Elevation of resting high-sensitivity troponin (hs-Tn) holds prognostic value in heart failure (HF), but its pathophysiological meaning is unclear. We aimed to investigate hs-Tn elevation after maximal exercise in patients with systolic HF and its neurohormonal and hemodynamic correlates: 30 patients diagnosed with systolic HF (left ventricular ejection fraction 32 ± 8%, mean ± SD), on guideline-directed medical therapy and not recognized inducible ischemia, underwent maximal cardiopulmonary stress test, with assay of plasma N -terminal proB-type natriuretic peptide (NT-proBNP), norepinephrine (NE), and hs-TnT (hs-TnT) at baseline, peak, and 1 and 4 hours after exercise. Cardiac output (CO) was measured during effort, with a rebreathing technique. The natural logarithm of the ratio between percentage (%) increase in CO and NT-proBNP (ln[CO%/NT-proBNP% increase]) was evaluated, as a noninvasive estimate of Frank–Starling adaptation to effort, with NT-proBNP variation considered as a surrogate of end-diastolic left ventricular pressure variation. Hs-TnT increased during exercise with a 4-hour peak (p = 0.001); 10 patients had hs-TnT increase >20%. Patients with Hs-TnT increase >20% were more symptomatic at rest (p = 0.039) and showed greater NE at peak exercise (p = 0.003) and less ln[CO%/NT-proBNP% increase] (p = 0.034). A lower ln[CO%/NT-proBNP% increase] correlated with greater NE at peak exercise ( r = −0.430, p = 0.018). In conclusion, acute troponin elevation after maximal exercise was detected in 1/3 of this series. The association of troponin release with NE, CO, and NT-proBNP changes after effort suggests a pathophysiological link among transient hemodynamic overload, adrenergic activation, and myocardial cell damage, likely identifying a clinical subset at greater risk for HF progression.
Neurohormonal activation plays a key role in pathophysiology of heart failure (HF). Activation of adrenergic and renin-angiotensin-aldosterone systems (RAAS) initially supports cardiac output (CO) after damage. Secretion of the B-type cardiac peptides with recognized vasodilator and natriuretic properties reflects either left ventricular filling pressure or the degree of neurohormonal activation. Sustained neurohormonal activation further worsens hemodynamics favoring cardiac remodeling and HF evolution to end stages. Ongoing myocardial damage (OMD) has been proposed as a mechanism of progression of cardiac remodeling and disease likely reflected by long-term troponin release, whose serum levels hold a prognostic value. Adrenergic signaling and mechanical stress due to hemodynamic overload during exercise have been proposed as triggers for troponin release by inducing cardiomyocyte death, with subsequent ventricular remodeling. As a result, further neurohormonal activation may occur, generating a vicious circle with progressive deterioration of cardiac function. A few studies have evaluated in vivo changes in troponin levels and its determinants after exercise, as a tool for the investigation of cardiac vulnerability and of its determinants. We aimed therefore to assess the relation among troponin release, neurohormonal activation, and hemodynamic response to maximal exercise.
Methods
We enrolled 30 stable outpatients with systolic dysfunction (left ventricular ejection fraction, LVEF <50%), diagnosed with HF by history, symptoms, and physical and instrumental findings in accordance to guidelines. Cardiac morphology and function were assessed by 2-dimensional Doppler echocardiography. All patients were on stable guideline-directed medical therapy (GMDT) for HF, with 100% of patients on β blockers and either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In patients with ischemic cardiomyopathy, inducible ischemia was excluded at a recent imaging stress test (i.e., within 3 months before enrollment). Exclusion criteria were New York Heart Association class IV, hospitalization for acute coronary syndrome or acute HF within 6 months before the enrollment, severe heart valve disease, severe chronic renal failure (estimated glomerular filtration rate <30 ml/min), severe lung disease, limitation to physical exercise other than HF. The study complies with the Declaration of Helsinki, and the protocol was approved by the institutional ethics committee. Informed consent was obtained from all subjects.
All patients underwent a symptom-limited cardiopulmonary stress test (CPT) conducted on a cycle-ergometer, according to a ramp protocol individualized to achieve target respiratory exchange ratio of at least 1.05 and exercise duration of 10 ± 2 minutes. Peak VO 2 (pVO 2 ) was considered as the mean VO 2 value in last 30 seconds of exercise. An offline evaluation of the slope of the ventilation versus carbon dioxide production relation in its linear part (VE/VCO 2 slope) was performed. All CPTs were performed by the same physician (LEP). All patients were familiar with CPT as they had already performed a proof CPT a few days before the index test.
Patients underwent biohumoral evaluation at baseline (basal), including standard laboratory test, and assays of high sensitivity troponin T (hs-TnT), norepinephrine (NE) and N -terminal fragment of B-type natriuretic peptide (NT-proBNP), plasma renin activity (PRA), and aldosterone. Blood samples were drawn at 8:00 A.M., after an overnight fasting and a 30-minute rest in supine position, through an indwelling venous cannula, according to a standardized experimental protocol. During effort, blood samples for NT-proBNP, NE, and hs-TnT were collected at peak exercise (peak); hs-TnT and NT-proBNP were also evaluated 1 and 4 hours after exercise. A 20% increase in hs-TnT from baseline levels was considered significant. NT-proBNP was assessed with electrochemiluminescence immunoassay (ECLIA; Elecsys 2010 analyzer; Roche Diagnostics, Basel, Switzerland); the analytical performance of ECLIA was tested in our laboratory as previously reported in detail ; NE was assayed by high-performance liquid chromatography (Chromosystems Diagnostics, GmbH, Munchen, Germany); hs-TnT was assessed with (Elecsys 2010 analyzer). PRA and aldosterone were measured by radioimmunoassay (DiaSorin S.r.l., Saluggia, Italy); analytical performance as tested in our laboratory was previously reported in detail. Glomerular filtration rate was estimated using Cockroft-Gault equation.
Noninvasive CO measurements were performed at rest and at peak exercise using the Innocor rebreathing system (Innovision A/S, Odense, Denmark). The inert gas rebreathing technique uses an oxygen-enriched mixture of an inert soluble gas (0.5% nitrous oxide) and an inert insoluble gas (0.1% sulfur hexafluoride). Details of the Innocor rebreathing system have been described elsewhere. Measurement of CO with inert gas rebreathing technique at peak exercise has been validated in a small sample of patients with chronic HF, showing a coefficient of variation for repeated measures of 10.8% and a good correlation with thermodilution and Fick methods. Patients who were unable to perform the inert gas rebreathing maneuver were excluded from the present study. The natural logarithm of the ratio between percentage (%) increase in CO and NT-proBNP (ln[CO%/NT-proBNP% increase]) was also computed: this ratio may be considered as a noninvasive estimate of the Frank–Starling adaptation to effort, using NT-proBNP increase as a surrogate of end-diastolic left ventricular pressure increase. For the analysis of this surrogate index, patients were also divided into 4 groups, according to the median value of the % increase in CO and NT-proBNP, respectively.
Statistical analysis was carried out using SPSS 16.0 (SPSS Inc., Chicago, Illinois). Data are expressed as mean ± standard deviation for normally distributed variables and as median and twenty-fifth to seventy-fifth percentile for non-normally distributed variables. Differences between 2 groups were evaluated with the Student t test for continuous variables and the Pearson chi-square test for categorical variables. Bonferroni post hoc test after repeated-measures and multiple comparisons analysis of variance was performed to assess differences in the time collection samples (basal, peak, and 1- and 4-hour) and the patients groups. Log-transformed values of original data were used in all statistical analyses for continuous variables (e.g., NT-proBNP, NE, PRA, aldosterone) known to have a non-normal distribution. Linear regression was used to assess the relation between different parameters. A p value <0.05 was considered significant.
Results
Physical effort induced an expected significant increase in CO (p <0.001), NE (p <0.001), NT-proBNP (p = 0.03; Figure 1 , Table 1 ). hs-TnT values increased significantly 4 hours after exercise (p = 0.01; Figure 1 , Table 1 ). Ten patients (33%) exhibited an effort-induced hs-TnT increase >20% from baseline. Resting values of hs-TnT correlated with basal NT-proBNP ( r = 0.264; p = 0.013), NE ( r = 0.277; p = 0.029), LVEF ( r = −0.204; p = 0.027), and CO ( r = −0.236; p = 0.021), whereas hs-TnT increase after effort correlated only with peak NE ( r = 0.457; p = 0.011) and with ln[CO%/NT-proBNP% increase] ( r = −0.602; p <0.001; Figure 2 ). Neither basal hs-TnT values nor exercise-induced hs-TnT elevation was different according to etiology (ischemic vs nonischemic). Greater peak values of NE were correlated with lesser values of ln[CO%/NT-proBNP% increase] ( r = −0.430, p = 0.018; Figure 2 ), whereas there was no relation between peak NE and LVEF, basal/peak CO, and basal/peak NT-proBNP.
| Variable | All (n =30) | hs-Troponin Increase | p | |
|---|---|---|---|---|
| < 20% (n=20) | >20% (n=10) | |||
| Age (years) | 62.5±11.5 | 63±119 | 61±11 | 0.577 |
| Male/female | 27/3 | 18/2 | 9/1 | 0.999 |
| NYHA class | 1.4±0.5 | 1.3±0.6 | 1.6±0.5 | 0.039 |
| Body mass index (kg/m 2 ) | 25.4±3.2 | 25±2.8 | 25±3 | 0.939 |
| Ischemic etiology | 9 (30%) | 6 (30%) | 3 (30%) | 0.999 |
| Diabetes mellitus | 10 (33%) | 7 (35%) | 3 (33%) | 0.458 |
| Left bundle branch block | 7 (23%) | 3 (15%) | 4 (40%) | 0.049 |
| Atrial fibrillation | 3 (10%) | 2 (10%) | 1 (10%) | 0.990 |
| Left ventricular ejection fraction (%) | 32.6±8.3 | 33.2±9 | 30.1±8 | 0.091 |
| Left ventricular end diastolic diameter (mm) | 62±7 | 60±7 | 64±7 | 0.205 |
| Left ventricular end systolic diameter (mm) | 51.4±8 | 50±7 | 53±7 | 0.379 |
| Systolic pulmonary artery pressure (mmHg) | 35±9.2 | 32±11 | 40±10 | 0.078 |
| Peak oxygen consumption (ml/Kg/min) | 15.9±5 | 16.2±4 | 15.4±6 | 0.654 |
| Ventilation/carbon dioxide production slope | 31±7 | 31±6 | 30±8 | 0.721 |
| Watt | 99±25 | 105±20 | 98±28 | 0.430 |
| Serum creatinine (mg/dL) | 1.06±0.26 | 1.09±0.3 | 0.99±0.02 | 0.355 |
| Hemoglobin (g/dL) | 13.7±1.3 | 13.6±1.2 | 13.8±0.8 | 0.713 |
| Basal hs-TnT (ng/L) | 17±13 | 17±12 | 16±11 | 0.254 |
| 4 hours hs-TnT (ng/L) | 22±14 | 17±13 | 25±14 | 0.070 |
| Basal NT-proBNP (ng/L) | 592; 207-1324 | 581;201-754 | 627; 187-762 | 0.233 |
| Peak NT-proBNP (ng/L) | 902; 240-1455 | 855;201-1098 | 949; 250-1158 | 0.791 |
| Basal norepineprhine (ng/L) | 471; 283-864 | 433;182-815 | 540; 352-898 | 0.528 |
| Peak norepineprhine (ng/L) | 2955; 1831-4582 | 2381;1666-3822 | 4741; 2208-5941 | 0.035 |
| Basal cardiac output (L/min) | 3.8±1.3 | 3.4±1.2 | 3.1±1.2 | 0.105 |
| Peak cardiac output (L/min) | 7.8±2.7 | 8.3±1.9 | 7.1±1.9 | 0.220 |
| Cardiac output increase (%) | 131±88 | 146±34 | 110±96 | 0.062 |
| lnCardiac output%/lnNT-proBNP % increase | 1.4; 0.9-1.9 | 2.2; 1.9-3.1 | 0.9; 0.3-1.2 | 0.034 |
Patients with >20% hs-TnT increase were more symptomatic at rest (p = 0.039) and exhibited more frequently left bundle branch block (p = 0.049; Table 1 ). In addition, they showed greater values of peak NE (p = 0.003), a trend toward less values of CO% increase (p = 0.062), and a less ln[CO%/NT-proBNP% increase] (p = 0.001), compared to those with <20% hs-TnT % increase ( Table 1 ).
When patients were divided according to CO and NT-proBNP changes during exercise, using the median value as cutoff, the subset of patients with no CO increase and with NT-proBNP increase, showed the greatest values of % increase in hs-TnT ( Figure 3 ) and peak NE ( Figure 3 ; Table 2 ). They were more symptomatic at rest (p = 0.038) and showed a greater incidence of left bundle branch block (p = 0.047), with no other difference for demographic, clinical, echocardiographic, or CPT parameters ( Table 2 ).
| Variable | Cardiac output% ↑ NT-proBNP%→ (n= 8) | Cardiac output % ↑ NT-proBNP%↑ (n= 7) | Cardiac output % → NT-proBNP%→ (n= 7) | Cardiac output % → NT-proBNP%↑ (n= 8) |
|---|---|---|---|---|
| Age (years) | 60±6 | 61±7 | 63±7 | 62±8 |
| Male/female | 87.5/12 (7/1) | 85.7/14.3 (6/1) | 100/0 (7/0) | 87.5/12.5 (7/1) |
| NYHA class | 1.2±0.6 | 1.3±0.4 | 1.5±0.7 | 1.9±0.5 ∗ † |
| Body mass index (kg/m 2 ) | 26±4 | 25±3 | 26±5 | 26±4 |
| Ischemic etiology | 37.5 (3) | 28 (2) | 28 (2) | 25 (2) |
| Diabetes mellitus | 37.5 (3) | 28.6 (2) | 42.9 (3) | 25 (2) |
| Left bundle branch block | 12.5 (1) | 14 (1) | 28 (2) | 37.5 (3) ∗ † |
| Atrial fibrillation | 25 (2) | 28 (2) | 28 (2) | 37.5 (3) |
| Left ventricular ejection fraction (%) | 34±11 | 32±8 | 32±9 | 32±8 |
| Left ventricular end diastolic diameter (mm) | 60±7 | 62±6 | 60±7 | 63±8 |
| Left ventricular end systolic diameter (mm) | 49±9 | 51±8 | 51±10 | 52±8 |
| Systolic pulmonary artery pressure (mmHg) | 36±6 | 37±8 | 36±7 | 38±5 |
| Peak oxygen consumption (ml/Kg/min) | 17±6 | 15±5 | 16±7 | 14±6 |
| Ventilation/carbon dioxide production slope | 29±8 | 32±10 | 30±5 | 33±8 |
| Watt | 100±39 | 95±35 | 97±23 | 88±25 |
| Serum creatinine (mg/dL) | 1.13±0.4 | 1±0.2 | 1.17±0.1 | 1±0.3 |
| Hemoglobin (g/dL) | 13.6±1.4 | 14.2±1.3 | 13.4±1.1 | 13.8±1.2 |
| Basal hs-TnT (ng/L) | 16±9 | 17±5 | 16±9 | 17±8 |
| 4h hs-TnT (ng/L) | 17±8 | 21±9 | 22±10 | 29±11 ∗ |
| Hs-TnT increase (%) | 8±7 | 14±7 | 15±8 | 39±9 ∗ † ‡ |
| Basal norepineprhine (ng/L) | 617; 204-1009 | 443; 206-910 | 568; 295-854 | 590; 301-1121 |
| Peak norepineprhine (ng/L) | 2550; 960 -4560 | 3245; 1709-4443 | 3251; 1847-4556 | 5120; 2156-7786 ∗ |
| lnCO%/lnNT-proBNP % increase | 3.1±0.8 | 1.8±0.8 | 1.6±0.89 | 0.5±0.6 ∗ |
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