The Prognostic Role of Global Longitudinal Strain and NT-proBNP in Heart Failure Patients Receiving Cardiac Resynchronization Therapy.

BACKGROUND: We aimed to evaluate whether baseline GLS (global longitudinal strain), NT-proBNP, and changes in these after cardiac resynchronization therapy (CRT) can predict long-term clinical outcomes and the echocardiographic-based response to CRT (defined by 15% relative reduction in left ventricular end-systolic volume). METHODS: We enrolled 143 patients with stable ischemic heart failure (HF) undergoing CRT-D implantation. NT-proBNP and echocardiography were obtained before and 6 months after. The patients were followed up (median: 58 months) for HF-related deaths and/or HF hospitalizations (primary endpoint) or HF-related deaths (secondary endpoint). RESULTS: A total of 84 patients achieved the primary and 53 the secondary endpoint, while 104 patients were considered CRT responders and 39 non-responders. At baseline, event-free patients had higher absolute GLS values (p < 0.001) and lower NT-proBNP serum levels (p < 0001) than those achieving the primary endpoint. A similar pattern was observed in favor of CRT responders vs. non-responders. On Cox regression analysis, baseline absolute GLS value (HR = 0.77; 95% CI, 0.51-1.91; p = 0.002) was beneficially associated with lower primary endpoint incidence, while baseline NT-proBNP levels (HR = 1.55; 95% CI, 1.43-2.01; p = 0.002) and diabetes presence (HR = 1.27; 95% CI, 1.12-1.98; p = 0.003) were related to higher primary endpoint incidence. CONCLUSIONS: In HF patients undergoing CRT-D, baseline GLS and NT-proBNP concentrations may serve as prognostic factors, while they may predict the echocardiographic-based response to CRT.

Left atrial reverse remodeling predicts long-term survival after cardiac resynchronization therapy.

BACKGROUND: Left ventricular (LV) reverse remodeling has been identified as a strong predictor of long-term survival in patients receiving CRT. Interestingly, CRT induces reverse remodeling in the left atrium (LA) as well. It is currently unknown to what extent LA reverse remodeling is correlated to long-term survival after CRT. This study aims to assess the long-term prognostic value of left atrium (LA) reverse remodeling in patients undergoing cardiac resynchronization therapy (CRT). METHODS: Baseline and 3-months follow-up echocardiograms after CRT implantation were prospectively assessed to determine changes in left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), left atrial volume (LAV), and left atrial reservoir strain (LASr). Multivariate Cox regression analysis was performed to identify predictors for long-term survival. RESULTS: In our study population of 99 patients with a mean follow-up of 6.3 ± 2.1 years, 43 patients (43%) reached the end-point of all-cause mortality. More extensive LA reverse remodeling, as measured by a relative increase in LASr, was observed in survivors compared to non-survivors (43 [29-64] % vs. 8 [2-28] %, P < 0.001, respectively). After multivariate analysis, delta LASr remained the only significant predictor of mortality [HR per 5%: 0.90 (0.86-0.95); AUC 0.78 (0.68-0.88)]. CONCLUSION: An increase in LASr is associated with favorable long-term outcome after CRT. The observed clinical importance of LA reverse remodeling after CRT asks for further validation in larger prospective cohorts.

Appointing nurses trained in organ donation to improve family consent rates.

BACKGROUND: One of the most important bottlenecks in the organ donation process worldwide is the high family refusal rate. AIMS AND OBJECTIVES: The main aim of this study was to examine whether family guidance by trained donation practitioners increased the family consent rate for organ donation. DESIGN: This was a prospective intervention study. METHODS: Intensive and coronary care unit nurses were trained in communication about donation (ie, trained donation practitioners) in two hospitals. The trained donation practitioners were appointed to guide the families of patients with a poor medical prognosis. When the patient became a potential donor, the trained donation practitioner was there to guide the family in making a well-considered decision about donation. We compared the family consent rate for donation with and without the guidance of a trained donation practitioner. RESULTS: The consent rate for donation with guidance by a trained donation practitioner was 58.8% (20/34), while the consent rate without guidance by a trained donation practitioner was 41.4% (41/99, P = 0.110) in those patients where the family had to decide on organ donation. CONCLUSIONS: Our data suggest that family guidance by a trained donation practitioner could benefit consent rates for organ donation. RELEVANCE TO CLINICAL PRACTICE: Trained nurses play an important role in supporting the families of patients who became potential donors to guide them through the decision-making process after organ donation request.

The Implementation of a Multidisciplinary Approach for Potential Organ Donors in the Emergency Department.

BACKGROUND: The aim of this study was to evaluate the implementation process of a multidisciplinary approach for potential organ donors in the emergency department (ED) in order to incorporate organ donation into their end-of-life care plans. METHODS: A new multidisciplinary approach was implemented in 6 hospitals in The Netherlands between January 2016 and January 2018. The approach was introduced during staff meetings in the ED, intensive care unit (ICU), and neurology department. When patients with a devastating brain injury had a futile prognosis in the ED, without contraindications for organ donation, an ICU admission was considered. Every ICU admission to incorporate organ donation into end-of-life care was systematically evaluated with the involved physicians using a standardized questionnaire. RESULTS: In total, 55 potential organ donors were admitted to the ICU to incorporate organ donation into end-of-life care. Twenty-seven families consented to donation and 20 successful organ donations were performed. Twenty-nine percent of the total pool of organ donors in these hospitals were admitted to the ICU for organ donation. CONCLUSIONS: Patients with a devastating brain injury and futile medical prognosis in the ED are an important proportion of the total number of donors. The implementation of a multidisciplinary approach is feasible and could lead to better identification of potential donors in the ED.

In vitro pharmacokinetic phantom for two-compartment modeling in DCE-MRI.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is an established minimally-invasive method for assessment of extravascular leakage, hemodynamics, and tissue viability. However, differences in acquisition protocols, variety of pharmacokinetic models, and uncertainty on physical sources of MR signal hamper the reliability and widespread use of DCE-MRI in clinical practice. Measurements performed in a controlled in vitro setup could be used as a basis for standardization of the acquisition procedure, as well as objective evaluation and comparison of pharmacokinetic models. In this paper, we present a novel flow phantom that mimics a two-compartmental (blood plasma and extravascular extracellular space/EES) vascular bed, enabling systemic validation of acquisition protocols. The phantom consisted of a hemodialysis filter with two compartments, separated by hollow fiber membranes. The aim of this phantom was to vary the extravasation rate by adjusting the flow in the two compartments. Contrast agent transport kinetics within the phantom was interpreted using two-compartmental pharmacokinetic models. Boluses of gadolinium-based contrast-agent were injected in a tube network connected to the hollow fiber phantom; time-intensity curves (TICs) were obtained from image series, acquired using a T1-weighted DCE-MRI sequence. Under the assumption of a linear dilution system, the TICs obtained from the input and output of the system were then analyzed by a system identification approach to estimate the trans-membrane extravasation rates in different flow conditions. To this end, model-based deconvolution was employed to determine (identify) the impulse response of the investigated dilution system. The flow rates in the EES compartment significantly and consistently influenced the estimated extravasation rates, in line with the expected trends based on simulation results. The proposed phantom can therefore be used to model a two-compartmental vascular bed and can be employed to test and optimize DCE-MRI acquisition sequences in order to determine a standardized acquisition procedure leading to consistent quantification results.

Noninvasive pulmonary transit time: A new parameter for general cardiac performance.

INTRODUCTION: Pulmonary transit time (PTT) assessed with contrast-enhanced ultrasound (CEUS) is a novel tool to evaluate cardiac function. PTT represents the time for a bolus of contrast to pass from the right to the left ventricle, measured according to the indicator dilution principles using CEUS. We investigated the hypothesis that PTT is a measure of general cardiac performance in patient populations eligible for cardiac resynchronization therapy (CRT). METHODS: The study population consisted of heart failure patients referred for CRT with NYHA class II-IV, left ventricular ejection fraction (LVEF)≤35% and QRS≥120 ms. CEUS, ECG, and blood were analyzed, and participants completed a quality of life questionnaire at baseline and 3 months after CRT implantation. Normalized PTT (nPTT) was calculated to compensate for the heart rate. Correlations were assessed with Pearson's or Spearman's coefficients and stratified for rhythm and NYHA class. RESULTS: The study population consisted of 94 patients (67 men) with a mean age of 70±8.9 years. (n)PTT was significantly correlated with left ventricular parameters (rs =-.487, P<.001), right ventricular parameters (r=-.282, P=.004), N-terminal pro-B-type natriuretic peptide (NT-proBNP) (rs =.475, P<.001), and quality of life (rs =.364, P<.001). Stronger significant correlations were found in patients in sinus rhythm. CONCLUSION: CEUS-derived PTT and nPTT correlate to a fair degree with measures of systolic and diastolic function, NT-pro-BNP, and quality of life. As CEUS-derived PTT can be obtained easily, noninvasively and at the bedside, it is a promising future measure of general cardiac performance.

Comparison of cardiac magnetic resonance imaging and bio-impedance spectroscopy for the assessment of fluid displacement induced by external leg compression.

Heart failure is marked by frequent hospital admissions, often as a consequence of pulmonary congestion. Current gold standard techniques for thoracic fluid measurement require invasive heamodynamic access and therefore they are not suitable for continuous monitoring. Changes in thoracic impedance (TI) may enable non-invasive early detection of congestion and prevention of unplanned hospitalizations. However, the usefulness of TI to assess thoracic fluid status is limited by inter-subject variability and by the lack of reliable normalization methods. Indicator dilution methods allow absolute fluid volume estimation; cardiac magnetic resonance (CMR) has been recently proposed to apply indicator dilution methods in a minimally-invasive manner. In this study, we aim to compare bio-impedance spectroscopy (BIS) and CMR for the assessment of thoracic fluid status, and to determine their ability to detect fluid displacement induced by a leg compression procedure in healthy volunteers. A pressure gradient was applied across each subject's legs for 5 min (100-60 mmHg, distal to proximal). Each subject underwent a continuous TI-BIS measurement during the procedure, and repeated CMR-based indicator dilution measurements on a 1.5 T scanner at baseline, during compression, and after pressure release. The Cole-Cole and the local density random walk models were used for parameter extraction from TI-BIS and indicator dilution measurements, respectively. Intra-thoracic blood volume index (ITBI) derived from CMR, and extracellular fluid resistance (R E) from TI-BIS, were considered as thoracic fluid status measures. Eight healthy volunteers were included in this study. An increase in ITBI of 45.2 ± 47.2 ml m-2 was observed after the leg inflation (13.1 ± 15.1% w.r.t. baseline, p < 0.05), while a decrease of -0.84 ± 0.39 Ω in R E (-1.7 ± 0.9% w.r.t. baseline, p < 0.05) was observed. ITBV and R E normalized by body mass index were strongly inversely correlated (r = -0.93, p < 0.05). In conclusion, an acute fluid displacement to the thoracic circulation was induced in healthy volunteers. Significant changes were observed in the considered thoracic fluid measures derived from BIS and CMR. Good correlation was observed between the two measurement techniques. Further clinical studies will be necessary to prospectively evaluate the value of a combination of the two techniques for prediction of re-hospitalizations after admission for heart failure.

Model-Based Characterization of the Transpulmonary Circulation by Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Heart Failure and Healthy Volunteers.

OBJECTIVES: Novel quantitative measures of transpulmonary circulation status may allow the improvement of heart failure (HF) patient management. In this work, we propose a method for the assessment of the transpulmonary circulation using measurements from indicator time intensity curves, derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) series. The derived indicator dilution parameters in healthy volunteers (HVs) and HF patients were compared, and repeatability was assessed. Furthermore, we compared the parameters derived using the proposed method with standard measures of cardiovascular function, such as left ventricular (LV) volumes and ejection fraction. MATERIALS AND METHODS: In total, 19 HVs and 33 HF patients underwent a DCE-MRI scan on a 1.5 T MRI scanner using a T1-weighted spoiled gradient echo sequence. Image loops with 1 heartbeat temporal resolution were acquired in 4-chamber view during ventricular late diastole, after the injection of a 0.1-mmol gadoteriol bolus. In a subset of subjects (8 HFs, 2 HVs), a second injection of a 0.3-mmol gadoteriol bolus was performed with the same imaging settings. The study was approved by the local institutional review board.Indicator dilution curves were derived, averaging the MR signal within regions of interest in the right and left ventricle; parametric deconvolution was performed between the right and LV indicator dilution curves to identify the impulse response of the transpulmonary dilution system. The local density random walk model was used to parametrize the impulse response; pulmonary transit time (PTT) was defined as the mean transit time of the indicator. λ, related to the Péclet number (ratio between convection and diffusion) for the dilution process, was also estimated. RESULTS: Pulmonary transit time was significantly prolonged in HF patients (8.70 ± 1.87 seconds vs 6.68 ± 1.89 seconds in HV, P < 0.005) and even stronger when normalized to subject heart rate (normalized PTT, 9.90 ± 2.16 vs 7.11 ± 2.17 in HV, dimensionless, P < 0.001). λ was significantly smaller in HF patients (8.59 ± 4.24 in HF vs 12.50 ± 17.09 in HV, dimensionless, P < 0.005), indicating a longer tail for the impulse response. Pulmonary transit time correlated well with established cardiovascular parameters (LV end-diastolic volume index, r = 0.61, P < 0.0001; LV ejection fraction, r = -0.64, P < 0.0001). The measurement of indicator dilution parameters was repeatable (correlation between estimates based on the 2 repetitions for PTT: r = 0.94, P < 0.001, difference between 2 repetitions 0.01 ± 0.60 second, for λ: r = 0.74, P < 0.01, difference 0.69 ± 4.39). CONCLUSIONS: Characterization of the transpulmonary circulation by DCE-MRI is feasible in HF patients and HVs. Significant differences are observed between indicator dilution parameters measured in HVs and HF patients; preliminary results suggest good repeatability for the proposed parameters.

Pulmonary transit time measurement by contrast-enhanced ultrasound in left ventricular dyssynchrony.

BACKGROUND: Pulmonary transit time (PTT) is an indirect measure of preload and left ventricular function, which can be estimated using the indicator dilution theory by contrast-enhanced ultrasound (CEUS). In this study, we first assessed the accuracy of PTT-CEUS by comparing it with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Secondly, we tested the hypothesis that PTT-CEUS correlates with the severity of heart failure, assessed by MRI and N-terminal pro-B-type natriuretic peptide (NT-proBNP). METHODS AND RESULTS: Twenty patients referred to our hospital for cardiac resynchronization therapy (CRT) were enrolled. DCE-MRI, CEUS, and NT-proBNP measurements were performed within an hour. Mean transit time (MTT) was obtained by estimating the time evolution of indicator concentration within regions of interest drawn in the right and left ventricles in video loops of DCE-MRI and CEUS. PTT was estimated as the difference of the left and right ventricular MTT. Normalized PTT (nPTT) was obtained by multiplication of PTT with the heart rate. Mean PTT-CEUS was 10.5±2.4s and PTT-DCE-MRI was 10.4±2.0s (P=0.88). The correlations of PTT and nPTT by CEUS and DCE-MRI were strong; r=0.75 (P=0.0001) and r=0.76 (P=0.0001), respectively. Bland-Altman analysis revealed a bias of 0.1s for PTT. nPTT-CEUS correlated moderately with left ventricle volumes. The correlations for PTT-CEUS and nPTT-CEUS were moderate to strong with NT-proBNP; r=0.54 (P=0.022) and r=0.68 (P=0.002), respectively. CONCLUSIONS: (n)PTT-CEUS showed strong agreement with that by DCE-MRI. Given the good correlation with NT-proBNP level, (n)PTT-CEUS may provide a novel, clinically feasible measure to quantify the severity of heart failure. CLINICAL TRIAL REGISTRY: NCT01735838.

Reliability, repeatability, and reproducibility of pulmonary transit time assessment by contrast enhanced echocardiography.

BACKGROUND: The aim of this study is to investigate the inter and intra-rater reliability, repeatability, and reproducibility of pulmonary transit time (PTT) measurement in patients using contrast enhanced ultrasound (CEUS), as an indirect measure of preload and left ventricular function. METHODS: Mean transit times (MTT) were measured by drawing a region of interest (ROI) in right and left cardiac ventricle in the CEUS loops. Acoustic intensity dilution curves were obtained from the ROIs. MTTs were calculated by applying model-based fitting on the dilution curves. PTT was calculated as the difference of the MTTs. Eight raters with different levels of experience measured the PTT (time moment 1) and repeated the measurement within a week (time moment 2). Reliability and agreement were assessed using intra-class correlations (ICC) and Bland-Altman analysis. Repeatability was tested by estimating the variance of means (ANOVA) of three injections in each patient at different doses. Reproducibility was tested by the ICC of the two time moments. RESULTS: Fifteen patients with heart failure were included. The mean PTT was 11.8 ± 3.1 s at time moment 1 and 11.7 ± 2.9 s at time moment 2. The inter-rater reliability for PTT was excellent (ICC = 0.94). The intra-rater reliability per rater was between 0.81-0.99. Bland-Altman analysis revealed a bias of 0.10 s within the rater groups. Reproducibility for PTT showed an ICC = 0.94 between the two time moments. ANOVA showed no significant difference between the means of the three different doses F = 0.048 (P = 0.95). The mean and standard deviation for PTT estimates at three different doses was 11.6 ± 3.3 s. CONCLUSIONS: PTT estimation using CEUS shows a high inter- and intra-rater reliability, repeatability at three different doses, and reproducibility by ROI drawing. This makes the minimally invasive PTT measurement using contrast echocardiography ready for clinical evaluation in patients with heart failure and for preload estimation.

Automatic indicator dilution curve extraction in dynamic-contrast enhanced imaging using spectral clustering.

Indicator dilution theory provides a framework for the measurement of several cardiovascular parameters. Recently, dynamic imaging and contrast agents have been proposed to apply the method in a minimally invasive way. However, the use of contrast-enhanced sequences requires the definition of regions of interest (ROIs) in the dynamic image series; a time-consuming and operator dependent task, commonly performed manually. In this work, we propose a method for the automatic extraction of indicator dilution curves, exploiting the time domain correlation between pixels belonging to the same region. Individual time intensity curves were projected into a low dimensional subspace using principal component analysis; subsequently, clustering was performed to identify the different ROIs. The method was assessed on clinically available DCE-MRI and DCE-US recordings, comparing the derived IDCs with those obtained manually. The robustness to noise of the proposed approach was shown on simulated data. The tracer kinetic parameters derived on real images were in agreement with those obtained from manual annotation. The presented method is a clinically useful preprocessing step prior to further ROI-based cardiac quantifications.

Maximum-likelihood estimation for indicator dilution analysis.

Indicator-dilution methods are widely used by many medical imaging techniques and by dye-, lithium-, and thermodilution measurements. The measured indicator dilution curves are typically fitted by a mathematical model to estimate the hemodynamic parameters of interest. This paper presents a new maximum-likelihood algorithm for parameter estimation, where indicator dilution curves are considered as the histogram of underlying transit-time distribution. Apart from a general description of the algorithm, semianalytical solutions are provided for three well-known indicator dilution models. An adaptation of the algorithm is also introduced to cope with indicator recirculation. In simulations as well as in experimental data obtained by dynamic contrast-enhanced ultrasound imaging, the proposed algorithm shows a superior parameter estimation accuracy over nonlinear least-squares regression. The feasibility of the algorithm for use in vivo is evaluated using dynamic contrast-enhanced ultrasound recordings obtained with the purpose of prostate cancer detection. The proposed algorithm shows an improved ability (increase in receiver-operating characteristic curve area of up to 0.13) with respect to existing methods to differentiate between healthy tissue and cancer.

Volume quantification by contrast-enhanced ultrasound: an in-vitro comparison with true volumes and thermodilution.

BACKGROUND: Contrast-enhanced ultrasound (CEUS) has recently been proposed as a minimally- invasive, alternative method for blood volume measurement. This study aims at comparing the accuracy of CEUS and the classical thermodilution techniques for volume assessment in an in-vitro set-up. METHODS: The in-vitro set-up consisted of a variable network between an inflow and outflow tube and a roller pump. The inflow and outflow tubes were insonified with an ultrasound array transducer and a thermistor was placed in each tube. Indicator dilution curves were made by injecting indicator which consisted of an ultrasound-contrast-agent diluted in ice-cold saline. Both acoustic intensity- and thermo-dilution curves were used to calculate the indicator mean transit time between the inflow and outflow tube. The volumes were derived by multiplying the estimated mean transit time by the flow rate. We compared the volumes measured by CEUS with the true volumes of the variable network and those measured by thermodilution by Bland-Altman and intraclass-correlation analysis. RESULTS: The measurements by CEUS and thermodilution showed a very strong correlation (rs = 0.94) with a modest volume underestimation by CEUS of -40 ± 28 mL and an overestimation of 84 ± 62 mL by thermodilution compared with the true volumes. Both CEUS and thermodilution showed a high statistically significant correlation with the true volume (rs = 0.97 (95% CI, 0.95 - 0.98; P<0.0001) and rs = 0.96 (95% CI, 0.94 - 0.98; P<0.0001, respectively). CONCLUSIONS: CEUS volume estimation provides a strong correlation with both the true volumes in-vitro and volume estimation by thermodilution. It may therefore represent an interesting alternative to the standard, invasive thermodilution technique.