Correction: Linking statistical shape models and simulated function in the healthy adult human heart.

[This corrects the article DOI: 10.1371/journal.pcbi.1008851.].

Linking statistical shape models and simulated function in the healthy adult human heart.

Cardiac anatomy plays a crucial role in determining cardiac function. However, there is a poor understanding of how specific and localised anatomical changes affect different cardiac functional outputs. In this work, we test the hypothesis that in a statistical shape model (SSM), the modes that are most relevant for describing anatomy are also most important for determining the output of cardiac electromechanics simulations. We made patient-specific four-chamber heart meshes (n = 20) from cardiac CT images in asymptomatic subjects and created a SSM from 19 cases. Nine modes captured 90% of the anatomical variation in the SSM. Functional simulation outputs correlated best with modes 2, 3 and 9 on average (R = 0.49 ± 0.17, 0.37 ± 0.23 and 0.34 ± 0.17 respectively). We performed a global sensitivity analysis to identify the different modes responsible for different simulated electrical and mechanical measures of cardiac function. Modes 2 and 9 were the most important for determining simulated left ventricular mechanics and pressure-derived phenotypes. Mode 2 explained 28.56 ± 16.48% and 25.5 ± 20.85, and mode 9 explained 12.1 ± 8.74% and 13.54 ± 16.91% of the variances of mechanics and pressure-derived phenotypes, respectively. Electrophysiological biomarkers were explained by the interaction of 3 ± 1 modes. In the healthy adult human heart, shape modes that explain large portions of anatomical variance do not explain equivalent levels of electromechanical functional variation. As a result, in cardiac models, representing patient anatomy using a limited number of modes of anatomical variation can cause a loss in accuracy of simulated electromechanical function.

Gaussian process manifold interpolation for probabilistic atrial activation maps and uncertain conduction velocity.

In patients with atrial fibrillation, local activation time (LAT) maps are routinely used for characterizing patient pathophysiology. The gradient of LAT maps can be used to calculate conduction velocity (CV), which directly relates to material conductivity and may provide an important measure of atrial substrate properties. Including uncertainty in CV calculations would help with interpreting the reliability of these measurements. Here, we build upon a recent insight into reduced-rank Gaussian processes (GPs) to perform probabilistic interpolation of uncertain LAT directly on human atrial manifolds. Our Gaussian process manifold interpolation (GPMI) method accounts for the topology of the atrium, and allows for calculation of statistics for predicted CV. We demonstrate our method on two clinical cases, and perform validation against a simulated ground truth. CV uncertainty depends on data density, wave propagation direction and CV magnitude. GPMI is suitable for probabilistic interpolation of other uncertain quantities on non-Euclidean manifolds. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

Pulmonary vein encirclement using an Ablation Index-guided point-by-point workflow: cardiovascular magnetic resonance assessment of left atrial scar formation.

AIMS: A point-by-point workflow for pulmonary vein isolation (PVI) targeting pre-defined Ablation Index values (a composite of contact force, time, and power) and minimizing interlesion distance may optimize the creation of contiguous ablation lesions whilst minimizing scar formation. We aimed to compare ablation scar formation in patients undergoing PVI using this workflow to patients undergoing a continuous catheter drag workflow. METHODS AND RESULTS: Post-ablation cardiovascular magnetic resonance imaging was performed in patients undergoing 1st-time PVI using a parameter-guided point-by-point workflow (n = 26). Total left atrial scar burden and the width and continuity of the pulmonary vein encirclement were determined on analysis of atrial late gadolinium enhancement sequences. Comparison was made with a cohort of patients (n = 20) undergoing PVI using continuous drag lesions. Mean post-ablation scar burden and scar width were significantly lower in the point-by-point group than in the control group (6.6 ± 6.8% vs. 9.6 ± 5.0%, P = 0.03 and 7.9 ± 3.6 mm vs. 10.7 ± 2.3 mm, P = 0.003). More complete bilateral pulmonary vein encirclements were seen in the point-by-point group (P = 0.038). All patients achieved acute PVI. CONCLUSION: Pulmonary vein isolation using a point-by-point workflow is feasible and results in a lower scar burden and scar width with more complete pulmonary vein encirclements than a conventional drag lesion approach.

Evaluation of a real-time magnetic resonance imaging-guided electrophysiology system for structural and electrophysiological ventricular tachycardia substrate assessment.

AIMS: Potential advantages of real-time magnetic resonance imaging (MRI)-guided electrophysiology (MR-EP) include contemporaneous three-dimensional substrate assessment at the time of intervention, improved procedural guidance, and ablation lesion assessment. We evaluated a novel real-time MR-EP system to perform endocardial voltage mapping and assessment of delayed conduction in a porcine ischaemia-reperfusion model. METHODS AND RESULTS: Sites of low voltage and slow conduction identified using the system were registered and compared to regions of late gadolinium enhancement (LGE) on MRI. The Sorensen-Dice similarity coefficient (DSC) between LGE scar maps and voltage maps was computed on a nodal basis. A total of 445 electrograms were recorded in sinus rhythm (range: 30-186) using the MR-EP system including 138 electrograms from LGE regions. Pacing captured at 103 sites; 47 (45.6%) sites had a stimulus-to-QRS (S-QRS) delay of ≥40 ms. Using conventional (0.5-1.5 mV) bipolar voltage thresholds, the sensitivity and specificity of voltage mapping using the MR-EP system to identify MR-derived LGE was 57% and 96%, respectively. Voltage mapping had a better predictive ability in detecting LGE compared to S-QRS measurements using this system (area under curve: 0.907 vs. 0.840). Using an electrical threshold of 1.5 mV to define abnormal myocardium, the total DSC, scar DSC, and normal myocardium DSC between voltage maps and LGE scar maps was 79.0 ± 6.0%, 35.0 ± 10.1%, and 90.4 ± 8.6%, respectively. CONCLUSION: Low-voltage zones and regions of delayed conduction determined using a real-time MR-EP system are moderately associated with LGE areas identified on MRI.

Magnetic resonance imaging guidance for the optimization of ventricular tachycardia ablation.

Catheter ablation has an important role in the management of patients with ventricular tachycardia (VT) but is limited by modest long-term success rates. Magnetic resonance imaging (MRI) can provide valuable anatomic and functional information as well as potentially improve identification of target sites for ablation. A major limitation of current MRI protocols is the spatial resolution required to identify the areas of tissue responsible for VT but recent developments have led to new strategies which may improve substrate assessment. Potential ways in which detailed information gained from MRI may be utilized during electrophysiology procedures include image integration or performing a procedure under real-time MRI guidance. Image integration allows pre-procedural magnetic resonance (MR) images to be registered with electroanatomical maps to help guide VT ablation and has shown promise in preliminary studies. However, multiple errors can arise during this process due to the registration technique used, changes in ventricular geometry between the time of MRI and the ablation procedure, respiratory and cardiac motion. As isthmus sites may only be a few millimetres wide, reducing these errors may be critical to improve outcomes in VT ablation. Real-time MR-guided intervention has emerged as an alternative solution to address the limitations of pre-acquired imaging to guide ablation. There is now a growing body of literature describing the feasibility, techniques, and potential applications of real-time MR-guided electrophysiology. We review whether real-time MR-guided intervention could be applied in the setting of VT ablation and the potential challenges that need to be overcome.

Local activation time sampling density for atrial tachycardia contact mapping: how much is enough?

Aims: Local activation time (LAT) mapping forms the cornerstone of atrial tachycardia diagnosis. Although anatomic and positional accuracy of electroanatomic mapping (EAM) systems have been validated, the effect of electrode sampling density on LAT map reconstruction is not known. Here, we study the effect of chamber geometry and activation complexity on optimal LAT sampling density using a combined in silico and in vivo approach. Methods and results: In vivo 21 atrial tachycardia maps were studied in three groups: (1) focal activation, (2) macro-re-entry, and (3) localized re-entry. In silico activation was simulated on a 4×4cm atrial monolayer, sampled randomly at 0.25-10 points/cm2 and used to re-interpolate LAT maps. Activation patterns were studied in the geometrically simple porcine right atrium (RA) and complex human left atrium (LA). Activation complexity was introduced into the porcine RA by incomplete inter-caval linear ablation. In all cases, optimal sampling density was defined as the highest density resulting in minimal further error reduction in the re-interpolated maps. Optimal sampling densities for LA tachycardias were 0.67 ± 0.17 points/cm2 (focal activation), 1.05 ± 0.32 points/cm2 (macro-re-entry) and 1.23 ± 0.26 points/cm2 (localized re-entry), P = 0.0031. Increasing activation complexity was associated with increased optimal sampling density both in silico (focal activation 1.09 ± 0.14 points/cm2; re-entry 1.44 ± 0.49 points/cm2; spiral-wave 1.50 ± 0.34 points/cm2, P < 0.0001) and in vivo (porcine RA pre-ablation 0.45 ± 0.13 vs. post-ablation 0.78 ± 0.17 points/cm2, P = 0.0008). Increasing chamber geometry was also associated with increased optimal sampling density (0.61 ± 0.22 points/cm2 vs. 1.0 ± 0.34 points/cm2, P = 0.0015). Conclusion: Optimal sampling densities can be identified to maximize diagnostic yield of LAT maps. Greater sampling density is required to correctly reveal complex activation and represent activation across complex geometries. Overall, the optimal sampling density for LAT map interpolation defined in this study was ∼1.0-1.5 points/cm2.

Simultaneous display of multiple three-dimensional electrophysiological datasets (dot mapping).

AIMS: Complex ablation procedures are supported by accurate representation of an increasing variety of electrophysiological and imaging data within electroanatomic mapping systems (EMS). This study aims to develop a novel method for representing multiple complementary datasets on a single cardiac chamber model. Validation of the system and its application to both atrial and ventricular arrhythmias is examined. METHODS AND RESULTS: Dot mapping was conceived to display multiple datasets by utilizing quantitative surface shading to represent one dataset and finely spaced dots to represent others. Dot positions are randomized within triangular (surface meshes) or tetrahedral (volumetric meshes) simplices making the approach directly transferrable to contemporary EMS. Test data representing uniform electrical activation (n = 10) and focal scarring (n = 10) were used to test dot mapping data perception accuracy. User experience of dot mapping with atrial and ventricular clinical data is evaluated. Dot mapping ensured constant screen dot density for regions of uniform dataset values, regardless of user manipulation of the cardiac chamber. Perception accuracy of dot mapping was equivalent to colour mapping for both propagation direction (1.5 ± 1.8 vs. 4.8 ± 5.3°, P = 0.24) and focal source localization (1.1 ± 0.7 vs. 1.4 ± 0.5 mm, P = 0.88). User acceptance testing revealed equivalent diagnostic accuracy and display fidelity when compared with colour mapping. CONCLUSION: Dot mapping provides the unique ability to display multiple datasets from multiple sources on a single cardiac chamber model. The visual combination of multiple datasets may facilitate interpretation of complex electrophysiological and imaging data.

The role of myocardial wall thickness in atrial arrhythmogenesis.

Changes in the structure and electrical behaviour of the left atrium are known to occur with conditions that predispose to atrial fibrillation (AF) and in response to prolonged periods of AF. We review the evidence that changes in myocardial thickness in the left atrium are an important part of this pathological remodelling process. Autopsy studies have demonstrated changes in the thickness of the atrial wall between patients with different clinical histories. Comparison of the reported tissue dimensions from pathological studies provides an indication of normal ranges for atrial wall thickness. Imaging studies, most commonly done using cardiac computed tomography, have demonstrated that these changes may be identified non-invasively. Experimental evidence using isolated tissue preparations, animal models of AF, and computer simulations proves that the three-dimensional tissue structure will be an important determinant of the electrical behaviour of atrial tissue. Accurately identifying the thickness of the atrial may have an important role in the non-invasive assessment of atrial structure. In combination with atrial tissue characterization, a comprehensive assessment of the atrial dimensions may allow prediction of atrial electrophysiological behaviour and in the future, guide radiofrequency delivery in regions based on their tissue thickness.

Improvement of Right Ventricular Hemodynamics with Left Ventricular Endocardial Pacing during Cardiac Resynchronization Therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) with biventricular epicardial (BV-CS) or endocardial left ventricular (LV) stimulation (BV-EN) improves LV hemodynamics. The effect of CRT on right ventricular function is less clear, particularly for BV-EN. Our objective was to compare the simultaneous acute hemodynamic response (AHR) of the right and left ventricles (RV and LV) with BV-CS and BV-EN in order to determine the optimal mode of CRT delivery. METHODS: Nine patients with previously implanted CRT devices successfully underwent a temporary pacing study. Pressure wires measured the simultaneous AHR in both ventricles during different pacing protocols. Conventional epicardial CRT was delivered in LV-only (LV-CS) and BV-CS configurations and compared with BV-EN pacing in multiple locations using a roving decapolar catheter. RESULTS: Best BV-EN (optimal AHR of all LV endocardial pacing sites) produced a significantly greater RV AHR compared with LV-CS and BV-CS pacing (P < 0.05). RV AHR had a significantly increased standard deviation compared to LV AHR (P < 0.05) with a weak correlation between RV and LV AHR (Spearman rs = -0.06). Compromised biventricular optimization, whereby RV AHR was increased at the expense of a smaller decrease in LV AHR, was achieved in 56% of cases, all with BV-EN pacing. CONCLUSIONS: BV-EN pacing produces significant increases in both LV and RV AHR, above that achievable with conventional epicardial pacing. RV AHR cannot be used as a surrogate for optimizing LV AHR; however, compromised biventricular optimization is possible. The beneficial effect of endocardial LV pacing on RV function may have important clinical benefits beyond conventional CRT.

A randomized prospective mechanistic cardiac magnetic resonance study correlating catheter stability, late gadolinium enhancement and 3 year clinical outcomes in robotically assisted vs. standard catheter ablation.

AIMS: To prospectively compare cardiac magnetic resonance late gadolinium enhancement (LGE) findings created by standard vs. robotically assisted catheter ablation lesions and correlate these with clinical outcomes. METHODS AND RESULTS: Forty paroxysmal atrial fibrillation patients (mean age 54 ± 13.8 years) undergoing first left atrial ablation were randomized to either robotic-assisted navigation (Hansen Sensei(®) X) or standard navigation. Pre-procedural, acute (24 h post-procedure) and late (beyond 3 months) scans were performed with LGE and T2W imaging sequences and percentage circumferential enhancement around the pulmonary vein (PV) antra were quantified. Baseline pre-procedural enhancements were similar in both groups. On acute imaging, mean % encirclements by LGE and T2W signal were 72% and 80% in the robotic group vs. 60% (P = 0.002) and 76%(P = 0.45) for standard ablation. On late imaging, the T2W signal resolved to baseline in both groups. Late gadolinium enhancement remained the predominant signal with 56% encirclement in the robotic group vs. 45% in the standard group (P = 0.04). At 6 months follow-up, arrhythmia-free patients had an almost similar mean LGE encirclement (robotic 64%, standard 60%, P = 0.45) but in recurrences, LGE was higher in the robotic group (43% vs. 30%, P = 0.001). At mean 3 years follow-up, 1.3 procedures were performed in the robotic group compared with 1.9 (P < 0.001) in the standard to achieve a success rate of 80% vs. 75%. CONCLUSION: Robotically assisted ablation results in greater LGE around the PV antrum. Effective lesions created through improved catheter stability and contact force during initial treatment may have a role in reducing subsequent re-do procedures.

Cardiac magnetic resonance and electroanatomical mapping of acute and chronic atrial ablation injury: a histological validation study.

AIMS: To provide a comprehensive histopathological validation of cardiac magnetic resonance (CMR) and endocardial voltage mapping of acute and chronic atrial ablation injury. METHODS AND RESULTS: 16 pigs underwent pre-ablation T2-weighted (T2W) and late gadolinium enhancement (LGE) CMR and high-density voltage mapping of the right atrium (RA) and both were repeated after intercaval linear radiofrequency ablation. Eight pigs were sacrificed following the procedure for pathological examination. A further eight pigs were recovered for 8 weeks, before chronic CMR, repeat RA voltage mapping and pathological examination. Signal intensity (SI) thresholds from 0 to 15 SD above a reference SI were used to segment the RA in CMR images and segmentations compared with real lesion volumes. The SI thresholds that best approximated histological volumes were 2.3 SD for LGE post-ablation, 14.5 SD for T2W post-ablation and 3.3 SD for LGE chronically. T2-weighted chronically always underestimated lesion volume. Acute histology showed transmural injury with coagulative necrosis. Chronic histology showed transmural fibrous scar. The mean voltage at the centre of the ablation line was 3.3 mV pre-ablation, 0.6 mV immediately post-ablation, and 0.3 mV chronically. CONCLUSION: This study presents the first histopathological validation of CMR and endocardial voltage mapping to define acute and chronic atrial ablation injury, including SI thresholds that best match histological lesion volumes. An understanding of these thresholds may allow a more informed assessment of the underlying atrial substrate immediately after ablation and before repeat catheter ablation for atrial arrhythmias.

Positive response to cardiac resynchronization therapy reduces arrhythmic events after elective generator change in patients with primary prevention CRT-D.

INTRODUCTION: Cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillators (ICD) are effective therapies for heart failure (HF) patients with cardiac dyssynchrony. Patients receiving primary prevention CRT-defibrillator that positively remodel might no longer qualify for ICD indication due to CRT-induced left ventricular ejection fraction (LVEF) improvement. We aimed to evaluate the outcome of CRT-D patients at the time of device replacement (DR). METHODS AND RESULTS: Patients undergoing primary prevention CRT-D DR were prospectively included from November 2007 to March 2011 in 2 centers. CRT response was as defined as ≥1 NYHA class improvement and an increase in LVEF ≥10%. Before DR, all patients underwent echocardiography and device interrogation. Patients without theoretical ongoing ICD indication (TOII) at DR were defined as those with LVEF ≥40% without appropriate ICD therapy (appropriate therapy) during the first ICD service-life. A total of 107 consecutive patients were enrolled. Sixty-one patients (57%) were considered CRT responders after the index procedure. At the time of DR (56.4 ± 14.4 months from initial implant), 87% of CRT responders were free of appropriate therapy, compared with 70% of CRT nonresponders (P = 0.02). Thirty-nine patients (37%) did not meet the criteria for TOII. During follow-up (mean 26.4 ± 14.4 months after DR), 37 patients (95%) without TOII were free of appropriate therapy versus 49 of 68 patients (72%) with ongoing TOII (P = 0.007). By multivariable analysis, the only independent predictor of appropriate therapy after DR was TOII (hazard ratio = 6.43; P = 0.01). CONCLUSION: Absence of theoretical ICD indication occurs in more than one-third of CRT-D patients undergoing DR. In addition, appropriate therapy rate is relatively low (2.2% per year) in this subgroup of patients.

Organizational index mapping to identify focal sources during persistent atrial fibrillation.

INTRODUCTION: Localized rotors have been implicated in the mechanism of persistent atrial fibrillation (AF). Although regions of highest dominant frequency (DF) on spectral analysis of the left atrium (LA) have been said to identify rotors, other mechanisms such as wavefront collisions will sporadically also generate an inconsistent distribution of high DF. We hypothesized that if drivers of AF were present, their distinctive spectral characteristics would result more from their temporal stability than their high frequency. METHODS AND RESULTS: Ten patients with persistent AF underwent LA noncontact mapping. Following subtraction of far-field ventricular components, noncontact electrograms at 256 sites underwent fast Fourier transform. Mean absolute difference in DF between 5 sequential 7-second segments of AF was defined as the DF variability (DFV) at each site. Mean ratio of the DF and its harmonics to the total power of the spectrum was defined as the organizational index (OI). Mean DFV was significantly lower in organized areas (OI > 1 SD above mean) than at all sites (0.34 ± 0.04 vs 0.46 ± 0.04 Hz; P < 0.001). When organized areas were ablated during wide-area circumferential ablation, AF organized in remote regions (LA appendage ΔOI ablated vs unablated: +0.21 [0.06-0.41] vs -0.04 [-0.14-0.05]; P = 0.005). CONCLUSIONS: At sites of organized activation, the activation frequency was also significantly more stable over time. This observation is consistent with the existence of focal sources, and inconsistent with a purely random activation pattern. Ablation of such regions is technically feasible, and was associated with organization of AF in remote atrial regions.

Patient-specific modeling of atrial fibrosis increases the accuracy of sinus rhythm simulations and may explain maintenance of atrial fibrillation.

Left atrial fibrosis is thought to contribute to the manifestation of atrial fibrillation (AF). Late Gadolinium enhancement (LGE) MRI has the potential to image regions of low perfusion, which can be related to fibrosis. We show that a simulation with a patient-specific model including left atrial regional fibrosis derived from LGE-MRI reproduces local activation in the left atrium more precisely than the regular simulation without fibrosis. AF simulations showed a spontaneous termination of the arrhythmia in the absence of fibrosis and a stable rotor center in the presence of fibrosis. The methodology may provide a tool for a deeper understanding of the mechanisms maintaining AF and eventually also for the planning of substrate-guided ablation procedures in the future.

A practical criterion for the rapid detection of single-loop and double-loop reentry tachycardias.

INTRODUCTION: Entrainment criteria for the diagnosis of reentrant atrial tachycardia can be difficult to apply and cannot detect double-loop reentry. We sought to develop and clinically test a new criterion for the diagnosis of single- and double-loop reentry. METHODS AND RESULTS: (1) Proposed criterion: after sequential overdrive pacing at 2 different locations and assessing the first ensuing beats of tachycardia, the difference in activation time recorded between 2 appropriate stationary positions changes by 1 or 2 tachycardia cycle lengths; a change of 2 tachycardia cycle lengths usually indicates double-loop reentry rather than only a single-loop. (2) Clinical testing: multiple overdrive pacing maneuvers were undertaken and analyzed in 5 patients with common flutter (single-loop reentry). In total, 23 pairs of overdrive pacing maneuvers were performed using electrodes in the coronary sinus and a distribution of positions in the right atrium. In 22/23 pairs of maneuvers, the change in Activation Difference was within 2.6 ± 12.4 milliseconds of the tachycardia cycle length, confirming single loop reentry. For double-loop reentry, the literature was reviewed and 3 cases of double-loop reentry were identified with sufficient data. In all of these cases, double-loop reentry was detected and also the zone containing the common isthmus was identified. CONCLUSION: The proposed criterion can diagnose single- and double-loop reentry atrial tachycardia using intracardiac recordings from any pair of well separated positions. The criterion does not require precise electrode placement or extensive activation mapping.

Pulmonary vein anatomy predicts freedom from atrial fibrillation using remote magnetic navigation for circumferential pulmonary vein ablation.

AIMS: Multidetector computed tomography (MDCT) is frequently used to guide circumferential pulmonary vein ablation (PVA) for treatment of atrial fibrillation (AF) as it offers accurate visualization of the left atrial (LA) and pulmonary vein (PV) anatomy. This study aimed to identify if PV anatomy is associated with outcomes following PVA using remote magnetic navigation (RMN). METHODS AND RESULTS: We analysed data from 138 consecutive patients and 146 ablation procedures referred for PVA due to drug-refractory symptomatic AF (age 63 ± 11 years; 57% men; 69% paroxysmal AF). The RMN using the stereotaxis system and open-irrigated 3.5 mm ablation catheters was used in all procedures. Prior to PVA, all patients underwent electrocardiogram-gated 64-MDCT for assessment of LA dimensions, PV anatomy, and electro-anatomical image integration during the procedure. Regular PV anatomy was found in 68%, a common left PV ostium was detected in 26%, and variant anatomy of the right PVs was detected in 6%. After a mean follow-up of 337 ± 102 days, 63% of the patients maintained sinus rhythm after the initial ablation, and 83% when including repeat PVA. Although acutely successful PV isolation did not differ between anatomical subgroups (regular 3.5 ± 0.8 vs. variant 3.2 ± 1.3; P = 0.31), AF recurrence was significantly higher in patients with non-regular PV anatomy (P = 0.04, hazard ratio 1.72). Pulmonary vein anatomy did not influence complication rates. CONCLUSION: Pulmonary vein anatomy assessed by MDCT is a good predictor of AF recurrence after PVA using RMN.

Catheter ablation of atrial fibrillation in heart failure.

Atrial fibrillation in the presence of heart failure is an independent predictor of mortality and is associated with increased hospitalizations and worsening New York Heart Association functional class. Despite these associations, large-scale trials have not shown a benefit in rhythm restoration. However, further analysis of these trials showed that patients who remained in sinus rhythm did have improved survival rates. Studies to examine the efficacy of catheter ablation of atrial fibrillation were therefore conducted and reported efficacy rates ranging from 50% to 92% at maintaining sinus rhythm with associated improvements in left ventricular ejection fraction, quality of life, and New York Heart Association functional class.