Abstract
Objective
To investigate the relationship between high-sensitivity cardiac troponin T (hs-cTnT) levels and sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM).
Methods
A referral HCM population with prospectively obtained hs-cTnT concentration from March 1, 2018, to April 23, 2020, was reviewed. Patients with end-stage renal disease or an abnormal hs-cTnT level not collected in an outpatient protocolled fashion were excluded. The hs-cTnT level was compared with demographic characteristics, comorbidities, conventional HCM-associated SCD risk factors, imaging, exercise testing, and prior cardiac events.
Results
Of 112 included patients, 69 (62%) had an elevated hs-cTnT concentration. The level of hs-cTnT correlated with known risk factors for SCD, including nonsustained ventricular tachycardia (P=.049) and septal thickness (P=.02). When patients were stratified by having a normal vs an elevated hs-cTnT concentration, patients with elevated hs-cTnT concentration were more likely to have experienced an implantable cardioverter-defibrillator discharge for ventricular arrhythmia, ventricular arrhythmia with hemodynamic instability, or cardiac arrest (incidence rate ratio, 2.96; 95% CI, 1.11 to 10.2). When sex-specific hs-cTnT cutoffs were removed, this association was no longer present (incidence rate ratio, 1.50; 95% CI, 0.66 to 3.60).
Conclusion
In a protocolized, outpatient HCM population, hs-cTnT elevations were common and were associated with more arrhythmic expressivity of the HCM substrate as indicated by previous ventricular arrhythmias and appropriate implantable cardioverter-defibrillator shocks only when sex-specific hs-cTnT cutoffs were used. Further research should use different hs-cTnT reference values by sex to determine whether an elevated hs-cTnT value is an independent risk factor for SCD in patients with HCM.
Abbreviations and Acronyms:
CAD (coronary artery disease), HCM (hypertrophic cardiomyopathy), hs-cTnT (high-sensitivity cardiac troponin T), ICD (implantable cardioverter-defibrillator), LAVi (left atrial volume index), LVEF (left ventricular ejection fraction), LVOT (left ventricular outflow tract), NSVT (nonsustained ventricular tachycardia), NYHA (New York Heart Association), SCD (sudden cardiac death)Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease of which the most severe complication, sudden cardiac death (SCD), occurs in a minority of patients.
1
Reported rates of SCD vary from 0.33 per 1000 person-years in an unselected young outpatient population up to 10 per 1000 HCM person-years in referral populations.2
One clinical challenge in HCM care is determination of SCD risk, as risk stratification models for SCD continue to appropriately evolve.The American College of Cardiology and American Heart Association joint guidelines traditionally emphasized the importance of a personal and family history of SCD, unexplained syncope, and extensive left ventricular hypertrophy, with additional consideration given to ambulatory nonsustained ventricular tachycardia (NSVT) and an abnormal blood pressure response to exercise.
3
Guidelines from the European Society of Cardiology advanced this approach by considering continuous variables as such (rather than binary), adding other markers of phenotypic severity (eg, age, left atrial size, obstruction), and providing a validated estimate of the magnitude of risk.- Gersh B.J.
- Maron B.J.
- Bonow R.O.
- et al.
American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Association for Thoracic Surgery; American Society of Echocardiography; American Society of Nuclear Cardiology; Heart Failure Society of America; Heart Rhythm Society; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons
2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
J Thorac Cardiovasc Surg. 2011; 142: 1303-1338
4
Subsequently, this natural evolution of SCD risk prediction progressed with the recognition of the value of the presence of apical aneurysm, extensive myocardial scar/fibrosis, or left ventricular systolic dysfunction.5
, 6
, 7
Notably, no current HCM SCD risk assessment algorithm uses biomarker data.The specific and sensitive nature of high-sensitivity troponin assays for myocardial damage makes this biomarker attractive as myocardial injury with subsequent scarring has been implicated as a major driver of SCD in HCM.
8
,9
Most previous studies have used the high-sensitivity cardiac troponin T (hs-cTnT) assay. Previous studies have found that hs-cTnT correlates with several SCD risk factors as well as with a composite end point of heart failure- and SCD-related events in patients with HCM.9
,10
One study was too small to probe hs-cTnT adequately, and the other focused more on the correlations with magnetic resonance imaging. Although women appeared to be more commonly at risk, sex-specific cutoff values were not used. In addition, there was exclusion of patients with coronary artery disease (CAD) or prior septal reduction therapy. This study sought to evaluate the correlation between hs-cTnT levels and SCD events in an outpatient referral population of patients with HCM without exclusions using sex-specific analyses for hs-cTnT.Methods
Selection of Patients
In March 2018, the Mayo Clinic HCM Clinic began collecting hs-cTnT values as part of the preconsultation laboratory evaluation for all patients presenting for outpatient HCM care. After institutional review board approval, an established database of patients including this population was queried to identify patients aged 18 years or older, without end-stage renal disease, and with an hs-cTnT measurement. Patients with an abnormal hs-cTnT level were included only when the measurement was obtained in a protocolled fashion on an outpatient basis before consultation or for research purposes rather than when clinically ill. The Mayo Clinic Department of Laboratory Medicine and Pathology cutoff values for hs-cTnT were used, and an abnormal hs-cTnT level was defined as above 10 ng/L for women and above 15 ng/L for men. These cutoff values were established by our laboratory group on the basis of review of the data in this area, including the normal range studies done during the validation of this assay in Europe.
11
,12
These values are similar to those of the Universal Sample Bank and significantly lower than the hs-cTnT 99th percentiles reported in the Roche Gen 5 (hs) cTnT package insert cleared by the Food and Drug Administration.11
,13
Data Collection
Patients’ demographic characteristics, symptoms, past medical history, family history, medications, Holter data, echocardiography data, and exercise testing data were collected. Family history of HCM was restricted to first-degree family members only. Risk factors for HCM-associated SCD were defined by previously published literature and were collected manually from each chart to ensure accuracy.
4
,5
Left atrial volume index (LAVi) was used for assessment of left atrial size rather than left atrial diameter, given the institutional preference of reporting this variable. Patients were identified as having CAD by billing diagnosis code, subsequently confirmed by manual review of relevant testing.Patient Testing
Plasma hs-cTnT concentration was measured in a protocolled fashion by the Cobas e immunoassay Troponin T Generation 5 method (Elecsys Troponin T Gen 5 STAT, version 03/2017; Roche Diagnostics). The limit of detection of the assay is reported to be 5 ng/L, but the Food and Drug Administration allows reporting only of values of 6 ng/L or greater. Left ventricular outflow tract (LVOT) gradient, maximum left ventricular wall thickness, and left ventricular ejection fraction (LVEF) were measured by 2-dimensional and Doppler echocardiography, in line with the recommendations from the American Society of Echocardiography.
14
Left atrial volume index was calculated by the biplane area-length method.15
Nonsustained ventricular tachycardia was based on review of Holter monitor data or other documentation on outside records. Abnormal blood pressure response to exercise was documented on exercise testing per a previously reported protocol.
16
Appropriateness of implantable cardioverter-defibrillator (ICD) discharge was based on device interrogation. When this information was not available, it was based on clinical presentation at the time of discharge. Ventricular arrhythmias were considered hemodynamically unstable if associated with loss of consciousness or hypotension. In patients who experienced multiple instances of the same type of arrhythmic event, it was counted only once for statistical analysis.
Statistical Analyses
All statistical analysis was performed with BlueSky Statistics software, version 7.20 (BlueSky Statistics LLC). Normally distributed continuous variables are reported as mean ± standard deviation; non-normally distributed variables are reported as median with interquartile range. Analyses were performed with hs-cTnT as a dichotomous variable, with patients divided into a normal hs-cTnT group and elevated hs-cTnT group by the aforementioned cutoff values. Nonparametric continuous variables were compared across 2 groups with Wilcoxon rank sum tests, and unpaired t-tests were used when they were parametric. The χ2 and Fisher exact tests were used to compare categorical variables between groups. Stepwise logistic regression with forward direction was then used to identify clinical predictors of having an elevated hs-cTnT concentration. Analyses were also performed with hs-cTnT as a continuous variable following logarithmic transformation. Pairs of continuous variables were examined for correlation using the Pearson correlation coefficient, and unpaired t-tests were used to compare log (hs-cTnT) between groups. Multiple linear regression analysis using the standard least squares penalty was then performed to find clinical predictors of log (hs-cTnT).
The association of group status with the odds of history of clinically significant arrythmias occurring before baseline collection of hs-cTnT concentration was estimated by logistic regression, reported as odds ratio. A composite of ICD discharge for ventricular arrhythmia, ventricular arrhythmia with hemodynamic instability, and cardiac arrest was created using the count method and compared between groups with Poisson regression. These variables were compiled into a composite measure because there was a low number of individual events and they represent similar clinical entities. Results of the Poisson regression analysis are displayed as an incidence rate ratio with 95% CIs. This analysis was repeated after exclusion of patients with a history of CAD and also repeated after removal of sex-specific cutoffs so that all hs-cTnT levels of 15 ng/L or lower were considered normal.
Results
Study Population
There were 112 patients included in the study, of whom 69 (62%) had an abnormal hs-cTnT level exceeding the established, sex-specific cutoff values (>10 ng/L for women and >15 ng/L for men). Baseline characteristics are outlined in Table 1. The study population was male predominant (65%), and men had a significantly higher mean hs-cTnT level than women (23 ng/L vs 16 ng/L; P=.02). Fifty-seven (51%) patients had a history of septal myectomy, and 2 (1.7%) previously underwent septal ablation. All study hs-cTnT levels were determined at least 3 months from septal reduction therapy. Twenty-two (20%) patients had a history of CAD, of whom 21 (19%) had coronary angiography available to confirm the diagnosis; 4 patients (3.8%) had prior myocardial infarctions. Cardiac magnetic resonance imaging was available for only 59% of the patient population, with few having the presence of late gadolinium enhancement, so these data were not included.
Table 1Baseline Characteristics and Comparison of hs-cTnT Groups
a
,,ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BSA, body surface area; CAD, coronary artery disease; HCM, hypertrophic cardiomyopathy; hs-cTnT, high-sensitivity cardiac troponin T; ICD, implantable cardioverter-defibrillator; LAVi, left atrial volume index; LV, left ventricle; LVEF, left ventricular ejection fraction; LVOTO, left ventricular outflow tract obstruction; NT-proBNP, N-terminal pro–B-type natriuretic peptide; NYHA, New York Heart Association; Vo2, oxygen consumption.
| Characteristic | (N=112) | Normal hs-cTnT (n=43) | High hs-cTnT (n=69) | P value |
|---|---|---|---|---|
| hs-cTnT, ng/L | 16 (11-25) | 10 (7-13) | 23 (17-33) | |
| Age, years | 63±14 | 58±12 | 66±14 | .004 |
| Race | .73 | |||
| White | 107 (96) | 41 (95) | 66 (97) | |
| Asian/Pacific Islander | 3 (3) | 1 (2) | 2 (3) | |
| African American | 1 (1) | 1 (2) | 0 | |
| Sex | .23 | |||
| Male | 73 (65) | 31 (72) | 42 (62) | |
| Female | 39 (35) | 12 (28) | 27(39) | |
| NYHA functional class | .34 | |||
| I | 27 (24) | 9 (23) | 18 (29) | |
| II | 38 (34) | 13 (33) | 25 (40) | |
| III-IV | 37 (33) | 18 (45) | 19 (30) | |
| ICD | 40 (36) | 11 (25) | 29 (42) | .08 |
| Family history of HCM (n=103) | 40 (36) | 17 (42) | 23 (38) | .75 |
| Previous myectomy | 57 (51) | 24 (56) | 33 (48) | .41 |
| Previous septal ablation | 2 (2) | 1 (3) | 1 (2) | >.99 |
| History of CAD | 22 (20) | 4 (9) | 18 (26) | .049 |
| Prior myocardial infarction | 4 (4) | 1 (3) | 3 (6) | .64 |
| Prior stroke (n=95) | 8 (7) | 2 (5) | 6 (11) | .46 |
| History of atrial fibrillation (n=96) | 19 (17) | 9 (24) | 10 (18) | .52 |
| Creatinine, mg/dL | 1.1 (0.9-1.2) | 1.0 (0.9-1.2) | 1.1 (1.0-1.3) | .003 |
| Glomerular filtration rate, mL/min per BSA | 66 (56-79) | 75 (66-88) | 61 (52-69) | <.001 |
| NT-proBNP, pg/mL | 550 (220-1200) | 260 (121-641) | 908 (395-1400) | <.001 |
| Medications | ||||
| β-receptor antagonist | 98 (88) | 37 (86) | 61 (90) | .56 |
| Calcium channel blocker | 67 (60) | 23 (54) | 44 (65) | .24 |
| ACE inhibitor/ARB | 40 (36) | 12 (28) | 28 (41) | 0.16 |
| Disopyramide | 12 (11) | 2 (5) | 10 (15) | 0.12 |
| Statin | 60 (54) | 19 (44) | 41 (60) | .09 |
| Aspirin | 75 (67) | 25 (58) | 50 (74) | .09 |
| Peak Vo2, mL/kg per minute (n=88) | 20 (16-26) | 22 (16-28) | 19 (16-24) | .15 |
| Peak Vo2 predicted, % (n=88) | 71 (58-87) | 74 (58-86) | 70 (59-87) | .96 |
| Systolic blood pressure, mm Hg | 126±19 | 128±20 | 125±18 | .47 |
| Diastolic blood pressure, mm Hg | 75±11 | 78±12 | 73±10 | .02 |
| Heart rate, beats/min | 69±11 | 68±11 | 70±11 | .21 |
| Maximum LV wall thickness, mm | 19 (16-23) | 19 (16-23) | 20 (16-23) | .12 |
| Septal thickness, mm | 18 (15-22) | 17 (13-19) | 19 (16-24) | .003 |
| Posterior wall thickness, mm (n=113) | 12 (11-14) | 11 (10-13) | 13 (11-14) | .06 |
| Resting outflow tract gradient, mm Hg | 4 (4-21) | 4 (4-13) | 4 (4-19) | .15 |
| LVOTO, mm Hg | ||||
| Nonobstructive | 73 (65) | 32 (74) | 41 (59) | .11 |
| Labile obstruction | 16 (14) | 6 (14) | 10 (14) | .94 |
| Resting obstruction | 23 (21) | 5 (12) | 18 (26) | .07 |
| LVEF, % | 65 (60-67) | 65 (63-68) | 64 (58-67) | .14 |
| LVEF <50% | 10 (9) | 2 (5) | 8(12) | 0.31 |
| LAVi, mL/m2 (n=111) | 45 (34-55) | 43 (30-53) | 45 (35-59) | .19 |
a ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BSA, body surface area; CAD, coronary artery disease; HCM, hypertrophic cardiomyopathy; hs-cTnT, high-sensitivity cardiac troponin T; ICD, implantable cardioverter-defibrillator; LAVi, left atrial volume index; LV, left ventricle; LVEF, left ventricular ejection fraction; LVOTO, left ventricular outflow tract obstruction; NT-proBNP, N-terminal pro–B-type natriuretic peptide; NYHA, New York Heart Association; Vo2, oxygen consumption.
b To convert creatinine values to μmol/L, multiply by 88.4; to convert NT-proBNP values to pmol/L, multiply by 0.118.
c Values are number (percentage), mean ± standard deviation, or median (interquartile range).
Group Comparison
When cohorts with normal hs-cTnT vs elevated hs-cTnT values were compared and stepwise regression was applied to all variables with a P value below .05, lower glomerular filtration rate (odds ratio, 0.94; 95% CI, −0.96 to −0.92; P=.01) and greater septal thickness (odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=.02) were identified as clinical predictors of having an elevated hs-cTnT level, whereas CAD was not.
SCD-Associated Risk Factors
Traditional risk factors for HCM-associated SCD were evaluated for correlation with hs-cTnT, both as continuous and dichotomous variables when possible. Table 2 lists the traditional risk factors for SCD and the correlation with log (hs-cTnT) when septal thickness, LVOT gradient, LVEF, and LAVi are reported as continuous variables. Here, septal thickness (beta coefficient, 0.01; 95% CI, 0.007 to 0.013; P=.02) and NSVT (beta coefficient, 0.17; 95% CI, 0.10 to 0.24; P=.049) had a positive correlation with log (hs-cTnT) in both univariate and multivariate analysis (model R2=0.36; F1,51=3.2; P=.004). When septal thickness, LVOT gradient, LVEF, and LAVi were included in the model as dichotomous variables, NSVT (beta coefficient, 0.17; 95% CI, 0.10 to 0.24; P=.02) was the only variable significantly associated with log (hs-cTnT) levels (model R2=0.22; F1,56=1.8; P=.09).
Table 2Comparison of SCD Risk Factors With Log (hs-cTnT)
| Risk factor | Univariable | Multivariable regression analysis | ||
|---|---|---|---|---|
| P value | Beta coefficient | Standard error | P value | |
| Family history SCD <50 years | .54 | −0.20 | 0.13 | .13 |
| Yes (n=105) | ||||
| No (n=7) | ||||
| Unexplained syncope | .72 | −0.01 | 0.07 | .91 |
| Yes (n=28) | ||||
| No (n=57) | ||||
| Septal thickness, mm | .005 (r=0.30) | 0.01 | 0.003 | .02 |
| BP response to exercise | .049 | 0.03 | 0.07 | .70 |
| Normal (n=32) | ||||
| Abnormal (n=60) | ||||
| NSVT | .04 | 0.17 | 0.07 | .049 |
| Yes (n=59) | ||||
| No (n=53) | ||||
| Left atrial volume index, mL/m2 | <.001 (r=0.35) | 0.003 | 0.001 | .06 |
| LVOT gradient, mm Hg | .14 (r=0.15) | 0.002 | 0.002 | .24 |
| LVEF, % | .01 (r=−0.25) | −0.01 | 0.005 | .31 |
| LV apical aneurysm | .13 | 0.11 | 0.12 | .34 |
| Yes (n=7) | ||||
| No (n=105) | ||||
Model R2=0.36; F1,51=3.2; P=.004.
a BP, blood pressure; hs-cTnT, high-sensitivity cardiac troponin T; LV, left ventricle; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; NSVT, nonsustained ventricular tachycardia; SCD, sudden cardiac death.
b Pearson correlation coefficient.
Cardiac Events
Table 3 displays the comparison of prior arrhythmic events between hs-cTnT groups. Fourteen total patients, 12 (17%) in the elevated hs-cTnT group and 2 (5%) in the normal group, experienced at least 1 appropriate ICD discharge due to ventricular arrhythmia with hemodynamic instability or cardiac arrest. Seven (10%) patients in the elevated hs-cTnT group experienced multiple events. Patients with an elevated hs-cTnT concentration were more likely to have a composite history of ICD discharge, unstable ventricular arrhythmia, or cardiac arrest (incidence rate ratio, 2.96; 95% CI, 1.11 to 10.2). Only 2 patients who experienced an arrhythmic event also had a history of CAD. When they were excluded, patients with an elevated hs-cTnT concentration were still more likely to have a composite history of ICD discharge, unstable ventricular arrhythmia, or cardiac arrest (incidence rate ratio, 3.25; 95% CI, 1.20 to 11.3; Table 4). When sex-specific cutoffs were removed and elevated hs-cTnT concentration was defined as above 15 ng/L, patients with an elevated hs-cTnT concentration were no longer more likely to have experienced an arrhythmic event (incidence rate ratio, 1.50; 95% CI, 0.66 to 3.60; Table 5).
| Event | Normal hs-cTnT (n=43) | High hs-cTnT (n=69) | Odds ratio or incidence rate ratio |
|---|---|---|---|
| Appropriate ICD discharge | 1 (2) | 9 (13) | 6.30 (0.77-51.6) |
| Unstable ventricular arrhythmia | 2 (5) | 8 (12) | 2.68 (0.54-13.3) |
| Cardiac arrest | 1 (2) | 3 (4) | 1.91 (0.19-18.9) |
| Composite history | 4 | 20 | 2.96 (1.11-10.2) |
a hs-cTnT, high-sensitivity cardiac troponin T; ICD, implantable cardioverter-defibrillator.
b Values are number (percentage) or odds ratio (95% CI) unless otherwise specified.
c Composite history is a total of all events in each group and is listed as the number of events with the difference shown as an incidence rate ratio (95% CI).
| Event | Normal hs-cTnT (n=39) | High hs-cTnT (n=51) | Odds ratio or incidence rate ratio |
|---|---|---|---|
| Appropriate ICD discharge | 1 (3) | 9 (18) | 8.14 (0.98-67.3) |
| Unstable ventricular arrhythmia | 2 (5) | 7 (14) | 2.9 (0.58-15.0) |
| Cardiac arrest | 1 (3) | 2 (4) | 1.55 (0.14-17.8) |
| Composite history | 4 | 17 | 3.25 (1.20-11.3) |
a CAD, coronary artery disease; hs-cTnT, high-sensitivity cardiac troponin T; ICD, implantable cardioverter-defibrillator.
b Values are number (percentage) or odds ratio (95% CI) unless otherwise specified.
c Composite history is a total of all events in each group and is listed as the number of events with the difference shown as an incidence rate ratio (95% CI).
| Event | Normal hs-cTnT (n=55) | High hs-cTnT (n=57) | Odds ratio or incidence rate ratio |
|---|---|---|---|
| Appropriate ICD discharge | 3 (5) | 7 (12) | 2.43 (0.59-9.91) |
| Unstable ventricular arrhythmia | 4 (7) | 6 (11) | 1.50 (0.40-5.63) |
| Cardiac arrest | 2 (4) | 2 (4) | 0.96 (0.13-7.09) |
| Composite history | 4 | 17 | 1.50 (0.66-3.60) |
a hs-cTnT, high-sensitivity cardiac troponin T; ICD, implantable cardioverter-defibrillator.
b Values are number (percentage) or odds ratio (95% CI) unless otherwise specified.
c Composite history is a total of all events in each group and is listed as the number of events with the difference shown as an incidence rate ratio (95% CI).
Discussion
The main findings of this study are that in a referral population without exclusion of HCM patients with prior septal myectomy or concomitant CAD, which have been excluded from previous analyses, hs-cTnT levels correlated with well-established clinical risk factors for SCD and elevated hs-cTnT levels were associated with previous arrhythmic events. Furthermore, this association between hs-cTnT concentration and arrhythmic events held true only when sex-specific cutoffs were used. The results of this study agree with several studies in more selected HCM populations.
9
,17
,18
Kubo et al
18
previously reported that patients with elevated hs-cTnT concentration were at increased risk of HCM-related cardiac events. When stratified by just arrhythmic events, the difference was not significant; however, they admitted that this was likely due to the small number of reported events. Notable differences between the study by Kubo et al and this one are that they did not include patients with prior septal reduction therapies and they had a lower proportion of patients with New York Heart Association (NYHA) class III-IV symptoms (5%). Subsequently, Liu et al17
also reported correlation between troponin and NSVT. In 755 patients with HCM who underwent ambulatory Holter monitoring, a cutoff value of 0.0265 ng/mL with a conventional cardiac troponin I assay was able to predict the occurrence of NSVT with a sensitivity of 68% and a specificity of 61.3%. In multivariable analysis, cardiac troponin I was the only predictor of NSVT when the model included other traditional risk factors for SCD. In addition, the largest study to date evaluating hs-cTnT in HCM, by Neubauer et al,9
found that in 2665 prospectively studied patients, an abnormal hs-cTnT concentration was more common in patients with a history of arrythmias. This study is additive because of inclusion of a higher proportion of patients with more advanced heart failure symptoms than in the multinational registry used by Neubauer et al,9
with 29% of our patients having NYHA III-IV symptoms vs 7.2%.A prospective study of patients with HCM by Gommans et al
10
reported that patients with elevation of hs-cTnT concentration were more likely to meet a composite end point of SCD- and heart failure–related outcomes. As in this study, hs-cTnT level did not correlate with abnormal blood pressure response to exercise, unexplained syncope, or family history of SCD. It is likely that hs-cTnT concentration was more affected by the extent of ventricular hypertrophy and the presence of interstitial fibrosis as found in prior studies.19
,20
This is compatible with the concept that hs-cTnT integrates the extent of cardiovascular disease present to provide a broader and therefore a potentially more valuable signal. Stable CAD (unstable CAD can cause increases in hs-cTnT) was more prevalent in the elevated hs-cTnT group but did not appear to be a major confounder. Subgroup analysis found that the composite history of arrhythmic events remained different between groups even after exclusion of patients with CAD.This study found that a high proportion of clinically stable patients with HCM have elevated hs-cTnT levels. Whereas the prevalence of elevated hs-cTnT concentration in this study population (62%) is higher than previously reported (18% to 54%), it is similar to previous studies (45%) using the higher manufacturer-recommended cutoff values.
9
,10
,18
,21
,22
The mechanism for myocyte injury leading to elevation in circulatory levels of the cardiac troponins in HCM has not been clearly defined, but prior studies have found that hs-cTnT concentration correlates with a number of variables in patients with HCM, including age, left ventricular wall thickness, left ventricular mass, left atrial size, diastolic function, NYHA class, left ventricular systolic function, LVOT obstruction, late gadolinium enhancement, atrial fibrillation, race, hypertension, N-terminal pro–B-type natriuretic peptide level, and creatinine concentration. Of these variables, left ventricular wall thickness is the most commonly reported variable associated with elevated levels of hs-cTnT. It may then be able to be inferred that hs-cTnT elevations come from oxygen supply and demand mismatch, microvascular and endothelial dysfunction, and replacement fibrosis, which has been found to correlate with hypertrophy.23
,24
This overlay of myocardial fibrosis is thought to be a substrate for electrical instability, which leads to arrhythmias, and may explain the correlation of hs-cTnT with NSVT and history of SCD-related events found in this study.8
A strength of this study is that it is one of few studies evaluating hs-cTnT in HCM using sex-specific hs-cTnT cutoff values.
9
Men had a significantly higher hs-cTnT level than women did. The 99th percentile of upper reference limit for hs-cTnT has consistently been proven to be different between men and women, and sex-specific cutoff values are recommended by the International Federation of Clinical Chemistry and in the Fourth Universal Definition of Myocardial Infarction.25
, 26
, 27
The hs-cTnT level was reclassified as normal in 12 women (31%) rather than as elevated when the male cutoff of 15 ng/L was used. After doing so, there was no longer an association between elevated hs-cTnT levels and prior arrhythmic events, which was the central finding of this study. This strengthens the argument that sex-specific cutoffs for hs-cTnT concentration must be used in future studies of this biomarker in HCM, or we risk furthering the gender disparities in medicine. The importance of sex in HCM continues to become more apparent as women tend to have more severe obstruction, more advanced heart failure, and worse overall survival compared with men.28
,29
Given the high prevalence of elevated hs-cTnT concentration and the low event rate of SCD in HCM, the role of hs-cTnT for individual patient risk stratification presents a dilemma. An analysis of log-transformed hs-cTnT with determinants of SCD found a modest association. The association between hs-cTnT and prior arrhythmic events was then evaluated with the standard cutoff values used to define normality at our institution rather than as a continuous variable because of the low number of patients and relatively rare, disease-associated event rate. Our data correlate presently elevated hs-cTnT levels to a history of arrhythmic events, but the optimal levels to predict SCD may not be the cutoff used for ischemic heart disease. Defining this threshold will require much larger data sets with prospective enrollment. Nonetheless, our data suggest that this approach will eventually be feasible.
This study has limitations. First, the population studied represents a tertiary referral center population, and results herein may not apply to a healthier, non-referral HCM cohort with even less inherent SCD risk. Second, there is the potential for confounding as hs-cTnT elevations are common in many different disease states, including renal dysfunction, which was in this study. We are not able to exclude this as a confounder or part of the pathogenesis of the previous arrhythmic events. Third, given the retrospective nature, this study is limited by the availability and quality of historical data, which can introduce significant bias. For this reason, data on cardiac magnetic resonance imaging were notably excluded because a low number of patients had adequate data, including measurements of late gadolinium enhancement, which has been found to correlate with hs-cTnT concentration.
9
Conclusion
This is the first study evaluating the biomarker hs-cTnT in a referral population of patients with HCM without excluding patients with CAD or prior septal reduction therapy. We demonstrate that abnormal elevations of hs-cTnT concentration are common among patients with HCM. The hs-cTnT levels are associated with having NSVT, the extent of septal hypertrophy, and a previous history of clinically significant and potentially lethal arrhythmic events but, notably, only when sex-specific hs-cTnT cutoffs are used.
Potential Competing Interests
Michael J. Ackerman (Consultant): Abbott, ARMGO Pharma, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Invitae, LQT Therapeutics, Medtronic, and UpToDate; (Equity/Royalty): AliveCor and Anumana.
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References
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Grant Support: This work was supported by the Mayo Clinic Tsai Family HCM Research Fund.
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