Bio Markers

7/31/2019 Bio Markers

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Biomarker indicates possible response to therapy.

Cariac biomarkers:

Neurohormones

Epi or norepi

ReninAngiotension

Aldosterone

Endothelin

Oxidative stress

Urinary or plasma isoprostanes

Ec matrix remodeling

Matrix metalloproteinases

InflammationC reactive protein

Tnf alpha and il1

Myocyte injury

Cardiac tropoin I or t

Myosin light chain kinases

Creatine kinase mb

Myocyte stress

Bnp and nt pro bnp

Anp and nt pro anp

Odd biomarkers:

Cardiac biomarker sodium calcium exchanger NCX-1 expression of NCX1

was significantly increased in moderate to severe MMVD dogs (not increased at all

with azotemia). Studied in healthy, MMVD and Renal failure. Measured by qPCR.

**not affected by renal disease (unlike BNP, ANP, Troponin)

Calcium reuptake related genes expression of sarcoplasmic reticulum

calcium reuptake gene SRCR genes. By mRNA expression. SERCA a2alpha was

unchanged with heart disease. HAX-1 and PLN went down or were reduced with

heart disease MMVD of moderate to severe disease. Serca a2aplha, hax-1 and plnare all sRCA genes.

Metalloproteinase eval MMP-2 and MMP-9 in dogs with MMVD. There

were no differences in MMPs amongst the MMVD severity groups. MMP-9 went

down with increased LVIDd and increased SHT.


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TRADITIONAL BIOMARKERS:

Leakage enzymes:

Cardiac troponin I

Cardiac troponin T

(these are mostly >95% bound to the contractile apparatus)

Function:

BNP

ANP and pro form.

Old school biomarkers

AST, LDH, CK, Myoglobin, Myosin Light Chain.

Troponins leak from damaged myocytes there is maintained protein homology

amongst all mammalian species. Stable at room temp for 4 days.

Troponin remains elevated longer, correlates better to extent of injury. Troponin

in experimental model actually peaked 5 days after injury.

Troponin t has a longer half life than troponin I .

Ctni is more sensitive than troponin t for injured cardiomyocytes.

Ctnt is more sensitive as prognostic and as a renal marker.

2 release patterns postulated acute versus sustained injury.

Troponin I - 0.25 ng/ml was indicative of HSA.

CTNi in occult DCM

Gehrard Wess paper - DCM Dobermans

apparently healthy dobes withDCM had elevated troponin despite that they had no VPCs or echo abnormalities.

Elevated beyond 0.22 predicted DCM.

HCM cats

Asymptomatic HCM

Active CHF


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Normal

Troponin cannot be used to separate heart failure from non cardiac cause of

resp distress and cats with heart disease and no heart failure are hard to separate

from either group. If the tni is really high it may mean something and if it really low

it is unlikely to mean something.

Babesiosis

Trauma

Gdv

Doxorubicin therapy

Oleaner or snake bit tox

Increased age

Renal disease

Immune mediated hemolytic anemia

Troponin I also elevates with pulmonary hypertension (pre or post capillary).

Post-capillary

consequence of increased severity of MMVD

CTNi is associated with severity of MMVD, Age and C-reactive Protein

Highly sensitive CTNi measures. CTNi was detected in moderate to severe

MMVD when compared to healthy dogs.

I stat has a nice low level of detection. 0.02ng/ml

ANP, BNP, CNP

Natriuretic peptide are synthesized as prohormones they are processed to smaller

mature forms and have an obligate c terminal 17 resideue disulfide ring.

Anp stored as propetide in atrial granules and is cleaved and enters circulation in

response to atrial stretch.

BNP also stored in granules responds to ventricular stretch. it is transcribed

on the go normally there are very low levels its production is ramped up with

stretch.

CNP found in chondrocytes. Has been found in proliferation / and differentiation

of vascular and neuronal system.

NT-pCNP as a diagnostic marker for sepsis (released from vascular endothelium in

response to sepsis). Was able to differentiate sepsis from SIRS (non septic sirs)

with a cut-off it worked.

3 natiuretic peptide receptors:


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A most important guanylate cyclase (GC) receptor a transmembrane receptor

on microvascular endothelium of lung and systemic vasculature its second

messenger is cGMP. Densely expressed. Binds ANP and BNP.

B similar to A but only binds the CNP.

C least interesting the clearance receptors degrades rapidly bc of this receptor

system. No biologic role other than mediating the internalization and degredation

of natriuretic peptides.

Clearance method (additional) NEP neprilysis cleaves the ring of anp, cnp and bnp

(but much less of bnp). Such that the degredation of cnp and anp are quicker.

Natriutic peptide exert their effects mostly on a receptor natiuresis, diuresis, renin

inhibition, aldosterone inhibition, vasodilation, increased endothelial permeability

within vasculature but improved vascular blocking in the lung.

Bnp knockout models have increased myocardial fibrosis

Anp knockout models have increased hypertension and volume

Hypoxia is a big trigger for release to bnp.

3 mechanisms of clearancereceptor mediated (C receptor) (nprc natriutic protein receptor C)

degredation by extracellular proteasis neprixylin is one

secretion into bodily fluids.

Pro hormone cleaved to nt-probnp then changed to active bnp form.

Exerts action by binding at kidney heart and endothelium.

STUDIES:Highly specific for differentiating normal from mmvd or dcm dogs (88-90% sens

spec)

Sensitivity as the bnp number goes up your sensitivity for diagnosis goes down but

your specificity goes up.


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CATS:

Connolly nt probnp could pick up occult heart disease and differentiate chf from

other

Sensitivity and specificity.

Use the spin snout box.Sens and specifity is slightly higher in cats than in dogs.

Values >265 had sens 91 and spec 85 in cats for chf versus other resp disease.

Ntprobnp occult cardiomyopathy if >99pmol/l gave a 100% specificity

Correlated positively to lvot, la to ao and lv hypertrophy.

Ntprobnp has a low sensitivity to predict asymptomatic hcm in the mainecoon cats.

Bnp goes up with hypertension and renal disease.

Hypertensive kd had the worst bnp values.

Natriutetic peptides are species specific not like troponin.

Sample handling

Turn around time

Magnitude of elevation varies with type of disesase

Critical illness, renal disease, pulmonary disease all affect values.

No effect with age, body condition score, reproductive status (bnp is affected byobesity in people but not dogs/cats). Pericardial effusion has significantly lower

probnp values.

Temporal variation happens with bnp sampled weekly there is variation some

varied by as much as 200 in nt-probnp measures.

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Bio Markers