The Subclinical Cardiomyopathy of Friedreich's Ataxia in a Pediatric Population.

BACKGROUND: Identification of a subclinical cardiomyopathy in pediatric patients with Friedreich's ataxia (FA) has not been well-described. METHODS: We performed echocardiography (Echo), cardiac magnetic resonance imaging (cMRI), and neurologic assessment in a cross-sectional analysis of 48 genetically confirmed FA subjects aged 9-17 years with moderate neurologic impairment but without a cardiovascular history. Echo- and cMRI-determined left ventricular mass were indexed (LVMI) to height in grams/m2.7. LV remodeling was categorized as concentric remodeling (CR), concentric hypertrophy (CH), or eccentric hypertrophy based upon Echo- determined relative LV wall thickness. RESULTS: Echo LVMI exceeded age-based normal values in 85% of subjects, and cMRI-determined LVMI correlated with depression of both diastolic and systolic tissue Doppler velocity (E': r = -0.65, P < .001, S': r = -0.46, P < .001) as well as increased early diastolic Doppler flow velocity/tissue velocity ratio (r= 0.55, P < .001), a marker of elevated LV filling pressure. Similar associations were found with echo-determined LV mass. Evidence of depressed LV relaxation and increased LV stiffness were observed in 88% and 71%, of subjects, respectively, despite a normal LV ejection fraction in almost all cases (mean = 60% + 7%). CR and CH were present in 40% and 44% of the study group, respectively, although significant depressions of E' and S' were observed only in subjects with CH (P < .005). CONCLUSIONS: A subclinical hypertrophic cardiomyopathy is common in pediatric FA patients and CH is associated with both diastolic and systolic dysfunction.

Correlation of echocardiographic findings with cerebral infarction in elderly adults: the AGES-Reykjavik study.

BACKGROUND AND PURPOSE: Chronic effects of hypertension may be observed in multiple end organs. Previous reports suggest that cardiovascular morphological features can mirror cerebral infarction. In this cross-sectional analysis of elderly subjects, we investigated the relationship of a comprehensive set of echocardiographic measures with cerebral infarction detected by MRI. METHODS: We compared echocardiographically determined left ventricular (LV) mass, left atrial volume, aortic root diameter, mitral annular calcification, and measures of diastolic function with cerebral infarction determined by MRI using logistic regression in a random sample drawn from the Age Gene/Environment Susceptibility-Reykjavik Study cohort. The model was first adjusted for age and gender, and then for age, gender, and vascular risk factors. RESULTS: Among 692 subjects aged 75 (standard deviation, 6) years, 28% had at least 1 cerebral infarct. When adjusted for age and gender, the presence of cerebral infarction was modestly related to LV mass (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.02) and left atrial volume (OR, 1.03; 95% CI, 1.01-1.05), as well as the lowest quartile of early-to-late pulsed Doppler velocity ratio (early-to-late pulsed Doppler velocity ratio <0.75; OR, 1.87; 95% CI, 1.22-2.87). The latter relation remained significant after adjustment for vascular risk factors and LV ejection fraction (OR, 1.82; 95% CI, 1.16-2.86). CONCLUSIONS: Of all echocardiographic parameters, LV filling abnormality as indicated by low early-to-late pulsed Doppler velocity ratio displayed the strongest association with cerebral infarction and this relationship was independent of vascular risk factors. This simple marker of cerebral infarction may be useful when evaluating older patients.

Determination of hospitalization type by investigator case report form or adjudication committee in a large heart failure clinical trial (ß-Blocker Evaluation of Survival Trial [BEST]).

BACKGROUND: End point committees are routinely used to adjudicate efficacy and safety end points in clinical trials. The 2,708-patient ß-Blocker Evaluation of Survival Trial (BEST) originally determined hospitalization type via investigator case report forms (CRFs), which captured whether a hospitalization was due to worsening heart failure (HF). Recently, the BEST End Points Committee (EPC) completed a blinded adjudication of all hospitalizations, allowing a comparison of the CRF method to the EPC method of determining hospitalization type. We sought to compare the investigator-determined mode of hospitalizations with the adjudicated events, to quantify the degree of agreement, and to compare the clinical trial results by method of event classification. METHODS: The BEST EPC reviewed all 5,086 hospitalizations that occurred in BEST. Events were identified using investigator-reported hospitalizations, as well as those documented by FDA Form 3500 (MedWatch) reports. RESULTS: The investigators identified more HF hospitalization events than adjudication (2,466 vs 1,729, P < .0001, paired analysis). Eight hundred thirty-four (34%) HF hospitalizations identified in CRFs were not confirmed by adjudication. Ninety-seven (6%) adjudicated events were not identified by the investigator reported method. One thousand six hundred thirty-two events were similarly identified by both methods. CONCLUSIONS: The EPC adjudication identified fewer HF hospitalizations than did the investigator reported method with no change in the hazard ratio for this end point. Our findings suggest that independent end point committees may improve reliability through reduced variance, thus providing similar outcome results with fewer events and no increase in CIs.

Myocardial structure and function by echocardiography in relation to glucometabolic status in elderly subjects from 2 population-based cohorts: a cross-sectional study.

BACKGROUND: Left ventricular (LV) diastolic dysfunction has been associated with impaired glucometabolic status. However, studies of older subjects are lacking. We examined associations between echocardiographic indices of LV diastolic function and LV mass index (LVMI) and glucometabolic status among middle-aged and elderly subjects free from heart disease, hypothesizing that the associations would be comparative to younger cohorts. METHODS: We examined the Age Gene/Environment Susceptibility Reykjavik Study (Iceland; n = 607, 76 +/- 6 years) and the Malmö Preventive Project Re-Examination Study (MPP-RES) cohorts (Sweden; n = 1,519, 67 +/- 6 years), evaluating associations with multivariable regression analysis. RESULTS: In the Age Gene/Environment Susceptibility Reykjavik Study, LVMI was positively correlated with glycosylated hemoglobin (HbA1c) (P = .001). Otherwise, echocardiographic variables were not associated with glucometabolic status. In the MPP-RES, LVMI increased with increasing glucometabolic disturbance among both older (70-80 years) and middle-aged (57-69 years) subjects. Among older subjects, HbA1c was positively correlated with 2 variables reflecting LV diastolic function: late transmitral peak flow velocity (A) (P = .001) and early transmitral peak flow velocity (E)/early diastolic peak tissue velocity (Em) (P = .046). In middle-aged MPP-RES subjects, increasing glucometabolic disturbance was correlated with increasing late diastolic peak tissue velocity (Am) (P = .002) and, after age adjustment, with increasing A (P = .001) and decreasing Em/Am (P = .009). With age adjustment, Am and A were positively correlated with fasting glucose and HbA1c. CONCLUSIONS: Contrary to our hypothesis, in 2 independent cohorts of older individuals, associations between glucometabolic status and LV diastolic function were generally weak. These contrast with previous reports, as well as with observations among middle-aged subjects in the present study. Changes in LV diastolic function may be more age-related than associated with glucose metabolism in older subjects.

Exercise capacity and idebenone intervention in children and adolescents with Friedreich ataxia.

OBJECTIVE: To determine the exercise capacity of children and adolescents with Friedreich's Ataxia (FA) and to evaluate the effects of 6 months of idebenone treatment on exercise capacity. DESIGN: Exploratory endpoint in a randomized double-blind, placebo-controlled, phase II clinical trial designed to investigate the effects of idebenone on a biomarker of oxidative stress. SETTING: Exercise physiology laboratory in a single clinical research center. PARTICIPANTS: Ambulatory subjects (N=48; age range, 9-17 y) with genetically confirmed FA. INTERVENTION: Idebenone administered orally 3 times a day for a total daily dose of approximately 5, 15, and 45 mg/kg or matching placebo for 6 months. MAIN OUTCOME MEASURES: Peak oxygen consumption per unit time (peak VO(2)) and peak work rate (WR) were measured during incremental exercise testing at baseline and after treatment. Echocardiography and neurologic assessments were also completed before and after treatment. RESULTS: Baseline mean peak VO(2) +/- SD was 746+/-246 mL/min (16.2+/-5.8 mL/kg/min), and WR was 40+/-23 W for all subjects. Peak VO(2) and WR were correlated with short guanine-adenine-adenine allele length and neurologic function. Relative left ventricular wall thickness was increased but left ventricular ejection fraction was normal in most subjects; there was no relationship between any exercise and echocardiographic measures. There were no significant changes in mean peak VO(2) or WR after idebenone treatment at any dose level relative to placebo. CONCLUSIONS: Exercise capacity in children and adolescents with FA was significantly impaired. The basis for the impairment appears to be multifactorial and correlated to the degree of neurologic impairment. Although idebenone has previously been shown potentially to improve features of FA, idebenone treatment did not increase exercise capacity relative to placebo.

Adaptive postprocessing techniques for myocardial tissue tracking with displacement-encoded MR imaging.

UNLABELLED: The purpose of this study was to prospectively assess the effects of two adaptive postprocessing techniques on the evaluation of myocardial function with displacement-encoded magnetic resonance (MR) imaging, including sensitivity for abnormal wall motion, with two-dimensional echocardiography as the reference standard. Sixteen patients (11 men, five women; age range, 26-74 years) and 12 volunteers (six men, six women; age range, 29-53 years) underwent breath-hold MR imaging. Institutional review board approval and informed consent were obtained. Adaptive phase-unwrapping and spatial filtering techniques were compared with conventional phase-unwrapping and spatial filtering techniques. Use of the adaptive techniques led to a reduced rate of failure with the phase-unwrapping technique from 18.9% to 0.6% (P < .001), resulted in lower variability of segmental strain measurements among healthy volunteers (P < .001 to P = .02), and increased the sensitivity of quantitative detection of abnormal segments in patients from 82.5% to 87.7% (P = .034). The adaptive techniques improved the semiautomated postprocessing of displacement-encoded cardiac images and increased the sensitivity of detection of abnormal wall motion in patients. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/246/1/229/DC1.

Exercise blood pressure and the risk of incident cardiovascular disease (from the Framingham Heart Study).

Exaggerated systolic blood pressure (BP) augmentation with exercise has been associated with impaired endothelial function and cardiovascular risk. However, previous studies were largely restricted to men, did not evaluate diastolic BP, and focused on peak exercise measures, which are influenced by effort and fitness level. The aim of this study was to determine the association of exercise BP responses with risk of incident cardiovascular disease (CVD). BP was assessed during stage 2 of the Bruce protocol and during recovery in 3,045 Framingham Study subjects (mean age 43 years; 53% women). The association between exercise BP and CVD events during 20 years of follow-up was examined using Cox proportional hazards models. In age- and sex-adjusted analyses, exercise systolic and diastolic BP were associated with incident CVD (adjusted hazard ratios [HRs] for top quintile 1.55, 95% confidence interval [CI] 1.18 to 2.04; and 1.77, 95% CI 1.35 to 2.31, respectively, relative to the lower 4 quintiles; p <0.005). After adjustment for BP at rest and conventional risk factors, exercise diastolic BP (HR 1.41, 95% CI 1.01 to 1.95, p = 0.04), but not exercise systolic BP (HR 0.97, 95% CI 0.68 to 1.38, p = 0.86), remained a significant predictor of CVD. Similarly, in recovery responses after exercise, only diastolic BP (HR 1.53, 95% CI 1.08 to 2.18, p = 0.02) predicted incident CVD in multivariable models. In conclusion, in middle-aged adults, diastolic BP during low-intensity exercise and recovery predicted incident CVD. Our findings support the concept that dynamic BP provides incremental information to BP at rest and suggest that exercise diastolic BP may be a better predictor than exercise systolic BP in this age group.

Ventilatory efficiency and resting hemodynamics in hypertrophic cardiomyopathy.

PURPOSE: In patients with systolic heart failure, the ability of cardiopulmonary exercise testing (CPX) variables to reflect pathophysiology is well established. The relationship between CPX and pathophysiology has, however, not been thoroughly investigated in patients with nonobstructive hypertrophic cardiomyopathy (NHCM). The objective of this study was to assess the ability of CPX variables to reflect resting hemodynamics in patients with nonobstructive hypertrophic cardiomyopathy NHCM. METHODS: We performed CPX and right heart catheterization on 83 subjects with NHCM (51 male/32 female, mean age = 38 +/- 10 yr, NYHA I-III mean = 1.7). Peak oxygen consumption ( O2) and minute ventilation/carbon dioxide ratio (V E/VCO2) at peak exercise were compared to resting hemodynamics including pulmonary artery systolic, diastolic and mean pressures (PASP, PADP and MPAP), and pulmonary capillary wedge pressure (PCWP). RESULTS: Elevations in PCWP (> or = 15 mm Hg), PASP (> or =30 and > or = 40 mm Hg), PADP (> 15 mm Hg) and MPAP (> or = 20 mm Hg) were detected in 22, 33, 10, and 23% of subjects, respectively. Peak V E/VCO2 (positive correlation) and peak VO2 (negative correlation) correlated modestly with all pressure measurements (r = 0.33-0.51, P < 0.01 for all measurements). By receiver operating curve analysis, a V E/VCO2 >35.5 exhibited the best diagnostic accuracy with a curve areas of 0.81 for PAP > or = 30 mm Hg (sensitivity/specificity = 86%/67%), 0.87 for PAP > or = 40 mm Hg (77%/100%), 0.86 for MPAP > 20 mm Hg (83%/79%), and 0.84 for PCWP > or = 15 mm Hg (80%/76%). CONCLUSIONS: CPX can accurately identify abnormal resting hemodynamics in patients with NHCM. Further testing of this modality in other forms of diastolic dysfunction may be warranted.

Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

BACKGROUND: The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. METHODS: We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. RESULTS: Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. CONCLUSIONS: Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated.

Echocardiographic predictors of morbidity and mortality in patients with advanced heart failure: the Beta-blocker Evaluation of Survival Trial (BEST).

OBJECTIVES: The aim of this study was to determine echocardiographic predictors of outcome in patients with advanced heart failure (HF) due to severe left ventricular (LV) systolic dysfunction in the Beta-blocker Evaluation of Survival Trial (BEST). BACKGROUND: Previous studies indicate that echocardiographic measurements of LV size and function, mitral deceleration time, and mitral regurgitation (MR) predict adverse outcomes in HF. However, complete quantitative echocardiograms evaluating all of these parameters have not been reported in a prospective randomized clinical trial in the era of modern HF therapy. METHODS: Complete echocardiograms were performed in 336 patients at 26 sites and analyzed by a core laboratory. A Cox proportional-hazards regression model was used to determine which echocardiographic variables predicted the primary end point of death or the secondary end point of death, HF hospitalization, or transplant. Significant variables were then entered into a multivariable model adjusted for clinical and demographic covariates. RESULTS: On multivariable analysis adjusted for clinical covariates, only LV end-diastolic volume index predicted death (events = 75), with a cut point of 120 ml/m(2). Three echocardiographic variables predicted the combined end point of death (events = 75), HF hospitalization (events = 97), and transplant (events = 9): LV end-diastolic volume index, mitral deceleration time, and the vena contracta width of MR. Optimal cut points for these variables were 120 ml/m(2), 150 ms, and 0.4 cm, respectively. CONCLUSIONS: Echocardiographic predictors of outcome in advanced HF include LV end-diastolic volume index, mitral deceleration time, and vena contracta width. These variables indicate that LV remodeling, increased LV stiffness, and MR are independent predictors of outcome in patients with advanced HF.

Myocardial contractile reserve by dobutamine stress echocardiography predicts improvement in ejection fraction with beta-blockade in patients with heart failure: the Beta-Blocker Evaluation of Survival Trial (BEST).

BACKGROUND: beta-Blockers improve survival and reduce hospitalization in chronic heart failure (CHF) by biologically improving left ventricular ejection fraction (LVEF). However, a good predictor of improvement with this therapy has not been identified. This substudy of BEST examined whether myocardial contractile reserve, as determined by dobutamine stress echocardiography, predicts improvement in LVEF. METHODS AND RESULTS: Seventy-nine patients with class III/IV CHF underwent dobutamine stress echocardiography before treatment with bucindolol (n=41) or placebo (n=38). Regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. WMSI was compared with change in LVEF after 3 months of therapy as determined by gated radionuclide scan. Change in WMSI correlated inversely with change in LVEF after 3 months of bucindolol (r=-0.72, P<0.0001) and was the most significant multivariate predictor of change in LVEF (P=0.0002). Patients with contractile reserve had demographics similar to those of patients without contractile reserve, including RVEF, LVEF, systolic blood pressure, and CHF duration. However, patients without contractile reserve had higher baseline plasma norepinephrine levels (687+/-333 versus 420+/-246 pg/mL, P<0.05) and greater decrease in plasma norepinephrine in response to bucindolol (-249+/-171 versus -35+/-277 pg/mL, P<0.05). CONCLUSIONS: This study suggests a direct relationship between contractile reserve and improvement in LVEF with beta-blocker therapy in patients with advanced CHF. Patients without contractile reserve have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may experience greater sympatholytic effects from bucindolol.

Left atrial volumetric remodeling is predictive of functional capacity in nonobstructive hypertrophic cardiomyopathy.

BACKGROUND: The left atrium is afterload sensitive, responding to immediate changes in left ventricular (LV) diastolic pressure, and left atrial volumetric remodeling has been reported in conditions associated with abnormal diastolic function. We examined the relationship between left atrial volumetric remodeling and objective measures of exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy (HCM). METHODS: We compared LA volume indices, other 2-dimensional and Doppler echocardiographic parameters, invasive hemodynamic measures, and magnetic resonance imaging (MRI)-derived LV mass with exercise duration, maximal oxygen uptake (MV* O2), anaerobic threshold (AT), and ventilatory efficiency (VE/V* CO2 slope) in 43 patients with nonobstructive HCM. Patients underwent cardiac catheterization within 48 hours and metabolic stress testing within 1 week of their echocardiogram and MRI examinations. RESULTS: Left atrial volume at end-ventricular systole (LA max) and end-atrial emptying (LA min) correlated with MV* O2 (r = -0.39, P < .01 for both), AT (r = -0.42, r = -0.39, respectively, P < .01 for both), and VE/V* CO2 slope (r = 0.45, P = .003; r = 0.41, P = .008). Patients with an LA max > or =33 mL/m2 had significantly lower MV* O2 (P = .025) and AT levels (P = .017) and higher VE/V* CO2 slope levels (P = .004) as compared with patients with a smaller LA size. In multivariate analysis, MRI-determined LV mass, which was not a univariate correlate of exercise tolerance, provided additional effect when combined with LA volume index. CONCLUSIONS: Left atrial volumetric remodeling predicts exercise capacity in nonobstructive HCM and may reflect chronic LV diastolic burden. This simple noninvasive measure of LA size may provide a long-term indication of the effects of chronically elevated filling pressures in patients with HCM and further studies testing its prognostic value are necessary.

Impact of nonfatal myocardial infarction on outcomes in patients with advanced heart failure and the effect of bucindolol therapy.

We sought to identify the clinical characteristics and outcomes of patients who had advanced heart failure and nonfatal myocardial infarction (MI) in the beta-Blocker Evaluation of Survival Trial (BEST) and to investigate whether bucindolol alters the risk of developing nonfatal MI. Of the 2,708 patients enrolled in the study, 142 had suspected MI and 69 had confirmed MI; there were 860 deaths overall. The rate of nonfatal MI in the BEST was low over the 4.1 years of follow-up (4.8% had suspected events and 2.4% had adjudicated events) and was similar to that in high-risk populations. Cox's proportional hazard model with 23 prespecified candidate variables associated advanced age, heart failure symptoms, male gender, ischemic etiology, diabetes, and hypertension with nonfatal MI or cardiovascular death. The 2-year mortality rate was 56% for the cohort that had suspected nonfatal MI versus 30% for the cohort that did not (p = 0.01). Likewise, the risk of hospitalization for congestive heart failure was twofold greater. Beta-blocker therapy with bucindolol resulted in a 52% decrease in suspected nonfatal MI (2.9% vs 5.5%, p = 0.001). In conclusion, nonfatal MI occurs at low rates but increases the risks for mortality and hospitalization in patients who have advanced heart failure. Beta-blocker therapy with bucindolol appears to attenuate the risk of nonfatal MI in this population.

Is functional capacity related to left atrial contractile function in nonobstructive hypertrophic cardiomyopathy?

The mechanisms underlying reduced exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy (NHCM) could include perturbations of ventricular relaxation, diastolic compliance, or compensatory atrial systolic function. We hypothesized that a loss of atrial contractility in NHCM patients leads to reduced functional capacity. To test this hypothesis, we compared resting noninvasive left atrial ejection phase indices in 49 consecutive patients with NHCM (ages 36+/-10 years; 41% female) and normal left ventricular ejection fraction (mean, 68%+/-8%) with objective metabolic exercise parameters. Left atrial active emptying fraction, ejection force, and kinetic energy failed to predict exercise capacity. Only left atrial total and active emptying volumes correlated weakly with minute volume/CO2 production slope (r=0.31 and r=0.33; p<0.05 for both). Furthermore, when subjects were stratified by New York Heart Association symptomatology, exercise parameters--but not atrial contractility--differed between groups. These data, obtained at rest, fail to suggest that NHCM-related heart failure symptoms are due to an atrial myopathy.

Mitral annular calcification is a predictor for incident atrial fibrillation.

BACKGROUND: Mitral annular calcification (MAC) has been associated with adverse cardiovascular disease outcomes and stroke in longitudinal and community-based cohorts. Prospective data are limited on its association with atrial fibrillation (AF). METHODS: We examined the association between MAC and the long-term risk of AF over 16 years of follow-up in participants in the original cohort of the Framingham Heart Study who attended a routine examination between 1979 and 1981. MAC was assessed by M-mode echocardiography. cox proportional-hazards models were used to estimate hazard ratios (hr) for incident af. RESULTS: Of 1126 subjects who had adequate echocardiographic assessment and were AF-free at baseline, 149 (13%) had MAC. There were 217 cases of incident AF (42 in subjects with MAC). The age- and sex-adjusted incidence rate was 362 per 10,000 person-years in subjects with MAC compared with 185 per 10,000 person-years in those without MAC. In multivariable-adjusted analyses, MAC was associated with an increased risk of AF (HR 1.6, 95% CI 1.1-2.2). This association was attenuated upon further adjustment for left atrial size (HR 1.4, 95% CI 0.9-2.0). CONCLUSIONS: The association between MAC and incident AF may be mediated partially through left atrial enlargement. These data suggest the importance of better understanding the mechanisms involved in cardiac valvular calcification.

The Role of Echocardiography in the Management of Patients with Massive Pulmonary Embolism.

Acute massive pulmonary embolus (PE) when undiagnosed may lead to hemodynamic compromise and death. Echocardiography offers several clues to the diagnosis of PE. We describe how transesophageal echo was used in the diagnosis and management of two patients with this disorder.