Using human genetics to understand the causes and consequences of circulating cardiac troponin I in the general population

AbstractCirculating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes is unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further used two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction and heart failure.We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1283 phecodes and 274 continuous traits in UK Biobank showed associations between a polygenic risk score for cTnI and cardiac arrhythmias, aspartate aminotransferase 1 and anthropometric measures. Excluding individuals with a known history of comorbidities did not materially change associations with cTnI. Using two-sample Mendelian randomization we confirmed the non-causal role of cTnI in acute myocardial infarction (5 948 cases, 355 246 controls). We found some indications for a causal role of cTnI in heart failure (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals).Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for acute myocardial infarction and heart failure development in the general population. Using genetically informed methods for causal inference of cTnI helps inform the role and value of measuring cTnI in the general population.

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A Possible Mechanism behind Faster Clearance and Higher Peak Concentrations of Cardiac Troponin I Compared with Troponin T in Acute Myocardial Infarction

Clinical Chemistry ◽

10.1093/clinchem/hvz003 ◽

2020 ◽

Vol 66 (2) ◽

pp. 333-341 ◽

Cited By ~ 3

Author(s):

Karin Starnberg ◽

Vincent Fridén ◽

Aida Muslimovic ◽

Sven-Erik Ricksten ◽

Susanne Nyström ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Acute Myocardial Infarction ◽

Cardiac Troponin ◽

Cardiac Tissue ◽

Troponin I ◽

Troponin T ◽

Cardiac Troponin I ◽

Human Cardiac Tissue

Abstract Background Although cardiac troponin I (cTnI) and troponin T (cTnT) form a complex in the human myocardium and bind to thin filaments in the sarcomere, cTnI often reaches higher concentrations and returns to normal concentrations faster than cTnT in patients with acute myocardial infarction (MI). Methods We compared the overall clearance of cTnT and cTnI in rats and in patients with heart failure and examined the release of cTnT and cTnI from damaged human cardiac tissue in vitro. Results Ground rat heart tissue was injected into the quadriceps muscle in rats to simulate myocardial damage with a defined onset. cTnT and cTnI peaked at the same time after injection. cTnI returned to baseline concentrations after 54 h, compared with 168 h for cTnT. There was no difference in the rate of clearance of solubilized cTnT or cTnI after intravenous or intramuscular injection. Renal clearance of cTnT and cTnI was similar in 7 heart failure patients. cTnI was degraded and released faster and reached higher concentrations than cTnT when human cardiac tissue was incubated in 37°C plasma. Conclusion Once cTnI and cTnT are released to the circulation, there seems to be no difference in clearance. However, cTnI is degraded and released faster than cTnT from necrotic cardiac tissue. Faster degradation and release may be the main reason why cTnI reaches higher peak concentrations and returns to normal concentrations faster in patients with MI.

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Role of Cardiac Troponin I Level in Predicting in Hospital Outcomes in Patients with ST-segment Elevation Myocardial Infarction in Erbil-Iraq

Diyala Journal of Medicine ◽

10.26505/djm.13013150123 ◽

2017 ◽

Vol 13 (1) ◽

pp. 1-7

Author(s):

Salam Naser Zangana ◽

◽

Abdul kareem A AL-Othman ◽

Namir G AL-Tawil ◽

Keyword(s):

Myocardial Infarction ◽

Cardiac Troponin ◽

Troponin I ◽

Cardiac Troponin I ◽

Hospital Outcomes ◽

St Segment Elevation ◽

Segment Elevation Myocardial Infarction ◽

St Segment

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Faculty Opinions recommendation of One-hour rule-in and rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725420089.793507697 ◽

2015 ◽

Author(s):

Patrick Ray

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Cardiac Troponin ◽

Troponin I ◽

High Sensitivity ◽

Cardiac Troponin I ◽

Rule Out

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Abstract 2425: Absence of Auto-Antibodies against Cardiac Troponin I Predicts Improvement of Left Ventricular Function after Acute Myocardial Infarction

Circulation ◽

10.1161/circ.118.suppl_18.s_724-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Florian Leuschner ◽

Jin Li ◽

Stefan Göser ◽

Lars Reinhardt ◽

Renate Öttl ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Stroke Volume ◽

Antibody Titer ◽

Cardiac Troponin ◽

Troponin I ◽

Cardiac Troponin I ◽

Igg Antibody ◽

Follow Up Study

Application of antibodies against cardiac troponin I (cTnI-Ab) can induce dilation and dysfunction of the heart in mice. Recently, we demonstrated that immunization with cTnI induces inflammation and fibrosis in myocardium of mice. Others have shown that autoanti-bodies to cTnI are present in patients with acute coronary syndrome. But little is known about the clinical relevance of detected cTnI-Ab. First, anti-cTnI and anti-cTnT antibody titers were measured in sera from 272 patients with dilated- (DCM) and 185 with ischemic- (ICM) cardiomyopathy. Secondly, 108 patients with acute myocardial infarction (AMI) were included for a follow-up study. Heart characteristics were determined by magnetic resonance imaging 4 days and 6 –9 months after AMI. Altogether, in 7,0% of patients with DCM and in 9,2% with ICM an anti-cTnI IgG antibody titer ≥1:160 was measured. In contrast, only in 1,7% of patients with DCM and in 0,5% with ICM an anti-cTnT IgG antibody titer ≥1:160 was detected. Ten out of 108 patients included in the follow-up study were tested positive for cTnI-Ab with IgG Ab titers ≥1:160. TnI-Ab negative patients showed a significant increase in LVEF and stroke volume 6 –9 months after AMI. In contrast, there was no significant increase in LVEF and stroke volume in TnI-Ab positive patients. We demonstrate for the first time that the prevalence of cTnI-Abs in patients with AMI has an impact on the improvement of the LVEF over a study period of 6 –9 months.

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Acceptable Analytical Variation May Exceed High-Sensitivity Cardiac Troponin I Cutoffs in Early Rule-Out and Rule-In Acute Myocardial Infarction Algorithms

Clinical Chemistry ◽

10.1373/clinchem.2016.255448 ◽

2016 ◽

Vol 62 (6) ◽

pp. 887-889 ◽

Cited By ~ 36

Author(s):

Peter A Kavsak ◽

Andrew C Don-Wauchope ◽

Stephen A Hill ◽

Andrew Worster

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Cardiac Troponin ◽

Troponin I ◽

High Sensitivity ◽

Cardiac Troponin I ◽

Analytical Variation ◽

Rule Out

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Comparable detection of acute myocardial infarction by creatine kinase MB isoenzyme and cardiac troponin I

Clinical Chemistry ◽

10.1093/clinchem/40.7.1291 ◽

1994 ◽

Vol 40 (7) ◽

pp. 1291-1295 ◽

Cited By ~ 197

Author(s):

J E Adams ◽

K B Schechtman ◽

Y Landt ◽

J H Ladenson ◽

A S Jaffe

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Creatine Kinase ◽

Cardiac Troponin ◽

Troponin I ◽

Characteristic Curve ◽

Cardiac Injury ◽

Cardiac Troponin I ◽

Creatine Kinase Mb ◽

Coronary Care

Abstract Although measurement of cardiac troponin I (cTnI) is, in some situations, more specific for detection of cardiac injury than is measurement of the MB isoenzyme of creatine kinase (MBCK), its sensitivity and specificity relative to MBCK for detection of myocardial infarction has not been established. Accordingly, we studied prospectively 199 consecutive patients admitted to the coronary care unit. Values of MBCK and cTnI mass were determined in all samples. Of the 188 patients admitted with a suspicion of acute myocardial ischemia, 89 were diagnosed as having an acute myocardial infarction on the basis of the patterns of MBCK values. Eighty-six of these patients also had increased cTnI (concordance, 96.6%); three did not. Of the patients diagnosed as without infarction, five with unstable angina and symptoms in the day(s) prior to admission had increased cTnI, for a cTnI specificity of 94.9%. Receiver operating characteristic curve analysis indicated that cTnI and MBCK had statistically indistinguishable diagnostic accuracies for the detection of acute myocardial infarction.

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