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Posts Tagged ‘atrial natriuretic peptide’


More on the Performance of High Sensitivity Troponin T and with Amino Terminal Pro BNP in Diabetes

Writer and Curator: Larry H. Bernstein, MD, FCAP

 

UPDATED on 8/7/2018

Siemens’ high-sensitivity Troponin I (TnIH) assaysgot FDA clearance for use in diagnosing acute myocardial infarction. (Cardiovascular Business) The first high-sensitivity Troponin T test was cleared last year, as MedPage Today reported.

SOURCE

https://www.medpagetoday.com/cardiology/prevention/74423?xid=nl_mpt_cardiobreak2018-08-06&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Ca

 

This is the final up to date review of the status of hs troponin T (or I) with or without the combined use of the Brain Type Natriuretic Peptide or its Amino Terminal peptide precursor.  In addition, a new identification of the role of the Atrial Natriuretic Peptide has been reported with respect to arrythmogenic activity.  On the one hand, the diagnostic value of the NT-proBNP has been seen as disappointing, in part because of the question of what information is gained by the test in overt known congestive heart failure, and in part because of uncertainty about following the test during a short hospital stay.  At least, this is the view of this reviewer.  However, in the last several years there has been an emphasis on the value this test adds to prediction of adverse outcomes.   In addition, there has been a hidden nvariable that has much to do with the original reference values that were established for age ranges, without any consideration of pathophysiology that might affect the values within those ranges, leading one to consider values in an aging population as normal, that might well be high.  Why is this?  Aging patients are more likely to have hypertension, and also the onset of type-2 diabetes mellitus, with cardiovascular disease consequences.  Type-2 diabetes mellitus (T2DM), for instance, is associated with insulin resistance and also fat gain with generation of adipokines, but the is also a hyalinization of insulin forming beta-cells of the pancreas, and there is hyalinization of glomeruli (glomerulosclerosis) and afferent arteriolonephrosclerosis with expected decline in glomerular filtrattion rate and hypertension as well.   Of course, this is also associated with hepatosteatosis.   Nevertheless, a reference range is established that takes none of this pathophysiology into account.   While a more reasonable approach has been pointed out, there has been no followup in the literature.

On the other hand, there has been much confusion over the restandardization of a high sensitivity troponin I or T test (hs-Tn(I or T).  The reference range declines precipitously, and there is a good identification of patients who are for the most part disease free, but there is no delineation of patients who are at high risk of acute coronary syndrome with plaque rupture, vs a  host of other cardiovascular conditions.  These have no relationship to plaque rupture, but may be serious and require further evaluation.  The question then becomes whether to admit for a hospital stay, to refer to clinic after an evaluation in the ICU without admission, or to do an extensive evaluation in the emergency department overnight before release for followup.  There is still another dimension of this that has to do with prediction of outcomes using hs-Tn(s) with or without the natriuretic peptides.  Another matter that is not for discussion in this article is the underutilization of hs-CRP.  Originally used for a marker of sepsis in the 1970s, it has come to be tied in with identification of an ongoing inflammatory condition.  Therefore, the existence of a known inflammatory condition in the family of autoimmune diseases, with one exception, might make it unnecessary.

The discussion is broken into three parts:

Part 1.   New findings on the troponins.
Part 2.  The use of combined hs-Tn with a natriuretic peptide (NT-proBNP)
Part 3.  Atrial natriuretic peptide

Part 1.    New findings on the troponins.

Troponin: more lessons to learn

C Liebetrau,HM Nef,andCW.Hamm*
KerckhoffHeartandThoraxCenter;DepartmentofCardiology,BadNauheim,
Germany; (GermanCentreforCardiovascularResearch),partnersite
RheinMain,BadNauheim, Germany; and UniversityofGiessen,Medizinische
KlinikI,KardiologieundAngiologie,Giessen,Germany
European Hear tJournal
http://dx.doi.org/10.1093/eurheartj/eht357This editorial refers to ‘Risk stratification in patients with acute chest pain
using three high-sensitivity cardiac troponin assays’,
by P. Haafetal. http://dx.doi.org/10.1093/eurheartj/eht218Cardiac troponin entered our diagnostic armamentarium 20 years ago and –
unlike any other biomarker –

  • is going through constant expansion in its application.

Troponin started out as a marker of risk in unstable angina’, then was used

  • as gold standard for risk stratification and therapy guiding in acute coronary syndrome
  •  served further to redefine myocardial infarction, and
  • has also become a risk factor in apparently healthy subjects.

The recently introduced high-sensitivity cardiac troponin (hs-cTn) assays

  • have not only expanded the potential of troponins, but
  • have also resulted in a certain amount of confusion
    • among unprepared users.

After many years troponins were accepted as the gold standard in

  • patients with chest pain by
  • classifying them into troponin-positive and
    • troponin-negative patients.

The new generation of hs-cTn assays has

  • improved the accuracy at the lower limit of detection and
  • provided incremental diagnostic information especially
    • in the early phase of myocardial infarction.

Moreover, low levels of measurable troponins

  • unrelated to ACS have been associated with
    • an adverse long-term outcome.

Several studies demonstrated that

  • these low levels of cardiac troponin measureable 
    • only by hs-Tn assays
  • are able to predict mortality in patients with ACS
  • as well as patients with assumed
    • stable coronary artery disease.

Furthermore, hs-cTn has the potential

  • to play a role in the care of patients
    • undergoing non-cardiac surgery.

The additional determination of hs-cTn

  • improves risk stratification despite
  • established risk scores providing both diagnosis and
  • for prognosis prediction in chest pain patients.

The daily clinical challenge in using the highly sensitive assays is to 

  • interpret the troponin concentrations, especially
  • in patients with concomitant diseases
    • independently from myocardial ischaemia
  • influencing cardiac troponin concentrations
    (e.g. chronic kidney disease, or stroke). 

The troponin test lost its ‘pregnancy test’ quality with the different users.
Different opinions exist on

  • the change of hs-cTn levels compared to simple ‘positive–negative’ interpretation
  • and thereby makes diagnosis finding more complex than before.

This uncertainty probably has the paradigm that

  • serial measurements of troponins are necessary, and also
    • boosted the number of diagnoses of ACS and
    • invasive diagnostic procedures in some locations.

This is more than understandable, with acute chest pain using

  • three high-sensitivity cardiac troponins with their respective baseline value
    • before the diagnosis of acute myocardial infarction (AMI) can be made.

What is a relevant change in concentrations compatible with acute myocardial necrosis and

  • what is only biological variation for the specific biomarker and assay?

Changes in serial measurements between 20% and 200% have been debated, and
the discussion is ongoing. Furthermore, it has been proposed that

  • absolute changes in cardiac troponin concentrations 
    • have a higher diagnostic accuracy for AMI
  • compared with relative changes, and

it might be helpful in distinguishing AMI from other causes of cardiac troponin elevation.

Do we obtain any helpful directives from experts and guidelines for our daily practice?
Foreseeing this dilemma, the 2011 European Society of Cardiology (ESC) Guidelines

  • on non ST-elevation ACS acted.
  • Minor elevations of  troponins were accepted as hs-cTn values in the ‘grey zone’.

This was and still is the rule, but

  • the ESC provided a general algorithm on how to manage patients with limited data.

The ‘Study Group on Biomarkers in Cardiology’ suggested

  • a rise of 50% from the baseline value at low concentrations.

However, this group of experts could also not find a substitute for the missing data

  • needed to validate the proposed recommendation.

The story is just too complex:

  • different troponin assays with
  • different epitope targets,
  • different patient populations,
  • different sampling protocols,
  • different follow-up lengths, and much more.

Therefore, any study that helps us to see better through the fog is welcome here.

Haaf et al. have now presented the results of their study of

  • different hs-cTn assays
    (hs-cTnT, Roche Diagnostics; hs-cTnI, Beckman-Coulter; and  hs-cTnI, Siemens)

    • with respect to the -outcome of patients with acute chest pain.

The authors examine 1117 consecutive patients presenting with acute chest pain.
[340 patients with ACS (30.5%)] from the Advantageous Predictors of Acute Coronary Syndrome
Evaluation (APACE) study. Blood was collected

  • directly on admission and
  • serially thereafter at 2, 3, and 6h.

Eighty-two patients (7.3%) died during the 2-year follow-up. The main finding of the study is that

  1. hs-cTnT predicts mortality more accurately than the hs-cTnI assays, 
  2. -that a single measurement is sufficient
  3. challenges causes of cardiac troponin elevation.

These results of APACE remain in contrast to recent findings from a GUSTO IV cohortof 1335 patients with ACS (Table1).

Table1 Studies investigating high sensitivity troponins for long-term prognosis

Variable                                                       APACE (n 5 1117)              GUSTO IV (n 5 1335)              PEACE (n 5 3567)

………………………………………………………………………………………………………………………………………………………….

Patient cohort                                                   Unstable                            Unstable                               Stable

Blood sampling                                     On admission,1,2,3,6h                    48h after
study randomization           Before randomization

No. of patients with detection limit             883 (79.1%)                                 UKN                                      UKN

No. of patients with hs-cTnT.
99thpercentile                                        401 (35.9%)                              1015 (76%)                          395 (10.9%)

No. of patients with hs-cTnI (Abbott).
detection limit                                           UKN                                             UKN                              3567 (98.5%)

No.of patients with hs-cTnI (Abbott).
99th percentile                                          UKN                                         988(74%)                           105 (2.9%)

No. of patients with NSTEMI                     170 (15.2%)                              100 (100%)                             0 (0%)

Follow-up                                               24 months                                  12 months                            5.2 years

Non-fatal AMI                                           UKN                                              UKN                               209 (5.9%)

Mortality or primary endpoint                    82 (7.3%)                                 119(8.9%)                           203 (5.7%)

………………………………………………………………………………………………………………………………………………………….

Key findings                                    cTnT better than cTnI                      cTnI ¼cTnT                   cTnI better than cTnT

Single cTn sample sufficient

AMI, acute mycordial infaction; cTn, cardiac tropononin; NSTEMI ,non-ST-elevation myocardial infarction; UKN, unknown

NSTEMI defined in the GUSTO IV trial:
  1. one or more episodes of angina lasting ≥ 5min,
  2. within 24h of admission and
  3. either a positive cardiac TnT or I test
    (above the upper limit of a normal for the local assay; during the years 1999 and 2000)
  4. or ≥ 0.5 mm of transient or persistent ST-segment depression.

the prognostic capacity of four different sensitive cardiac troponin assays were compared

  1. hs-cTnT; Roche Diagnostics,
  2. cTnI and hs-cTnI;
  3. Abbott Diagnostics, and
  4. Acc-cTnI; Beckman-Coulter.

In total, 119 patients (8.9%) died during the 1-year follow-up. Looking at their

  • receiver operating characteristic curve (ROC) analyses,
  • there were only negligible diffferences
    • in the area under the curves between the assays.

Contrasting results have also been reported in patients(n 1/4 3.623)

  • with stable coronary artery disease and preserved systolic left ventricular function

from the PEACE trial (Table1).

During a median follow-up period of 5.2 years,

  • there were 203 (5.6%) cardiovascular deaths or
  • first hospitalization for heart failure.

Concentrations of hs-cTnI (Abbott Diagnostics) at or above

  • the limit of detection of the assay were measured in 3567 patients (98.5%), but
  • concentrations of hs-cTnI at or above the gender-specific 99th percentile
    • were found in only 105 patients (2.9%).

This study revealed that

  • there was a strong and graded association
  • between increasing quartiles of hs-cTnI concentrations and
  • the risk for cardiovascular death or heart failure.

Hs-cTnI provided incremental prognostication information

  • over conventional risk markers and
  • other established cardiovascular biomarkers,
  • including hs-cTnT.

In contrast to the APACE results, only hs-cTnI, but

  • no ths-cTnT, was significantly
  • associated with the risk for AMI.

Is there a real difference between cardiac troponin T and cardiac troponin I

  • in predicting long term prognosis?

The question arises of whether there is a true clinically relevant

  • difference between cTnT and cTnI.

Given the biochemical and analytical differences,the two

  • troponins display rather similar serum profiles during AMI.

While minor biological differences between cTnT and cTnI are

  • apparently not relevant for diagnosis
  • and clinical management in the acute setting of ACS.

This is a provocative theory, but appears premature in our opinion.
Above all, the results of the current study appear

  • too inconsistent to allow such conclusions.

In the present study, hs-cTnT (Roche Diagnostics) outperformed

  • hs-cTnI (Siemens and Beckman-Coulter) in terms of
  • very long term prediction of cardiovascular death and
    • heart failure in stable patients.

We don’t know how hs-cTnI from Abbott Diagnostics

  • performs in the APACE consort.

The number of patients and endpoints provided

  • by the APACE registry are rather low.
  • The results could, therefore, be a chance finding.

It is far too early to favour one high sensitivity assay over the other. The findings need confirmation.

Implications for clinical practice

There is no doubt that high-sensitivity assays

  • are the analytical method of choice
    • in terms of risk stratification in patients with ACS.

What is new?
A single measurement of hs-cTn seems to be adequate

  • for long-term risk stratification in patients without AMI.

However, the question of which troponin might be preferable

  • for long-term risk stratification remains unanswered.

Part 2. ability of high-sensitivity cTnT and NT pro-BNP to predict cardiovascular events and death in patients with T2DM

Hillis GS; Welsh P; Chalmers J; Perkovic V; Chow CK; Li Q; Jun M; Neal B; Zoungas S; Poulter N; Mancia G; Williams B; Sattar N; Woodward M
Diabetes Care.  2014; 37(1):295-303 (ISSN: 1935-5548)

OBJECTIVE

Current methods of risk stratification in patients with

  • type 2 diabetes are suboptimal.

The current study assesses the ability of

  • N-terminal pro-B-type natriuretic peptide (NT-proBNP) and
  • high-sensitivity cardiac troponin T (hs-cTnT)

to improve the prediction of cardiovascular events and death in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A nested case-cohort study was performed in 3,862 patients who participated in the Action in Diabetes and Vascular Disease:

Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.

RESULTS

Seven hundred nine (18%) patients experienced a

  • major cardiovascular event

(composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and

  • 706 (18%) died during a median of 5 years of follow-up.

In Cox regression models, adjusting for all established risk predictors,

  • the hazard ratio for cardiovascular events for NT-proBNP was 1.95 per 1 SD increase (95% CI 1.72, 2.20) and
  • the hazard ratio for hs-cTnT was 1.50 per 1 SD increase (95% CI 1.36, 1.65). The hazard ratios for death were
    • 1.97 (95% CI 1.73, 2.24) and
    • 1.52 (95% CI 1.37, 1.67), respectively.

The addition of either marker improved 5-year risk classification for cardiovascular events
(net reclassification index in continuous model,

  • 39% for NT-proBNP and 46% for hs-cTnT).

Likewise, both markers greatly improved the accuracy with which the 5-year risk of death was predicted.
The combination of both markers provided optimal risk discrimination.

CONCLUSIONS

NT-proBNP and hs-cTnT appear to greatly improve the accuracy with which the

  • risk of cardiovascular events or death can be estimated in patients with type 2 diabetes.

PreMedline Identifier: 24089534


Part 3. M-Atrial Natriuretic Peptide

M-Atrial Natriuretic Peptide and Nitroglycerin in a Canine Model of Experimental Acute Hypertensive Heart Failure:
Differential Actions of 2 cGMP Activating Therapeutics.

Paul M McKie, Alessandro Cataliotti, Tomoko Ichiki, S Jeson Sangaralingham, Horng H Chen, John C Burnett
Journal of the American Heart Association 01/2014; 3(1):e000206. http://dx.doi.org/10.1161/JAHA.113.000206
Source: PubMed

ABSTRACT

Systemic hypertension is a common characteristic in

  • acute heart failure (HF).

This increasingly recognized phenotype

  • is commonly associated with renal dysfunction and
  • there is an unmet need for renal enhancing therapies.

In a canine model of HF and acute vasoconstrictive hypertension

  • we characterized and compared the cardiorenal actions of M-atrial natriuretic peptide (M-ANP),
    a novel particulate guanylyl cyclase (pGC) activator, and
  • nitroglycerin, a soluble guanylyl cyclase (sGC) activator.

HF was induced by rapid RV pacing (180 beats per minute) for 10 days. On day 11, hypertension was induced by continuous angiotensin II
infusion. We characterized the cardiorenal and humoral actions

  • prior to,
  • during, and
  • following intravenous infusions of
  1. M-ANP (n=7),
  2. nitroglycerin (n=7),
  3. and vehicle (n=7) infusion.

Mean arterial pressure (MAP) was reduced by

  1. M-ANP (139±4 to 118±3 mm Hg, P<0.05) and
  2. nitroglycerin (137±3 to 116±4 mm Hg, P<0.05);

similar findings were recorded for

  1. pulmonary wedge pressure (PCWP) with M-ANP (12±2 to 6±2 mm Hg, P<0.05)
  2. and nitroglycerin (12±1 to 6±1 mm Hg, P<0.05).

M-ANP enhanced renal function with significant increases (P<0.05) in

  • glomerular filtration rate (38±4 to 53±5 mL/min),
  • renal blood flow (132±18 to 236±23 mL/min), and
  • natriuresis (11±4 to 689±37 mEq/min) and
  • also inhibited aldosterone activation (32±3 to 23±2 ng/dL, P<0.05), whereas

nitroglycerin had no significant (P>0.05) effects on these renal parameters or aldosterone activation.

Our results advance

the differential cardiorenal actions of

  • pGC (M-ANP) and sGC (nitroglycerin) mediated cGMP activation.

These distinct renal and aldosterone modulating actions make

M-ANP an attractive therapeutic for HF with concomitant hypertension, where

  • renal protection is a key therapeutic goal.
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