(Circulation. 1997;96:2953-2958.)
© 1997 American Heart Association, Inc.
Articles |
Circulating Cardiac Troponin I in Severe Congestive Heart Failure
From the Department of Cardiology and INSERM U-390, University Hospital of Montpellier (E.M.); Sanofi Recherche (C.C.); and the Faculty of Pharmacy, CNRS UMR-9921 (B.P.), Montpellier, France.
Correspondence to Emile Missov, MD, INSERM U-390, Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier Cedex 05, France. E-mail missov{at}u390.montp.inserm.fr
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Abstract |
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Background Spontaneous progression of severe congestive heart failure is structurally characterized by cellular degeneration and multiple foci of myocardial cell death. The cardiac muscle isoform of troponin I is uniquely expressed in the adult human myocardium, and an increase in its circulating levels is highly indicative of myocardial injury. Accordingly, we addressed the usefulness of cardiac troponin I as a sensitive and specific molecular marker of congestive heart failure in patients with severely reduced left ventricular performance.
Methods and Results A new generation single-step immunoenzymoluminometric assay with high analytical sensitivity was used to assess cardiac troponin I in patients with severe congestive heart failure, healthy blood donors, and hospitalized control subjects without known cardiac disease. The cardiac troponin I concentration (mean±SEM) was 72.1±15.8 pg/mL in heart failure patients and 20.4±3.2 and 36.5±5.5 pg/mL in healthy and hospitalized control subjects, respectively (P<.01 versus heart failure patients). When both control groups were considered, the mean cardiac troponin I level was 25.4±2.9 pg/mL (P<.01 versus heart failure patients). Creatine kinase MB mass and myoglobin concentrations remained within the normal range in all groups.
Conclusions These data (1) provide the first evidence for ongoing myofibrillar degradation and increased cardiac troponin I levels in patients with advanced heart failure and (2) show potential usefulness of cardiac troponin I as a specific and sensitive new serum marker molecule in severe congestive heart failure.
Key Words: cardiac troponin I • heart failure
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Introduction |
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Congestive heart failure is a dynamic process with changing rate of progression and risk profile with time that adversely affects quality of life and markedly shortens survival. One-year mortality rates range from 40% to
50% in patients with NYHA functional class III and IV
symptoms.1 2 A prominent feature of the syndrome is the
dissociation between signs of congestion and exercise intolerance and
the structural and functional changes in the myocardium.
Heart failure relates to complex long-term neurohormonal alterations
and to abnormal myocardial structure.3 4 The transition of
asymptomatic cardiac dysfunction to symptomatic
heart failure is associated with extensive remodeling of the muscular,
collagenous, and vascular compartments of the myocardium.
Morphological changes that are typical of advanced heart failure
include noncontiguous areas of myocardial cell death and foci of
replacement fibrosis.5 6 Irreversible progression of
congestive heart failure is known to occur, but the underlying
mechanisms remain unclear, possibly because of inadequate sensitivity
of the measures used.
The troponin proteins are found in cardiac and skeletal muscle tissue
as products of separate genes. They are located in the myofibril,
where they regulate the interaction of actin monomers with the myosin
heavy chain. The cAMP-dependent phosphorylation of
troponin I at two adjacent serine residues in the amino-terminal of the
molecule causes a decrease in the affinity of calcium for the
calcium-binding troponin C and inhibition of actin-myosin
interactions.7 Troponin I exists in three isoforms: slow
skeletal, fast skeletal, and cardiac muscle–specific
isoforms.8 The cardiac muscle isoform of troponin I is a
24-kD protein uniquely expressed in the adult human heart. It differs
from the slow-twitch and fast-twitch skeletal muscle isoforms in that
(1) it possesses 31 additional amino-terminal residues and (2) the
remaining amino acid sequence shows 
40% dissimilarity from both the
slow and fast skeletal muscle isoforms. Importantly, the skeletal
muscle does not express cardiac troponin I throughout ontogeny, during
regenerative muscle disease, or in response to pathological stimuli,
which confers to the cardiac isoform absolute specificity for the
myocardium.9 10 11
We have recently developed a new-generation, highly sensitive immunoenzymoluminometric assay for quantitative determination of the cardiac muscle isoform of troponin I in human serum. The assay operates at the picomolar concentration range and allows for the measurement of extremely low concentrations of cardiac troponin I. The lower limit of detection is 3 pg/mL. We were particularly interested in a fundamental hypothesis; specifically, whether the use of an immunoassay with high analytical performance could provide evidence for cardiac troponin I release in congestive heart failure due to systolic dysfunction of the left ventricle, reflected in a severely compromised left ventricular ejection fraction. This hypothesis is consistent with a basic biological phenomenon in the failing human myocardium, namely, myofibrilolysis, and relates to the pathophysiology of congestive heart failure.
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Methods |
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Patients
This study was performed with the approval of the institutional review board, and 115 subjects gave informed consent. Thirty-five consecutive NYHA functional class III and IV patients had clinically stable severe congestive heart failure with dyspnea and fatigue at rest or modest exertion. The median duration of symptoms exceeded 6 months in all of them. Conventional therapy for congestive heart failure consisted of digoxin, diuretics, and ACE inhibitors, with long-acting oral nitrate preparations as additional vasodilator therapy and amiodarone to control ventricular rate or ectopic activity in some patients. None had suffered acute myocardial infarction or unstable angina, and none had undergone cardiac or noncardiac surgery within 30 days of inclusion. Patients with severe pulmonary disease, acute or chronic renal and liver disease, uncontrolled hypertension, or inflammatory illness were not eligible. Fifty-five healthy blood donors (28 men; mean age, 47 years) were included as control population. An additional cohort of 25 untreated patients (12 men; mean age, 52 years) had malignancies of the blood-forming tissues (leukemias and lymphomas) and no clinical, ECG, or echocardiographic evidence for cardiac disease. They were included as hospitalized control subjects.
Left ventricular ejection fraction was obtained from ECG-gated equilibrium blood pool radionuclide angiography in the best septal view in both hospitalized control subjects and heart failure patients. Venous blood for determination of cardiac troponin I, CK-MB fraction, and myoglobin was collected on dry tubes from an antecubital vein, allowed to clot for 30 minutes at room temperature, and centrifuged for 10 minutes at 4°C (3500 rpm). Sera were stored in aliquots at -80°C for subsequent analysis and were frozen and thawed only once. All biochemical markers remain stable if handled as described.
Cardiac Troponin I Immunoassay
The analytical performance of an immunoassay is usually
expressed in terms of sensitivity, specificity, precision, and
accuracy.
Sensitivity and specificity. Sensitivity is defined as the lowest value that can be statistically distinguished from zero concentration. In this preliminary research application, cardiac troponin I was quantitatively determined with a newly developed, highly sensitive immunoenzymoluminometric assay, which operates at the picomolar concentration range. The lower limit of detection of the assay is 3 pg/mL. This sensitivity is obtained by use of a luminescent substrate and modification of a previously described and extensively validated enzyme immunoassay based on two different monoclonal antibodies (MAbs).12 The 8E1 and 11E12 MAbs had been selected from a library of monoclonal antibodies obtained by lymphocyte hybridization technique and paired on the basis of their high specificity and affinity for the human cardiac troponin I isoform.13 They recognize independent epitopes of the protein. The first epitope is mapped in the unique sequence of 31 additional amino acid residues at the amino-terminal of the molecule not found in the skeletal muscle isoforms of troponin I and is recognized by the 11E12 MAb. The second epitope is located in the carboxy-terminal half of the protein and is recognized by the 8E1 MAb.13 14 The specificity of these monoclonal antibodies for the human cardiac isoform of troponin I is extremely high, and there is no detectable cross-reactivity (<0.01%) with the skeletal muscle isoforms of troponin I, even for concentrations >200 ng/mL.
Precision and accuracy. Precision refers to the magnitude of random errors and the reproducibility of measurements. Intra-assay and interassay precision testing resulted in coefficients of variation of 11% for within-run reproducibility and of 15% for run-to-run reproducibility. These coefficients describe the variability of data points with the SD as a percent of the average value. Accuracy refers to the extent to which all measurements agree with a true concentration value. Accuracy was assessed by a standard dilution test with satisfactory results, and the spiking test showed a recovery close to 100%, which is particularly important in measurement of serum or plasma samples because of their heterogeneity.
Principle of the immunoassay. Briefly, the solid phase of the assay is a polystyrene tube coated with the 8E1 anti–cardiac troponin I MAb. Revelation is performed with the peroxidase-labeled MAb 11E12. The samples and standards and the labeled tracer antibody are incubated in the coated tubes at room temperature. After washes, the enzymatic activity is revealed by addition of a luminescent substrate. The generated signal is directly proportional to the concentration of cardiac troponin I available in the sample. All samples were run in quadruplicate, and the average value is reported.
Cardiac Troponin I Standard Assay, CK-MB Isoenzyme, and
Myoglobin Assays
In addition to the new-generation, highly sensitive immunoassay,
cardiac troponin I concentration was also assessed by an established
assay (upper reference limit, 0.1 ng/mL)
simultaneously with CK-MB isoenzyme mass (upper reference
limit, 6 ng/mL) and myoglobin concentrations (upper reference
limit, 90 ng/mL) on an Access immunoassay system
analyzer (all from Diagnostics Pasteur). Results
from highly hemolyzed and severely lipemic samples were not used for
statistical purposes. All measurements were performed blindly without
knowledge of patients' history or clinical data.
Statistical Analysis
All statistics were performed with the SAS version 6.08
statistical package (SAS Institute Inc). Data are expressed as
mean±SEM. The 95% CIs of the mean and the median (25th, 75th
percentile) values are also provided. Nonparametric
Kruskall-Wallis ANOVA was used to test between-group differences. Post
hoc comparisons were performed by the Mann-Whitney U test
and adjusted for multiple tests. The null hypothesis was rejected for
values of P<.01.
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Results |
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Severe congestive heart failure was the final clinical pathway in patients with ischemic and idiopathic dilated cardiomyopathies. Their radionuclide left ventricular ejection fraction was abruptly and similarly decreased regardless of the underlying cause and, not surprisingly, tended to be somewhat higher in patients with class III symptoms. The characteristics of congestive heart failure patients are detailed in Table 1
. Left ventricular
ejection fraction was within the normal range in all hospitalized
control patients (0.69±0.01).
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Cardiac Troponin I Levels
The use of a highly sensitive immunoassay permitted the detection
of cardiac troponin I in sera from healthy and hospitalized control
subjects. The mean cardiac troponin I mass concentrations were
20.4±3.2 and 36.5±5.5 pg/mL in the healthy population and in
the hospitalized control subjects, respectively. When both control
groups were considered, the mean cardiac troponin I value was found to
be 25.4±2.9 pg/mL in this cohort of 80 control subjects. In
patients with congestive heart failure, the mean cardiac troponin I
concentration was 72.1±15.8 pg/mL, significantly higher
(P<.01) than in healthy blood donors, hospitalized control
subjects, and the entire control population. These results are detailed
in Table 2. No clear differences were
seen between patients with idiopathic and ischemic
cardiomyopathies or between NYHA class III and
class IV patients in this population sample, despite a moderate
increase of all biochemical markers in patients with idiopathic dilated
cardiomyopathy and in patients with NYHA class IV
symptoms (data not shown).
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When cardiac troponin I levels were assessed with the standard cardiac troponin I assay (upper reference limit, 0.1 ng/mL), in 8 of 35 congestive heart failure patients (23%), the assay failed to provide any evidence for a measurable protein concentration; in 26 patients, the cardiac troponin I values were below the upper reference limit; and in only 1 patient, a clearly positive cardiac troponin I value of 0.206 ng/mL was detected. The mean cardiac troponin I concentrations were virtually identical in heart failure patients and in the control population with this standard assay (0.02±0.01 versus 0.01±0.002 ng/mL).
CK-MB Mass and Myoglobin Levels
CK-MB mass and myoglobin concentrations were in the normal
reference range for each immunoassay in all groups. However, congestive
heart failure patients demonstrated an absolute increase in the CK-MB
and myoglobin levels that paralleled the increase of cardiac
troponin I (Table 2
). Of the 35 congestive heart failure patients, 8
(23%) had CK-MB levels that exceeded the assay upper reference limit
of 6 ng/mL. Importantly, when patients were stratified according
to the CK-MB cutoff, all markers of myocardial injury clearly tended to
be increased in the group of CK-MB–positive heart failure patients
(Table 3).
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Discussion |
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This study is the first written report to provide evidence for substantially increased levels of a myofibrillar protein in patients with advanced heart failure (Figure
, panel A). However, the reported
levels for cardiac troponin I both in the control population and in
heart failure patients are far below the levels presently in use to
diagnose acute myocardial infarction,12 15 16 to document
perioperative myocardial injury,17 or to
detect myocardial injury in critically ill patients.18
They are sensitively detected only because of the high analytical
performance of the immunoassay and are expressed in units of
picograms per milliliter. Otherwise, cardiac troponin I levels remain
undetectable or far below the upper reference limit of 0.1 ng/mL
when sera are assessed with a conventional cardiac troponin I assay.
Importantly, the increase in the absolute CK-MB and myoglobin
concentrations reported in heart failure patients in the present
study is subtle compared with the multiples of upper reference limit
increase usually seen in patients with acute myocardial injury (Table 2).
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Cardiac Troponin I in Blood Donors and Hospitalized Control
Subjects
Studies of protein metabolism are important because of
the continuous turnover of cardiac proteins and the central role of
protein synthesis and degradation in physiological
and pathological conditions. The intracardiac proteolytic events that
commit a structurally bound protein to complete hydrolysis to free
amino acids have not been unambiguously delineated in the normal
myocyte. However, protein breakdown seems to be dependent on two basic
mechanisms. One is lysosomal and involves proteolytic enzymes. The
second is cytosolic and requires ATP and conjugation of proteins to
ubiquitin.19 20 A third and unsuspected possibility is
suggested by the reported cardiac troponin I values in the healthy
blood donor control population. These values imply leakage of
intracellular compounds from terminally differentiated
cardiomyocytes and might suggest programmed cell death at
some constitutive level, with regeneration of myocytes in the normal
myocardium. The hypothesis is consistent with an
extracardiac physiological turnover process for the
protein, a similar pathway being described for low-molecular-weight
proteins, including myoglobin.21 However, it is difficult
to provide a definite interpretation of these data. An alternative
explanation would suggest that the values of cardiac troponin I in the
control population reflect minor analytical fluctuation of the results
and an unspecific seric effect in the very low range of detection due
to the high sensitivity of the immunoassay. Improving the operating
characteristics of the assay most likely will result in a very low
background and in an increased signal-to-noise ratio, further reducing
the fluctuation of the generated signal in the low end of the standard
curve. These are exciting hypotheses, and future work will be aimed at
arbitrating between them.
The levels of cardiac troponin I in hospitalized control patients
appeared to be slightly increased compared with the healthy blood donor
control population (Table 2). Hospitalized control subjects have the
characteristic features of hematologic malignancies, including severe
anemia and hypoxemia, hypotension and tachycardia, and
increased cardiac output. The myocardium of these patients
is therefore exposed to a large spectrum of stresses that is likely to
induce some level of subtle cardiac injury by chronically decreasing
myocardial oxygen supply and/or increasing myocardial oxygen
consumption. These patients are also at an age when
atherosclerosis is likely to be present, and some
of them may have had some degree of unsuspected intrinsic
coronary artery disease. The cardiac troponin I level for the
entire cohort of control subjects provides an estimate of what a
reference mean cardiac troponin I value could be in a large and
unselected control population with the use of this new, highly
sensitive assay. Once again, it should be emphasized that this value is
close to the low end of the standard curve and does not necessarily
represent a definite reference value. Improved analytical
performance of the immunoassay and a larger control population
will most likely further refine this value.
Cardiac Troponin I in Heart Failure Patients
None of the heart failure patients included in the present
study had evidence of acute myocardial infarction or injury. The serum
concentrations of CK-MB mass and myoglobin were not significantly
increased above the upper reference limits for both assays in any
patients. Importantly, the reported clearly positive cardiac troponin I
levels, detected by a highly sensitive assay, are far below the 0.1
ng/mL cutoff limit presently in use to diagnose acute
myocardial injury with a standard cardiac troponin I
assay.12 17 However, we have previously shown that
increased cardiac troponin I levels can be sporadically measured in
some severe congestive heart failure patients even with such an
assay,22 and in the present study, we also detected a
patient with a clearly positive cardiac troponin I value. Taken
together, these data provide strong evidence that the level of the
marker protein measured in any sample depends on the sensitivity and
specificity of the assay used to detect it.
Severe congestive heart failure is associated with noncontiguous areas of myocardial cell death, structural abnormalities in viable myocytes, and progressive interstitial fibrosis, which lead to worsening heart failure through cardiac remodeling.5 6 23 We theorize that the levels of cardiac troponin I in heart failure patients reflect cellular injury and ongoing degradative processes of the contractile apparatus. These levels are most likely part of the remodeling of the myocardium, and they sensitively monitor the cell death that accompanies the spontaneous progression of heart failure. The progressive impairment of cardiac structure and function occurs through a number of putative processes that include neurohormonal factors, oxidative stress, and a number of cytokines. Each of these factors can promote cardiac cell death by producing either myocyte necrosis5 23 24 or myocyte apoptosis through activation of specific genetic pathways.25 26 Both processes may be more common forms of myocardial cell death than initially believed, because focal and diffuse loss of contractile units constitutes the major structural characteristic of advanced heart failure and conditions the progression of the disease.
The presence of myofibrillar proteins in sera from congestive heart
failure patients suggests that these myofibrils are degraded within the
myocardium before their protein content is subsequently
released into the circulation. Myocyte injury results in damage to
contractile proteins and is a key mechanism responsible for the release
of the structurally bound cardiac troponin I.24
Experimental data further support this hypothesis and provide a
plausible explanation for impaired
contractility.27 Extensive and
functionally significant breakdown and release of cardiac troponin I,
tropomyosin, 
-actinin, and myosin light chain 1 have also been
demonstrated in tissue and effluent samples in a rat cardiac model of
ischemia-reperfusion injury.28 These data
strengthen our fundamental hypothesis of myofibril degradation and
strongly support the finding of increased cardiac troponin I
circulating levels in patients with a chronically injured
myocardium. Another potential mechanism for release of
cardiac troponin I might be dependent on leakage of a cytosolic pool of
functionally unbound protein, because the membranes of injured myocytes
lose their properties of semipermeability and allow exposure of the
intracellular milieu to the extracellular environment. However, such a
possibility has not been definitively proved for cardiac troponin
I,16 29 and the cytosolic pool, if any, of the protein can
be estimated at <2%.
A different sequence of events in cardiac protein degradation is likely to occur in the normal and in the failing human myocardium. Changes in the cardiac protein composition occur under pathophysiological conditions and are accompanied by modifications in protein synthesis and breakdown.30 These processes are controlled by substrate and energy availability and by mechanical factors.19 Increased proteolytic rate has been documented in animal models of heart failure.31 In the failing human myocardium, the degradation of cardiac troponin I might promote a compensatory upregulation of the synthesis rate in the cytosol and speed up the turnover of the protein. As a consequence, a constitutive increase of the myocardial cardiac troponin I content is likely to occur. Eventually, the deficient regulation of synthesis and breakdown of different myocardial proteins, including cardiac troponin I, could provide a mechanistic explanation for the deficient contraction in the chronically injured myocardium.
CK-MB and Myoglobin in Heart Failure Patients
CK-MB and myoglobin lack the absolute specificity of cardiac
troponin I for the myocardium. Both are cytosolic enzymes
that are not intrinsically linked to the myofibril. They appear only
transiently in plasma after injury, and an increase in their
concentration could result from membrane damage or even from cytosolic
leakage only. Neither CK-MB mass nor myoglobin reflects the low-level
but chronic structural degradation of the contractile
apparatus involved in the remodeling process that
ultimately produces a mechanically inefficient heart. Regardless of
these considerations, the absolute increases in both CK-MB mass and
myoglobin mean concentrations (Figure, panels B and C) strongly support
the finding of high cardiac troponin I in patients diagnosed with
severe congestive heart failure.
Clinical Implications
The cardiac troponin I levels in heart failure patients raise
several important hypotheses: specifically, whether serial cardiac
troponin I measurements could be beneficial for managing congestive
heart failure and preventing progression of disease. Optimal treatment
might seek to normalize cardiac troponin I levels in patients with
increased baseline values, and future studies will be necessary to
determine whether normalization is associated with better compensation
of heart failure and/or a better prognosis. Cardiac troponin I could be
used to assess the effects of different treatment approaches, including
inotropic drug support, and monitor their therapeutic effectiveness. If
this hypothesis gains support, it would provide a clearer rationale for
early or even prophylactic strategies. This novel approach
is likely to be more sensitive, convenient, and cost-effective in
providing a cardiac-specific tool for refinement of the clinical
assessment of risk and follow-up of patients diagnosed with severe
congestive heart failure. Studies also have to be focused on cardiac
troponin I levels in a population of patients with mild to moderate
symptomatic heart failure. They might add substantial
novelty to our understanding of the remodeling process at the cellular
and subcellular levels and the timing and rate of progression of
chronic congestive heart failure.
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Acknowledgments |
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We are grateful to Dr Allan Jaffe for critical review of the manuscript and many helpful suggestions and to Dr Véronique Bourgeois and Dr Marie-Christine Picot for statistical advice.
Received April 23, 1997; revision received June 9, 1997; accepted June 19, 1997.
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L. W. Stevenson, T. H. Le Jemtel, E. U. Alt, L. W. Stevenson, T. H. Le Jemtel, and E. U. Alt Hemodynamic Goals Are Relevant Circulation, February 21, 2006; 113(7): 1020 - 1033. [Full Text] [PDF]
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D. L. Mann and M. R. Bristow Mechanisms and Models in Heart Failure: The Biomechanical Model and Beyond Circulation, May 31, 2005; 111(21): 2837 - 2849. [Full Text] [PDF]
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 J. J. Kottwitz, D. E. Preziosi, M. A. Miller, J. A. Ramos-Vara, D. J. Maggs, and J. D. Bonagura Heart Failure Caused by Toxoplasmosis in a Fennec Fox (Fennecus zerda) J. Am. Anim. Hosp. Assoc., November 1, 2004; 40(6): 501 - 507. [Abstract] [Full Text] [PDF]
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E. R. Perna, S. M. Macin, J. P. C. Canella, N. Augier, J. L. R. Stival, J. R. Cialzeta, A. E. Pitzus, E. H. Garcia, R. Obregon, M. Brizuela, et al. Ongoing Myocardial Injury in Stable Severe Heart Failure: Value of Cardiac Troponin T Monitoring for High-Risk Patient Identification Circulation, October 19, 2004; 110(16): 2376 - 2382. [Abstract] [Full Text] [PDF]
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 Y Sato, T Kita, Y Takatsu, and T Kimura Biochemical markers of myocyte injury in heart failure Heart, October 1, 2004; 90(10): 1110 - 1113. [Abstract] [Full Text] [PDF]
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 C. Roongsritong, I. Warraich, and C. Bradley Common Causes of Troponin Elevations in the Absence of Acute Myocardial Infarction: Incidence and Clinical Significance Chest, May 1, 2004; 125(5): 1877 - 1884. [Abstract] [Full Text] [PDF]
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S. A. Jortani, S. D. Prabhu, and R. Valdes Jr Strategies for Developing Biomarkers of Heart Failure Clin. Chem., February 1, 2004; 50(2): 265 - 278. [Abstract] [Full Text] [PDF]
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D. Ritter, P. A. Lee, J. F. Taylor, L. Hsu, J. D. Cohen, H. D. Chung, and K. S. Virgo Troponin I in Patients without Chest Pain Clin. Chem., January 1, 2004; 50(1): 112 - 119. [Abstract] [Full Text] [PDF]
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 M. Imazio, B. Demichelis, E. Cecchi, R. Belli, A. Ghisio, M. Bobbio, and R. Trinchero Cardiac troponin i in acute pericarditis J. Am. Coll. Cardiol., December 17, 2003; 42(12): 2144 - 2148. [Abstract] [Full Text] [PDF]
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J. Ishii, W. Cui, F. Kitagawa, T. Kuno, Y. Nakamura, H. Naruse, Y. Mori, T. Ishikawa, Y. Nagamura, T. Kondo, et al. Prognostic Value of Combination of Cardiac Troponin T and B-Type Natriuretic Peptide after Initiation of Treatment in Patients with Chronic Heart Failure Clin. Chem., December 1, 2003; 49(12): 2020 - 2026. [Abstract] [Full Text] [PDF]
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T Goto, H Takase, T Toriyama, T Sugiura, K Sato, R Ueda, and Y Dohi Circulating concentrations of cardiac proteins indicate the severity of congestive heart failure Heart, November 1, 2003; 89(11): 1303 - 1307. [Abstract] [Full Text] [PDF]
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T. B. Horwich, J. Patel, W. R. MacLellan, and G. C. Fonarow Cardiac Troponin I Is Associated With Impaired Hemodynamics, Progressive Left Ventricular Dysfunction, and Increased Mortality Rates in Advanced Heart Failure Circulation, August 19, 2003; 108(7): 833 - 838. [Abstract] [Full Text] [PDF]
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C. P. Cannon and A. G.G. Turpie Unstable Angina and Non-ST-Elevation Myocardial Infarction: Initial Antithrombotic Therapy and Early Invasive Strategy Circulation, June 3, 2003; 107(21): 2640 - 2645. [Full Text] [PDF]
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R. Labugger, J. A. Simpson, M. Quick, H. A. Brown, C. E. Collier, I. Neverova, and J. E. Van Eyk Strategy for Analysis of Cardiac Troponins in Biological Samples with a Combination of Affinity Chromatography and Mass Spectrometry Clin. Chem., June 1, 2003; 49(6): 873 - 879. [Abstract] [Full Text] [PDF]
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C. M. O'Connor, W. A. Gattis, K. F. Adams Jr, V. Hasselblad, B. Chandler, A. Frey, I. Kobrin, M. Rainisio, M. R. Shah, J. Teerlink, et al. Tezosentan in patients with acuteheart failure and acute coronary syndromes: Results of the randomized intravenous tezosentan study (ritz-4) J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1452 - 1457. [Abstract] [Full Text] [PDF]
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J. Kamblock, L. Payot, B. Iung, P. Costes, T. Gillet, C. Le Goanvic, P. Lionet, B. Pagis, J. Pasche, C. Roy, et al. Does rheumatic myocarditis really exists? Systematic study with echocardiography and cardiac troponin I blood levels Eur. Heart J., May 1, 2003; 24(9): 855 - 862. [Abstract] [Full Text] [PDF]
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M. E. Bertrand, M. L. Simoons, K. A.A. Fox, L. C. Wallentin, C. W. Hamm, E. McFadden, P. J. De Feyter, G. Specchia, and W. Ruzyllo Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation Eur. Heart J., December 1, 2002; 23(23): 1809 - 1840. [Full Text] [PDF]
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D. A. Colantonio, W. Pickett, R. J. Brison, C. E. Collier, and J. E. Van Eyk Detection of Cardiac Troponin I Early after Onset of Chest Pain in Six Patients Clin. Chem., April 1, 2002; 48(4): 668 - 671. [Full Text] [PDF]
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 I Weinberg, T Cukierman, and T Chajek-Shaul Troponin T elevation in lobar lung disease Postgrad. Med. J., April 1, 2002; 78(918): 244 - 245. [Abstract] [Full Text] [PDF]
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C-K Wong and H D White Recognising "painless" heart attacks Heart, January 1, 2002; 87(1): 3 - 5. [Full Text] [PDF]
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 N.J. Alp, J.A. Bell, and M. Shahi A rapid troponin-I-based protocol for assessing acute chest pain QJM, December 1, 2001; 94(12): 687 - 694. [Abstract] [Full Text] [PDF]
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A. S. Jaffe Testing the wrong hypothesis: the failure to recognize the limitations of troponin assays J. Am. Coll. Cardiol., October 1, 2001; 38(4): 999 - 1001. [Full Text] [PDF]
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 N. Guler, M. Bilge, B. Eryonucu, K. Uzun, M. E. Avci, and H. Dulger Cardiac Troponin I Levels in Patients with Left Heart Failure and Cor Pulmonale Angiology, May 1, 2001; 52(5): 317 - 322. [Abstract] [PDF]
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E. M. Hoogerwaard, Y. Schouten, A. J. van der Kooi, J. P.M.C. Gorgels, M. de Visser, and G. T.B. Sanders Troponin T and Troponin I in Carriers of Duchenne and Becker Muscular Dystrophy with Cardiac Involvement Clin. Chem., May 1, 2001; 47(5): 962 - 963. [Full Text] [PDF]
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T. Meyer, L. Binder, N. Hruska, H. Luthe, and A. B. Buchwald Cardiac troponin I elevation in acute pulmonary embolism is associated with right ventricular dysfunction J. Am. Coll. Cardiol., November 1, 2000; 36(5): 1632 - 1636. [Abstract] [Full Text] [PDF]
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A. S. Jaffe, J. Ravkilde, R. Roberts, U. Naslund, F. S. Apple, M. Galvani, and H. Katus It's Time for a Change to a Troponin Standard Circulation, September 12, 2000; 102(11): 1216 - 1220. [Full Text] [PDF]
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C. W. Hamm and E. Braunwald A Classification of Unstable Angina Revisited Circulation, July 4, 2000; 102(1): 118 - 122. [Abstract] [Full Text] [PDF]
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K. M. ver Elst, H. D. Spapen, D. N. Nguyen, C. Garbar, L. P. Huyghens, and F. K. Gorus Cardiac Troponins I and T Are Biological Markers of Left Ventricular Dysfunction in Septic Shock Clin. Chem., May 1, 2000; 46(5): 650 - 657. [Abstract] [Full Text] [PDF]
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S J MAYNARD, I B A MENOWN, and A A J ADGEY Troponin T or troponin I as cardiac markers in ischaemic heart disease Heart, April 1, 2000; 83(4): 371 - 373. [Full Text]
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 J. Schaper, A. Elsasser, and S. Kostin The Role of Cell Death in Heart Failure Circ. Res., October 29, 1999; 85(9): 867 - 869. [Full Text] [PDF]
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D. L. Mann Mechanisms and Models in Heart Failure : A Combinatorial Approach Circulation, August 31, 1999; 100(9): 999 - 1008. [Full Text] [PDF]
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 C. Lowbeer, A. Ottosson-Seeberger, S. A. Gustafsson, R. Norrman, J. Hulting, and A. Gutierrez Increased cardiac troponin T and endothelin-1 concentrations in dialysis patients may indicate heart disease Nephrol. Dial. Transplant., August 1, 1999; 14(8): 1948 - 1955. [Abstract] [Full Text] [PDF]
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A. H.B. Wu, F. S. Apple, W. B. Gibler, R. L. Jesse, M. M. Warshaw, and R. Valdes Jr. National Academy of Clinical Biochemistry Standards of Laboratory Practice: Recommendations for the Use of Cardiac Markers in Coronary Artery Diseases Clin. Chem., July 1, 1999; 45(7): 1104 - 1121. [Abstract] [Full Text] [PDF]
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X. Huang, Y. Pi, K. J. Lee, A. S. Henkel, R. G. Gregg, P. A. Powers, and J. W. Walker Cardiac Troponin I Gene Knockout : A Mouse Model of Myocardial Troponin I Deficiency Circ. Res., January 22, 1999; 84(1): 1 - 8. [Abstract] [Full Text] [PDF]
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