Background
Left ventricular (LV) function can be accurately assessed using two-dimensional speckle-tracking echocardiography. The association between reduced LV global longitudinal strain (LVGLS) magnitude and risk for mortality in heart transplant recipients is unclear. The aim of this study was to test the hypothesis that LVGLS could predict 1-year mortality in heart transplant recipients.
Methods
A total of 176 consecutive adult primary single-organ orthotopic heart transplant recipients were retrospectively evaluated. Of these, 167 had acceptable echocardiographic image quality and were included in the study. N-terminal pro–B-type natriuretic peptide, creatinine, C-reactive protein, and invasive hemodynamic parameters were measured, and echocardiography was performed 1 to 3 weeks after heart transplantation. LVGLS was averaged from regional strain in 16 LV segments.
Results
During the first year, 15 patients (9%) died 86 ± 72 days after heart transplantation. LVGLS and LV ejection fraction were decreased in magnitude in nonsurvivors ( P < .05). They were older and had higher donor ages. Mean pulmonary capillary wedge pressures were similar in the two groups, while all other hemodynamic parameters were increased in nonsurvivors ( P < .05). LVGLS was the only significant ( P = .02) noninvasive independent predictor, with a hazard ratio of 1.42 (95% confidence interval, 1.07–1.88; P = .02) per 1% decrease in strain magnitude, while pulmonary vascular resistance was a significant ( P < .001) invasive predictor, with a hazard ratio of 3.98 (95% confidence interval, 2.01–7.87) of 1-year mortality in multivariate Cox regression analysis.
Conclusions
Reduced LV function and increased pulmonary vascular resistance are related to poor prognosis in heart transplant recipients. Early assessment of LVGLS might be a noninvasive predictor of 1-year mortality in these patients.
End-stage heart failure is a significant problem in the Western world. Heart transplantation (HTx) remains the gold standard therapy for selected patients with end-stage heart failure, with 1-year survival approaching 90%. Graft dysfunction is a major cause of morbidity and mortality in heart transplant recipients. Advances in the treatment of antibody-mediated rejection and acute cellular rejection have increased early transplant survival. However, not all cases of early cardiac allograft dysfunction can be explained by the currently known histopathologic mechanisms of allograft rejection.
The search for noninvasive techniques to assess cardiac allograft function remains a high priority objective for HTx professionals. Global left ventricular (LV) systolic function, most commonly assessed by echocardiographic LV ejection fraction (LVEF), is an important predictor of outcomes. LVEF, however, presents a number of challenges related to image quality, assumptions of LV geometry, and expertise and is limited to assessing changes in ventricular cavity size during the cardiac cycle. This traditional volume-based echocardiographic parameter provides an indirect assessment of myocardial function and is insensitive to early changes in cardiomyopathy. In accordance with this, LVEF tends to be stable over time and does not always correlate with endomyocardial biopsy–proven rejection without hemodynamic compromise.
Two-dimensional (2D) speckle-tracking echocardiography (STE) is a semiautomated quantitative technique for the assessment of cardiac function on the basis of grayscale images. Strain echocardiography has been introduced as an accurate tool for assessment of regional and global myocardial function and has been demonstrated to be more sensitive and accurate compared with conventional echocardiographic measures of systolic function, such as fractional shortening and LVEF, especially in early stages of myocardial disease. Strain is a measure of deformation, an intrinsic mechanical property, and measures myocardial systolic function more directly compared with conventional cavity-based echocardiographic measures.
Although LV global longitudinal strain (LVGLS) measurements have been tested in an increasing number of clinical conditions, the association between reduced LVGLS magnitude and risk for mortality in heart transplant recipients remains unclear. We hypothesized that reduced LV function assessed by LVGLS shortly after HTx is associated with increased 1-year mortality in heart transplant recipients.
Methods
In total, 176 consecutive adult primary orthotopic heart transplant recipients at the national HTx center (Oslo University Hospital, Rikshospitalet, Oslo, Norway) between August 2001 and August 2007 were retrospectively evaluated for eligibility in this study. Of these patients, 167 had analyzable echocardiographic studies, performed 13 ± 6 days after HTx ( Table 1 ).
| Variable | Nonsurvivors ( n = 15) | Survivors ( n = 152) | P ∗ |
|---|---|---|---|
| Demographics | |||
| Age (y) | 62 (55 to 65) | 56 (49 to 61) | .02 |
| Male gender | 10 (67%) | 121 (80%) | .25 |
| Medical history | |||
| Hypertension | 1 (7%) | 10 (7%) | .99 |
| Heart rate (beats/min) | 90 (74 to 102) | 85 (80 to 98) | .23 |
| Diabetes mellitus | 1 (7%) | 19 (13%) | .63 |
| Ischemic heart disease | 9 (60%) | 76 (50%) | .50 |
| Body mass index (kg/m 2 ) | 25 (24 to 31) | 24 (22 to 27) | .38 |
| Body surface area (m 2 ) | 2.0 (1.8 to 2.2) | 2.0 (1.8 to 2.1) | .68 |
| Donor characteristics | |||
| Age (y) | 46 (29 to 56) | 41 (32 to 50) | .004 |
| Male gender | 6 (40%) | 86 (57%) | .22 |
| Gender mismatch | 4 (27%) | 49 (32%) | .66 |
| Ischemic time (min) | 190 (63 to 206) | 185 (65 to 222) | .62 |
| Post-HTx hemodynamic data | |||
| Mean pulmonary artery pressure (mm Hg) | 22 (17 to 30) | 20 (16 to 26) | .007 |
| Mean pulmonary capillary wedge pressure (mm Hg) | 8 (6 to 14) | 11 (8 to 16) | .28 |
| Cardiac output (L/min) | 5.4 (4.2 to 6.7) | 5.7 (4.7 to 6.7) | .03 |
| PVR (Wood units) | 2.4 (1.8 to 3.3) | 1.5 (1.1 to 2.1) | <.001 |
| Post-HTx echocardiographic data | |||
| LV end-diastolic volume (mL) | 139 (114 to 176) | 115 (97 to 140) | .70 |
| LV end-diastolic volume indexed for body surface area (mL/m 2 ) | 66 (60 to 82) | 59 (50 to 70) | .76 |
| LV end-systolic volume (mL) | 81 (73 to 111) | 60 (51 to 73) | .06 |
| LV end-systolic volume indexed for body surface area (mL/m 2 ) | 41 (37 to 52) | 32 (26 to 38) | .02 |
| LVEF (%) | 34 (30 to 42) | 46 (41 to 54) | <.001 |
| LVGLS (%) | −7.9(−5.7 to −10.8) | −13.7(−11.8 to −15.4) | <.001 |
| Biochemical data at the time of the echocardiographic study | |||
| N-terminal pro–B-type natriuretic peptide (pmol/L) | 1,639 (855 to 2,903) | 1,165 (548 to 2,210) | .25 |
| Creatinine (μmol/mL) | 99 (91 to 141) | 104 (76 to 140) | .27 |
| Glomerular filtration rate (mL/min/1.73 m 2 ) | 67 (49 to 76) | 62 (43 to 85) | .15 |
| C-reactive protein (mg/mL) | 28 (15 to 51) | 26 (13 to 48) | .008 |
| Acute biopsy and/or autopsy-detected rejections during the first year | |||
| Acute cellular rejection grade 2R or higher and/or antibody-mediated rejection | 9 (60%) | 56 (37%) | .08 |
Peak systolic longitudinal myocardial strain by 2D STE was assessed in 16 LV segments and averaged to calculate LVGLS, an index of global LV function ( Figure 1 ).
The indications for HTx conformed to criteria that are generally accepted internationally. Data regarding patient demographics, donor characteristics, and baseline biochemistry were collected from our HTx database, approved by the institutional review board, and the hospital’s dialysis records.
All patients received immunosuppressive therapy per local protocol. No cytotoxic induction therapy was given. Maintenance therapy included prednisolone, cyclosporine A, or tacrolimus, and azathioprine or mycophenolate mofetil. Pravastatin 40 mg was introduced in all patients 2 weeks after HTx. Rejection monitoring was performed by weekly biopsies up to 8 weeks and thereafter at weeks 10 and 12 and at 6 and 12 months after HTx. Rejection criteria were based on the grading system of the International Society for Heart and Lung Transplantation. Rejections classified earlier, according to the 1990 rejection nomenclature, were converted to the 2005 grading system.
N-terminal pro–B-type natriuretic peptide, C-reactive protein, and serum creatinine were collected on the day of the echocardiographic study. Serum creatinine was used to calculate glomerular filtration rate on the basis of the Modification of Diet in Renal Disease formula.
Written informed consent was given by all study participants. The study was in compliance with the Declaration of Helsinki and was approved by the regional committees for medical and health research ethics.
Right-Heart Catheterization
Right-heart catheterization was performed using a Swan-Ganz pulmonary artery thermodilution catheter (Baxter Health Care Corporation, Santa Ana, CA) 12 ± 8 days after HTx. The mean pulmonary artery pressure and the mean pulmonary capillary wedge pressure were obtained. Cardiac output was measured by thermodilution. The transpulmonary gradient was obtained by subtracting mean pulmonary capillary wedge pressure from mean pulmonary artery pressure. Pulmonary vascular resistance (PVR) was obtained in Wood units by dividing transpulmonary gradient by cardiac output.
Two-Dimensional Echocardiography
All patients underwent echocardiography (Vivid 5 and 7; GE Vingmed Ultrasound AS, Horten, Norway). Cine loops from three standard apical views (four chamber, two chamber, and apical long axis) were recorded using grayscale harmonic imaging. LVEF was assessed using the modified Simpson method. Data were digitally stored for offline analysis using dedicated software (EchoPAC; GE Vingmed Ultrasound AS). The echocardiographic data were analyzed blinded to all clinical information.
2D STE
The endocardial borders were traced semiautomatically by manually marking two positions on both sides of the mitral annulus and one at the apex, allowing automatic tracing of the endocardial borders in the end-systolic frame of the 2D images in each of the three apical views for the assessment of longitudinal strain. The 18 segments obtained from EchoPAC were converted to a standardized 16-segment LV model by averaging the strain values of corresponding apical segments in the apical long-axis and four-chamber planes. Strain (relative tissue deformation) was evaluated on a frame-by-frame basis by automatic tracking of acoustic markers (speckles) throughout the cardiac cycle. The operator manually adjusted the region of interest in segments that failed to track properly. Any segments that subsequently failed to track were excluded. Peak systolic longitudinal myocardial strain by 2D STE was assessed in 16 LV segments and averaged to calculate LVGLS.
Statistical Analysis
Analyses were carried out using a standard statistical software program (SPSS version 18; SPSS, Inc., Chicago, IL). Data are expressed as numbers and percentages, mean ± SD, and medians and interquartile ranges (IQRs). The χ test (for categorical variables), and Mann-Whitney U test (for continuous variables) were used to determine differences between two groups.
The value closest to the upper left corner of the receiver operating characteristic curves determined the optimal sensitivity and specificity for the ability of recipient age, donor age, LVEF, LVGLS, PVR, and C-reactive protein to predict 1-year mortality and was used to define the optimal cutoff values for Kaplan-Meier analyses for LVEF and LVGLS.
Survival was expressed using Cox regression analysis and Kaplan-Meier analysis, and log-rank analysis was used to test for significance. Univariate Cox regression analysis was performed to establish the relationship between 1-year mortality and baseline demographics, right-heart catheterization parameters, biochemical markers, and measures of LV function. LVEF, LVGLS, and PVR demonstrated univariate statistical significance < .05 and were thus selected for inclusion in a multivariate Cox regression analysis to determine the independent prognostic value of LVGLS for the prediction of 1-year mortality. The number of events ( n = 15) was small, so to avoid overanalyzing the influence of different variables on adverse events, recipient age, donor age, and C-reactive protein, although they demonstrated univariate statistical significance < .05, were not included in the multivariate Cox regression analysis. Because of internal correlation in the group of significant invasive right-heart catheterization variables, PVR was selected to be included in the multivariate analysis because it integrates several invasive variables, including mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, and cardiac output. In addition, PVR has previously demonstrated independent ability to predict long-term survival in heart transplant recipients. We calculated the integrated discrimination index and the net reclassification improvement between models following the methodology of Pencina et al. , including the same variables as used in the multivariate analysis. Reproducibility was expressed using intraclass correlation coefficients. Two-tailed P values < .05 were considered significant.
Results
We retrospectively evaluated 176 consecutive adult primary orthotopic heart transplant recipients. Assessment of LVGLS was not feasible because of poor image quality in one nonsurvivor (6%) and eight survivors (5%). Of 2,672 myocardial segments, 2,173 (81%) were analyzed.
During the first year, 15 patients (9%) died 86 ± 72 days after HTx. All heart transplant recipients received inotropes the first 3 to 5 days after transplantation. Five nonsurvivors (33%) and 32 survivors (21%) were hemodynamically unstable and needed inotropes, including catecholamines, calcium sensitizers, or phosphodiesterase inhibitors at the time of the echocardiographic study. The primary cause of death was grade 2R or higher acute cellular rejection in two patients. Importantly, a combination of acute cellular rejection and antibody-mediated rejection was present in seven patients at the time of death. These patients had a tendency to lower LVGLS magnitude (median, −7.9%; IQR, −7.4% to −9.1%) compared with nonsurvivors with acute cellular rejection alone (median, −12.2%; IQR, −9.3% to −15.1%) ( P = .08). Nonsurvivors with rejection died later (median, 125 days; IQR, 35 to 163 days) than nonsurvivors without rejection (median, 17 days; IQR, 11 to 81 days) ( P = .05). The primary causes of death in all nonsurvivors are shown in Table 2 . Among the survivors, 48 experienced one or more episodes of biopsy-proven grade 2R or higher acute cellular rejection, and eight experienced antibody-mediated rejection within the first year.
| Patient | Primary cause of death | Complicating factors | Days to death | Status on the date of echocardiography | Inotropes |
|---|---|---|---|---|---|
| 1 | HIT | 10 | Unstable | Yes | |
| 2 | Sepsis | MODS | 11 | Unstable | Yes |
| 3 | ARDS | MODS | 16 | Unstable | Yes |
| 4 | Sepsis | MODS | 18 | Unstable | Yes |
| 5 | ACR | MODS | 32 | Stable | No |
| 6 | ACR and AMR | MODS | 33 | Unstable | Yes |
| 7 | ACR and AMR | 36 | Stable | No | |
| 8 | Perioperative MI | Postoperative VT/VF | 54 | Stable | No |
| 9 | ACR and AMR | 111 | Stable | No | |
| 10 | ACR and AMR | 124 | Stable | No | |
| 11 | ACR and AMR | MODS/sepsis | 139 | Stable | No |
| 12 | ACR and AMR | 152 | Stable | No | |
| 13 | CMV infection | MODS/sepsis | 160 | Stable | No |
| 14 | ACR and AMR | 171 | Stable | No | |
| 15 | ACR | 226 | Stable | No |
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