https://orcid.org/0009-0003-9434-7485
Abstract
Cardiac myosin binding protein C (cMyC) is a novel, cardiac-specific biomarker with an early release profile after acute ischemic myocardial injury. Whether cMyC reflects chronic myocardial injury and left ventricular remodelling in the general population is unknown. The aims of the study were to test the hypotheses that cMyC concentrations are associated with cardiovascular risk factors, biomarkers of chronic myocardial injury, and imaging biomarkers of cardiac anatomy, function, and fibrosis.
Circulating cMyC and cardiac troponin I and T concentrations were measured in 3672 individuals from the general population, born in 1950, who underwent echocardiography. One-hundred-ninety-nine participants with measured cMyC completed a cardiovascular magnetic resonance (CMR) examination for assessment of myocardial fibrosis.
Circulating cMyC was measurable in 99.6% of study participants and in 99.0% of CMR substudy participants. cMyC was positively associated with left ventricular mass and left atrial volume and inversely associated with renal function and indices of left ventricular systolic and diastolic function. In participants with available late gadolinium enhancement images for the assessment of focal fibrosis (n = 197), cMyC was positively associated with indices of focal myocardial fibrosis.
In the general population, circulating cMyC concentrations are associated with cardiovascular risk factors, reflect left ventricular remodelling, including focal myocardial fibrosis, and systolic and diastolic dysfunction independently of traditional risk factors.
Introduction
Chronic, subclinical myocardial injury is an important intermediary pathogenetic step towards myocardial fibrosis and the development of left ventricular (LV) systolic and diastolic dysfunction (1, 2). Circulating and imaging biomarkers that reflect the process of chronic myocardial injury and are associated with the development of myocardial fibrosis and LV dysfunction may provide pathophysiological insight. During the past decade, using high-sensitivity assays, we and others have shown that circulating cardiac troponin T (cTnT) and I (cTnI) are detectable in the majority of the general population and strongly associate with incident heart failure (HF) and cardiovascular (CV) death (3–5). Cardiovascular magnetic resonance (CMR) investigations in the general population have demonstrated that cTnT concentrations are significantly associated with the presence of diffuse and focal myocardial fibrosis (1, 6). The association between cardiac troponins and diffuse myocardial fibrosis is only moderately strong (6), suggesting that novel, cardiac-specific biomarkers could potentially enhance risk stratification.
Cardiac myosin binding protein C (cMyC) is part of the contractile apparatus in cardiac myocytes and represents a novel cardiac-specific biomarker that may quantify acute and chronic myocardial injury more accurately than cardiac troponins (7–9). The rapid release kinetics of cMyC suggests that it can be used as a clinically useful biomarker in acute settings (7, 10–12). Because of its relative abundance in myocardial tissue compared to cardiac troponins, cMyC may potentially be a more sensitive marker of chronic subclinical myocardial injury compared to cardiac troponins and provide valuable diagnostic and prognostic information in various clinical settings.
Recently, a high-sensitivity immunoassay for cMyC has been developed and become commercially available (9). This high-sensitivity assay permits the measurement of very low cMyC concentrations in healthy individuals. Limited data is available concerning cMyC in chronic settings (13), and no data from contemporary large-scale epidemiological studies are yet available. Using data from the population-based Norwegian, age-cohort Akershus Cardiac Examination (ACE) 1950 Study (14), we hypothesized that cMyC concentrations are associated with cardiovascular risk factors, biochemical biomarkers of myocardial injury, and imaging biomarkers of cardiac anatomy, function, and fibrosis, and based on these associations, holds potential for use as a biomarker in the identification of high-risk individuals in the general population above and beyond cardiac troponins.
Materials and Methods
Study participants
The ACE 1950 Study is a prospective, population-based cohort of 3706 individuals residing in Akershus County, Norway (14). All inhabitants born in 1950 and residing in Akershus County in 2011 were invited to participate (n = 5827). Baseline examinations of the participants were conducted in the period from September 2012 to May 2015 in 3706 subjects who were willing to participate at 2 study sites (Akershus University Hospital and Bærum Hospital). The study design has been reported in detail previously (14). For baseline analysis, we included all participants with measurements of cTnI, cTnT, and cMyC (Fig. 1).
Flow chart of the study population. Abbreviations: ACE, Akershus Cardiac Examination; CMR, cardiovascular magnetic resonance; cMyC, cardiac myosin binding protein C; cTnI, cardiac troponin I; cTnT, cardiac troponin T; ECV, extracellular volume fraction; eGFR, estimated glomerular filtration rate; ICD, implantable cardioverter defibrillator; LGE, late gadolinium enhancement; LV, left ventricular.
The study and substudy protocols were approved by the Regional Committee for Medical Research Ethics prior to the initiation of data collection and comply with the Declaration of Helsinki. All participants provided informed written consent. Definitions of comorbidities are summarized in online Supplemental Table 1.
ACE 1950 CMR Substudy
For the ACE 1950 CMR substudy, 364 participants from the ACE 1950 Study were invited. To include participants from the general population with low and high risk for cardiovascular disease (CVD), invitations were based on concentrations of cardiac troponin I at baseline examination with equal sex distribution. Of those invited, 143 did not respond, declined participation, or were not able to participate (Fig. 1). Of the 221 with normal renal function (estimated glomerular filtration rate [eGFR] > 60 mL/min/1.73 m2) and no known coronary artery disease (CAD) at study baseline, 201 completed a CMR examination. All CMR examinations were performed at Akershus University Hospital between 2018 and 2019, 4 to 7 years after baseline examination.
Biochemical analysis
Fasting venous blood samples were collected from all study participants at the study baseline visit and frozen at −80°C. Standard biochemical analyses including hemoglobin (Hb), white blood count, C-reactive protein (CRP), glucose, Hb A1c, cholesterol (total, high-density lipoprotein [HDL]), triglycerides, and creatinine were performed immediately by routine hospital laboratory clinical chemistry. We used CRP concentrations above or equal to 3 mg/L to denote low-grade systemic inflammation. We used the Chronic Kidney Disease Epidemiology Collaboration equation to estimate eGFR (15). cMyC was measured with a high-sensitivity assay by Millipore Sigma on the Erenna platform (Millipore Sigma). The limit of detection (LoD) for the assay is 0.4 ng/L, the lower limit of quantitation (LLOQ) is 1.2 ng/L and the upper limit of quantitation (ULOQ) is 2000 ng/L. The upper reference limit has not been determined, but one earlier study suggested that normal values were below 87 ng/L based on measurements in 359 patients referred for coronary angiography who had coronary artery stenosis <50% and cTnT <14 ng/L (8). Data on coefficients of variation derived from control material from Millipore Sigma are presented in online Supplemental Fig. 1. Data on plate-to-plate coefficients of variation for the cMyC analysis are presented in online Supplemental Figs. 2 and 3, and we observed a plate-to-plate coefficient of variation of 17% for both control samples on a total of 51 analysis plates. Details of the analyses of high-sensitivity cTnI (Singulex Clarity System, Singulex Inc.) and cTnT (Cobas Platform 8000, e801, Roche Diagnostics) have previously been reported (16, 17). For cMyC, biomarker concentrations below the LLOQ were designated a value of 0.6 ng/L (50% of the LLOQ) and biomarker concentrations above the ULOQ were designated a value of 2000 ng/L (equal to the ULOQ). For the remaining biomarkers, concentrations below the LoD were designated a value of 50% of the LoD. Concentrations at or above the LLOQ/LoD were defined as measurable.
Echocardiography and cardiovascular magnetic resonance imaging
The echocardiographic assessment has been described in detail previously (18). Details of echocardiographic and cardiovascular magnetic resonance imaging analysis can be found in the online Supplemental Methods under Supplemental Data.
Statistical analysis
Baseline data are reported as absolute numbers (proportion) or median (interquartile range [IQR]) unless otherwise stated. Continuous variables were analyzed using the Mann–Whitney U-test or Kruskal–Wallis test, and categorical variables with the χ2 test or Fisher exact test, as appropriate. For calculation of the 97.5th and 99th percentiles of cMyC, cTnI, and cTnT, participants with cardiovascular disease were excluded and the remaining participants were categorized according to CV risk factors and echocardiographic indices. The percentiles were calculated according to CLSI guideline C28-A3c using nonparametric methods with binomial exact 95% confidence intervals, and outlier exclusion according to the Reed criterion. Correlations were assessed by Spearman rank correlation. Concentrations of biomarkers (cMyC, cTnI, and cTnT) were transformed using the natural logarithm prior to use in the regression models.
Associations with potential clinical and demographic determinants, including several conventional CV risk factors, were assessed by uni- and multivariable linear regression analyses. All potential clinical and demographic determinants examined were used as adjustment variables in the multivariable linear regression analyses. Echocardiographic variables of interest were chosen according to standard echocardiographic assessment and standardized using z scores. In multivariable models, echocardiographic variables were adjusted for a priori selected factors implicated in myocardial injury. Additional sensitivity analyses were performed by adding cTnT to the model to assess the incremental benefit of cMyC over cTnT, and with stratification for sex. Due to biomarker transformation with a natural logarithm, coefficients from the linear regression models were interpreted as proportional differences. For analyses with CMR indices of fibrosis, extracellular volume fraction (ECV) (%), our measure of diffuse fibrosis, was dichotomized according to the 4th sex-specific quartile. Focal (late gadolinium enhancement [LGE]) scars were grouped according to presence and scar type. Participants with both ischemic and nonischemic scar types present were grouped as ischemic scar. Uni- and multivariable logistic regression analyses were used to assess associations between circulating biomarkers and ECV, presence of LGE scar, and presence of LGE scar subtypes. Uni- and multivariable linear regression analyses were used to assess associations with continuous measures of ECV and LGE scar volume, for all participants and in participants with scar only. We adjusted for the same variables as in analyses with echocardiographic determinants except for CAD, which was omitted due to this being an exclusion criterion in the CMR substudy. Associations with cMyC vs cTnT and cTnI were compared using the Hausman specification test. We assumed statistical significance at P < 0.05. The statistical analyses were performed with Stata 17.0 (StataCorp LP).
Results
Baseline characteristics of the ACE 1950 study participants
Baseline cMyC measurements were available from 3672 individuals born in 1950 recruited from the general population. The median age was 63.9 (63.4 to 64.4) years and 51.3% were men. Medical history included myocardial infarction (MI) in 4.3%, coronary artery disease in 7.1%, HF in 1.6%, stroke in 3.8%, atrial fibrillation in 4.5%, arterial hypertension in 62.0%, and diabetes mellitus in 8.6% (Table 1).
Baseline characteristics according to quartiles of cMyC.
| Quartiles of cMyC | ||||||
|---|---|---|---|---|---|---|
| Total | Quartile 1 | Quartile 2 | Quartile 3 | Quartile 4 | P for trend | |
| N | 3672 | 918 | 918 | 918 | 918 | |
| cMyC, ng/L | 0.6 to 1869.1 | <3.6 | 3.6 to 5.1 | 5.1 to 7.9 | ≥7.9 | |
| Demographics | ||||||
| Age, years | 63.9 (63.4 to 64.4) | 63.6 (63.3 to 64.2) | 63.8 (63.4 to 64.4) | 64.0 (63.5 to 64.5) | 64.2 (63.6 to 64.6) | <0.001 |
| Male sex, n (%) | 1882 (51.3%) | 282 (30.7%) | 402 (43.8%) | 533 (58.1%) | 665 (72.4%) | <0.001 |
| Body mass index, kg/m2 | 26.7 (24.2 to 29.6) | 25.7 (23.4 to 28.5) | 26.4 (23.8 to 29.3) | 27.1 (24.8 to 30.2) | 27.6 (25.1 to 30.3) | <0.001 |
| Self-reported ethnicity | ||||||
| Northern European White | 3591 (97.8%) | 900 (98.0%) | 881(96.0%) | 906 (98.7%) | 904 (98.6%) | 0.018 |
| Asian | 68 (1.9%) | 14 (1.5%) | 31 (3.4%) | 10 (1.1%) | 13 (1.4%) | |
| African | 6 (0.2%) | 2 (0.2%) | 3 (0.3%) | 1 (0.1%) | 0 (0.0%) | |
| Latin-American | 3 (0.1%) | 1 (0.1%) | 2 (0.2%) | 0 (0.0%) | 0 (0.0%) | |
| Other | 3 (0.1%) | 1 (0.1%) | 1 (0.1%) | 1 (0.1%) | 0 (0.0%) | |
| Clinical characteristics | ||||||
| Waist-to-hip ratio | 0.9 (0.8 to 1.0) | 0.9 (0.8 to 0.9) | 0.9 (0.8 to 1.0) | 0.9 (0.9 to 1.0) | 1.0 (0.9 to 1.0) | <0.001 |
| Current smoker, n (%) | 524 (14.4%) | 136 (15.0%) | 144 (15.8%) | 125 (13.7%) | 119 (13.0%) | 0.33 |
| Alcohol consumption, units per 2 weeksa | 6 (2 to 11) | 5 (2 to 10) | 6 (2 to 11) | 6 (2 to 12) | 6 (2 to 11) | 0.027 |
| Heart rate, beats/min | 62 (56 to 69) | 64 (58 to 70) | 62 (57 to 69) | 62 (56 to 68) | 60 (54 to 68) | <0.001 |
| Systolic blood pressure, mmHg | 137 (125 to 149) | 133 (120 to 145) | 135 (124 to 147) | 138 (127 to 151) | 141 (128 to 154) | <0.001 |
| Diastolic blood pressure, mmHg | 77 (70 to 84) | 75 (68 to 81) | 75 (69 to 83) | 78 (72 to 84.5) | 79 (72 to 86) | <0.001 |
| Medical history | ||||||
| Myocardial infarction, n (%) | 158 (4.3%) | 16 (1.7%) | 21 (2.3%) | 38 (4.1%) | 83 (9.0%) | <0.001 |
| Coronary artery disease, n (%) | 261 (7.1%) | 27 (2.9%) | 50 (5.4%) | 59 (6.4%) | 125 (13.6%) | <0.001 |
| Heart failure, n (%) | 60 (1.6%) | 7 (0.8%) | 11 (1.2%) | 14 (1.5%) | 28 (3.1%) | 0.001 |
| Stroke, n (%) | 138 (3.8%) | 15 (1.6%) | 27 (2.9%) | 50 (5.4%) | 46 (5.0%) | <0.001 |
| Diabetes mellitusb, n (%) | 314 (8.6%) | 51 (5.6%) | 73 (8.0%) | 79 (8.6%) | 111 (12.1%) | <0.001 |
| Hypertension, n (%) | 2276 (62.0%) | 460 (50.1%) | 529 (57.7%) | 615 (67.0%) | 672 (73.2%) | <0.001 |
| Atrial fibrillation, n (%) | 164 (4.5%) | 16 (1.7%) | 24 (2.6%) | 48 (5.2%) | 76 (8.3%) | <0.001 |
| Medication | ||||||
| Diuretics, n (%) | 113 (3.1%) | 17 (1.9%) | 28 (3.1%) | 25 (2.7%) | 43 (4.7%) | 0.006 |
| β-blockers, n (%) | 491 (13.4%) | 74 (8.1%) | 94 (10.2%) | 129 (14.1%) | 194 (21.1%) | <0.001 |
| Calcium antagonists, n (%) | 296 (8.1%) | 59 (6.4%) | 61 (6.6%) | 73 (8.0%) | 103 (11.2%) | <0.001 |
| ACE-I/ARB, n (%) | 991 (27.0%) | 175 (19.1%) | 219 (23.9%) | 262 (28.5%) | 335 (36.5%) | <0.001 |
| Statins, n (%) | 958 (26.1%) | 185 (20.2%) | 236 (25.7%) | 237 (25.8%) | 300 (32.7%) | <0.001 |
| Insulin, n (%) | 40 (1.1%) | 6 (0.7%) | 6 (0.7%) | 10 (1.1%) | 18 (2.0%) | 0.031 |
| Non-insulin antidiabetics, n (%) | 176 (4.8%) | 28 (3.1%) | 40 (4.4%) | 45 (4.9%) | 63 (6.9%) | 0.002 |
| Antiplatelets, n (%) | 627 (17.1%) | 108 (11.8%) | 145 (15.8%) | 173 (18.8%) | 201 (21.9%) | <0.001 |
| Clinical chemistry | ||||||
| CRP ≥3 mg/L, n (%) | 775 (21.2%) | 176 (19.3%) | 184 (20.1%) | 205 (22.4%) | 210 (23.0%) | 0.16 |
| Hb A1c, mmol/molc | 39 (37 to 41) | 39 (37 to 41) | 39 (37 to 41) | 39 (37 to 42) | 39 (37 to 42) | 0.039 |
| Total cholesterol, mg/dLd | 209 (182 to 236) | 213 (189 to 240) | 213 (182 to 240) | 209 (182 to 236) | 201 (170 to 232) | <0.001 |
| HDL cholesterol, mg/dLd | 58 (46 to 70) | 58 (50 to 73) | 58 (46 to 73) | 58 (46 to 70) | 50 (43 to 66) | <0.001 |
| Triglycerides, mg/dLe | 106 (80 to 151) | 97 (71 to 142) | 97 (71 to 142) | 106 (80 to 151) | 106 (80 to 151) | <0.001 |
| eGFR, mL/min/1.73 m2 | 85.1 (75.3 to 92.6) | 87.3 (77.8 to 93.7) | 85.9 (76.6 to 92.7) | 83.8 (74.0 to 92.0) | 83.2 (73.1 to 91.7) | <0.001 |
| Creatinine, mg/dLf | 0.8 (0.7 to 1.0) | 0.8 (0.7 to 0.9) | 0.8 (0.7 to 0.9) | 0.9 (0.8 to 1.0) | 0.9 (0.8 to 1.0) | <0.001 |
| cTnI, ng/L | 1.0 (0.7 to 1.7) | 0.7 (0.5 to 0.9) | 0.9 (0.7 to 1.2) | 1.3 (0.9 to 1.7) | 2.0 (1.3 to 3.0) | <0.001 |
| cTnI above 99th percentileg, n (%) | 86 (2.3%) | 10 (1.1%) | 7 (0.8%) | 8 (0.9%) | 61 (6.6%) | <0.001 |
| cTnT, ng/L | 6 (5 to 9) | 5 (4 to 6) | 6 (4 to 7) | 7 (5 to 9) | 9 (6 to 12) | <0.001 |
| cTnT above 99th percentile (EU)h, n (%) | 301 (8.2%) | 38 (4.1%) | 39 (4.2%) | 56 (6.1%) | 168 (18.3%) | <0.001 |
| cTnT above 99th percentile (US)i, n (%) | 85 (2.3%) | 11 (1.2%) | 11 (1.2%) | 14 (1.5%) | 49 (5.3%) | <0.001 |
| Quartiles of cMyC | ||||||
|---|---|---|---|---|---|---|
| Total | Quartile 1 | Quartile 2 | Quartile 3 | Quartile 4 | P for trend | |
| N | 3672 | 918 | 918 | 918 | 918 | |
| cMyC, ng/L | 0.6 to 1869.1 | <3.6 | 3.6 to 5.1 | 5.1 to 7.9 | ≥7.9 | |
| Demographics | ||||||
| Age, years | 63.9 (63.4 to 64.4) | 63.6 (63.3 to 64.2) | 63.8 (63.4 to 64.4) | 64.0 (63.5 to 64.5) | 64.2 (63.6 to 64.6) | <0.001 |
| Male sex, n (%) | 1882 (51.3%) | 282 (30.7%) | 402 (43.8%) | 533 (58.1%) | 665 (72.4%) | <0.001 |
| Body mass index, kg/m2 | 26.7 (24.2 to 29.6) | 25.7 (23.4 to 28.5) | 26.4 (23.8 to 29.3) | 27.1 (24.8 to 30.2) | 27.6 (25.1 to 30.3) | <0.001 |
| Self-reported ethnicity | ||||||
| Northern European White | 3591 (97.8%) | 900 (98.0%) | 881(96.0%) | 906 (98.7%) | 904 (98.6%) | 0.018 |
| Asian | 68 (1.9%) | 14 (1.5%) | 31 (3.4%) | 10 (1.1%) | 13 (1.4%) | |
| African | 6 (0.2%) | 2 (0.2%) | 3 (0.3%) | 1 (0.1%) | 0 (0.0%) | |
| Latin-American | 3 (0.1%) | 1 (0.1%) | 2 (0.2%) | 0 (0.0%) | 0 (0.0%) | |
| Other | 3 (0.1%) | 1 (0.1%) | 1 (0.1%) | 1 (0.1%) | 0 (0.0%) | |
| Clinical characteristics | ||||||
| Waist-to-hip ratio | 0.9 (0.8 to 1.0) | 0.9 (0.8 to 0.9) | 0.9 (0.8 to 1.0) | 0.9 (0.9 to 1.0) | 1.0 (0.9 to 1.0) | <0.001 |
| Current smoker, n (%) | 524 (14.4%) | 136 (15.0%) | 144 (15.8%) | 125 (13.7%) | 119 (13.0%) | 0.33 |
| Alcohol consumption, units per 2 weeksa | 6 (2 to 11) | 5 (2 to 10) | 6 (2 to 11) | 6 (2 to 12) | 6 (2 to 11) | 0.027 |
| Heart rate, beats/min | 62 (56 to 69) | 64 (58 to 70) | 62 (57 to 69) | 62 (56 to 68) | 60 (54 to 68) | <0.001 |
| Systolic blood pressure, mmHg | 137 (125 to 149) | 133 (120 to 145) | 135 (124 to 147) | 138 (127 to 151) | 141 (128 to 154) | <0.001 |
| Diastolic blood pressure, mmHg | 77 (70 to 84) | 75 (68 to 81) | 75 (69 to 83) | 78 (72 to 84.5) | 79 (72 to 86) | <0.001 |
| Medical history | ||||||
| Myocardial infarction, n (%) | 158 (4.3%) | 16 (1.7%) | 21 (2.3%) | 38 (4.1%) | 83 (9.0%) | <0.001 |
| Coronary artery disease, n (%) | 261 (7.1%) | 27 (2.9%) | 50 (5.4%) | 59 (6.4%) | 125 (13.6%) | <0.001 |
| Heart failure, n (%) | 60 (1.6%) | 7 (0.8%) | 11 (1.2%) | 14 (1.5%) | 28 (3.1%) | 0.001 |
| Stroke, n (%) | 138 (3.8%) | 15 (1.6%) | 27 (2.9%) | 50 (5.4%) | 46 (5.0%) | <0.001 |
| Diabetes mellitusb, n (%) | 314 (8.6%) | 51 (5.6%) | 73 (8.0%) | 79 (8.6%) | 111 (12.1%) | <0.001 |
| Hypertension, n (%) | 2276 (62.0%) | 460 (50.1%) | 529 (57.7%) | 615 (67.0%) | 672 (73.2%) | <0.001 |
| Atrial fibrillation, n (%) | 164 (4.5%) | 16 (1.7%) | 24 (2.6%) | 48 (5.2%) | 76 (8.3%) | <0.001 |
| Medication | ||||||
| Diuretics, n (%) | 113 (3.1%) | 17 (1.9%) | 28 (3.1%) | 25 (2.7%) | 43 (4.7%) | 0.006 |
| β-blockers, n (%) | 491 (13.4%) | 74 (8.1%) | 94 (10.2%) | 129 (14.1%) | 194 (21.1%) | <0.001 |
| Calcium antagonists, n (%) | 296 (8.1%) | 59 (6.4%) | 61 (6.6%) | 73 (8.0%) | 103 (11.2%) | <0.001 |
| ACE-I/ARB, n (%) | 991 (27.0%) | 175 (19.1%) | 219 (23.9%) | 262 (28.5%) | 335 (36.5%) | <0.001 |
| Statins, n (%) | 958 (26.1%) | 185 (20.2%) | 236 (25.7%) | 237 (25.8%) | 300 (32.7%) | <0.001 |
| Insulin, n (%) | 40 (1.1%) | 6 (0.7%) | 6 (0.7%) | 10 (1.1%) | 18 (2.0%) | 0.031 |
| Non-insulin antidiabetics, n (%) | 176 (4.8%) | 28 (3.1%) | 40 (4.4%) | 45 (4.9%) | 63 (6.9%) | 0.002 |
| Antiplatelets, n (%) | 627 (17.1%) | 108 (11.8%) | 145 (15.8%) | 173 (18.8%) | 201 (21.9%) | <0.001 |
| Clinical chemistry | ||||||
| CRP ≥3 mg/L, n (%) | 775 (21.2%) | 176 (19.3%) | 184 (20.1%) | 205 (22.4%) | 210 (23.0%) | 0.16 |
| Hb A1c, mmol/molc | 39 (37 to 41) | 39 (37 to 41) | 39 (37 to 41) | 39 (37 to 42) | 39 (37 to 42) | 0.039 |
| Total cholesterol, mg/dLd | 209 (182 to 236) | 213 (189 to 240) | 213 (182 to 240) | 209 (182 to 236) | 201 (170 to 232) | <0.001 |
| HDL cholesterol, mg/dLd | 58 (46 to 70) | 58 (50 to 73) | 58 (46 to 73) | 58 (46 to 70) | 50 (43 to 66) | <0.001 |
| Triglycerides, mg/dLe | 106 (80 to 151) | 97 (71 to 142) | 97 (71 to 142) | 106 (80 to 151) | 106 (80 to 151) | <0.001 |
| eGFR, mL/min/1.73 m2 | 85.1 (75.3 to 92.6) | 87.3 (77.8 to 93.7) | 85.9 (76.6 to 92.7) | 83.8 (74.0 to 92.0) | 83.2 (73.1 to 91.7) | <0.001 |
| Creatinine, mg/dLf | 0.8 (0.7 to 1.0) | 0.8 (0.7 to 0.9) | 0.8 (0.7 to 0.9) | 0.9 (0.8 to 1.0) | 0.9 (0.8 to 1.0) | <0.001 |
| cTnI, ng/L | 1.0 (0.7 to 1.7) | 0.7 (0.5 to 0.9) | 0.9 (0.7 to 1.2) | 1.3 (0.9 to 1.7) | 2.0 (1.3 to 3.0) | <0.001 |
| cTnI above 99th percentileg, n (%) | 86 (2.3%) | 10 (1.1%) | 7 (0.8%) | 8 (0.9%) | 61 (6.6%) | <0.001 |
| cTnT, ng/L | 6 (5 to 9) | 5 (4 to 6) | 6 (4 to 7) | 7 (5 to 9) | 9 (6 to 12) | <0.001 |
| cTnT above 99th percentile (EU)h, n (%) | 301 (8.2%) | 38 (4.1%) | 39 (4.2%) | 56 (6.1%) | 168 (18.3%) | <0.001 |
| cTnT above 99th percentile (US)i, n (%) | 85 (2.3%) | 11 (1.2%) | 11 (1.2%) | 14 (1.5%) | 49 (5.3%) | <0.001 |
Abbreviations: cMyC, cardiac myosin binding protein C; ACE-I, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blocker; CRP, C-reactive protein; Hb A1c, glycosylated hemoglobin; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate; cTnI, cardiac troponin I; cTnT, cardiac troponin T.
a1 unit of alcohol = 12 g of alcohol.
bSelf-reported diabetes mellitus or use of antidiabetic medication or elevated glucose tests (both Hb A1c ≥48 mmol/mol [6.5%] and fasting blood glucose ≥126 mg/dL [7.0 mmol/L]).
cHb A1c can be converted from percentage to mmol/mol by using the following formula: 0.09148*Hb A1c mmol/mol + 2.152.
dTo convert cholesterol concentrations from mg/dL to mmol/L, multiply by 0.02586.
eTo convert triglyceride concentrations from mg/dL to mmol/L, multiply by 0.01129.
fTo convert creatinine concentrations from mg/dL to μmol/L, multiply by 88.4.
g≥6.74 ng/L for both sexes.
h≥9 ng/L for women and ≥16 ng/L for men.
i≥14 ng/L for women and ≥22 ng/L for men.
Baseline characteristics according to quartiles of cMyC.
| Quartiles of cMyC | ||||||
|---|---|---|---|---|---|---|
| Total | Quartile 1 | Quartile 2 | Quartile 3 | Quartile 4 | P for trend | |
| N | 3672 | 918 | 918 | 918 | 918 | |
| cMyC, ng/L | 0.6 to 1869.1 | <3.6 | 3.6 to 5.1 | 5.1 to 7.9 | ≥7.9 | |
| Demographics | ||||||
| Age, years | 63.9 (63.4 to 64.4) | 63.6 (63.3 to 64.2) | 63.8 (63.4 to 64.4) | 64.0 (63.5 to 64.5) | 64.2 (63.6 to 64.6) | <0.001 |
| Male sex, n (%) | 1882 (51.3%) | 282 (30.7%) | 402 (43.8%) | 533 (58.1%) | 665 (72.4%) | <0.001 |
| Body mass index, kg/m2 | 26.7 (24.2 to 29.6) | 25.7 (23.4 to 28.5) | 26.4 (23.8 to 29.3) | 27.1 (24.8 to 30.2) | 27.6 (25.1 to 30.3) | <0.001 |
| Self-reported ethnicity | ||||||
| Northern European White | 3591 (97.8%) | 900 (98.0%) | 881(96.0%) | 906 (98.7%) | 904 (98.6%) | 0.018 |
| Asian | 68 (1.9%) | 14 (1.5%) | 31 (3.4%) | 10 (1.1%) | 13 (1.4%) | |
| African | 6 (0.2%) | 2 (0.2%) | 3 (0.3%) | 1 (0.1%) | 0 (0.0%) | |
| Latin-American | 3 (0.1%) | 1 (0.1%) | 2 (0.2%) | 0 (0.0%) | 0 (0.0%) | |
| Other | 3 (0.1%) | 1 (0.1%) | 1 (0.1%) | 1 (0.1%) | 0 (0.0%) | |
| Clinical characteristics | ||||||
| Waist-to-hip ratio | 0.9 (0.8 to 1.0) | 0.9 (0.8 to 0.9) | 0.9 (0.8 to 1.0) | 0.9 (0.9 to 1.0) | 1.0 (0.9 to 1.0) | <0.001 |
| Current smoker, n (%) | 524 (14.4%) | 136 (15.0%) | 144 (15.8%) | 125 (13.7%) | 119 (13.0%) | 0.33 |
| Alcohol consumption, units per 2 weeksa | 6 (2 to 11) | 5 (2 to 10) | 6 (2 to 11) | 6 (2 to 12) | 6 (2 to 11) | 0.027 |
| Heart rate, beats/min | 62 (56 to 69) | 64 (58 to 70) | 62 (57 to 69) | 62 (56 to 68) | 60 (54 to 68) | <0.001 |
| Systolic blood pressure, mmHg | 137 (125 to 149) | 133 (120 to 145) | 135 (124 to 147) | 138 (127 to 151) | 141 (128 to 154) | <0.001 |
| Diastolic blood pressure, mmHg | 77 (70 to 84) | 75 (68 to 81) | 75 (69 to 83) | 78 (72 to 84.5) | 79 (72 to 86) | <0.001 |
| Medical history | ||||||
| Myocardial infarction, n (%) | 158 (4.3%) | 16 (1.7%) | 21 (2.3%) | 38 (4.1%) | 83 (9.0%) | <0.001 |
| Coronary artery disease, n (%) | 261 (7.1%) | 27 (2.9%) | 50 (5.4%) | 59 (6.4%) | 125 (13.6%) | <0.001 |
| Heart failure, n (%) | 60 (1.6%) | 7 (0.8%) | 11 (1.2%) | 14 (1.5%) | 28 (3.1%) | 0.001 |
| Stroke, n (%) | 138 (3.8%) | 15 (1.6%) | 27 (2.9%) | 50 (5.4%) | 46 (5.0%) | <0.001 |
| Diabetes mellitusb, n (%) | 314 (8.6%) | 51 (5.6%) | 73 (8.0%) | 79 (8.6%) | 111 (12.1%) | <0.001 |
| Hypertension, n (%) | 2276 (62.0%) | 460 (50.1%) | 529 (57.7%) | 615 (67.0%) | 672 (73.2%) | <0.001 |
| Atrial fibrillation, n (%) | 164 (4.5%) | 16 (1.7%) | 24 (2.6%) | 48 (5.2%) | 76 (8.3%) | <0.001 |
| Medication | ||||||
| Diuretics, n (%) | 113 (3.1%) | 17 (1.9%) | 28 (3.1%) | 25 (2.7%) | 43 (4.7%) | 0.006 |
| β-blockers, n (%) | 491 (13.4%) | 74 (8.1%) | 94 (10.2%) | 129 (14.1%) | 194 (21.1%) | <0.001 |
| Calcium antagonists, n (%) | 296 (8.1%) | 59 (6.4%) | 61 (6.6%) | 73 (8.0%) | 103 (11.2%) | <0.001 |
| ACE-I/ARB, n (%) | 991 (27.0%) | 175 (19.1%) | 219 (23.9%) | 262 (28.5%) | 335 (36.5%) | <0.001 |
| Statins, n (%) | 958 (26.1%) | 185 (20.2%) | 236 (25.7%) | 237 (25.8%) | 300 (32.7%) | <0.001 |
| Insulin, n (%) | 40 (1.1%) | 6 (0.7%) | 6 (0.7%) | 10 (1.1%) | 18 (2.0%) | 0.031 |
| Non-insulin antidiabetics, n (%) | 176 (4.8%) | 28 (3.1%) | 40 (4.4%) | 45 (4.9%) | 63 (6.9%) | 0.002 |
| Antiplatelets, n (%) | 627 (17.1%) | 108 (11.8%) | 145 (15.8%) | 173 (18.8%) | 201 (21.9%) | <0.001 |
| Clinical chemistry | ||||||
| CRP ≥3 mg/L, n (%) | 775 (21.2%) | 176 (19.3%) | 184 (20.1%) | 205 (22.4%) | 210 (23.0%) | 0.16 |
| Hb A1c, mmol/molc | 39 (37 to 41) | 39 (37 to 41) | 39 (37 to 41) | 39 (37 to 42) | 39 (37 to 42) | 0.039 |
| Total cholesterol, mg/dLd | 209 (182 to 236) | 213 (189 to 240) | 213 (182 to 240) | 209 (182 to 236) | 201 (170 to 232) | <0.001 |
| HDL cholesterol, mg/dLd | 58 (46 to 70) | 58 (50 to 73) | 58 (46 to 73) | 58 (46 to 70) | 50 (43 to 66) | <0.001 |
| Triglycerides, mg/dLe | 106 (80 to 151) | 97 (71 to 142) | 97 (71 to 142) | 106 (80 to 151) | 106 (80 to 151) | <0.001 |
| eGFR, mL/min/1.73 m2 | 85.1 (75.3 to 92.6) | 87.3 (77.8 to 93.7) | 85.9 (76.6 to 92.7) | 83.8 (74.0 to 92.0) | 83.2 (73.1 to 91.7) | <0.001 |
| Creatinine, mg/dLf | 0.8 (0.7 to 1.0) | 0.8 (0.7 to 0.9) | 0.8 (0.7 to 0.9) | 0.9 (0.8 to 1.0) | 0.9 (0.8 to 1.0) | <0.001 |
| cTnI, ng/L | 1.0 (0.7 to 1.7) | 0.7 (0.5 to 0.9) | 0.9 (0.7 to 1.2) | 1.3 (0.9 to 1.7) | 2.0 (1.3 to 3.0) | <0.001 |
| cTnI above 99th percentileg, n (%) | 86 (2.3%) | 10 (1.1%) | 7 (0.8%) | 8 (0.9%) | 61 (6.6%) | <0.001 |
| cTnT, ng/L | 6 (5 to 9) | 5 (4 to 6) | 6 (4 to 7) | 7 (5 to 9) | 9 (6 to 12) | <0.001 |
| cTnT above 99th percentile (EU)h, n (%) | 301 (8.2%) | 38 (4.1%) | 39 (4.2%) | 56 (6.1%) | 168 (18.3%) | <0.001 |
| cTnT above 99th percentile (US)i, n (%) | 85 (2.3%) | 11 (1.2%) | 11 (1.2%) | 14 (1.5%) | 49 (5.3%) | <0.001 |
| Quartiles of cMyC | ||||||
|---|---|---|---|---|---|---|
| Total | Quartile 1 | Quartile 2 | Quartile 3 | Quartile 4 | P for trend | |
| N | 3672 | 918 | 918 | 918 | 918 | |
| cMyC, ng/L | 0.6 to 1869.1 | <3.6 | 3.6 to 5.1 | 5.1 to 7.9 | ≥7.9 | |
| Demographics | ||||||
| Age, years | 63.9 (63.4 to 64.4) | 63.6 (63.3 to 64.2) | 63.8 (63.4 to 64.4) | 64.0 (63.5 to 64.5) | 64.2 (63.6 to 64.6) | <0.001 |
| Male sex, n (%) | 1882 (51.3%) | 282 (30.7%) | 402 (43.8%) | 533 (58.1%) | 665 (72.4%) | <0.001 |
| Body mass index, kg/m2 | 26.7 (24.2 to 29.6) | 25.7 (23.4 to 28.5) | 26.4 (23.8 to 29.3) | 27.1 (24.8 to 30.2) | 27.6 (25.1 to 30.3) | <0.001 |
| Self-reported ethnicity | ||||||
| Northern European White | 3591 (97.8%) | 900 (98.0%) | 881(96.0%) | 906 (98.7%) | 904 (98.6%) | 0.018 |
| Asian | 68 (1.9%) | 14 (1.5%) | 31 (3.4%) | 10 (1.1%) | 13 (1.4%) | |
| African | 6 (0.2%) | 2 (0.2%) | 3 (0.3%) | 1 (0.1%) | 0 (0.0%) | |
| Latin-American | 3 (0.1%) | 1 (0.1%) | 2 (0.2%) | 0 (0.0%) | 0 (0.0%) | |
| Other | 3 (0.1%) | 1 (0.1%) | 1 (0.1%) | 1 (0.1%) | 0 (0.0%) | |
| Clinical characteristics | ||||||
| Waist-to-hip ratio | 0.9 (0.8 to 1.0) | 0.9 (0.8 to 0.9) | 0.9 (0.8 to 1.0) | 0.9 (0.9 to 1.0) | 1.0 (0.9 to 1.0) | <0.001 |
| Current smoker, n (%) | 524 (14.4%) | 136 (15.0%) | 144 (15.8%) | 125 (13.7%) | 119 (13.0%) | 0.33 |
| Alcohol consumption, units per 2 weeksa | 6 (2 to 11) | 5 (2 to 10) | 6 (2 to 11) | 6 (2 to 12) | 6 (2 to 11) | 0.027 |
| Heart rate, beats/min | 62 (56 to 69) | 64 (58 to 70) | 62 (57 to 69) | 62 (56 to 68) | 60 (54 to 68) | <0.001 |
| Systolic blood pressure, mmHg | 137 (125 to 149) | 133 (120 to 145) | 135 (124 to 147) | 138 (127 to 151) | 141 (128 to 154) | <0.001 |
| Diastolic blood pressure, mmHg | 77 (70 to 84) | 75 (68 to 81) | 75 (69 to 83) | 78 (72 to 84.5) | 79 (72 to 86) | <0.001 |
| Medical history | ||||||
| Myocardial infarction, n (%) | 158 (4.3%) | 16 (1.7%) | 21 (2.3%) | 38 (4.1%) | 83 (9.0%) | <0.001 |
| Coronary artery disease, n (%) | 261 (7.1%) | 27 (2.9%) | 50 (5.4%) | 59 (6.4%) | 125 (13.6%) | <0.001 |
| Heart failure, n (%) | 60 (1.6%) | 7 (0.8%) | 11 (1.2%) | 14 (1.5%) | 28 (3.1%) | 0.001 |
| Stroke, n (%) | 138 (3.8%) | 15 (1.6%) | 27 (2.9%) | 50 (5.4%) | 46 (5.0%) | <0.001 |
| Diabetes mellitusb, n (%) | 314 (8.6%) | 51 (5.6%) | 73 (8.0%) | 79 (8.6%) | 111 (12.1%) | <0.001 |
| Hypertension, n (%) | 2276 (62.0%) | 460 (50.1%) | 529 (57.7%) | 615 (67.0%) | 672 (73.2%) | <0.001 |
| Atrial fibrillation, n (%) | 164 (4.5%) | 16 (1.7%) | 24 (2.6%) | 48 (5.2%) | 76 (8.3%) | <0.001 |
| Medication | ||||||
| Diuretics, n (%) | 113 (3.1%) | 17 (1.9%) | 28 (3.1%) | 25 (2.7%) | 43 (4.7%) | 0.006 |
| β-blockers, n (%) | 491 (13.4%) | 74 (8.1%) | 94 (10.2%) | 129 (14.1%) | 194 (21.1%) | <0.001 |
| Calcium antagonists, n (%) | 296 (8.1%) | 59 (6.4%) | 61 (6.6%) | 73 (8.0%) | 103 (11.2%) | <0.001 |
| ACE-I/ARB, n (%) | 991 (27.0%) | 175 (19.1%) | 219 (23.9%) | 262 (28.5%) | 335 (36.5%) | <0.001 |
| Statins, n (%) | 958 (26.1%) | 185 (20.2%) | 236 (25.7%) | 237 (25.8%) | 300 (32.7%) | <0.001 |
| Insulin, n (%) | 40 (1.1%) | 6 (0.7%) | 6 (0.7%) | 10 (1.1%) | 18 (2.0%) | 0.031 |
| Non-insulin antidiabetics, n (%) | 176 (4.8%) | 28 (3.1%) | 40 (4.4%) | 45 (4.9%) | 63 (6.9%) | 0.002 |
| Antiplatelets, n (%) | 627 (17.1%) | 108 (11.8%) | 145 (15.8%) | 173 (18.8%) | 201 (21.9%) | <0.001 |
| Clinical chemistry | ||||||
| CRP ≥3 mg/L, n (%) | 775 (21.2%) | 176 (19.3%) | 184 (20.1%) | 205 (22.4%) | 210 (23.0%) | 0.16 |
| Hb A1c, mmol/molc | 39 (37 to 41) | 39 (37 to 41) | 39 (37 to 41) | 39 (37 to 42) | 39 (37 to 42) | 0.039 |
| Total cholesterol, mg/dLd | 209 (182 to 236) | 213 (189 to 240) | 213 (182 to 240) | 209 (182 to 236) | 201 (170 to 232) | <0.001 |
| HDL cholesterol, mg/dLd | 58 (46 to 70) | 58 (50 to 73) | 58 (46 to 73) | 58 (46 to 70) | 50 (43 to 66) | <0.001 |
| Triglycerides, mg/dLe | 106 (80 to 151) | 97 (71 to 142) | 97 (71 to 142) | 106 (80 to 151) | 106 (80 to 151) | <0.001 |
| eGFR, mL/min/1.73 m2 | 85.1 (75.3 to 92.6) | 87.3 (77.8 to 93.7) | 85.9 (76.6 to 92.7) | 83.8 (74.0 to 92.0) | 83.2 (73.1 to 91.7) | <0.001 |
| Creatinine, mg/dLf | 0.8 (0.7 to 1.0) | 0.8 (0.7 to 0.9) | 0.8 (0.7 to 0.9) | 0.9 (0.8 to 1.0) | 0.9 (0.8 to 1.0) | <0.001 |
| cTnI, ng/L | 1.0 (0.7 to 1.7) | 0.7 (0.5 to 0.9) | 0.9 (0.7 to 1.2) | 1.3 (0.9 to 1.7) | 2.0 (1.3 to 3.0) | <0.001 |
| cTnI above 99th percentileg, n (%) | 86 (2.3%) | 10 (1.1%) | 7 (0.8%) | 8 (0.9%) | 61 (6.6%) | <0.001 |
| cTnT, ng/L | 6 (5 to 9) | 5 (4 to 6) | 6 (4 to 7) | 7 (5 to 9) | 9 (6 to 12) | <0.001 |
| cTnT above 99th percentile (EU)h, n (%) | 301 (8.2%) | 38 (4.1%) | 39 (4.2%) | 56 (6.1%) | 168 (18.3%) | <0.001 |
| cTnT above 99th percentile (US)i, n (%) | 85 (2.3%) | 11 (1.2%) | 11 (1.2%) | 14 (1.5%) | 49 (5.3%) | <0.001 |
Abbreviations: cMyC, cardiac myosin binding protein C; ACE-I, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blocker; CRP, C-reactive protein; Hb A1c, glycosylated hemoglobin; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate; cTnI, cardiac troponin I; cTnT, cardiac troponin T.
a1 unit of alcohol = 12 g of alcohol.
bSelf-reported diabetes mellitus or use of antidiabetic medication or elevated glucose tests (both Hb A1c ≥48 mmol/mol [6.5%] and fasting blood glucose ≥126 mg/dL [7.0 mmol/L]).
cHb A1c can be converted from percentage to mmol/mol by using the following formula: 0.09148*Hb A1c mmol/mol + 2.152.
dTo convert cholesterol concentrations from mg/dL to mmol/L, multiply by 0.02586.
eTo convert triglyceride concentrations from mg/dL to mmol/L, multiply by 0.01129.
fTo convert creatinine concentrations from mg/dL to μmol/L, multiply by 88.4.
g≥6.74 ng/L for both sexes.
h≥9 ng/L for women and ≥16 ng/L for men.
i≥14 ng/L for women and ≥22 ng/L for men.
Demographic and clinical determinants of cMyC
Circulating concentrations of cMyC were measurable in 99.6% of study participants, while concentrations of cTnT were measurable in 75.0% (P < 0.001 compared to cMyC) and cTnI in 99.8% (P = 0.07 compared to cMyC). Concentrations of cMyC showed a skewed distribution and were higher in men than in women (Fig. 2); comparator concentrations for cardiac troponins are shown in online Supplemental Figs. 4 and 5. Participants at study baseline with cMyC concentrations in the highest quartile had elevated CV risk and more established CVD, with older age, higher blood pressure and body mass index, and a higher proportion had a history of arterial hypertension, diabetes mellitus, coronary artery disease, stroke, and atrial fibrillation. Increasing quartiles of cMyC were positively associated with cTnI and cTnT, and inversely associated with eGFR, heart rate, and total and HDL cholesterol, whereas no associations with CRP were observed (Table 1). Concentrations of cMyC correlated with concentrations of cTnT (r = 0.44, P < 0.001) and cTnI (r = 0.59, P < 0.001). The overall 99th percentile varied from 27.1 ng/L to 115.8 ng/L, across models with increasing risk factors and echocardiographic signs of myocardial disease (online Supplemental Table 2). Corresponding values for cTnT were 18 to 24 ng/L (online Supplemental Table 3) and 8.0 to 11.1 ng/L for cTnI (online Supplemental Table 4). The lowest cMyC 99th percentile (17.8 ng/L) was seen in apparently healthy women without CV risk factors, normal eGFR, N-terminal pro-B-type natriuretic peptide (NT-proBNP), LV ejection fraction and LV mass. Men with similar characteristics had a 99th percentile of 27.5 ng/L.
Distribution of cardiac myosin binding protein C concentrations in women (left) and men (right). Values censored at lower limit of quantitation (1.2 ng/L). Color figure available at https://dbpia.nl.go.kr/clinchem.
Echocardiographic determinants of cMyC
Increasing quartiles of cMyC were positively associated with LV mass index, end-systolic and end-diastolic volumes, and LA volume index, and inversely associated with LV systolic function (online Supplemental Table 5). Increasing quartiles of cMyC were also positively associated with echocardiographic indices of LV filling pressure (ratio between peak early diastolic transmitral velocity by pulsed Doppler and peak early diastolic mitral annulus tissue Doppler velocity [E/e′]), as well as with estimated pulmonary arterial pressure (expressed as tricuspid regurgitation maximum velocity).
Determinants of cMyC Versus Cardiac Troponins
The association between cMyC concentrations and sex was weaker than for both cTnI and cTnT (online Supplemental Table 6 and Table 2). The association with age was stronger for cMyC than for cTnI and cTnT concentrations. The inverse association with renal function was stronger for cMyC (−8.4%; 95% CI, −10.6% to −6.1%) than for cTnI (−1.8%; 95% CI, −3.9% to 0.3%, P < 0.001 for comparison) and for cTnT (−5.9%; 95% CI, −7.5% to −4.2%; P for comparison = 0.035). This difference between cMyC and cTnT was attenuated in adjusted analyses, but cMyC remained more strongly associated with renal function compared to cTnI. The relative strengths of the associations between cMyC vs cardiac troponins and echocardiographic variables are detailed in online Supplemental Table 7. cMyC was associated with all echocardiographic variables apart from LV relative wall thickness and tricuspid annulus planar systolic excursion (TAPSE) (Table 3).
Comparison of potential demographic and clinical determinants of cMyC, cTnI, and cTnT in adjusted analyses.a
| Effect (95% CI) | P for comparison with cMyCb | ||||
|---|---|---|---|---|---|
| cMyC | cTnI | cTnT | cTnI | cTnT | |
| Age, per year | 25.9 (22.0 to 29.8) %c | −5.1 (−8.6 to −1.5) % | −8.7 (−11.4 to −6.0) % | <0.001 | <0.001 |
| Male sex | 39.0 (33.2 to 44.7) %c | 53.8 (48.6 to 59.0) % | 57.7 (53.7 to 61.6) % | <0.001 | <0.001 |
| BMI, per 10 units | 7.2 (0.6 to 13.8) %d | 16.2 (10.2 to 22.3) % | 15.6 (11.1 to 20.1) % | 0.011 | 0.022 |
| Current smoker | −2.2 (−9.5 to 5.1) % | −6.3 (−13.0 to 0.3) % | 1.5 (−3.5 to 6.5) % | 0.29 | 0.37 |
| Alcohol consumption, units per 2 weekse | −0.0 (−0.3 to 0.2) % | −0.1 (−0.4 to 0.1) % | −0.0 (−0.2 to 0.2) % | 0.56 | 0.98 |
| Coronary artery disease | 19.9 (9.4 to 30.5) %c | 21.4 (11.8 to 31.0) % | −0.5 (−7.7 to 6.7) % | 0.79 | <0.001 |
| Heart failure | 10.7 (−9.8 to 31.3) % | 17.7 (−1.0 to 36.4) % | 20.2 (6.1 to 34.2) % | 0.60 | 0.35 |
| Stroke | 2.6 (−10.6 to 15.7) % | 5.9 (−6.1 to 17.9) % | 13.4 (4.4 to 22.4) % | 0.52 | 0.046 |
| Diabetes mellitus | 5.5 (−4.0 to 14.9) % | −0.9 (−9.5 to 7.7) % | 16.5 (10.0 to 23.0) % | 0.19 | 0.027 |
| Hypertension | 11.3 (5.8 to 16.7) %c | 20.0 (15.1 to 25.0) % | 7.4 (3.7 to 11.1) % | 0.003 | 0.18 |
| Atrial fibrillation | 15.9 (3.6 to 28.2) %d | 18.6 (7.4 to 29.8) % | 14.8 (6.4 to 23.2) % | 0.64 | 0.85 |
| CRP ≥3 mg/L | 2.4 (−4.0 to 8.8) % | −1.2 (−7.1 to 4.6) % | 3.4 (−1.0 to 7.8) % | 0.30 | 0.76 |
| Total cholesterol, per 10 mg/dL | −0.0 (−0.7 to 0.7) % | −0.3 (−1.0 to 0.3) % | −0.7 (−1.2 to −0.2) % | 0.44 | 0.07 |
| HDL cholesterol, per 10 mg/dL | 1.0 (−0.8 to 2.8) % | 4.2 (2.6 to 5.9) % | 2.2 (1.0 to 3.4) % | 0.001 | 0.19 |
| Triglycerides, per 10 mg/dL | 0.2 (−0.3 to 0.6) % | 0.2 (−0.2 to 0.6) % | 0.1 (−0.2 to 0.4) % | 0.86 | 0.73 |
| eGFR, per 10 mL/min/1.73 m2 | −7.5 (−9.7 to −5.4) %c | −2.8 (−4.8 to −0.9) % | −8.0 (−9.5 to −6.6) % | <0.001 | 0.68 |
| Effect (95% CI) | P for comparison with cMyCb | ||||
|---|---|---|---|---|---|
| cMyC | cTnI | cTnT | cTnI | cTnT | |
| Age, per year | 25.9 (22.0 to 29.8) %c | −5.1 (−8.6 to −1.5) % | −8.7 (−11.4 to −6.0) % | <0.001 | <0.001 |
| Male sex | 39.0 (33.2 to 44.7) %c | 53.8 (48.6 to 59.0) % | 57.7 (53.7 to 61.6) % | <0.001 | <0.001 |
| BMI, per 10 units | 7.2 (0.6 to 13.8) %d | 16.2 (10.2 to 22.3) % | 15.6 (11.1 to 20.1) % | 0.011 | 0.022 |
| Current smoker | −2.2 (−9.5 to 5.1) % | −6.3 (−13.0 to 0.3) % | 1.5 (−3.5 to 6.5) % | 0.29 | 0.37 |
| Alcohol consumption, units per 2 weekse | −0.0 (−0.3 to 0.2) % | −0.1 (−0.4 to 0.1) % | −0.0 (−0.2 to 0.2) % | 0.56 | 0.98 |
| Coronary artery disease | 19.9 (9.4 to 30.5) %c | 21.4 (11.8 to 31.0) % | −0.5 (−7.7 to 6.7) % | 0.79 | <0.001 |
| Heart failure | 10.7 (−9.8 to 31.3) % | 17.7 (−1.0 to 36.4) % | 20.2 (6.1 to 34.2) % | 0.60 | 0.35 |
| Stroke | 2.6 (−10.6 to 15.7) % | 5.9 (−6.1 to 17.9) % | 13.4 (4.4 to 22.4) % | 0.52 | 0.046 |
| Diabetes mellitus | 5.5 (−4.0 to 14.9) % | −0.9 (−9.5 to 7.7) % | 16.5 (10.0 to 23.0) % | 0.19 | 0.027 |
| Hypertension | 11.3 (5.8 to 16.7) %c | 20.0 (15.1 to 25.0) % | 7.4 (3.7 to 11.1) % | 0.003 | 0.18 |
| Atrial fibrillation | 15.9 (3.6 to 28.2) %d | 18.6 (7.4 to 29.8) % | 14.8 (6.4 to 23.2) % | 0.64 | 0.85 |
| CRP ≥3 mg/L | 2.4 (−4.0 to 8.8) % | −1.2 (−7.1 to 4.6) % | 3.4 (−1.0 to 7.8) % | 0.30 | 0.76 |
| Total cholesterol, per 10 mg/dL | −0.0 (−0.7 to 0.7) % | −0.3 (−1.0 to 0.3) % | −0.7 (−1.2 to −0.2) % | 0.44 | 0.07 |
| HDL cholesterol, per 10 mg/dL | 1.0 (−0.8 to 2.8) % | 4.2 (2.6 to 5.9) % | 2.2 (1.0 to 3.4) % | 0.001 | 0.19 |
| Triglycerides, per 10 mg/dL | 0.2 (−0.3 to 0.6) % | 0.2 (−0.2 to 0.6) % | 0.1 (−0.2 to 0.4) % | 0.86 | 0.73 |
| eGFR, per 10 mL/min/1.73 m2 | −7.5 (−9.7 to −5.4) %c | −2.8 (−4.8 to −0.9) % | −8.0 (−9.5 to −6.6) % | <0.001 | 0.68 |
Abbreviations: cMyC, cardiac myosin binding protein C; cTnI, cardiac troponin I; cTnT, cardiac troponin T; CI, confidence interval; BMI, body mass index; CRP, C-reactive protein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate.
aAdjusted for all variables listed.
bComparison of associations with cMyC vs cTnI and cTnT.
cP < 0.001
dP < 0.05.
e1 unit of alcohol = 12 g of alcohol.
Comparison of potential demographic and clinical determinants of cMyC, cTnI, and cTnT in adjusted analyses.a
| Effect (95% CI) | P for comparison with cMyCb | ||||
|---|---|---|---|---|---|
| cMyC | cTnI | cTnT | cTnI | cTnT | |
| Age, per year | 25.9 (22.0 to 29.8) %c | −5.1 (−8.6 to −1.5) % | −8.7 (−11.4 to −6.0) % | <0.001 | <0.001 |
| Male sex | 39.0 (33.2 to 44.7) %c | 53.8 (48.6 to 59.0) % | 57.7 (53.7 to 61.6) % | <0.001 | <0.001 |
| BMI, per 10 units | 7.2 (0.6 to 13.8) %d | 16.2 (10.2 to 22.3) % | 15.6 (11.1 to 20.1) % | 0.011 | 0.022 |
| Current smoker | −2.2 (−9.5 to 5.1) % | −6.3 (−13.0 to 0.3) % | 1.5 (−3.5 to 6.5) % | 0.29 | 0.37 |
| Alcohol consumption, units per 2 weekse | −0.0 (−0.3 to 0.2) % | −0.1 (−0.4 to 0.1) % | −0.0 (−0.2 to 0.2) % | 0.56 | 0.98 |
| Coronary artery disease | 19.9 (9.4 to 30.5) %c | 21.4 (11.8 to 31.0) % | −0.5 (−7.7 to 6.7) % | 0.79 | <0.001 |
| Heart failure | 10.7 (−9.8 to 31.3) % | 17.7 (−1.0 to 36.4) % | 20.2 (6.1 to 34.2) % | 0.60 | 0.35 |
| Stroke | 2.6 (−10.6 to 15.7) % | 5.9 (−6.1 to 17.9) % | 13.4 (4.4 to 22.4) % | 0.52 | 0.046 |
| Diabetes mellitus | 5.5 (−4.0 to 14.9) % | −0.9 (−9.5 to 7.7) % | 16.5 (10.0 to 23.0) % | 0.19 | 0.027 |
| Hypertension | 11.3 (5.8 to 16.7) %c | 20.0 (15.1 to 25.0) % | 7.4 (3.7 to 11.1) % | 0.003 | 0.18 |
| Atrial fibrillation | 15.9 (3.6 to 28.2) %d | 18.6 (7.4 to 29.8) % | 14.8 (6.4 to 23.2) % | 0.64 | 0.85 |
| CRP ≥3 mg/L | 2.4 (−4.0 to 8.8) % | −1.2 (−7.1 to 4.6) % | 3.4 (−1.0 to 7.8) % | 0.30 | 0.76 |
| Total cholesterol, per 10 mg/dL | −0.0 (−0.7 to 0.7) % | −0.3 (−1.0 to 0.3) % | −0.7 (−1.2 to −0.2) % | 0.44 | 0.07 |
| HDL cholesterol, per 10 mg/dL | 1.0 (−0.8 to 2.8) % | 4.2 (2.6 to 5.9) % | 2.2 (1.0 to 3.4) % | 0.001 | 0.19 |
| Triglycerides, per 10 mg/dL | 0.2 (−0.3 to 0.6) % | 0.2 (−0.2 to 0.6) % | 0.1 (−0.2 to 0.4) % | 0.86 | 0.73 |
| eGFR, per 10 mL/min/1.73 m2 | −7.5 (−9.7 to −5.4) %c | −2.8 (−4.8 to −0.9) % | −8.0 (−9.5 to −6.6) % | <0.001 | 0.68 |
| Effect (95% CI) | P for comparison with cMyCb | ||||
|---|---|---|---|---|---|
| cMyC | cTnI | cTnT | cTnI | cTnT | |
| Age, per year | 25.9 (22.0 to 29.8) %c | −5.1 (−8.6 to −1.5) % | −8.7 (−11.4 to −6.0) % | <0.001 | <0.001 |
| Male sex | 39.0 (33.2 to 44.7) %c | 53.8 (48.6 to 59.0) % | 57.7 (53.7 to 61.6) % | <0.001 | <0.001 |
| BMI, per 10 units | 7.2 (0.6 to 13.8) %d | 16.2 (10.2 to 22.3) % | 15.6 (11.1 to 20.1) % | 0.011 | 0.022 |
| Current smoker | −2.2 (−9.5 to 5.1) % | −6.3 (−13.0 to 0.3) % | 1.5 (−3.5 to 6.5) % | 0.29 | 0.37 |
| Alcohol consumption, units per 2 weekse | −0.0 (−0.3 to 0.2) % | −0.1 (−0.4 to 0.1) % | −0.0 (−0.2 to 0.2) % | 0.56 | 0.98 |
| Coronary artery disease | 19.9 (9.4 to 30.5) %c | 21.4 (11.8 to 31.0) % | −0.5 (−7.7 to 6.7) % | 0.79 | <0.001 |
| Heart failure | 10.7 (−9.8 to 31.3) % | 17.7 (−1.0 to 36.4) % | 20.2 (6.1 to 34.2) % | 0.60 | 0.35 |
| Stroke | 2.6 (−10.6 to 15.7) % | 5.9 (−6.1 to 17.9) % | 13.4 (4.4 to 22.4) % | 0.52 | 0.046 |
| Diabetes mellitus | 5.5 (−4.0 to 14.9) % | −0.9 (−9.5 to 7.7) % | 16.5 (10.0 to 23.0) % | 0.19 | 0.027 |
| Hypertension | 11.3 (5.8 to 16.7) %c | 20.0 (15.1 to 25.0) % | 7.4 (3.7 to 11.1) % | 0.003 | 0.18 |
| Atrial fibrillation | 15.9 (3.6 to 28.2) %d | 18.6 (7.4 to 29.8) % | 14.8 (6.4 to 23.2) % | 0.64 | 0.85 |
| CRP ≥3 mg/L | 2.4 (−4.0 to 8.8) % | −1.2 (−7.1 to 4.6) % | 3.4 (−1.0 to 7.8) % | 0.30 | 0.76 |
| Total cholesterol, per 10 mg/dL | −0.0 (−0.7 to 0.7) % | −0.3 (−1.0 to 0.3) % | −0.7 (−1.2 to −0.2) % | 0.44 | 0.07 |
| HDL cholesterol, per 10 mg/dL | 1.0 (−0.8 to 2.8) % | 4.2 (2.6 to 5.9) % | 2.2 (1.0 to 3.4) % | 0.001 | 0.19 |
| Triglycerides, per 10 mg/dL | 0.2 (−0.3 to 0.6) % | 0.2 (−0.2 to 0.6) % | 0.1 (−0.2 to 0.4) % | 0.86 | 0.73 |
| eGFR, per 10 mL/min/1.73 m2 | −7.5 (−9.7 to −5.4) %c | −2.8 (−4.8 to −0.9) % | −8.0 (−9.5 to −6.6) % | <0.001 | 0.68 |
Abbreviations: cMyC, cardiac myosin binding protein C; cTnI, cardiac troponin I; cTnT, cardiac troponin T; CI, confidence interval; BMI, body mass index; CRP, C-reactive protein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate.
aAdjusted for all variables listed.
bComparison of associations with cMyC vs cTnI and cTnT.
cP < 0.001
dP < 0.05.
e1 unit of alcohol = 12 g of alcohol.
Comparison of potential echocardiographic determinants of cMyC, cTnI, and cTnT in adjusted analysesa.
| Effect (95% CI) | P for comparison with cMyCb | ||||
|---|---|---|---|---|---|
| cMyC | cTnI | cTnT | cTnI | cTnT | |
| LV end-diastolic volume index | 10.3 (7.5 to 13.1) %c | 14.9 (12.4 to 17.4) % | 7.9 (6.0 to 9.8) % | 0.001 | 0.08 |
| LV mass index | 13.0 (10.3 to 15.6) %c | 17.6 (15.2 to 20.0) % | 6.1 (4.3 to 8.0) % | 0.001 | <0.001 |
| LV relative wall thickness | 0.3 (−2.2 to 2.9) % | 1.0 (−1.4 to 3.3) % | 0.4 (−1.4 to 2.1) % | 0.66 | 0.98 |
| LV ejection fraction | −9.5 (−12.1 to −6.8) %c | −6.1 (−8.5 to −3.6) % | −5.5 (−7.3 to −3.6) % | 0.026 | 0.011 |
| LV global longitudinal strain | −5.8 (−9.2 to −2.5) %c | −6.0 (−9.0 to −3.1) % | −3.8 (−6.1 to −1.6) % | 0.92 | 0.24 |
| E' | −8.2 (−10.8 to −5.7) %c | −6.4 (−8.7 to −4.1) % | −4.3 (−6.0 to −2.5) % | 0.18 | 0.004 |
| E/e' ratio | 8.2 (5.5 to 10.8) %c | 7.6 (5.2 to 9.9) % | 5.3 (3.4 to 7.1) % | 0.70 | 0.05 |
| Tricuspid annulus planar systolic excursion | −2.4 (−4.9 to 0.2) % | 2.0 (−0.3 to 4.3) % | −1.6 (−3.4 to 0.1) % | 0.004 | 0.63 |
| Tricuspid regurgitation maximum velocity | 7.2 (4.1 to 10.2) %c | 2.3 (−0.3 to 4.9) % | 5.2 (3.2 to 7.2) % | 0.002 | 0.25 |
| LA volume index | 11.2 (8.6 to 13.8) %c | 16.1 (13.8 to 18.5) % | 8.1 (6.3 to 9.9) % | <0.001 | 0.019 |
| Effect (95% CI) | P for comparison with cMyCb | ||||
|---|---|---|---|---|---|
| cMyC | cTnI | cTnT | cTnI | cTnT | |
| LV end-diastolic volume index | 10.3 (7.5 to 13.1) %c | 14.9 (12.4 to 17.4) % | 7.9 (6.0 to 9.8) % | 0.001 | 0.08 |
| LV mass index | 13.0 (10.3 to 15.6) %c | 17.6 (15.2 to 20.0) % | 6.1 (4.3 to 8.0) % | 0.001 | <0.001 |
| LV relative wall thickness | 0.3 (−2.2 to 2.9) % | 1.0 (−1.4 to 3.3) % | 0.4 (−1.4 to 2.1) % | 0.66 | 0.98 |
| LV ejection fraction | −9.5 (−12.1 to −6.8) %c | −6.1 (−8.5 to −3.6) % | −5.5 (−7.3 to −3.6) % | 0.026 | 0.011 |
| LV global longitudinal strain | −5.8 (−9.2 to −2.5) %c | −6.0 (−9.0 to −3.1) % | −3.8 (−6.1 to −1.6) % | 0.92 | 0.24 |
| E' | −8.2 (−10.8 to −5.7) %c | −6.4 (−8.7 to −4.1) % | −4.3 (−6.0 to −2.5) % | 0.18 | 0.004 |
| E/e' ratio | 8.2 (5.5 to 10.8) %c | 7.6 (5.2 to 9.9) % | 5.3 (3.4 to 7.1) % | 0.70 | 0.05 |
| Tricuspid annulus planar systolic excursion | −2.4 (−4.9 to 0.2) % | 2.0 (−0.3 to 4.3) % | −1.6 (−3.4 to 0.1) % | 0.004 | 0.63 |
| Tricuspid regurgitation maximum velocity | 7.2 (4.1 to 10.2) %c | 2.3 (−0.3 to 4.9) % | 5.2 (3.2 to 7.2) % | 0.002 | 0.25 |
| LA volume index | 11.2 (8.6 to 13.8) %c | 16.1 (13.8 to 18.5) % | 8.1 (6.3 to 9.9) % | <0.001 | 0.019 |
Abbreviations: cMyC, cardiac myosin binding protein C; cTnI, cardiac troponin I; cTnT, cardiac troponin T; CI, confidence interval; LV, left ventricular; E′, peak early diastolic mitral annulus tissue Doppler velocity; E, peak early diastolic transmitral velocity by pulsed Doppler; LA, left atrial.
aAll potential echocardiographic determinants are per 1 Z-score. Adjusted for age, sex, estimated glomerular filtration rate, prior hypertension, diabetes mellitus, coronary artery disease, and heart failure.
bComparison of associations with cMyC vs cTnI and cTnT.
cP < 0.001
Comparison of potential echocardiographic determinants of cMyC, cTnI, and cTnT in adjusted analysesa.
| Effect (95% CI) | P for comparison with cMyCb | ||||
|---|---|---|---|---|---|
| cMyC | cTnI | cTnT | cTnI | cTnT | |
| LV end-diastolic volume index | 10.3 (7.5 to 13.1) %c | 14.9 (12.4 to 17.4) % | 7.9 (6.0 to 9.8) % | 0.001 | 0.08 |
| LV mass index | 13.0 (10.3 to 15.6) %c | 17.6 (15.2 to 20.0) % | 6.1 (4.3 to 8.0) % | 0.001 | <0.001 |
| LV relative wall thickness | 0.3 (−2.2 to 2.9) % | 1.0 (−1.4 to 3.3) % | 0.4 (−1.4 to 2.1) % | 0.66 | 0.98 |
| LV ejection fraction | −9.5 (−12.1 to −6.8) %c | −6.1 (−8.5 to −3.6) % | −5.5 (−7.3 to −3.6) % | 0.026 | 0.011 |
| LV global longitudinal strain | −5.8 (−9.2 to −2.5) %c | −6.0 (−9.0 to −3.1) % | −3.8 (−6.1 to −1.6) % | 0.92 | 0.24 |
| E' | −8.2 (−10.8 to −5.7) %c | −6.4 (−8.7 to −4.1) % | −4.3 (−6.0 to −2.5) % | 0.18 | 0.004 |
| E/e' ratio | 8.2 (5.5 to 10.8) %c | 7.6 (5.2 to 9.9) % | 5.3 (3.4 to 7.1) % | 0.70 | 0.05 |
| Tricuspid annulus planar systolic excursion | −2.4 (−4.9 to 0.2) % | 2.0 (−0.3 to 4.3) % | −1.6 (−3.4 to 0.1) % | 0.004 | 0.63 |
| Tricuspid regurgitation maximum velocity | 7.2 (4.1 to 10.2) %c | 2.3 (−0.3 to 4.9) % | 5.2 (3.2 to 7.2) % | 0.002 | 0.25 |
| LA volume index | 11.2 (8.6 to 13.8) %c | 16.1 (13.8 to 18.5) % | 8.1 (6.3 to 9.9) % | <0.001 | 0.019 |
| Effect (95% CI) | P for comparison with cMyCb | ||||
|---|---|---|---|---|---|
| cMyC | cTnI | cTnT | cTnI | cTnT | |
| LV end-diastolic volume index | 10.3 (7.5 to 13.1) %c | 14.9 (12.4 to 17.4) % | 7.9 (6.0 to 9.8) % | 0.001 | 0.08 |
| LV mass index | 13.0 (10.3 to 15.6) %c | 17.6 (15.2 to 20.0) % | 6.1 (4.3 to 8.0) % | 0.001 | <0.001 |
| LV relative wall thickness | 0.3 (−2.2 to 2.9) % | 1.0 (−1.4 to 3.3) % | 0.4 (−1.4 to 2.1) % | 0.66 | 0.98 |
| LV ejection fraction | −9.5 (−12.1 to −6.8) %c | −6.1 (−8.5 to −3.6) % | −5.5 (−7.3 to −3.6) % | 0.026 | 0.011 |
| LV global longitudinal strain | −5.8 (−9.2 to −2.5) %c | −6.0 (−9.0 to −3.1) % | −3.8 (−6.1 to −1.6) % | 0.92 | 0.24 |
| E' | −8.2 (−10.8 to −5.7) %c | −6.4 (−8.7 to −4.1) % | −4.3 (−6.0 to −2.5) % | 0.18 | 0.004 |
| E/e' ratio | 8.2 (5.5 to 10.8) %c | 7.6 (5.2 to 9.9) % | 5.3 (3.4 to 7.1) % | 0.70 | 0.05 |
| Tricuspid annulus planar systolic excursion | −2.4 (−4.9 to 0.2) % | 2.0 (−0.3 to 4.3) % | −1.6 (−3.4 to 0.1) % | 0.004 | 0.63 |
| Tricuspid regurgitation maximum velocity | 7.2 (4.1 to 10.2) %c | 2.3 (−0.3 to 4.9) % | 5.2 (3.2 to 7.2) % | 0.002 | 0.25 |
| LA volume index | 11.2 (8.6 to 13.8) %c | 16.1 (13.8 to 18.5) % | 8.1 (6.3 to 9.9) % | <0.001 | 0.019 |
Abbreviations: cMyC, cardiac myosin binding protein C; cTnI, cardiac troponin I; cTnT, cardiac troponin T; CI, confidence interval; LV, left ventricular; E′, peak early diastolic mitral annulus tissue Doppler velocity; E, peak early diastolic transmitral velocity by pulsed Doppler; LA, left atrial.
aAll potential echocardiographic determinants are per 1 Z-score. Adjusted for age, sex, estimated glomerular filtration rate, prior hypertension, diabetes mellitus, coronary artery disease, and heart failure.
bComparison of associations with cMyC vs cTnI and cTnT.
cP < 0.001
Baseline characteristics of participants and demographic and clinical determinants of cMyC In CMR Substudy participants
Among the 199 participants with cMyC measurement and CMR examination, median age was 63.9 (62.4 to 65.2) and 51.3% were men. Comorbidities included HF in 1.5%, stroke in 1.5%, atrial fibrillation in 3.5%, arterial hypertension in 52.3%, and diabetes mellitus in 4.5%. Concentrations of cMyC were measurable in 99.0% of CMR substudy participants, while concentrations of cTnT were measurable in 53.3% (P = 0.006 compared to cMyC) and cTnI in 99.5% (P = 0.88 compared to cMyC). Participants who completed a CMR examination with cMyC in the highest quartile were more often males, had higher levels of cardiac troponins, and lower eGFR compared to participants with cMyC in the lowest quartile and as such had increased CV risk (online Supplemental Table 8).
CMR Determinants of cMyC
Participants with cMyC concentrations in the 4th quartile at study baseline had elevated CMR-determined LV mass index and end-diastolic volumes, but lower LV ejection fraction 4 to 7 years later (online Supplemental Table 9). Elevated cMyC did not associate with ECV among the 191 (96%) participants with available ECV measurement. Participants with available LGE sequence (197 [99%]) and cMyC in the highest quartile had a significantly higher proportion of LGE scars, including ischemic and nonischemic subtypes, than those in the lower (1–3) cMyC quartiles (Supplemental Table 9).
Associations between cMyC And CMR Indices of fibrosis
Neither cMyC, cTnI, nor cTnT were associated with ECV in the logistic or linear regression analyses (Table 4, online Supplemental Tables 10–12). In unadjusted analyses, cMyC (odds ratio [OR] 2.3; 95% CI, 1.5–3.4), cTnI (OR 2.1; 95% CI, 1.5–2.8), and cTnT (OR 2.1; 95% CI, 1.5–3.0) were all associated with the presence of any LGE scar. These results remained statistically significant in adjusted models (Table 4). All circulating biomarkers were associated with ischemic and nonischemic subtypes of LGE scars (Supplemental Table 9 and Table 4). No differences were seen in the associations between cMyC or cardiac troponins with CMR indices of myocardial fibrosis in logistic or linear regression analyses (Table 4, Supplemental Tables 10–12).
Comparison of associations of cMyC, cTnI, and cTnT with CMR indices of fibrosis in adjusted analysesa.
| OR (95% CI) | Pb | OR (95% CI) | Pb | OR (95% CI) | Pb | OR (95% CI) | Pb | |
|---|---|---|---|---|---|---|---|---|
| ECV | LGE | Ischemic | Nonischemic | |||||
| cMyC | 0.9 (0.6 to 1.3) | — | 2.1 (1.4 to 3.2)c | — | 1.9 (1.2 to 2.9)c | — | 1.9 (1.2 to 3.0)c | — |
| cTnI | 1.0 (0.8 to 1.2) | 0.57 | 1.9 (1.4 to 2.6) | 0.78 | 2.3 (1.5 to 3.5) | 0.44 | 1.7 (1.2 to 2.4) | 0.72 |
| cTnT | 1.1 (0.8 to 1.5) | 0.22 | 1.9 (1.3 to 2.8) | 0.73 | 2.3 (1.3 to 4.1) | 0.39 | 1.6 (1.0 to 2.6) | 0.67 |
| OR (95% CI) | Pb | OR (95% CI) | Pb | OR (95% CI) | Pb | OR (95% CI) | Pb | |
|---|---|---|---|---|---|---|---|---|
| ECV | LGE | Ischemic | Nonischemic | |||||
| cMyC | 0.9 (0.6 to 1.3) | — | 2.1 (1.4 to 3.2)c | — | 1.9 (1.2 to 2.9)c | — | 1.9 (1.2 to 3.0)c | — |
| cTnI | 1.0 (0.8 to 1.2) | 0.57 | 1.9 (1.4 to 2.6) | 0.78 | 2.3 (1.5 to 3.5) | 0.44 | 1.7 (1.2 to 2.4) | 0.72 |
| cTnT | 1.1 (0.8 to 1.5) | 0.22 | 1.9 (1.3 to 2.8) | 0.73 | 2.3 (1.3 to 4.1) | 0.39 | 1.6 (1.0 to 2.6) | 0.67 |
Abbreviations: cMyC, cardiac myosin binding protein C; cTnI, cardiac troponin I; cTnT, cardiac troponin T; CMR, cardiovascular magnetic resonance; OR, odds ratio; CI, confidence interval; ECV, extracellular volume fraction; LGE, late gadolinium enhancement.
aAdjusted for age, sex, eGFR, prior hypertension, diabetes mellitus, and heart failure.
bComparison of associations with cMyC.
cP < 0.01.
Comparison of associations of cMyC, cTnI, and cTnT with CMR indices of fibrosis in adjusted analysesa.
| OR (95% CI) | Pb | OR (95% CI) | Pb | OR (95% CI) | Pb | OR (95% CI) | Pb | |
|---|---|---|---|---|---|---|---|---|
| ECV | LGE | Ischemic | Nonischemic | |||||
| cMyC | 0.9 (0.6 to 1.3) | — | 2.1 (1.4 to 3.2)c | — | 1.9 (1.2 to 2.9)c | — | 1.9 (1.2 to 3.0)c | — |
| cTnI | 1.0 (0.8 to 1.2) | 0.57 | 1.9 (1.4 to 2.6) | 0.78 | 2.3 (1.5 to 3.5) | 0.44 | 1.7 (1.2 to 2.4) | 0.72 |
| cTnT | 1.1 (0.8 to 1.5) | 0.22 | 1.9 (1.3 to 2.8) | 0.73 | 2.3 (1.3 to 4.1) | 0.39 | 1.6 (1.0 to 2.6) | 0.67 |
| OR (95% CI) | Pb | OR (95% CI) | Pb | OR (95% CI) | Pb | OR (95% CI) | Pb | |
|---|---|---|---|---|---|---|---|---|
| ECV | LGE | Ischemic | Nonischemic | |||||
| cMyC | 0.9 (0.6 to 1.3) | — | 2.1 (1.4 to 3.2)c | — | 1.9 (1.2 to 2.9)c | — | 1.9 (1.2 to 3.0)c | — |
| cTnI | 1.0 (0.8 to 1.2) | 0.57 | 1.9 (1.4 to 2.6) | 0.78 | 2.3 (1.5 to 3.5) | 0.44 | 1.7 (1.2 to 2.4) | 0.72 |
| cTnT | 1.1 (0.8 to 1.5) | 0.22 | 1.9 (1.3 to 2.8) | 0.73 | 2.3 (1.3 to 4.1) | 0.39 | 1.6 (1.0 to 2.6) | 0.67 |
Abbreviations: cMyC, cardiac myosin binding protein C; cTnI, cardiac troponin I; cTnT, cardiac troponin T; CMR, cardiovascular magnetic resonance; OR, odds ratio; CI, confidence interval; ECV, extracellular volume fraction; LGE, late gadolinium enhancement.
aAdjusted for age, sex, eGFR, prior hypertension, diabetes mellitus, and heart failure.
bComparison of associations with cMyC.
cP < 0.01.
Sensitivity analyses
Demographic and clinical variables (age, male sex, CAD, hypertension, and eGFR) and echocardiographic variables (LV end-diastolic volume index, LV mass index, LV ejection fraction, LV global longitudinal strain, E′, and E/e′ ratio) remained significantly associated with concentrations of cMyC after adjustment for cTnT (online Supplemental Table 13). The associations between cMyC and the ischemic subtype of LGE scars, and scar volumes, were attenuated after adjustment for cTnT (online Supplemental Tables 14 and 15). We found significant interactions of sex with history of coronary artery disease, diabetes mellitus, LV mass index, and E/e′ ratio, and concentrations of cMyC (online Supplemental Tables 16 and 17).
Discussion
The current study provides new and important information concerning the novel cardiac-specific biomarker cMyC in the general population setting. We report 5 principal novel findings in the current study. First, using a high-sensitivity assay, cMyC concentrations are detectable in >99% of a middle-aged population-based sample and, as the Singulex troponin I assay is no longer produced for clinical use, in a greater proportion than the high-sensitivity assays for cardiac troponins that are currently commercially available (19). Second, cMyC associates with many conventional cardiovascular risk factors in the general population, suggesting that it integrates information concerning cardiovascular risk. Third, in the general population setting, circulating cMyC concentrations associate strongly with other markers of cardiac cell injury, in particular with cTnI and somewhat less strongly with cTnT. Fourth, cMyC associates with major indices of cardiac anatomy and function, including LV mass, left atrial and ventricular volumes and function, and noninvasive indices of LV filling pressure and pulmonary artery pressures. Finally, cMyC concentrations associate with future ischemic and nonischemic focal scars that are present 4 to 7 years after the baseline examination, but not with diffuse fibrosis.
cMyC As a cardiovascular biomarker in the acute setting
Although for many years recognized as an important part of the contractile apparatus of cardiomyocytes, it is not until recently that a high-sensitivity assay for cMyC has become commercially available. Accordingly, limited clinical data concerning the performance of cMyC as a cardiovascular biomarker are available, and most relate to the use of cMyC compared to cardiac troponins in the acute ischemic injury setting. In a study of 174 patients with suspected MI presenting less than 3 h after chest pain onset, ratios of cMyC/cTnI were much higher initially than in subsequent blood samples (7). The earlier rise of cMyC compared to cTnI may be attributed to differing release mechanisms or a greater abundance of cMyC in the cytosol. In a subsequent study, cMyC was measured in a European multicenter cohort of patients with suspected MI (10). Again, cMyC performed favourably to cardiac troponins, most notably in early presenters. Further, cMyC has satisfactory analytic variability in clinically relevant concentrations, supporting wider implementation in different patient settings (20).
cMyC As a cardiovascular biomarker in the chronic setting
So far, sparse data are available in the chronic setting, but one study using the same cMyC assay as in our study has assessed the correlates and prognostic value of cMyC in aortic stenosis (13). The study encompassed 2 modestly sized cohorts of patients with aortic stenosis (n = 161 and n = 104), as well as a small, healthy control group, and cMyC was found to be associated with LV hypertrophy, as well as imaging and histologic markers of fibrosis (13). The current study confirms and extends most of these observations in a largely unselected population of individuals of 63 to 65 years of age by demonstrating associations with CMR-determined focal fibrosis and echocardiographic indices of LV mass and systolic function. The association with structural myocardial disease is indirectly reflected by the observation that the 99th percentile decreased after excluding participants with CV risk factors and echocardiographic imaging indices compatible with myocardial pathology.
Diffuse fibrosis is a ubiquitous and detrimental alteration of the myocardial interstitium in chronic cardiac disease (21) but is considered to occur early in response to myocardial injury, preceding progression to cardiomyocyte death and focal fibrosis (22). Like our study, the aforementioned study of aortic stenosis patients assessed diffuse fibrosis by calculating ECV. They demonstrated an association between cMyC and ECV that, somewhat surprisingly, was not observed in our cohort. Our general population cohort is not free of possible triggers of diffuse fibrosis, but our participants are more likely to be less burdened with fibrotic changes secondary to pressure overload compared to aortic stenosis patients. Our general population participants are more likely to be similar to the healthy controls of the aortic stenosis study, in which no association between cMyC and ECV was found. Furthermore, as diffuse fibrosis and corresponding increases in ECV are reversible (23) and deposition can be upregulated post-MI (24), over time we may find an association between cMyC and ECV as chronic cardiac disease progresses in our study population. None of the biomarkers of myocardial injury in the current study were associated with diffuse fibrosis, in contrast to previous findings in a large general population cohort (6), and our findings should be validated in other cohorts to determine if cMyC has a role in prognostication of diffuse fibrosis.
Overall, our findings support the theory that chronic, low-level elevation of cMyC concentrations is reflective of cardiac hypertrophy and increased rate of cardiomyocyte cell death with subsequent focal fibrosis. Cardiac troponins are generally considered to be markers of cardiac injury and not to play any causal role in the development of HF. The proteolytic cleavage of cMyC is regulated by several kinases (25), and data from a single study suggested that cleavage products of cMyC may possess cardiotoxic properties (26). To what extent these unconfirmed experimental observations translate into clinically relevant cardiotoxicity remains unknown. Although the renal clearance mechanisms of cMyC remain poorly defined, concentrations of cMyC correlated inversely with renal function. Interestingly, the associations between cMyC and renal function appeared to be stronger than associations between cardiac troponins I and T and renal function. Similarly, it has been shown that cMyC and cTnT, as opposed to cTnI, show physiological circadian rhythm, indicating similarities in either excretion, metabolism, or both (27).
Given that both cMyC and cardiac troponins are parts of the contractile apparatus of cardiomyocytes, it is not surprising that these biomarkers correlate relatively closely. Accordingly, the associations of cMyC with cardiovascular risk factors and echocardiographic indices of cardiac anatomy and function were generally of the same order of magnitude as those of cardiac troponins. Further studies with outcome data in large population-based samples will be required to determine if these associations translate into similar or better performance as prognostic indicators.
Study limitations
Limitations of the current study include a narrow age distribution, as all participants were born in 1950, and limited ethnic and geographic diversity due to participants being primarily of Northern European White ancestry and at inclusion lived in a single Norwegian county. Age, ethnicity, and geography could influence cMyC concentrations and, as such, results may not be generalizable to community-dwelling individuals of differing ages, ethnicities, and lifestyles. Accordingly, the 97.5th and 99th percentiles reported should not be considered representative of concentrations across age groups. ECV and LGE provide measurements of fibrosis at the time of CMR performed 4 to 7 years after cMyC measurement at study baseline examination, and it is not possible to conclude with certainty when the fibrosis was deposited over the years from baseline to CMR examination.
Conclusion
Using a novel high-sensitivity assay, cMyC can be detected and quantified in the great majority of middle-aged individuals in the general population. cMyC concentrations are associated with CV risk factors, reflect LV remodelling, focal fibrosis, and systolic and diastolic dysfunction.
Supplemental Material
Supplemental material is available at Clinical Chemistry online.
Nonstandard Abbreviations
cMyC, cardiac myosin binding protein C; CMR, cardiovascular magnetic resonance; LV, left ventricular; cTnT, cardiac troponin T; cTnI, cardiac troponin I; HF, heart failure; eGFR, estimated glomerular filtration rate; LoD, limit of detection; LLOQ, lower limit of quantification; ULOQ, upper limit of quantification; CV, cardiovascular; ECV, extracellular volume fraction; LGE, late gadolinium enhancement.
Author Contributions
The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list.
Michael F. Paus (Data curation-Equal, Formal analysis-Lead, Investigation-Equal, Writing—original draft-Lead, Writing—review & editing-Equal), Magnus N. Lyngbakken (Conceptualization-Equal, Data curation-Equal, Formal analysis-Equal, Investigation-Equal, Project administration-Equal, Supervision-Equal, Writing—original draft-Equal, Writing—review & editing-Equal), Arnljot Tveit (Funding acquisition-Equal, Project administration-Lead, Supervision-Equal, Writing—review & editing-Equal), Kjetil Steine (Investigation-Equal, Project administration-Equal, Writing—review & editing-Equal), Trygve Berge (Project administration-Equal, Writing—review & editing-Equal), Julia B. Skranes (Project administration-Equal, Writing—review & editing-Equal), Erika N. Aagaard (Data curation-Equal, Investigation-Equal, Writing—review & editing-Equal), Brede Kvisvik (Data curation-Equal, Investigation-Equal, Writing—review & editing-Equal), Jon Brynildsen (Project administration-Equal, Writing—review & editing-Equal), Siri L. Heck (Conceptualization-Equal, Data curation-Equal, Methodology-Equal, Project administration-Equal, Writing—review & editing-Equal), Thakshani Wimalanathan (Data curation-Equal, Investigation-Equal, Writing—review & editing-Equal), Kristin M. Aakre (Methodology-Equal, Writing—review & editing-Equal), Helge Røsjø (Funding acquisition-Equal, Project administration-Lead, Writing—review & editing-Equal), and Torbjørn Omland (Conceptualization-Equal, Funding acquisition-Equal, Project administration-Lead, Supervision-Equal, Writing—original draft-Equal, Writing—review & editing-Equal)
Authors’ Disclosures or Potential Conflicts of Interest
Upon manuscript submission, all authors completed the author disclosure form.
Research Funding
This work was supported by Vestre Viken Hospital Trust, Akershus University Hospital, and the Kristian Gerhard Jebsen Foundation (grant number SKGJ-MED-024). It was also supported by the Norwegian Research Council, Norwegian Health Association, South-Eastern Norway Regional Health Authority (former funding scheme FRIMEDBIO), and the University of Oslo. Roche Diagnostics provided reagents for cTnT free of charge.
Disclosures
M.F. Paus has received a speaker honorarium from Abbott Diagnostics. K.M. Aakre has served on advisory boards for Roche Diagnostics, Siemens Healtineers, Radiometer, and SpinChip, received consultant honoraria from CardiNor, a lecturing honorarium from Siemens Healthineers, Mindray, and Snibe Diagnostic, and research grants from Siemens Healthineers and Roche Diagnostics. K.M. Aakre is an Associate Editor for Clinical Biochemistry and Chair of the IFCC Committee of Clinical Application of Cardiac Biomarkers. T. Omland has received personal fees from Abbott Diagnostics, Bayer, CardiNor, NovoNordisk, and Roche Diagnostics, and research support via Akershus University Hospital from Abbott Diagnostics, CardiNor, ChromaDex, Novartis, and Roche Diagnostics.
Role of Sponsor
The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, preparation of manuscript, or final approval of manuscript.
Acknowledgments
We thank our study participants for their participation. We also thank our dedicated study staff at the Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, the Clinical Trial Unit, Division of Medicine, Akershus University Hospital, and the Department of Diagnostic Imaging, Akershus University Hospital. Finally, we thank Joanna Sulkowska for help creating code to export CMR raw data.
