in patients undergoing percutaneous cardiac intervention are associated with an increased risk of death within 6 months

Approach to Laboratory Diagnosis of ACS

-Diagnostic EKG changes = AMI -T-wave inversion=Acute ischemia -ST-elevation=Acute ischemia, Earliest indicator -Q-waves=Acute infarction (Established MI) -Serial measurements of biomarkers should be performed *On admit, 6-9 hr later, 12-24 hr(depends on hosp protocol)* -Caveat=*decision to proceed with urgent recanalization/thrombolytic tx should be based on clinical history and EKG changes, due to the delay inherent in the rise of biomarkers*(often 1-12 hours before detectable) and the lab testing itself.

Myoglobin

-Heme protein -*Rises the most rapidly following myocardial injury* -Rise in 1-3 hours -Peak at 6-9 hours -Normal within 24 hours -This is elevated in all muscle damage. It is *no longer used as a cardiac biomarker, only for ruling out myositis and as a marker of extensive muscle damage in trauma patients*. -*NOT sensitive or specific for AMI testing*

Silent MI

-No clinical or physical findings are present -Diabetes and hypertension -Cardiac markers may be only indication

discuss which markers are most specific and sensitive in the diagnosis and follow-up of - Congestive heart failure (CHF)

*BNP and NT-proBNP* -Diagnosis of heart failure -Stratification of CHF -Normal BNP <100 pg/mL or < 100ng/L (SI units) -*Critical values are >100 pg/mL*

In an MI, identify which markers rise first and stay elevated longer, which are most specific!

*Cardiac TnI (cTnI) and cardiac TnT (cTnT)* -Rise above the upper reference limit relatively rapidly usually *within 2-4 hours & peak within 24-48 hours* -*Stay elevated for 7-10 *( sometimes 14) days Most beneficial for *detecting MI six or more hours after onset* of symptoms -cTnl good for early and late diagnosis -*cTnT*: Standardization is greater, slightly more sensitive *(better*) -New high sensitivity *HScTnT and HScTnI may be better for detecting earlier increases*/lower levels of troponin in MI. -*Reinfarction*- usually CK-MB is used because it tends to *decline more rapidly post uncomplicated MI* -*Total CK*: *rises in 4-8 hours* after injury; Peaks in 24 hours; Normal in 48-72 hours (not specific) -*CK-MB*: *Rises in 2-4hours*, Peak levels in 24 hours, Returns to normal in 48-72 hours (Sensitivity and specificity approaches 95%)

Natriuretic Peptides Vasodilator effects

-*Dilate veins* = increase venous compliance -Decrease central venous pressure -*Reduces cardiac output (decrease ventricular preload)* -*Dilate arteries* -Decrease systemic vascular resistance -Decrease systemic arterial pressure

More general guide lines

-*Early markers of myocardial damage* CK-MB isoforms Troponin -*Definitive markers of myocardial damage* Cardiac Troponin I or T Markers utilized should be based on availability, time of presentation in relation to onset of symptoms <6 hours : CK-MB isoforms, Troponins* >6 hours : Troponins

Natriuretic Peptides Renal Effects

-*Increase GFR and filtration fraction* 1) Natriuresis 2) Diuresis (both of which are *potassium sparing*) -*Decrease renin release* 1) *⬇︎ angiotensin II* -Further *diuresis and natriuresis* -Vasodilation, decreased systemic vascular resistance 2) *⬇︎ aldosterone* -further *diuresis and natriuresis*

Natriuretic Peptides actions on ventricular and vascular hypertrophy and remodeling?

-*Inhibition* of pathophysiologic mechanisms responsible for ventricular and vascular hypertrophy and remodeling

Lactate Dehydrogenase (LDH)

-*Obsolete for diagnosis of AMI* -Catalyzes the formation of lactate from pyruvate -*Rises in 24-48 hours* -Peaks in 1-3 days -Returns to baseline in 8-14 days -Limited because of its wide distribution -*Lack of specifity* -Isoenzymes (LDH1-LDH5) help to distinguish site of origin -*LDH1 predominates in the heart with some LDH2 Ratio of LDH1:LDH2* was used historically

C-reactive Protein

-*Peptide produced in the liver in response to inflammation* -*Proinflammatory and procoagulant activities*: ⟹ Induces production of tissue factor by monocytes ⟹ Causes endothelial cells to express adhesion molecules ⟹ Binding of apolipoprotein-B containing molecules (LDL, VLDL) ⟹ Recruitment of inflammatory cells -New ultra-sensitive assays detect small increases -marker of prognosis for recurrent events in patients with stable coronary disease -More predictive of future cardiac events than LDL

General Guidelines

-*There is no perfect marker* -NEVER rely on a single measurement -Trends are as important as absolute values -Collect blood samples ASAP to get an accurate baseline -*NEVER diagnose AMI solely on the basis of biomarkers* -Interpret inconsistent results with caution -*Cardiac reperfusion: rise sooner; peak higher Washout phenomena* (KNOW THIS) -Increases in biomarkers tend to correlate with the size of the infarction(higher the marker level the larger the infarction)

Discuss which markers are most specific and sensitive in the diagnosis and follow-up of MI

-*Troponins* highly specific for MI Cardiac Specific troponin T *(cTnT)* Cardiac Specific troponin I *(cTnI)* -Sensitivity 84-90% and specificity 80-95% *Creatine kinase from heart (CK-MB)* (Sensitivity and specificity approaches 95%) More specific for myocardial injury than total CK -*Reinfarction (10% of AMIs)- CKMB rises or reappears after 3 days* -Elevated CK-MB2 and *increased ratio of CK-MB2 to CK-MB1 of >1.5 has increased sensitivity over CK-MB alone* and may be *detected as early as 2 hours* after a MI -*Unchanged levels of CK-MB and Troponin over a period of 2 days EXCludes a diagnosis of MI*

Natriuretic Peptides Long-term regulation of sodium and water balance, blood pressure, arterial pressure

-*Two major pathways* 1) Vasodilator effects 2) Renal effects --Natriuresis --diuresis

Acute Myocardial Infarction (AMI) Physical findings

-Anxious, restless -Pallor -Perspiration with cool skin -Tachycardia and/or hypertension and bradycardia and/or hypotension -Abnormal heart sounds

Physiologic Modifiers of CNH Levels

-Circadian variations -Age (increase with age) -Gender (f>>m due to sex hormones) -Renal insufficiency -Left ventricular dysfunction -Clinical evidence of heart failure -Myocardial necrosis -Severe CAD -Diet (esp. high sodium intake) -ACE inhibitors

Natriuretic Peptides

-Divided into *Atrial (ANP) and B-type (BNP)* *⬆︎ hypervolemic states and CHF* -Heart failure (*respond to atrial distention*) -Renal failure (*responds to angiotensin II stimulation*) -Liver cirrhosis ⟹ *Natural antagonists to the renin-angiotensin aldosterone (ARA) system* (also, Endothelin Cytokines vasopressin) ⟹ Particularly *important in regulating fluid balance in patients with hemodynamic stress* -*Vasodilation and hypotensive* effect -Promotion of *natriuresis and diuresis* -*INHIBIT of the sympathetic NS* -⬇︎ Blood volume, ⬇︎ Arterial and venous pressure -⬇︎ pulmonary capillary wedge pressure ⬇︎ CO -*Produced/stored as pre-hormones in atrial myocytes, short 1/2 life*

Creatine Kinase (CK)

-Enzyme that phosphorylates creatine -Found in skeletal muscle, myocardium, and brain -Circulating CK is directly related to muscle mass -*Excellent sensitivity but very poor specificity* -Total CK is *NOT utilized in the evaluation of patients with probable MI without other biomarkers* -Skeletal Muscle CK-MM (95%) -Myocardium CK-MB (5%) -Brain CK-BB -Ratio of CK-MB to total CK is used to distinguish cardiac from skeletal CK since CK-MB is found in both -*(CK-MB/Total CK) x 100 = Relative Index (RI)* -*RI > 5%(>2%) is suggestive of myocardial injury over skeletal muscle* (Harrison says 2.5%) -Clinical correlation is always required!

Lipid testing

-Multiple measurements should be obtained within 2 months, At least 1 week apart -A 1% reduction in cholesterol is associated with a 1.5-3% reduction in CHD -LDL should be aggressively lowered -*Serum cholesterol measured at age 22 is a predictor of CHD for the next 40 years*

Acute Myocardial Infarction (AMI) clinical presentation

-Often associated with physical exercise, emotional stress or illness -Most frequently occurs a few hours after waking -*Heavy, squeezing, crushing chest pain* is typical but not always present -*Women often present with atypical symptoms* or none at all

Nesiritide (Natrecor)

-Recombinant form of B-type natriuretic peptide -Facilitates fluid hemostasis similarly to BNP -Counter regulation of the renin-angiotensin-aldosterone system -Promotes vasodilation, natriuresis and diuresis

What endocrine function does a heart serve?

-Secretes a family of related peptide hormones: Cardiac Natriuretic Hormones (CNH's) or Natriuretic Peptides

C-type Natiuretic peptide and Urodilatin

-Structurally related to ANP/BNP family -Secreted by noncardiac tissues *Endothelium (C-type natiuretic peptide)* *Kidney (urodilatin)*

Typical protocol for cTn testing

-Suspected AMI- clinical evaluation and ECG. ECG shows STEMI⟹ lytic tx. -ECG does not show STEMI⟹ Draw initial cTn test. -cTn negative⟹ retest at 6- 9 hours X 2( sometimes 3), this is because it may take several hours for cTn to rise post myocyte necrosis -If after several hours presenting symptoms have resolved & cTn remains negative <r> ACS ruled out -*The higher the cTn level the larger the volume of infarcted muscle and the worse the prognosis*

B-type(Brain) Natriuretic Peptide

-Synthesized *within the ventricles (77%)* and the brain -*Secreted* predominately from the *left ventricle*