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Posts Tagged ‘Troponin T’


Troponin T elevation has 20-fold increased ESRD rate

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Troponin T Predicts End-Stage Renal Disease, Death

NEPHROLOGY 10.23.2015

Salynn Boyles

http://www.medpagetoday.com/Nephrology/ESRD/54258?xid=nl_mpt_DHE_2015-10-24&eun=g337145d0r

The presence of elevated cardiac troponin T in the blood was found to be an early independent predictor of end-stage renal disease and death in both African Americans and whites with hypertension or a family history of high blood pressure, researchers said.

Cardiac troponin T (cTnT) testing is routinely used to diagnose myocardial infarction or assess heart muscle damage in this setting, and several studies suggest that minimally elevated cTnT levels are associated with greater all-cause death risk in older people and in patients with chronic kidney failure.

The newly published study is the first to suggest a role for cTnT as a predictor of end-stage renal disease in patients with hypertension, nephrologistLaTonya Hickson, MD, and colleagues from the Mayo Clinic in Rochester, Minn., wrote in the journal Mayo Clinic Proceedings.

At 10-year follow-up, the estimated cumulative incidence of end-stage renal disease (ESRD) was 27.4% among study participants with abnormal cTnT levels (0.01 ng/mL or higher), compared to 1.3% among participants with lower cTnT levels.

“As patient populations grow older with increasing multimorbidity, identifying those at the highest risk of death or end-stage renal disease could improve patient management strategies,” the researchers wrote.

In an interview with MedPage Today, Hickson noted that cTnT predicted long-term ESRD and death independently of traditional risk factors for cardiovascular disease or end-stage renal disease

Several other recent studies have shown that a highly sensitive assay for cTnT, not yet clinically available in the U.S., can predict death and cardiovascular disease in community-dwelling older people.

For example, an analysis of 4,221 older people participating in the NHLBI’s Cardiovascular Health Study found that elevated levels of cTnT measured with such an assay were associated with a higher risk for cardiovascular death and heart failureindependent of other biomarkers.

Hickson said the idea for examining cTnT as a potential predictor of ESRD stemmed from earlier research by the Mayo team showing an increased risk for death associated with the highest cTnT levels among patients with kidney failure undergoing transplants.

“We now use this marker at Mayo to assess these patients,” she said.

The study included just over 3,000 participants in the National Heart, Lung, and Blood Institute’s GENOA study, originally designed to identify genetic determinants of hypertension in various racial groups.

Just under half (45%) of the participants were white residents of the Rochester, Minn., area and the rest were African American residents of Jackson, Miss. At baseline, a total of 71.3% were hypertensive and 32.5% had evidence of abnormal kidney function (glomerular filtration rate of less than 60 mL/min per 1.73 m2). About half (51.6%) had high sensitivity C-reactive protein levels greater than 3 mg/L.

Just 2.2% (66 of 3,050) had abnormal cTnT levels of 0.01 ng/mL or higher.

In addition to the 20-fold increase seen in risk for ESRD among those with abnormal cTnT, their estimated cumulative incidence of death at 10 years was 47%, compared to 7.3% among those with normal cTnT.

“Abnormal cTnT levels were strongly associated with ESRD and death,” the researchers wrote. “This effect was attenuated but was still highly significant after adjustment for demographic characteristics, estimated glomerular filtration rate, and traditional risk factors for ESRD,” they wrote, with an adjusted hazard ratio of 2.81 (95% CI 1.3-5.9) for ESRD and 3.46 (95% CI 2.3-5.1) for death.

Potential study limitations cited by the researchers included the lack of baseline measurement of urine protein excretion rates in addition to electrocardiogram and echocardiogram studies, “which may have provided insight into the presence of left ventricular hypertrophy, a condition previously associated with abnormal cTnT levels.”

They also noted that limiting the cohort to people with hypertension or belonging to hypertensive families may impact the study’s generalizability.

The researchers concluded that as patient populations grow older and develop more health issues, identifying those with the greatest risk for ESRD will become more important.

“Unfortunately, abnormal cTnT levels, measured with the standard assay, are relatively uncommon and thus do not improve risk prediction enough to support routine use,” they wrote. “Further study is needed to determine whether there is a particular patient group in which cTnT screening would meaningfully improve discrimination between the low- and high-risk patients for these sequelae.”

Funding for this research was provided by the Mayo Foundation, the National Institues of Health, and a Mary Kathryn and Michael B. Panitch Career Development Award.

Co-author Allan S. Jaffe reported receiving consulting fees from “most of the major diagnostic companies.” The other researchers reported no relevant relationships with industry.

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Diagnostic Value of Cardiac Biomarkers


Diagnostic Value of Cardiac Biomarkers

Author and Curator: Larry H Bernstein, MD, FCAP 

These presentations covered several views of the utilization of cardiac markers that have evolved for over 60 years.  The first stage was the introduction of enzymatic assays and isoenzyme measurements to distinguish acute hepatitis and acute myocardial infarction, which included lactate dehydrogenase (LD isoenzymes 1, 2) at a time that late presentation of the patient in the emergency rooms were not uncommon, with the creatine kinase isoenzyme MB declining or disappeared from the circulation.  The world health organization (WHO) standard definition then was the presence of two of three:

1. Typical or atypical precordial pressure in the chest, usually with radiation to the left arm

2. Electrocardiographic changes of Q-wave, not previously seen, definitive; ST- elevation of acute myocardial injury with repolarization;
T-wave inversion.

3. The release into the circulation of myocardial derived enzymes –
creatine kinase – MB (which was adapted to measure infarct size), LD-1,
both of which were replaced with troponins T and I, which are part of the actomyosin contractile apparatus.

The research on infarct size elicited a major research goal for early diagnosis and reduction of infarct size, first with fibrinolysis of a ruptured plaque, and this proceeded into the full development of a rapidly evolving interventional cardiology as well as cardiothoracic surgery, in both cases, aimed at removal of plaque or replacement of vessel.  Surgery became more imperative for multivessel disease, even if only one vessel was severely affected.

So we have clinical history, physical examination, and emerging biomarkers playing a large role for more than half a century.  However, the role of biomarkers broadened.  Patients were treated with antiplatelet agents, and a hypercoagulable state coexisted with myocardial ischemic injury.  This made the management of the patient reliant on long term followup for Warfarin with the international normalized ratio (INR) for a standardized prothrombin time (PT), and reversal of the PT required transfusion with thawed fresh frozen plasma (FFP).  The partial thromboplastin test (PPT) was necessary in hospitalization to monitor the heparin effect.

Thus, we have identified the use of traditional cardiac biomarkers for:

1. Diagnosis
2. Therapeutic monitoring

The story is only the beginning.  Many patients who were atypical in presentation, or had cardiovascular ischemia without plaque rupture were problematic.  This led to a concerted effort to redesign the troponin assays for high sensitivity with the concern that the circulation should normally be free of a leaked structural marker of myocardial damage. But of course, there can be a slow leak or a decreased rate of removal of such protein from the circulation, and the best example of this would be the patient with significant renal insufficiency, as TnT is clear only through the kidney, and TNI is clear both by the kidney and by vascular endothelium.  The introduction of the high sensitivity assay has been met with considerable confusion, and highlights the complexity of diagnosis in heart disease.  Another test that is used for the diagnosis of heart failure is in the class of natriuretic peptides (BNP, pro NT-BNP, and ANP), the last of which has been under development.

While there is an exponential increase in the improvement of cardiac devices and discovery of pharmaceutical targets, the laboratory support for clinical management is not mature.  There are miRNAs that may prove valuable, matrix metalloprotein(s), and potential endothelial and blood cell surface markers, they require

1. codevelopment with new medications
2. standardization across the IVD industry
3. proficiency testing applied to all laboratories that provide testing
4. the measurement  on multitest automated analyzers with high capability in proteomic measurement  (MS, time of flight, MS-MS)

nejmra1216063_f1   Atherosclerotic Plaques Associated with Various Presentations               nejmra1216063_f2     Inflammatory Pathways Predisposing Coronary Arteries to Rupture and Thrombosis.        atherosclerosis progression

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Troponin I in acute decompensated heart failure: insights from the ASCEND-HF study

 

Writer and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN 

Felker GM, Hasselblad V, Tang WH, Hernandez AF, Armstrong PW, et al.
Eur J Heart Fail. 2012 Nov;14(11):1257-64. http://dx.doi.org/10.1093/eurjhf/hfs110 Epub 2012 Jul 4.

AIMS: We examined the prognostic importance of cardiac troponin I (cTnI) in a cohort of patients enrolled in the ASCEND-HF study of nesiritide in acute decompensated heart failure (ADHF). Circulating troponins are a prognostic marker in patients with ADHF. Contemporary assays with greater sensitivity require reassessment of the significance of troponin elevation in HF.

METHODS: Cardiac troponin I was measured in a core laboratory in 808 ADHF patients enrolled in the ASCEND-HF biomarkers substudy using a sensitive assay (VITROS Trop I ES, Ortho Clinical Diagnostics) with a lower limit of detection of 0.012 ng/mL and a 99th percentile upper reference limit (URL) of 0.034 ng/mL. Patients with clinical evidence of acute coronary syndrome or troponin >5× the URL were excluded. Multivariable modelling was used to assess the relationship between log(cTnI) and in-hospital and post-discharge outcomes.

RESULTS:

  • Baseline cTnI was undetectable in 22% and
  • elevated above the 99th percentile URL in 50% of subjects.

cTnI levels did not differ based on HF etiology. After multivariable adjustment, higher cTnI was associated with worsened in-hospital outcomes such as

  • length of stay (P = 0.01) and
  • worsening HF during the index hospitalization (P = 0.01), but
  • was not associated with worsened post-discharge outcomes at 30 or 180 days.

The relationship between cTnI and outcomes was generally linear and

  • there was no evidence of a threshold effect at any particular level of cTnI.

CONCLUSION:

  • cTnI is elevated above the 99th percentile URL in 50% of ADHF patients and
  • predicts in-hospital outcome, but
  • is not an independent predictor of long-term outcomes.

This reviewer finds the results quite interesting, and the study was done with care.   The Ortho Diagnostics method of cTnI is high-sensitivity assay, so that the lowest measureable level at < 10% CV is manyfold lower than the 4th generation assay.

Prior to the hs-cTNI, the diagnostic cutoff for

  • AMI was 1.0 ng/ml vs
  • the cTnT at 0.1 ng/ml using a ROC curve.

AMI did occur below the ROC cutoff in both cases, but the reasons for elevations other than AMI were determined to be CRF, and this was more accurate (a small probability with the cTnT between 0.085 and 0.1 ng/ml.

However, the findings in this study did indeed exclude symptomatic ACS, or cTnI at the level not > 5x ULN.  [0.17 ng/ml] with the hs-TnI.  The hs-cTnI assay opened up the identification of non-ACS elevation related to cardiomyocyte damage unrelated to plaque rupture, but related to a persistent coronary ischemia, possibly related to cardiomegaly and/or vascular rigidity.

Test Limitations

Troponins are not normally present in serum, so any amount present in serum (measured at the 99th percentile of the upper limit of normal at a 10% imprecision) indicates structural damage to the heart, although not necessarily AMI.

  • Both troponin I (TnI) and troponin T (TnT) are affected by renal insufficiency, but TnT is to a greater extent
  •  100% of TnT is excreted in urine, but 70% of TnI is degraded by vascular endothelium; this means that minor elevations of troponins have to be considered in the context of comorbidities, especially renal impairment, and risk factors
  • Among heart failure patients, the objective parameter of NT-proBNP seems more useful to delineate the “cardiorenal syndrome” than the previous criteria of a clinical diagnosis of heart failure

However, the NT-proBNP is best interpreted by using the log(NT-proBNP)/eGFR with an adjustment.

These investigators used the log(cTnI), which I would not have thought of in this case, but it is important to do because the distribution of the peptide levels in the study population would be nonparametric.  The median values at the time points are not given.  Actually, there are presumably, not definitely, two populations – if you were to infer short- and long-term outcomes measured as 30-days, and 180-days.  That a baseline cTNI was undetectable in 22% of patients is actually not so different than would be found in a random selection from patients presenting to the emergency department.  It should not be a surprise that the test as a single predictor, did not meet the requirement for long-term prediction of outcome, despite agreement with the in-hospital outcome.   This is consistent with the absence of ACS.

[1] Troponins (Cardiac-specific Troponin I and Troponin T).  LH Bernstein.  http://PathologyOutlines.com/Chemistry
[
2] Effect of renal function loss on NT-proBNP level variations. LH Bernstein, MY Zions, SA Haq, S Zarich, J Rucinski, B Seamonds, et al.  Clin Biochem 2009; 42(10-11):1091-1098. ICID: 937529  http://dx.doi.org/10.1016/j.clinbiochem.2009.02.027.
[3] Enhancing the diagnostic performance of troponins in the acute care setting. SA Haq, M Tavakol, S Silber, L Bernstein, J Kneifati-Hayek, M Schleffer, et al.  J Emerg Med 2008; x:x  ICID: 937619
http://www.nymethodistemergencymedicine.com/program/research.html   
[4] Comparison of test characteristics of cardiac troponin T in patients with normal renal function and chronic renal failure evaluated in the emergency department. S Silber, L Melniker, E Haines, LH Bernstein.
Academic Emergency Medicine 2006; 13(5):S1186-187.   ICID: 939943     http://www.nymethodistemergencymedicine.com/program/research.html
[5}  The ACC/ESC Recommendation for 99th Percentile of the Reference Normal Troponin I Overestimates the Risk of an Acute Myocardial Infarction: a novel enhancement in the diagnostic performance of troponins. “6th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke.” S Haq, M Tavakol, LH Bernstein, J Kneifati-Hayek, M Schlefer, S Silber, T Sacchi, J Pima. Circulation 2005; 111(20):e313-313. ICID: 939931
http://pt.wkhealth.com/pt/re/circ/toc.00003017-200505240-00000.htm
[6]  Minor elevations in troponin T values enhance risk assessment in emergency department patients with suspected myocardial ischemia: analysis of novel troponin T cut-off values. SW Zarich, K Bradley, ID Mayall, LH Bernstein.
Clin Chim Acta 2004; 343(1-2):223-229.  ICID: 825515     http://www.ncbi.nlm.nih.gov/pubmed/15115700
[7]  GOLDmineR: improving models for classifying patients with chest pain. L Bernstein, K Bradley, SW  Zarich.  Yale J Biol Med  2002; 75(4):183-198.  ICID: 825624
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588788/

Other related articles published on this Open Access Online Scientific Journal, include the following:

High-Sensitivity Cardiac Troponin Assays- Preparing the United States for High-Sensitivity Cardiac Troponin Assays

Reporter: Larry Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/06/13/high-sensitivity-cardiac-troponin-assays/

Dealing with the Use of the High Sensitivity Troponin (hs cTn) Assays

Larry Bernstein and Aviva Lev-Ari
https://pharmaceuticalintelligence.com/2013/05/18/dealing-with-the-use-of-the-hs-ctn-assays/

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA
Aviva Lev-Ari
https://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

  • Redberg’s conclusions are correct for the initial screening. The issue has been whether to do further testing for low or intermediate risk patients.
  • The most intriguing finding that is not at all surprising is that the CCTA added very little in the suspect group with small or moderate risk.
  • The ultra sensitive troponin threw the ROC out the window
  • The improved assay does pick up minor elevations of troponin in the absence of MI.

Critical Care | Abstract | Cardiac ischemia in patients with septic …
Aviva Lev-Ari
https://pharmaceuticalintelligence.com/2013/06/26/critical-care-abstract-cardiac-ischemia-in-patients-with-septic/

  • refer to:  Cardiac ischemia in patients with septic shock randomized to vasopressin or norepinephrine

Mehta S, Granton J,  Gordon AC, Cook DJ, et al.
Critical Care 2013, 17:R117   http://dx.doi.org/10.1186/cc12789
Troponin and CK levels, and rates of ischemic ECG changes were similar in the VP and NE groups. In multivariable analysis

  • only APACHE II was associated with 28-day mortality (OR 1.07, 95% CI 1.01-1.14, p=0.033).

Assessing Cardiovascular Disease with Biomarkers
larryhbern
https://pharmaceuticalintelligence.com/2012/12/25/assessing-cardiovascular-disease-with-biomarkers/

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Troponin activation. Troponin C (red) binds Ca...

Troponin activation. Troponin C (red) binds Ca2+, which stabilizes the activated state, where troponin I (yellow) is no longer bound to actin. Troponin T (blue) anchors the complex on tropomyosin. (Photo credit: Wikipedia)

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