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Cardiac myosin-binding protein C: a potential early biomarker of myocardial injury.

Baker JO, Tyther R, Liebetrau C, Clark J, Howarth R, Patterson T, Möllmann H, Nef H, Sicard P, Kailey B, Devaraj R, Redwood SR, Kunst G, Weber E, Marber MS - Basic Res. Cardiol. (2015)

Bottom Line: Using novel antibodies raised against the cardiac-specific N-terminus of cMyC, we used confocal microscopy, immunoblotting and immunoassay to document its location and release.Compared to cTnT measured using a contemporary high-sensitivity commercial assay, cMyC peaks earlier (STEMI, 9.3 ± 3.1 vs 11.8 ± 3.4 h, P < 0.007; TASH, 9.7 ± 1.4 vs 21.6 ± 1.4 h, P < 0.0001), accumulates more rapidly (during first 4 h after TASH, 25.8 ± 1.9 vs 4.0 ± 0.4 ng/L/min, P < 0.0001) and disappears more rapidly (post-CABG, decay half-time 5.5 ± 0.8 vs 22 ± 5 h, P < 0.0001).Our results demonstrate that following defined myocardial injury, the rise and fall in the serum of cMyC is more rapid than that of cTnT.

View Article: PubMed Central - PubMed

Affiliation: King's College London BHF Centre, The Rayne Institute, St Thomas' Hospital, 4th Floor Lambeth Wing, Westminster Bridge Road, London, SE1 7EH, UK.

ABSTRACT
Cardiac troponins are released and cleared slowly after myocardial injury, complicating the diagnosis of early, and recurrent, acute myocardial infarction. Cardiac myosin-binding protein C (cMyC) is a similarly cardiac-restricted protein that may have different release/clearance kinetics. Using novel antibodies raised against the cardiac-specific N-terminus of cMyC, we used confocal microscopy, immunoblotting and immunoassay to document its location and release. In rodents, we demonstrate rapid release of cMyC using in vitro and in vivo models of acute myocardial infarction. In patients, with ST elevation myocardial infarction (STEMI, n = 20), undergoing therapeutic ablation of septal hypertrophy (TASH, n = 20) or having coronary artery bypass surgery (CABG, n = 20), serum was collected prospectively and frequently. cMyC appears in the serum as full-length and fragmented protein. Compared to cTnT measured using a contemporary high-sensitivity commercial assay, cMyC peaks earlier (STEMI, 9.3 ± 3.1 vs 11.8 ± 3.4 h, P < 0.007; TASH, 9.7 ± 1.4 vs 21.6 ± 1.4 h, P < 0.0001), accumulates more rapidly (during first 4 h after TASH, 25.8 ± 1.9 vs 4.0 ± 0.4 ng/L/min, P < 0.0001) and disappears more rapidly (post-CABG, decay half-time 5.5 ± 0.8 vs 22 ± 5 h, P < 0.0001). Our results demonstrate that following defined myocardial injury, the rise and fall in the serum of cMyC is more rapid than that of cTnT. We speculate that these characteristics could enable earlier diagnosis of myocardial infarction and reinfarction in suspected non-STEMI, a population not included in this early translational study.

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The accumulation of cMyC (open symbols) compared to cTnT (closed symbols) after myocardial injury caused by surgical revascularization. Venous blood was collected over 3 days following CABG. a Summary data of absolute quantification of cMyC versus cTnT over time following CABG (n = 20). Insetfigure is a zoom of the last five time points expressed as a % of peak concentration achieved in each patient. This normalization was used to remove the visual bias caused by the greater absolute concentration of cMyC. b Shows the concentration versus time relationship for cMyC and cTnT for each of the 20 individual patients summarized on (a). The monoexponential used for curve-fitting to determine clearance half-times is drawn as a continuous line. The decay half-time for cMyC is considerably shorter than for cTnT (5.5 ± 0.8 vs 22 ± 5 h, P < 0.0001)
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Fig5: The accumulation of cMyC (open symbols) compared to cTnT (closed symbols) after myocardial injury caused by surgical revascularization. Venous blood was collected over 3 days following CABG. a Summary data of absolute quantification of cMyC versus cTnT over time following CABG (n = 20). Insetfigure is a zoom of the last five time points expressed as a % of peak concentration achieved in each patient. This normalization was used to remove the visual bias caused by the greater absolute concentration of cMyC. b Shows the concentration versus time relationship for cMyC and cTnT for each of the 20 individual patients summarized on (a). The monoexponential used for curve-fitting to determine clearance half-times is drawn as a continuous line. The decay half-time for cMyC is considerably shorter than for cTnT (5.5 ± 0.8 vs 22 ± 5 h, P < 0.0001)

Mentions: The duration of admission for STEMI and TASH is too short to get an adequate profile of clearance. To examine this we used serum collected during an investigation of the effects of ciclosporin on cardiac protection during coronary artery bypass surgery where myocardial injury was assessed using serum biomarkers collected before, and 6, 12, 24, 48 and 72 h after surgery. The biomarker release profile differs markedly from that during TASH (compare Figs. 4a to 5a) with both markers achieving their peak concentration at 6 h, with cMyC (open symbols) falling substantially at 12 h. This probably reflects myocardial washout by brisk reperfusion on release of the aortic cross clamp. Figure 5b shows comparative rates of clearance of cMyC and hscTnT (closed symbols) from the serum for individual patients with corresponding monoexponential curves of best fit. Based on these time constants, the decay half-time for cMyC is considerably shorter than for cTnT (5.5 ± 0.8 vs 22 ± 5 h, P < 0.0001).Fig. 5


Cardiac myosin-binding protein C: a potential early biomarker of myocardial injury.

Baker JO, Tyther R, Liebetrau C, Clark J, Howarth R, Patterson T, Möllmann H, Nef H, Sicard P, Kailey B, Devaraj R, Redwood SR, Kunst G, Weber E, Marber MS - Basic Res. Cardiol. (2015)

The accumulation of cMyC (open symbols) compared to cTnT (closed symbols) after myocardial injury caused by surgical revascularization. Venous blood was collected over 3 days following CABG. a Summary data of absolute quantification of cMyC versus cTnT over time following CABG (n = 20). Insetfigure is a zoom of the last five time points expressed as a % of peak concentration achieved in each patient. This normalization was used to remove the visual bias caused by the greater absolute concentration of cMyC. b Shows the concentration versus time relationship for cMyC and cTnT for each of the 20 individual patients summarized on (a). The monoexponential used for curve-fitting to determine clearance half-times is drawn as a continuous line. The decay half-time for cMyC is considerably shorter than for cTnT (5.5 ± 0.8 vs 22 ± 5 h, P < 0.0001)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4383815&req=5

Fig5: The accumulation of cMyC (open symbols) compared to cTnT (closed symbols) after myocardial injury caused by surgical revascularization. Venous blood was collected over 3 days following CABG. a Summary data of absolute quantification of cMyC versus cTnT over time following CABG (n = 20). Insetfigure is a zoom of the last five time points expressed as a % of peak concentration achieved in each patient. This normalization was used to remove the visual bias caused by the greater absolute concentration of cMyC. b Shows the concentration versus time relationship for cMyC and cTnT for each of the 20 individual patients summarized on (a). The monoexponential used for curve-fitting to determine clearance half-times is drawn as a continuous line. The decay half-time for cMyC is considerably shorter than for cTnT (5.5 ± 0.8 vs 22 ± 5 h, P < 0.0001)
Mentions: The duration of admission for STEMI and TASH is too short to get an adequate profile of clearance. To examine this we used serum collected during an investigation of the effects of ciclosporin on cardiac protection during coronary artery bypass surgery where myocardial injury was assessed using serum biomarkers collected before, and 6, 12, 24, 48 and 72 h after surgery. The biomarker release profile differs markedly from that during TASH (compare Figs. 4a to 5a) with both markers achieving their peak concentration at 6 h, with cMyC (open symbols) falling substantially at 12 h. This probably reflects myocardial washout by brisk reperfusion on release of the aortic cross clamp. Figure 5b shows comparative rates of clearance of cMyC and hscTnT (closed symbols) from the serum for individual patients with corresponding monoexponential curves of best fit. Based on these time constants, the decay half-time for cMyC is considerably shorter than for cTnT (5.5 ± 0.8 vs 22 ± 5 h, P < 0.0001).Fig. 5

Bottom Line: Using novel antibodies raised against the cardiac-specific N-terminus of cMyC, we used confocal microscopy, immunoblotting and immunoassay to document its location and release.Compared to cTnT measured using a contemporary high-sensitivity commercial assay, cMyC peaks earlier (STEMI, 9.3 ± 3.1 vs 11.8 ± 3.4 h, P < 0.007; TASH, 9.7 ± 1.4 vs 21.6 ± 1.4 h, P < 0.0001), accumulates more rapidly (during first 4 h after TASH, 25.8 ± 1.9 vs 4.0 ± 0.4 ng/L/min, P < 0.0001) and disappears more rapidly (post-CABG, decay half-time 5.5 ± 0.8 vs 22 ± 5 h, P < 0.0001).Our results demonstrate that following defined myocardial injury, the rise and fall in the serum of cMyC is more rapid than that of cTnT.

View Article: PubMed Central - PubMed

Affiliation: King's College London BHF Centre, The Rayne Institute, St Thomas' Hospital, 4th Floor Lambeth Wing, Westminster Bridge Road, London, SE1 7EH, UK.

ABSTRACT
Cardiac troponins are released and cleared slowly after myocardial injury, complicating the diagnosis of early, and recurrent, acute myocardial infarction. Cardiac myosin-binding protein C (cMyC) is a similarly cardiac-restricted protein that may have different release/clearance kinetics. Using novel antibodies raised against the cardiac-specific N-terminus of cMyC, we used confocal microscopy, immunoblotting and immunoassay to document its location and release. In rodents, we demonstrate rapid release of cMyC using in vitro and in vivo models of acute myocardial infarction. In patients, with ST elevation myocardial infarction (STEMI, n = 20), undergoing therapeutic ablation of septal hypertrophy (TASH, n = 20) or having coronary artery bypass surgery (CABG, n = 20), serum was collected prospectively and frequently. cMyC appears in the serum as full-length and fragmented protein. Compared to cTnT measured using a contemporary high-sensitivity commercial assay, cMyC peaks earlier (STEMI, 9.3 ± 3.1 vs 11.8 ± 3.4 h, P < 0.007; TASH, 9.7 ± 1.4 vs 21.6 ± 1.4 h, P < 0.0001), accumulates more rapidly (during first 4 h after TASH, 25.8 ± 1.9 vs 4.0 ± 0.4 ng/L/min, P < 0.0001) and disappears more rapidly (post-CABG, decay half-time 5.5 ± 0.8 vs 22 ± 5 h, P < 0.0001). Our results demonstrate that following defined myocardial injury, the rise and fall in the serum of cMyC is more rapid than that of cTnT. We speculate that these characteristics could enable earlier diagnosis of myocardial infarction and reinfarction in suspected non-STEMI, a population not included in this early translational study.

Show MeSH
Related in: MedlinePlus