Benjamin H. Freed

Real-time 3D echocardiographic quantification of left atrial volume: multicenter study for validation with CMR

OBJECTIVES We studied in a multicenter setting the accuracy and reproducibility of 3-dimensional echocardiography (3DE)-derived measurements of left atrial volume (LAV) using new, dedicated volumetric software, side by side with 2-dimensional echocardiography (2DE), using cardiac magnetic resonance (CMR) imaging as a reference. BACKGROUND Increased LAV is associated with adverse cardiovascular outcomes. Although LAV measurements are routinely performed using 2DE, this methodology is limited because it is view dependent and relies on geometric assumptions regarding left atrial shape. Real-time 3DE is free of these limitations and accordingly is an attractive alternative for the evaluation of LAV. However, few studies have validated 3DE-derived LAV measurements against an accepted independent reference standard, such as CMR imaging. METHODS We studied 92 patients with a wide range of LAV who underwent CMR (1.5-T) and echocardiographic imaging on the same day. Images were analyzed to obtain maximal and minimal LAV: CMR images using standard commercial tools, 2DE images using a biplane area-length technique, and 3DE images using Tomtec LA Function software. Intertechnique comparisons included linear regression and Bland-Altman analyses. Reproducibility of all 3 techniques was assessed by calculating the percentage of absolute differences in blinded repeated measurements. Kappa statistics were used to compare 2DE and 3DE classification of normal/enlarged against the CMR reference. RESULTS 3DE-derived LAV values showed higher correlation with CMR than 2DE measurements (r = 0.93 vs. r = 0.74 for maximal LAV; r = 0.88 vs. r = 0.82 for minimal LAV). Although 2DE underestimated maximal LAV by 31 ± 25 ml and minimal LAV by 16 ± 32 ml, 3DE resulted in a minimal bias of -1 ± 14 ml for maximal LAV and 0 ± 21 ml for minimal LAV. Interobserver and intraobserver variability of 2DE and 3DE measurements of maximal LAV were similar (7% to 12%) and approximately 2 times higher than CMR (4% to 5%). 3DE classified enlarged atria more accurately than 2DE (kappa: 0.88 vs. 0.71). CONCLUSIONS Compared with CMR reference, 3DE-derived LAV measurements are more accurate than 2DE-based analysis, resulting in fewer patients with undetected atrial enlargement.

Prognostic Importance of Pathophysiologic Markers in Patients With Heart Failure and Preserved Ejection Fraction

Background— Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome associated with multiple pathophysiologic abnormalities, including left ventricular (LV) diastolic dysfunction, longitudinal LV systolic dysfunction, abnormal ventricular-arterial coupling, pulmonary hypertension, and right ventricular (RV) remodeling/dysfunction. However, the relative prognostic significance of each of these pathophysiologic abnormalities in HFpEF is unknown. Methods and Results— We prospectively studied 419 patients with HFpEF using echocardiography and sphygmomanometry to assess HFpEF pathophysiologic markers. Cox proportional hazards analyses were used to determine the associations between pathophysiologic markers and outcomes. Mean age was 65±12 years; 62% were women; 39% were black; comorbidities were common; and study participants met published criteria for HFpEF. RV abnormalities were frequent: 28% had abnormal tricuspid annular plane systolic excursion, 15% had reduced RV fractional area change, and 34% had RV hypertrophy. During a median follow-up time of 18 months, 102 (24%) were hospitalized for HF and 175 (42%) experienced the composite end point of cardiovascular hospitalization or death. Decreased LV compliance, measured as reduced LV end-diastolic volume at an idealized LV end-diastolic pressure of 20 mm Hg (EDV20), and RV remodeling, as indicated by increased RV wall thickness, were the 2 pathophysiologic markers most predictive of worse outcomes: adjusted hazard ratio per 1 SD decrease in EDV20=1.39 (95% confidence interval [CI], 1.10–1.75; P=0.006), and hazard ratio per 1 SD increase in RV wall thickness=1.37 (95% CI, 1.16–1.61; P<0.001). These associations persisted after additional adjustment for markers of HF severity. By contrast, markers of LV relaxation, longitudinal LV systolic dysfunction, and ventricular-arterial coupling were not significantly associated with adverse outcomes. Conclusions— In patients with HFpEF, reduced LV compliance and RV remodeling are the strongest pathophysiologic predictors of adverse outcomes.

Late gadolinium enhancement cardiovascular magnetic resonance predicts clinical worsening in patients with pulmonary hypertension

BackgroundLate gadolinium enhancement (LGE) occurs at the right ventricular (RV) insertion point (RVIP) in patients with pulmonary hypertension (PH) and has been shown to correlate with cardiovascular magnetic resonance (CMR) derived RV indices. However, the prognostic role of RVIP-LGE and other CMR-derived parameters of RV function are not well established. Our aim was to evaluate the predictive value of contrast-enhanced CMR in patients with PH.MethodsRV size, ejection fraction (RVEF), and the presence of RVIP-LGE were determined in 58 patients with PH referred for CMR. All patients underwent right heart catheterization, exercise testing, and N-terminal pro-brain natriuretic peptide (NT-proBNP) evaluation; results of which were included in the final analysis if performed within 4 months of the CMR study. Patients were followed for the primary endpoint of time to clinical worsening (death, decompensated right ventricular heart failure, initiation of prostacyclin, or lung transplantation).ResultsOverall, 40/58 (69%) of patients had RVIP-LGE. Patients with RVIP- LGE had larger right ventricular volume index, lower RVEF, and higher mean pulmonary artery pressure (mPAP), all p < 0.05. During the follow-up period of 10.2 ± 6.3 months, 19 patients reached the primary endpoint. In a univariate analysis, RVIP-LGE was a predictor for adverse outcomes (p = 0.026). In a multivariate analysis, CMR-derived RVEF was an independent predictor of clinical worsening (p = 0.036) along with well-established prognostic parameters such as exercise capacity (p = 0.010) and mPAP (p = 0.001).ConclusionsThe presence of RVIP-LGE in patients with PH is a marker for more advanced disease and poor prognosis. In addition, this study reveals for the first time that CMR-derived RVEF is an independent non-invasive imaging predictor of adverse outcomes in this patient population.

QTc prolongation is associated with impaired right ventricular function and predicts mortality in pulmonary hypertension

BACKGROUND In rodent models of pulmonary hypertension (PH) and right ventricular hypertrophy (RVH), the QTc interval is prolonged, reflecting downregulation of repolarizing Kv channels in RV myocytes. The significance of QTc prolongation in human PH is unknown. We hypothesized that QTc prolongation occurs in human PH, is associated with RVH and decreased RV function, and predicts adverse prognosis. METHODS Patients receiving a PAH-specific therapy (a prostanoid, endothelin-receptor antagonist and/or a phosphodiesterase-5 inhibitor), who had a 12-lead electrocardiogram (ECG) (n=202) were compared to age- and sex-matched controls (n=100). The duration of QTc on ECG was correlated with invasive hemodynamics (n=156) and with the status of the RV, as measured by Brain Natriuretic Peptide (NT-proBNP, n=145) and magnetic resonance imaging (n=24). Survival of the entire PH cohort and a subgroup with WHO Groups 1 and 4 PAH was prospectively determined from the Social Security Death Index. RESULTS QTc intervals were longer in PH vs. controls (454.8 ± 29 ms vs. 429.8 ± 18 ms, p<0.001) and did not differ based on PAH-specific therapy. NT-proBNP increased proportionately with QTc and was higher for those in the upper quintile (QTc ≥ 480 ms) vs. those with QTc<480 ms (4004 ± 6682 pg/mL vs. 1501 ± 1822 pg/mL, p<0.001). The QTc interval also correlated directly with increasing RV end-diastolic volume (r=.67, p<0.001) and mass (r=.0.51, p<0.05), and inversely with RV ejection fraction (r=-.49, p<0.05). In the entire PH cohort and WHO Groups 1 and 4 subgroup, QTc ≥ 480 ms and cardiac index were independent predictors of mortality. CONCLUSIONS QTc prolongation in PH patients reflects the status of the RV and is an independent predictor of mortality.

Association of chronic kidney disease with abnormal cardiac mechanics and adverse outcomes in patients with heart failure and preserved ejection fraction.

Chronic kidney disease (CKD) is associated with worse outcomes in heart failure with preserved ejection fraction (HFpEF). Whether this association is due the effect of CKD on intrinsic abnormalities in cardiac function is unknown. We hypothesized that CKD is independently associated with worse cardiac mechanics in HFpEF.

Percutaneous Transcatheter Aortic Valve Closure Successfully Treats Left Ventricular Assist Device–Associated Aortic Insufficiency and Improves Cardiac Hemodynamics

OBJECTIVES This study sought to assess the effectiveness of a novel percutaneous method to treat left ventricular assist device (LVAD)-associated severe aortic insufficiency (AI) in a series of patients determined to be poor reoperative candidates. BACKGROUND The increased use of continuous-flow LVAD in advanced heart failure has led to marked changes in the management of patients with this condition. However, secondary AI can become a significant complication. METHODS Five patients with continuous-flow LVAD and severe post-LVAD AI underwent percutaneous transcatheter aortic valve closure from September to October 2011 at a single quaternary care academic medical center. All patients had LVAD implanted as destination therapy. LVAD parameters, hemodynamics, and echocardiographic measurements were obtained before and after aortic valve closure. RESULTS All patients underwent successful closure with the Amplatzer cribriform device (AGA Medical, Plymouth, Minnesota) via a percutaneous transcatheter femoral approach with a significant reduction of AI from severe to trivial. Cardiac hemodynamics improved, and the pulmonary capillary wedge pressure was reduced in all patients. There was no change in mitral or tricuspid regurgitation, LVAD power, or pulsatility index. CONCLUSIONS Percutaneous transcatheter closure of the aortic valve effectively treats LVAD-associated AI and reduces pulmonary capillary wedge pressure. This procedure should be considered to treat LVAD-associated AI in patients who are poor candidates for repeat operation. Further data are needed to assess long-term results.

TCT-379 Percutaneous Transcatheter Aortic Valve Closure Successfully Treats Left Ventricular Assist Device-Associated Aortic Insufficiency and Improves Cardiac Hemodynamics

The increased use of continuous-flow LVADs in advanced heart failure has led to marked changes in the management of patients with this condition. However, secondary AI can become a significant complication. Our objective was to assess the effectiveness of a novel percutaneous method to treat left

Prognostic Utility and Clinical Significance of Cardiac Mechanics in Heart Failure With Preserved Ejection Fraction: Importance of Left Atrial Strain.

Background—Left atrial (LA) enlargement is associated with adverse events in heart failure with preserved ejection fraction (HFpEF). However, the role of LA mechanics (ie, LA strain measures) in HFpEF has not been well studied. We hypothesized that in HFpEF, reduced (worse) LA strain is a key pathophysiologic abnormality and is a stronger correlate of adverse events than left ventricular or right ventricular longitudinal strain. Methods and Results—We evaluated baseline LA function in 308 patients with HFpEF who were followed up longitudinally for adverse outcomes. All patients underwent speckle-tracking echocardiography for measurement of left ventricular longitudinal strain, right ventricular free wall strain, and LA booster, conduit, and reservoir strains. The clinical and prognostic significance of left ventricular, right ventricular, and LA strain measures was assessed by regression analyses. The mean age was 65±13 years, 64% were women, 26% had atrial fibrillation, and LA enlargement was present in the majority of patients (67%). Decreased LA reservoir strain was associated with increased pulmonary vascular resistance (P<0.0001) and decreased peak oxygen consumption (P=0.0001). Of the left ventricular, right ventricular, and LA strain measures, LA reservoir strain was the strongest correlate of adverse events and was independently associated with the composite outcome of cardiovascular hospitalization or death (adjusted hazard ratio per 1-SD decrease in LA strain, 1.54; 95% CI, 1.15–2.07; P=0.006). Conclusions—Abnormal indices of LA mechanics (particularly LA reservoir strain) are powerful clinical and prognostic factors in HFpEF. Unloading the LA and augmentation of LA function may be important future therapeutic targets in HFpEF. Registration Information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01030991.

Sample Size and Cost Analysis for Pulmonary Arterial Hypertension Drug Trials Using Various Imaging Modalities to Assess Right Ventricular Size and Function End Points

Background—Placebo-controlled trials for pulmonary arterial hypertension are no longer acceptable because new therapies must show clinically significant effects on top of standard treatment. The purpose of this study was to estimate sample sizes and imaging costs for the planning of a hypothetical pulmonary arterial hypertension drug trial using imaging to detect changes in right ventricular size and function in response to combined therapy. Methods and Results—Same-day cardiovascular MR (CMR) and 2-dimensional (2D) and 3D transthoracic echocardiography (2DTTE and 3DTTE) were performed in 22 patients with pulmonary arterial hypertension (54±13 years of age) twice, 6 months apart. Short-axis CMR cines and full-volume 3DTTE data sets of the right ventricle were used to measure end-diastolic volume and ejection fraction. Fractional area change was obtained from 2DTTE. Sample size calculations used a 2-sample t test model incorporating differences between baseline and 6-month measurements. Cost estimates were made using the Medicare fee schedule. No significant differences were noted between baseline and follow-up measurements. Large SDs reflected variable progression of disease in individual patients on standard therapy and measurement variability. These sources of variability resulted in intertechnique differences in sample sizes: to detect a change of 5% to 15% in 3DTTE-derived right ventricular ejection fraction and fractional area change or change of 15 to 30 mL in 3DTTE right ventricular end-diastolic volume; sample sizes were 2× to 2.5× those required by CMR. As a result, the total cost of a trial using complete TTE was greater than CMR, which was greater than limited TTE. Conclusions—Because of lower measurement variability, CMR is more cost saving in pulmonary arterial hypertension drug trials than echocardiography, unless limited TTE is used.

Considerations when measuring myocardial perfusion reserve by cardiovascular magnetic resonance using regadenoson

BackgroundAdenosine cardiovascular magnetic resonance (CMR) can accurately quantify myocardial perfusion reserve. While regadenoson is increasingly employed due to ease of use, imaging protocols have not been standardized. We sought to determine the optimal regadenoson CMR protocol for quantifying myocardial perfusion reserve index (MPRi) – more specifically, whether regadenoson stress imaging should be performed before or after rest imaging.MethodsTwenty healthy subjects underwent CMR perfusion imaging during resting conditions, during regadenoson-induced hyperemia (0.4 mg), and after 15 min of recovery. In 10/20 subjects, recovery was facilitated with aminophylline (125 mg). Myocardial time-intensity curves were used to obtain left ventricular cavity-normalized myocardial up-slopes. MPRi was calculated in two different ways: as the up-slope ratio of stress to rest (MPRi-rest), and the up-slope ratio of stress to recovery (MPRi-recov).ResultsIn all 20 subjects, MPRi-rest was 1.78 ± 0.60. Recovery up-slope did not return to resting levels, regardless of aminophylline use. Among patients not receiving aminophylline, MPRi-recov was 36 ± 16% lower than MPRi-rest (1.13 ± 0.38 vs. 1.82 ± 0.73, P = 0.001). In the 10 patients whose recovery was facilitated with aminophylline, MPRi-recov was 20 ± 24% lower than MPRi-rest (1.40 ± 0.35 vs. 1.73 ± 0.43, P = 0.04), indicating incomplete reversal. In 3 subjects not receiving aminophylline and 4 subjects receiving aminophylline, up-slope at recovery was greater than at stress, suggesting delayed maximal hyperemia.ConclusionsMPRi measurements from regadenoson CMR are underestimated if recovery perfusion is used as a substitute for resting perfusion, even when recovery is facilitated with aminophylline. True resting images should be used to allow accurate MPRi quantification. The delayed maximal hyperemia observed in some subjects deserves further study.Trial registrationClinicalTrials.gov NCT00871260