Benefit of exercise therapy for systolic heart failure in relation to disease severity and etiology-findings from the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training study.

BACKGROUND: This post hoc analysis of the HF-ACTION cohort explores the primary and secondary results of the HF-ACTION study by etiology and severity of illness. METHODS: HF-ACTION randomized stable outpatients with reduced left ventricular (LV) function and heart failure (HF) symptoms to either supervised exercise training plus usual care or to usual care alone. The primary outcome was all-cause mortality or all-cause hospitalization; secondary outcomes included all-cause mortality, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or HF hospitalization. The interaction between treatment and risk variable, etiology or severity as determined by risk score, New York Heart Association class, and duration of cardiopulmonary exercise test was examined in a Cox proportional hazards model for all clinical end points. RESULTS: There was no interaction between etiology and treatment for the primary outcome (P = .73), cardiovascular (CV) mortality or CV hospitalization (P = .59), or CV mortality or HF hospitalization (P = .07). There was a significant interaction between etiology and treatment for the outcome of mortality (P = .03), but the interaction was no longer significant when adjusted for HF-ACTION adjustment model predictors (P = .08). There was no significant interaction between treatment effect and severity, except a significant interaction between cardiopulmonary exercise duration and training was identified for the primary outcome of all-cause mortality or all-cause hospitalization. CONCLUSION: Consideration of symptomatic (New York Heart Association classes II to IV) patients with HF with reduced LV function for participation in an exercise training program should be made independent of the cause of HF or the severity of the symptoms.

Relationship of technetium-99m tetrofosmin-gated rest single-photon emission computed tomography myocardial perfusion imaging to death and hospitalization in heart failure patients: results from the nuclear ancillary study of the HF-ACTION trial.

BACKGROUND: We hypothesized that the severity of resting perfusion abnormalities assessed by the summed rest score (SRS) would be associated with a higher rate of adverse outcomes in patients with heart failure (HF) and reduced left ventricular (LV) ejection fraction (EF). METHODS: A subset of 240 subjects from HF-ACTION underwent resting technetium-99m tetrofosmin-gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). Images were evaluated using a 17-segment model to derive the SRS and additional nuclear variables. RESULTS: After adjusting for prespecified covariates, SRS was significantly associated with the primary end point (hazard ratio 0.98, 95% confidence interval [CI] 0.97-1.00, P = .04), with a higher SRS corresponding to lower risk of an event. This association was not present in the unadjusted analysis. The relationship between SRS and the primary outcome was likely due to a higher event ratein patients with ischemic HF and a low SRS. The LV phase SD was not predictive of the primary outcome (hazard ratio 1.00, 95% confidence interval 0.99-1.01, P = .49). In a post hoc analysis, nuclear variables provided incremental prognostic information when added to clinical information (P = .006). CONCLUSIONS: Gated SPECT MPI provides important information in patients with HF and reduced LVEF. In the adjusted analysis, SRS has an unexpected relationship with the primary end point. Phase SD was not associated with the primary end point. Rest-gated SPECT MPI provides incrementally greater prognostic information than clinical information alone.

Myocardial perfusion, function, and dyssynchrony in patients with heart failure: baseline results from the single-photon emission computed tomography imaging ancillary study of the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) Trial.

BACKGROUND: There are currently limited data on the relationships between resting perfusion abnormalities, left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) functional class, and exercise capacity as defined by peak VO(2) and 6-minute walk test in patients with heart failure (HF) and reduced LVEF. Furthermore, the association between resting perfusion abnormalities and left ventricular dyssynchrony is currently unknown. This article addresses the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) gated SPECT imaging (gSPECT) substudy baseline results. METHODS: HF-ACTION was a multicenter, randomized controlled trial of aerobic exercise training versus usual care in 2,331 stable patients with LVEF of < or = 35% and NYHA class II to IV HF symptoms treated with optimal medical therapy. Subjects enrolled in the HF-ACTION substudy underwent resting Tc-99m tetrofosmin gSPECT at baseline (n = 240). Images were evaluated for extent and severity of perfusion abnormalities using a 17-segment and a 5-degree gradation severity score (summed rest score [SRS]). Left ventricular function and dyssynchrony were assessed using validated available commercial software. RESULTS: The average age of patients enrolled was 59, 69% were male, 63% were white, and 33% were African American. Of the 240 participants, 129 (54%) were ischemic and 111 (46%) were nonischemic in etiology. The median LVEF by gSPECT for the entire cohort was 26%. Among the nuclear variables, there was a modest correlation between LVEF and SRS (r = -0.31, P < .0001) and there were stronger correlations between phase SD and SRS (r = 0.66, P < .0001) as well as phase SD and LVEF (r = -0.50, P < .0001). Patients with NYHA class III symptoms had more severe and significant degrees of dyssynchrony (median phase SD 54 degrees ) than those with NYHA class II symptoms (median phase SD 39 degrees, P = .001). Patients with an ischemic etiology had a higher SRS (P < .0001) and significantly more dyssynchrony (P < .0001) than those who were nonischemic. However, there was no difference in LVEF or objective measures of exercise capacity between these groups. With respect to peak VO(2), there was a weak correlation with LVEF (r = 0.18, P = .006) and no correlation with SRS (r = -0.04, P = 0.59) or with dyssynchrony (r = -0.13, P = .09). A weak but statistically significant correlation between SRS and 6-minute walk was observed (r = -0.15, P = .047). CONCLUSIONS: Gated SPECT imaging can provide important information in patients with HF due to severe LV dysfunction including quantitative measures of global systolic function, perfusion, and dyssynchrony. These measurements are modestly but significantly related to symptom severity and objective measures of exercise capacity.

Left Ventricular Assist Device Inflow Angle and Pump Positional Change Over Time Adverse Impact on Left Ventricular Assist Device Function.

BACKGROUND: This study investigates the impact of left ventricular assist device (LVAD) inflow cannula angulation, pump positional change over time, and the incidence of thrombotic pump dysfunction in a large cohort of HeartMate II (HM2) patients. METHODS: Patients (n = 326) who received primary HM2 LVAD between January 2008 and December 2013 at a single institution were retrospectively reviewed. Patients who underwent pump exchange (PE) for pump dysfunction, patients who had pump dysfunction (PD) but did not require pump exchange, and patients with normal LVAD pump dysfunction (NL) were compared. Pump positional change and angle of the inflow cannula with respect to the angle between inflow cannula and the LVAD body (IL angle) were measured from routine chest radiograph at postoperation, before discharge, and follow-up. Pump positional change was assessed based on pump positional differences between discharge and follow-up. Patients were also grouped by IL acute angulation (less than 65 degrees) and pump positional change. RESULTS: There were 21, 15, and 290 patients in the PE group, PD group, and NL group, respectively. There were significant differences in IL angle between PE and NL at all timepoints: postoperation (PD 63.6 ± 12.5, NL 70.6 ± 12.3; p = 0.018), before discharge (PD 64.4 ± 12.8, NL 69.5 ± 10.5; p = 0.039), and follow-up (PD 62.6 ± 14.2, NL 67.9 ± 11.2; p = 0.002). However, the IL angle was insignificant between PE and PD groups and between PD and NL groups. Sixty-seven percent of the PE group had pump positional change as opposed to 36% of the NL group (p = 0.019). Eighty-four of 101 patients with pump positional change and 75 of 91 patients with acute angulation at postoperation did not have pump dysfunction. CONCLUSIONS: Pump positional change may contribute to LVAD dysfunction or failure, but it does not entirely account for observed pump dysfunction or failure.

Blood transfusions decrease the incidence of acute rejection in cardiac allograft recipients.

BACKGROUND: Cardiac transplant recipients frequently receive a large number of transfusions. The objective of this study was to determine whether there is an association between total number of blood transfusions and cardiac allograft rejection. METHODS: A retrospective analysis of all cardiac transplants between October 1, 1997, and December 31, 2001, was performed. Total number of transfusions, total number of rejection episodes Grade 3A or more, rejection-free survival, and overall survival were analyzed. Comparisons between patients bridged to transplantation with a Novacor left ventricular assist device (LVAD) and the primary transplant group were also made. RESULTS: Eighty-two patients were transplanted. Fifteen were bridged to transplantation, and 67 underwent primary heart transplantation. Age and sex were similar for the LVAD group and the primary transplant group (45 +/- 11 vs 47 +/- 15 years and 67% vs 58% male sex, respectively). Mean follow-up was 658 +/- 486 days for the LVAD group and 708 +/- 548 days for the primary transplant group. Transfusions received were 50 +/- 34 U of packed red blood cells for the LVAD group and 7 +/- 12 for the primary transplant group (p < 0.001). There were no differences in donor characteristics between the 2 groups. The incidence of acute rejection within 1 year was 27% for the LVAD group and 39% for the primary transplant group (p = .28). Freedom from rejection was 71% at 1 year in the LVAD group compared with 59% for the primary transplant group (p = 0.39). In all 82 patients, the total number of transfusions was inversely correlated with the development of acute rejection (p = 0.011). Survival was 80% and 62% for the LVAD group at 1 and 3 years after transplantation and 88% and 85%, respectively, for the primary transplant group (p = 0.045). CONCLUSIONS: The number of blood transfusions received by heart transplant recipients is inversely related with the number of acute rejection episodes.

Dilated Cardiomyopathy: Normalized Multiparametric Myocardial Strain Predicts Contractile Recovery.

BACKGROUND: Left ventricular contractile injury in dilated cardiomyopathy (DCM) may occur in a consistently heterogeneous distribution, suggesting that early-injury sentinel regions may have prognostic significance. Heightened surveillance of these regions with high-resolution contractile metrics may predict recovery in DCM. METHODS: Multiple three-dimensional strain parameters were calculated at each of 15,300 left ventricular grid points from systolic displacement data obtained from cardiac magnetic resonance imaging in 124 test subjects. In 24 DCM patients, Z-scores for two strain parameters at each grid point were calculated by comparison of patient-specific strain values to respective point-specific mean and standard deviation values from a normal human strain database (n = 100). Multiparametric strain Z-scores were averaged over six left ventricular regions at basilar, mid, and apical levels (18 subregions). Patients with DCM were stratified into three groups on the basis of a blinded review of clinical contractile recovery (complete, n = 7; incomplete, n = 7; none, n = 10). RESULTS: Basilar-septal subregions were consistently heavily injured. Basilar-septal Z-scores were significantly larger (worse) than those for the rest of the left ventricle (2.73 ± 1.27 versus 2.22 ± 0.83; p = 0.011) and lateral wall (2.73 ± 1.27 versus 1.44 ± 0.72; p < 0.001). All patients with sentinel region average multiparametric strain Z-scores less than two standard deviations (n = 6) experienced complete recovery, whereas 17 of 18 DCM patients with Z-scores greater than two standard deviations experienced incomplete or no contractile recovery. CONCLUSIONS: Contractile injury in DCM is heterogeneous, with basilar-septal regions injured more than lateral regions. The targeting of early-injury sentinel regions for heightened surveillance with high-resolution metrics of microregional contractile function may accurately predict recovery on medical therapy. A two standard deviation Z-score threshold may predict contractile recovery.

Predicting maximal HR in heart failure patients on ß-blockade therapy.

PURPOSE: Standards for estimating maximal HR are important when interpreting the adequacy of physiologic stress during exercise testing, assessing chronotropic response, and prescribing an exercise training regimen. The equation 220 - age is used to estimate maximum HR; however, it overestimates measured maximal HR in patients taking ß-adrenergic blockade (ßB) therapy. This study developed and validated a practical equation to predict maximal HR in patients with heart failure (HF) taking ßB therapy. METHODS: Data from symptom-limited exercise tests completed on patients with systolic HF participating in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training trial and taking a ßB agent were used to develop a simplified equation, which was validated using bootstrapping. RESULTS: The simplified derived equation was 119 + 0.5 (resting HR) - 0.5 (age) - (0, if test was completed using a treadmill; 5, if using a stationary bike). The R2 and SEE were 0.28 and 18 beats·min(-1), respectively. Validation of this equation yielded a mean R and SEE of 0.28 and 18 beats·min(-1), respectively. For the equation 220 - age, the R2 was -2.93, and the SEE was 43 beats·min(-1). CONCLUSIONS: We report a valid and simple population-specific equation for estimating peak HR in patients with HF taking ßB therapy. This equation should be helpful when evaluating chronotropic response or assessing if a maximum effort was provided during exercise testing. We caution, however, that the magnitude of the variation (SEE = 18 beats·min(-1)) associated with this prediction equation may make it impractical when prescribing exercise intensity.

Risk assessment for continuous flow left ventricular assist devices: does the destination therapy risk score work? An analysis of over 1,000 patients.

OBJECTIVES: This study sought to assess the utility of the Destination Therapy Risk Score (DTRS) in patients with continuous flow left ventricular assist devices (LVAD). BACKGROUND: The DTRS was developed to predict the risk of 90-day in-hospital mortality with pulsatile flow LVAD as destination therapy (DT). Despite ongoing use in patients with continuous flow devices, its utility has not been studied in such populations. METHODS: The DTRS was determined in 1,124 patients with the continuous flow HeartMate II (Thoratec Corporation, Pleasanton, California) LVAD as a bridge to transplant (BTT, n = 486) and DT (n = 638) and 114 DT patients with the pulsatile flow HeartMate XVE (Thoratec Corporation). Patients were divided into risk groups based on DTRS: low (0-8), medium (9-16), and high (>16). RESULTS: The 90-day in-hospital mortality for low-, medium-, and high-risk groups was 8%, 7%, and 16%, respectively, for BTT patients; 9%, 12%, and 19%, respectively, for DT patients; and 11%, 18%, and 25%, respectively, for XVE DT patients. The high-risk groups had more than a 2-fold increased risk of mortality compared with the low-risk groups. However, the area under the receiver-operating characteristic curve for 90-day in-hospital mortality yielded modest values ranging from 0.54 to 0.58 for the HeartMate II BTT and DT groups, respectively. Survival rates over 2 years were statistically significantly different as stratified by the 3 DTRS groups for patients implanted for DT but not for BTT. CONCLUSIONS: DTRS provides poor discrimination of mortality for BTT patients and only modest discrimination for DT patients receiving continuous flow LVAD.

Modest increase in peak VO2 is related to better clinical outcomes in chronic heart failure patients: results from heart failure and a controlled trial to investigate outcomes of exercise training.

BACKGROUND: The prognostic ability of a single measurement of peak oxygen uptake (VO(2)) is well established in patients with chronic heart failure. The relation between a change in peak VO(2) and clinical outcomes is not well defined. METHODS AND RESULTS: This investigation determined whether an increase in peak VO(2) was associated with a lower risk of the primary end point of time to all-cause mortality or all-cause hospitalization and 3 secondary end points. In Heart Failure and a Controlled Trial to Investigate Outcomes of Exercise Training, an exercise training trial for patients with systolic heart failure, cardiopulmonary exercise tests were performed at baseline and ≈3 months later in 1620 participants. Median peak VO(2) in the combined sample increased from 15.0 (11.9-18.0 Q1-Q3) to 15.4 (12.3-18.7 Q1-Q3) mL·kg(-1)·min(-1). Every 6% increase in peak VO(2,) adjusted for other significant predictors, was associated with a 5% lower risk of the primary end point (hazard ratio=0.95; CI=0.93-0.98; P<0.001); a 4% lower risk of the secondary end point of time to cardiovascular mortality or cardiovascular hospitalization (hazard ratio=0.96; CI=0.94-0.99; P<0.001); an 8% lower risk of cardiovascular mortality or heart failure hospitalization (hazard ratio=0.92; CI=0.88-0.96; P<0.001); and a 7% lower all-cause mortality (hazard ratio=0.93; CI=0.90-0.97; P<0.001). CONCLUSIONS: Among patients with chronic systolic heart failure, a modest increase in peak VO(2) over 3 months was associated with a more favorable outcome. Monitoring the change in peak VO(2) for such patients may have benefit in assessing prognosis.

Magnetic resonance imaging-based multiparametric systolic strain analysis and regional contractile heterogeneity in patients with dilated cardiomyopathy.

BACKGROUND: Myocardial systolic strain patterns in dilated cardiomyopathy are considered non-homogeneous but have not been investigated with magnetic resonance imaging (MRI)-based multiparametric systolic strain analysis. Left ventricular (LV) 3-dimensional (3D) multiparametric systolic strain analysis is sensitive to regional contractility and is generated from sequential MRI of tissue-tagging gridline-point displacements. METHODS: Sixty normal human volunteers underwent MRI-based 3D systolic strain analysis to supply normal average and standard deviation values for each of three strain parameters at each of 15,300 individual LV grid-points. Patient-specific multiparametric systolic strain data from each dilated cardiomyopathy patient (n = 10) were then subjected to a point-by-point comparison (n = 15,300 LV points) to the normal strain database for three individual strain components (45,900 database comparisons per patient). The resulting composite multiparametric Z-score values (standard deviation from normal average) were color contour mapped over patient-specific 3D LV geometry to detect the normalized regional contractile patterns associated with dilated cardiomyopathy. RESULTS: Average multiparametric strain Z-score values varied significantly according to ventricular level (p = 0.001) and region (p = 0.003). Apical Z-scores were significantly less than those in both the base (p = 0.037) and mid-ventricle (p = 0.002), whereas anterolateral wall Z-scores were less than those in the anteroseptal (p = 0.023) and posteroseptal walls (p = 0.028). CONCLUSIONS: MRI-based multiparametric systolic strain analysis suggests that myocardial systolic strain in patients with dilated cardiomyopathy has a heterogeneous regional distribution and, on average, falls almost 2 standard deviations from normal.