Methods

Fifty-seven patients referred to a cardiothoracic center (Oslo University Hospital, Rikshospitalet, Oslo, Norway) for presurgical evaluation were consecutively included in the study. All patients had a diagnosis of moderate to severe AS. A complete echocardiographic study was performed per standard views and guidelines by Vivid 7 (GE Vingmed, Horten, Norway). Images were stored in Echopac (GE Vingmed) and later processed and evaluated by an experienced researcher (T.E.) blinded to biomarker levels. Left ventricular (LV) ejection fraction was determined according to the Simpson method and LV mass and relative wall thickness by standard formulas. Patients with grade ≥3 aortic regurgitation were excluded. Blood samples were obtained by venipuncture at time of echocardiography, immediately put on ice, centrifuged within 30 minutes, and then stored at −80°C before transport to Akershus University Hospital for analysis. Troponin levels were determined on an autoanalyzer (Cobas e411, Roche Diagnostics, Basel, Switzerland) using the highly sensitive assay and the fourth-generation assay (n = 54), and N-terminal pro–B-type natriuretic peptide (NT–pro-BNP) levels were measured by the pro-BNP II assay (all assays from Roche Diagnostics). Other biochemical substances were determined by standard assays. Clinical and follow-up data were obtained directly from patients or from chart records, and New York Heart Association functional class was determined by an end-point committee of 2 cardiologist (T.E., T.O.) with discrepancy (4.7%) resolved by consensus. Coronary artery disease was defined as history of angina pectoris or previous myocardial infarction or evidence of significant stenosis of an epicardial coronary artery on angiogram (≥50% diameter stenosis on an artery or graft with the segment not perfused by collateral circulation). Spearman rank correlation and multivariable linear regression analysis were employed to identify factors associated with hs-cTnT levels (transformed by natural logarithm for regression analysis). Prognostic accuracy of biomarkers for mortality and optimal cutoffs were assessed by receiver operating characteristics curve analysis with area under the curve presented with 95% confidence intervals. Kaplan–Meier plots according to biomarker quartiles were generated and crude risk compared by log-rank test, and adjusted risk estimates were assessed by multivariate Cox proportional hazard regression analysis with hs-cTnT, NT–pro-BNP, age, gender, body mass index, estimated glomerular filtration rate, functional class, status of aortic valvular surgery, co-morbidities ( Table 1 ), and echocardiographic parameters ( Table 2 ) included in the model (forward selection). The study was approved by the regional ethics committee and all patients signed an informed consent before study commencement.

Results

Patient characteristics are presented in Table 1 . Patients were elderly, had slightly impaired renal function, and were clinical stable. A large proportion of patients had significant co-morbidities. Echocardiography confirmed the diagnosis of AS in all patients, and most patients had evidence of moderate to severe AS with myocardial hypertrophy but with relatively preserved left atrial and ventricular dimensions ( Table 2 ). Furthermore, patients exhibited evidence of diastolic dysfunction, and most patients had preserved systolic LV function.

All patients had detectable cTnT levels with the highly sensitive assay (detection limit 0.003 μg/L), whereas only 9 patients (17%) had levels above the detection limit (0.01 μg/L) with the fourth-generation assay. Median hs-cTnT level was 0.18 μg/L (quartiles 1 to 3 0.13 to 0.30, range 0.08 to 0.98) and 41 patients (72%) had hs-cTnT levels above the ninety-ninth percentile limit (>0.014 μg/L) of the general population. The hs-cTnT levels correlated positively with LV dimension, peak velocity, and pressure gradients across the aortic valve and with LV mass and end-diastolic posterior wall dimension ( Table 3 ). There was a borderline significant correlation between hs-cTnT levels and fractional shortening, whereas hs-cTnT levels did not correlate with LV ejection fraction or echocardiographic indexes of diastolic function. There was no significant increase in hs-cTnT levels in patients with coronary artery disease compared to other patients (0.19 μg/L, quartiles 1 to 3 0.15 to 0.35, vs 0.17 μg/L, quartiles 1 to 3 0.11 to 0.25, p = 0.20). In a comprehensive regression model that included all indexes presented in Tables 1 and 2 and explained 60% of the variance in hs-cTnT levels (r = 0.60), estimated glomerular filtration rate (p <0.001), LV mass (p = 0.001), diabetes mellitus (p = 0.007), and fractional shortening (p = 0.03) were the only variables significantly associated with hs-cTnT levels. Similar results were obtained in a model that included only patients with coronary angiography (n = 52). NT–pro-BNP levels were above the detection limit in all patients ( Table 1 ) and correlated with hs-cTnT levels (r = 0.48, p <0.001) and several echocardiographic indexes of function, dimension, and structure ( Table 3 ).

Table 3

Correlations between high-sensitivity cardiac troponin T and N-terminal pro–B-type natriuretic peptide levels and parameters of myocardial structure and function in patients with aortic stenosis

Variable	hs-cTnT		NT–pro-BNP
	Rho	p Value	Rho	p Value
Left atrial area (cm 2 )	0.20	0.13	0.37	0.005
Left ventricular end-diastolic dimension (cm)	0.28	0.03	0.35	0.007
Left ventricular ejection fraction (%)	−0.13	0.35	−0.39	0.003
Fractional shortening (%)	−0.25	0.06	−0.38	0.003
Left ventricular cardiac index (L/min/m 2 )	0.13	0.32	−0.06	0.64
Aortic valve area (cm 2 )	−0.22	0.10	−0.37	0.005
Maximum aortic valve velocity (m/s)	0.30	0.02	0.29	0.03
Aortic valve mean pressure gradient (mm Hg)	0.28	0.04	0.31	0.02
Interventricular septal end-diastolic dimension (cm)	0.22	0.11	0.13	0.32
Left ventricular end-diastolic posterior wall dimension (cm)	0.28	0.03	0.26	0.04
E/é	0.10	0.50	0.14	0.30
E/A ratio	−0.01	0.97	0.10	0.47
Mitral valve deceleration time (ms)	−0.22	0.10	−0.34	0.01
Relative wall thickness	0.06	0.64	−0.06	0.64
Left ventricular mass (g)	0.37	0.005	0.41	0.001

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