Right ventricular (RV) dysfunction adversely affects prognosis in patients with chronic heart failure (CHF) due to left ventricular (LV) dysfunction. However, little evidence exists regarding the prognostic role of RV systolic and diastolic function indexes in combination with plasma B-type natriuretic peptide (BNP) in advanced CHF. Thus, 102 consecutive hospitalized patients with advanced CHF (New York Heart Association classes III to IV) due to LV systolic dysfunction (LV ejection fraction <35%) were studied by 2-dimensional conventional and tissue Doppler imaging (TDI) echocardiography of the left and right ventricles. Plasma BNP was also measured. Patients were followed for 6 months for major cardiovascular events (cardiovascular death and/or CHF-related hospitalization). During follow-up, 13 patients died and 63 patients reached the combined end point of cardiovascular death or CHF-related hospitalization. By univariate analysis, RV TDI systolic velocity, dilated cardiomyopathy, digoxin treatment (all p values <0.01), and female gender (p <0.05) were associated with increased cardiovascular death. Transmitral Doppler to mitral annular TDI early diastolic velocity ratio, RV TDI early diastolic velocity (p <0.05), and ratio of early to late RV diastolic TDI velocities (p <0.01) predicted the combined end point. In multivariate analysis, decreased RV systolic velocity, dilated cardiomyopathy, and female gender (all p values <0.05) were independent predictors of cardiovascular death, whereas increased ratio of early to late RV diastolic TDI velocities (p <0.01) and increased BNP (p <0.05) predicted the combined end point. In conclusion, RV TDI indexes combined with increased plasma BNP additively predict adverse cardiac outcomes in advanced CHF.
Several studies have shown that the impaired systolic function of the right ventricle is a powerful predictor of adverse outcome in patients with chronic heart failure (CHF), independently of left ventricular (LV) dysfunction. Moreover, impaired tricuspid annular plane systolic excursion, which is marker of right ventricular (RV) systolic dysfunction obtained from conventional M-mode echocardiography, has been associated with increased mortality in patients with CHF or in those with moderate to severe mitral regurgitation secondary to dilated cardiomyopathy. In contrast, only few studies have focused on the prognostic value of newer echocardiographic markers of RV diastolic and systolic function that are based on tissue Doppler imaging (TDI) in patients with CHF. In contrast, plasma B-type natriuretic peptide (BNP) is a powerful neurohormonal prognostic factor in CHF. However, no efficient data exist regarding the prognostic role of this biochemical marker in patients with CHF and RV dysfunction. The present study investigated the prognostic value of RV TDI indexes in combination with plasma BNP levels in hospitalized patients with CHF secondary to LV dysfunction.
Methods
This study included 102 consecutive patients with advanced CHF (New York Heart Association classes III to IV) and LV systolic dysfunction (LV ejection fraction <35%) due to ischemic or idiopathic dilated cardiomyopathy, who were hospitalized for syndrome worsening. On admission, patients were evaluated clinically by echocardiography and routine laboratory testing and by measurement of plasma levels of BNP. Patients with acute coronary syndrome, severe valvulopathy, and atrial fibrillation (because of an inability to obtain all primarily examined RV tissue Doppler parameters) were not included. Patients with atrial fibrillation comprised 24% (n = 32) of the initially screened patients with CHF (n = 134). The study was approved by the institutional ethics committee, and written consent was given by each patient.
All patients were studied by M-mode and 2-dimensional echocardiography and conventional Doppler and TDI on admission. The following indexes were determined: (1) LV end-diastolic and end-systolic diameters from parasternal long-axis view, (2) LV ejection fraction, calculated by modified Simpson rule, (3) early and late transmitral diastolic inflow velocities and deceleration time by pulse-wave Doppler, and (4) LV tissue Doppler early diastolic velocity from the apical 4-chamber view at the lateral mitral valve annulus. In addition, the ratio of early transmitral diastolic inflow velocity to early diastolic velocity was calculated. (5) RV tissue Doppler velocities from the apical 4-chamber view with the cursor located at the RV free wall at the level of the tricuspid annulus. Three waves were recorded: 1 systolic and 2 diastolic early and late transmitral diastolic inflow velocities. All echocardiographic measurements were performed using a General Electric Vivid 7 phased-array system (GE Medical Systems, Milwaukee, Wisconsin). Velocities were measured on-line at a sweep speed of 50 mm/s. All parameters were calculated as a mean of 5 consecutive cycles. Studies were analyzed off-line by a second blinded observer for 10 patients. Intraobserver variabilities were 3% for RV TDI systolic velocity, 3% for early transmitral diastolic inflow velocity, and 4% for late transmitral diastolic inflow velocity, respectively. Interobserver variabilities were 4% for systolic velocity, 5% for early transmitral diastolic inflow velocity, and 5% for late transmitral diastolic inflow velocity, respectively.
Plasma BNP was measured using the rapid Triage BNP assay (Biosite, Inc., San Diego, California).
Patients were followed for 6 months starting after hospital discharge or, in case a study end point was reached, until the day of the event. Study end points consisted of (1) cardiovascular death and (2) a composite of cardiovascular death or hospitalization due to worsening of CHF (event-free survival).
Statistical analysis was performed using SPSS 13.0 (SPSS, Inc., Chicago, Illinois). Continuous variables are expressed as mean ± SD. Kolmogorov-Smirnov test was used to check the normality of distributions of continuous variables. Standard univariate statistical techniques were used to test differences between subgroups of patients with and without major cardiovascular events: chi-square test for ordinal categorical variables, unpaired Student’s t test for normally distributed continuous variables, and Mann-Whitney test for non-normally distributed continuous variables. Parameters that were found to differ significantly at baseline between the compared subgroups of patients were entered into a Cox multivariate model to determine which of them were independently related to cardiovascular mortality and morbidity. For multivariate Cox regression analysis, all continuous variables were considered as dichotomous after determination of optimal cut-off values by receiver operating characteristic analysis. Kaplan-Meier survival and event-free survival curves were constructed by dividing patients in subgroups according to cut-off values of independent predictors of outcome among the primarily studied RV TDI function indexes. Comparison of event rates among subgroups was tested by log-rank test. For all methods, a p value <0.05 was considered statistically significant.
Results
Baseline clinical, laboratory, and echocardiographic characteristics of the study population are presented in Table 1 . Patients were equally distributed between New York Heart Association classes III (52%) and IV (48%), had severe LV systolic and diastolic dysfunctions, and severely decreased RV TDI systolic velocity (8 ± 2.5 cm/s) and diastolic velocities (early transmitral diastolic inflow velocity 7.5 ± 3 cm/s, late transmitral diastolic inflow velocity 9 ± 4 cm/s).
| Parameter | Value |
|---|---|
| Sample | 102 |
| Follow-up (days) | 180 (20–180) |
| Age (years) | 63 ± 10 |
| Men | 91 (89%) |
| Women | 11 (11%) |
| Cause of heart failure | |
| Ischemic | 67 (66%) |
| Idiopathic dilated | 35 (34%) |
| New York Heart Association class | |
| III | 53 (52%) |
| IV | 49 (48%) |
| Medications | |
| β blockers | 80 (78%) |
| Angiotensin-converting enzyme inhibitors | 83 (81%) |
| Angiotensin receptor blockers | 9 (9%) |
| Diuretics | 102 (100%) |
| Aldosterone antagonists | 82 (80%) |
| Digoxin | 46 (45%) |
| Systolic blood pressure (mm Hg) | 100 ± 15 |
| Heart rate (beats/min) | 73 ± 14 |
| Glomerular filtration rate (ml/min/1.73 m 2 ) | 50 ± 12 |
| Plasma B-type natriuretic peptide (pg/ml) | 1,204 ± 787 |
| Serum sodium (mmol/L) | 140 ± 5 |
| Left ventricular end-diastolic diameter (mm) | 70 ± 9 |
| Left ventricular end-systolic diameter (mm) | 63 ± 10 |
| Left ventricular ejection fraction (%) | 23 ± 6 |
| Mitral valve early transmitral diastolic inflow velocity (cm/s) | 87 ± 29 |
| Mitral valve late transmitral diastolic inflow velocity (cm/s) | 48 ± 27 |
| Mitral valve early transmitral diastolic inflow velocity/late transmitral diastolic inflow velocity | 2.8 ± 2.7 |
| Left ventricular tissue Doppler imaging early transmitral diastolic inflow velocity (early diastolic velocity) (cm/s) | 7 ± 3 |
| Left ventricular early transmitral diastolic inflow velocity/early diastolic velocity | 15 ± 9 |
| Right ventricular tissue Doppler imaging systolic velocity (cm/s) | 8 ± 2.5 |
| Right ventricular tissue Doppler imaging early transmitral diastolic inflow velocity (cm/s) | 7.5 ± 3 |
| Right ventricular tissue Doppler imaging late transmitral diastolic inflow velocity (cm/s) | 9 ± 4 |
| Right ventricular tissue Doppler imaging early transmitral diastolic inflow velocity/late transmitral diastolic inflow velocity | 1.1 ± 0.9 |
During follow-up, 13 patients died from cardiovascular reasons, and 63 patients reached the combined end point of death or hospitalization due to CHF decompensation. Table 2 lists differences in baseline variables by univariate analysis in study patients stratified according to whether or not they reached the study end points. Regarding cardiovascular mortality, female gender, dilated cardiomyopathy as the cause of CHF, New York Heart Association class IV, use of digoxin, higher plasma BNP levels, and more severely decreased RV TDI systolic velocity were associated with higher death rates. Regarding the composite of cardiovascular mortality or CHF hospitalization, New York Heart Association class IV, higher plasma BNP levels, transmitral early/late transmitral diastolic inflow velocity, LV early transmitral diastolic inflow velocity/early diastolic velocity ratio, RV TDI early/late transmitral diastolic inflow velocity ratio; and more severely depressed RV TDI late transmitral diastolic inflow velocity were related to higher cardiovascular event rates. By receiver operating characteristic analyses, cut-off values were determined for plasma BNP (1,115 pg/ml, sensitivity 77%, specificity 67%, area under the curve 0.716, p = 0.013), RV TDI systolic velocity (7.3 cm/s, sensitivity 88%, specificity 56%, area under the curve 0.715, p = 0.047) for cardiovascular death, and BNP (762 pg/ml, sensitivity 88%, specificity 56%, area under the curve 0.689, p = 0.003), LV early transmitral diastolic inflow velocity/early diastolic velocity (11.7, sensitivity 62%, specificity 66%, area under the curve 0.659, p = 0.019), and RV early/late transmitral diastolic inflow velocity (0.68, sensitivity 75%, specificity 73%, area under the curve 0.771, p <0.0001) for the composite end point. Multivariate Cox regression analysis was performed separately for cardiovascular death and the composite end point and included the parameters that differed significantly at baseline between patients with and without each study end point. As presented in Table 3 , female gender and RV TDI systolic velocity <7.3 cm/s were revealed as independent predictors of cardiovascular death. In addition, BNP ≥762 pg/ml and RV TDI early/late transmitral diastolic inflow velocity ratio ≥0.68 were found as predictors of combined cardiovascular death or CHF-related hospitalization. Kaplan-Meier curves for survival stratified according to cut-off value of RV systolic velocity are shown in Figure 1 (chi-square 4.42, p = 0.036). Kaplan-Meier curves for event-free survival according to cut-off values of BNP (chi-square 18.631, p <0.0001), RV early/late transmitral diastolic inflow velocity (chi-square 14.344, p <0.0001), and the combination of BNP and early/late transmitral diastolic inflow velocity (chi-square 30.375, p <0.0001) are shown in Figure 2 . As shown in Figure 2 , patients who had BNP ≥762 pg/ml and RV early/late transmitral diastolic inflow velocity ≥0.68 increases comprised the group with the shortest event-free interval (mean survival ± SE 79 ± 9 days) compared to subgroups with BNP or early/late transmitral diastolic inflow velocity increases (133 ± 17 and 157 ± 14 days, respectively) and the subgroup with the 2 parameters below the determined cut-off values (167 ± 9 days).
| Variable | Event-Free Survival | Survival | ||||
|---|---|---|---|---|---|---|
| Event | No Event | p Value | Death | Alive | p Value | |
| Sample | 63 | 39 | 13 | 89 | ||
| Follow-up (days) | 58 (20–180) | 180 (90–180) | 59 (20–180) | 180 (90–180) | ||
| Age (years) | 63 ± 9 | 62 ± 10 | 0.386 | 60 ± 11 | 63 ± 9 | 0.2 |
| Men | 56 (89%) | 35 (90%) | 0.892 | 9 (69%) | 82 (92%) | 0.013 |
| Women | 7 (11%) | 4 (10%) | 4 (31%) | 7 (8%) | ||
| Cause of heart failure | ||||||
| Ischemic | 43 (68%) | 24 (62%) | 0.488 | 4 (31%) | 63 (71%) | 0.005 |
| Idiopathic dilated | 20 (32%) | 15 (39%) | 9 (69%) | 26 (29%) | ||
| New York Heart Association class | ||||||
| III | 23 (37%) | 30 (77%) | <0.0001 | 2 (15%) | 51 (57%) | 0.005 |
| IV | 40 (64%) | 9 (23%) | 11 (85%) | 38 (43%) | ||
| Medications | ||||||
| β blockers | 46 (73%) | 33 (85%) | 0.173 | 9 (69%) | 70 (79%) | 0.448 |
| Angiotensin-converting enzyme inhibitors | 49 (78%) | 33 (85%) | 0.398 | 10 (77%) | 72 (81%) | 0.736 |
| Angiotensin receptor I blockers | 5 (8%) | 3 (8%) | 0.694 | 0 (0%) | 8 (9%) | 0.26 |
| Diuretic | 63 (100%) | 39 (100%) | NA | 13 (100%) | 89 (100%) | NA |
| Aldosterone antagonists | 52 (83%) | 30 (77%) | 0.487 | 12 (92%) | 70 (79%) | 0.247 |
| Digoxin | 30 (48%) | 12 (31%) | 0.093 | 10 (77%) | 32 (36%) | 0.005 |
| Systolic blood pressure (mm Hg) | 98 ± 14 | 103 ± 15 | 0.215 | 97 ± 14 | 100 ± 15 | 0.434 |
| Heart rate (beats/min) | 71 ± 9 | 76 ± 20 | 0.464 | 70 ± 9 | 73 ± 14 | 0.516 |
| Glomerular filtration rate (ml/min/1.73 m 2 ) | 48 ± 12 | 52 ± 12 | 0.190 | 47 ± 14 | 50 ± 12 | 0.48 |
| B-type natriuretic peptide (pg/ml) | 1,350 ± 751 | 976 ± 799 | 0.001 | 1,473 ± 588 | 1,093 ± 778 | 0.016 |
| Serum sodium (mmol/L) | 139 ± 6 | 140 ± 3 | 0.451 | 137 ± 7 | 140 ± 5 | 0.266 |
| Left ventricular end-diastolic diameter (mm) | 70 ± 8 | 69 ± 10 | 0.754 | 72 ± 10 | 69 ± 9 | 0.491 |
| Left ventricular end-systolic diameter (mm) | 63 ± 10 | 62 ± 10 | 0.635 | 64 ± 9 | 63 ± 10 | 0.657 |
| Left ventricular ejection fraction (%) | 22 ± 6 | 25 ± 6 | 0.084 | 21 ± 5 | 24 ± 6 | 0.132 |
| Mitral valve early transmitral diastolic inflow velocity (cm/s) | 90 ± 31 | 83 ± 25 | 0.308 | 100 ± 30 | 85 ± 28 | 0.075 |
| Mitral valve late transmitral diastolic inflow velocity (m/s) | 45 ± 28 | 53 ± 24 | 0.212 | 39 ± 27 | 50 ± 26 | 0.211 |
| Mitral valve early transmitral diastolic inflow velocity/late transmitral diastolic inflow velocity | 3.2 ± 3.1 | 2.0 ± 1.7 | 0.048 | 3.9 ± 3.6 | 2.6 ± 2.5 | 0.105 |
| Left ventricular tissue Doppler imaging early diastolic velocity (cm/s) | 7 ± 3 | 8 ± 3 | 0.113 | 6 ± 1 | 8 ± 2 | 0.46 |
| Left ventricular early transmitral diastolic inflow velocity/early diastolic velocity | 16 ± 10 | 12 ± 6 | 0.04 | 20 ± 15 | 14 ± 7 | 0.121 |
| Right ventricular tissue Doppler imaging systolic velocity (m/s) | 8 ± 3 | 8 ± 2 | 0.412 | 6.6 ± 1 | 8 ± 2.6 | 0.003 |
| Right ventricular tissue Doppler imaging early transmitral diastolic inflow velocity (m/s) | 8 ± 3 | 7 ± 3 | 0.073 | 7 ± 2 | 8 ± 3 | 0.511 |
| Right ventricular tissue Doppler imaging late transmitral diastolic inflow velocity (m/s) | 8 ± 5 | 11 ± 4 | 0.004 | 8 ± 4 | 9 ± 5 | 0.46 |
| Right ventricular tissue Doppler imaging early transmitral diastolic inflow velocity/late transmitral diastolic inflow velocity | 1.4 ± 1.0 | 0.7 ± 0.6 | <0.0001 | 1.0 ± 0.5 | 1.1 ± 1.0 | 0.594 |
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