Jose Rivero

Circulating Cell Adhesion Molecules Are Correlated With Ultrasound-Based Assessment of Carotid Atherosclerosis

Although cellular adhesion molecules (CAMs) are hypothesized to play an important role in atherogenesis, the relationship between CAMs and systemic atherosclerosis is uncertain. Among 92 outpatients (48 men; mean+/-SD age, 65+/-9 years), we evaluated the association of soluble vascular CAM-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) with carotid intimal-medial thickness (IMT), an index of early atherosclerosis. All subjects underwent a 2-dimensional ultrasound examination of both carotid arteries at the distal common carotid arteries and bifurcation. sVCAM-1 and sICAM-1 levels measured by enzyme-linked immunosorbent assay were significantly correlated with mean IMT of the common carotid artery (r=0.34 and r=0.30, respectively; P<0.01) and carotid bifurcation (r=0.31 and r=0.26, respectively; P<0.05), whereas sVCAM-1 was also positively associated with maximal carotid IMT (r=0.35, P<0.01). Adjustment for age attenuated the association between sVCAM-1 and common (r=0.16, P=0.13) and bifurcation (r=0.18, P=0.07) carotid IMT but had minimal effect on the associations between sICAM-1 and carotid measurements (r=0.32, P<0.01; r=0.23, P<0.05; for common and bifurcation IMT, respectively). Age-adjusted sICAM-1 levels increased in a stepwise fashion across common carotid IMT tertiles (253+/-27 versus 275+/-24 versus 384+/-26 pg/mL for the lowest, intermediate, and highest IMT tertiles, respectively; P<0.01). A similar trend was also found between sVCAM-1 levels and common carotid IMT tertiles (625+/-60 versus 650+/-53 versus 714+/-58 pg/mL; P<0.15). These associations were minimally affected in analyses adjusting for hypertension, diabetes, smoking, low and high density lipoprotein cholesterol, lipoprotein(a), and homocysteine, or in a subgroup analysis limited to those with no prior history of atherothrombotic disease. These data demonstrate a positive association between serum CAMs with carotid IMT and further support the hypothesis that systemic inflammation may have a role in atherosclerotic lesion development.

Echocardiographic Strain Imaging to Assess Early and Late Consequences of Sarcomere Mutations in Hypertrophic Cardiomyopathy

Background—Genetic testing identifies sarcomere mutation carriers (G+) before clinical diagnosis of hypertrophic cardiomyopathy (HCM), allowing characterization of initial disease manifestations. Previous studies demonstrated that impaired relaxation develops before left ventricular hypertrophy (LVH). The precise impact of sarcomere mutations on systolic function in early and late disease is unclear. Methods and Results—Comprehensive echocardiography with strain imaging was performed on 146 genotyped individuals with mutations in 5 sarcomere genes. Contractile parameters were compared in 68 preclinical (G+/LVH−), 40 overt (G+/LVH+) subjects with HCM, and 38 mutation (−) normal control relatives. All subjects had normal left ventricular ejection fraction. In preclinical HCM, global and regional peak systolic strain (ϵsys) and longitudinal systolic strain rate were not significantly different from controls, but early diastolic mitral annular velocity (Ea) was reduced by 13%. In overt HCM, there was a significant 27% and 14% decrease in global longitudinal ϵsys and systolic strain rate, respectively, compared with both preclinical HCM and controls (P<0.013 for all comparisons), and a 33% reduction in Ea. Conclusions—Sarcomere mutations have disparate initial effects on diastolic and systolic functions. Preclinical HCM is characterized by impaired relaxation but preserved systolic strain. In contrast, both diastolic and longitudinal systolic abnormalities are present in overt disease despite normal ejection fraction. We propose that diastolic dysfunction is an early consequence of sarcomere mutations, whereas systolic dysfunction results from mutations combined with subsequent pathological remodeling. Identifying mechanistic pathways triggered by these mutations may begin to reshape the clinical paradigm for treatment, based on early diagnosis and disease prevention.

Subtle Abnormalities in Contractile Function Are an Early Manifestation of Sarcomere Mutations in Dilated Cardiomyopathy

Background—Sarcomere mutations cause both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM); however, the steps leading from mutation to disease are not well described. By studying mutation carriers before a clinical diagnosis develops, we characterize the early manifestations of sarcomere mutations in DCM and investigate how these manifestations differ from sarcomere mutations associated with HCM. Methods and Results—Sixty-two genotyped individuals in families with sarcomeric DCM underwent clinical evaluation including strain echocardiography. The group included 12 subclinical DCM mutation carriers with normal cardiac dimensions and left ventricular ejection fraction (LVEF ≥55%), 21 overt DCM subjects, and 29 related mutation (-) normal controls. Results were compared with a previously characterized cohort of 60 subclinical HCM subjects (sarcomere mutation carriers without left ventricular hypertrophy). Systolic myocardial tissue velocity, longitudinal, circumferential, and radial strain, and longitudinal and radial strain rate were reduced by 10%–23% in subclinical DCM mutation carriers compared with controls (P<0.001 for all comparisons), after adjusting for age and family relations. No significant differences in diastolic parameters were identified comparing the subclinical and control cohorts. The opposite pattern of contractile abnormalities with reduced diastolic but preserved systolic function was seen in subclinical HCM. Conclusions—Subtle abnormalities in systolic function are present in subclinical DCM mutation carriers, despite normal left ventricular size and ejection fraction. In contrast, impaired relaxation and preserved systolic function appear to be the predominant early manifestations of sarcomere mutations that lead to HCM. These findings support the theory that the mutation’s intrinsic impact on sarcomere function influences whether a dilated or hypertrophic phenotype develops.

E/e' Ratio in Patients with Unexplained Dyspnea: Lack of Accuracy in Estimating Left Ventricular Filling Pressure

Background— Elevated left ventricular filling pressure is a cardinal feature of heart failure with preserved ejection fraction. Mitral E/e′ ratio has been proposed as a noninvasive measure of left ventricular filling pressure. We studied the accuracy of E/e′ to estimate and track changes of left ventricular filling pressure in patients with unexplained dyspnea. Methods and Results— We performed supine and upright transthoracic echocardiography in 118 patients with unexplained dyspnea who underwent right heart catheterization. Supine E/e′ ratio modestly but significantly correlated with supine pulmonary arterial wedge pressure (PAWP; r =0.36; P <0.001) and demonstrated poor agreement with PAWP values (Bland–Altman limits of agreement of −8.3 to 8.3 mm Hg; range, 6.5–21.2 mm Hg). Similarly, E/e′ ratio cut off of 13 performed poorly in identifying patients with elevated left ventricular filling pressure (sensitivity 6%, specificity 90%). The receiver-operating characteristic area of E/e′ was 0.65 (95% confidencce interval, 0.50–0.79). With change from the supine to upright position, PAWP decreased (−5±4 mm Hg; P <0.001) as did both E wave (−17±15 cm/s; P <0.001) and e′ (−2.7±2.7 cm/s; P <0.001) velocities, whereas E/e′ remained stable (+0.2±2.6; P =0.57). Positional change in PAWP correlated modestly with change in E-wave ( r =0.37; P <0.001) velocity. There was no appreciable relationship between change in PAWP and change in average E/e′ ( r =−0.04; P =0.77) and in half the patients the change in PAWP and E/e′ were directionally opposite. Conclusions— In patients with unexplained dyspnea, E/e′ ratio neither accurately estimates PAWP nor identifies patients with elevated PAWP consistent with heart failure with preserved ejection fraction. Positional changes in E/e′ ratio do not reflect changes in PAWP.Background—Elevated left ventricular filling pressure is a cardinal feature of heart failure with preserved ejection fraction. Mitral E/e′ ratio has been proposed as a noninvasive measure of left ventricular filling pressure. We studied the accuracy of E/e′ to estimate and track changes of left ventricular filling pressure in patients with unexplained dyspnea. Methods and Results—We performed supine and upright transthoracic echocardiography in 118 patients with unexplained dyspnea who underwent right heart catheterization. Supine E/e′ ratio modestly but significantly correlated with supine pulmonary arterial wedge pressure (PAWP; r=0.36; P<0.001) and demonstrated poor agreement with PAWP values (Bland–Altman limits of agreement of −8.3 to 8.3 mm Hg; range, 6.5–21.2 mm Hg). Similarly, E/e′ ratio cut off of 13 performed poorly in identifying patients with elevated left ventricular filling pressure (sensitivity 6%, specificity 90%). The receiver-operating characteristic area of E/e′ was 0.65 (95% confidencce interval, 0.50–0.79). With change from the supine to upright position, PAWP decreased (−5±4 mm Hg; P<0.001) as did both E wave (−17±15 cm/s; P<0.001) and e′ (−2.7±2.7 cm/s; P<0.001) velocities, whereas E/e′ remained stable (+0.2±2.6; P=0.57). Positional change in PAWP correlated modestly with change in E-wave (r=0.37; P<0.001) velocity. There was no appreciable relationship between change in PAWP and change in average E/e′ (r=−0.04; P=0.77) and in half the patients the change in PAWP and E/e′ were directionally opposite. Conclusions—In patients with unexplained dyspnea, E/e′ ratio neither accurately estimates PAWP nor identifies patients with elevated PAWP consistent with heart failure with preserved ejection fraction. Positional changes in E/e′ ratio do not reflect changes in PAWP.

Right ventricular dysfunction during intensive pharmacologic unloading persists after mechanical unloading.

BACKGROUND Right ventricular (RV) dysfunction is associated with adverse outcomes in heart failure (HF). Mechanical unloading should be more effective than pharmacologic therapy to reduce RV afterload and improve RV function. We compared RV size and function after aggressive medical unloading therapy to that achieved in the same patients after 3 months of left ventricular assist device (LVAD) support. METHODS AND RESULTS We studied 20 patients who underwent isolated LVAD placement (9 pulsatile and 11 axial flow). Echocardiograms were performed after inpatient optimization with diuretic and inotropic therapy and compared with studies done after 3 months of LVAD support. After medical optimization right atrial pressure was 11 +/- 5 mm Hg, mean pulmonary artery pressure 36 +/- 11 mm Hg, pulmonary capillary wedge pressure 23 +/- 9 mm Hg, and cardiac index 2.0 +/- 0.6 L.min.m(2). Preoperatively, RV dysfunction was moderate (2.6 +/- 0.9 on a 0 to 4 scale), RV diameter at the base was 3.1 +/- 0.6 cm, and mid-RV was 3.5 +/- 0.6 cm. After median LVAD support of 123 days (92 to 170), RV size and global RV dysfunction (2.6 +/- 0.9) failed to improve, despite reduced RV afterload. CONCLUSIONS RV dysfunction seen on intensive medical therapy persisted after 3 months of LVAD unloading therapy. Selection of candidates for isolated LV support should anticipate persistence of RV dysfunction observed on inotropic therapy.

Assessment of myocardial viability and left ventricular function in patients supported by a left ventricular assist device

BACKGROUND Chronically supported left ventricular assist device (LVAD) patients may be candidates for novel therapies aimed at promoting reverse remodeling and myocardial recovery. However, the effect of hemodynamic unloading with a LVAD on myocardial viability and LV function in chronically supported LVAD patients has not been fully characterized. We aimed to develop a non-invasive imaging protocol to serially quantify native cardiac structure, function, and myocardial viability while at reduced LVAD support. METHODS Clinically stable (n = 18) ambulatory patients (83% men, median age, 61 years) supported by a HeartMate II (Thoratec, Pleasanton, CA) LVAD (median durations of heart failure 4.6 years and LVAD support 7 months) were evaluated by echocardiography and technetium-99m ((99m)Tc)-sestamibi single photon emission computed tomography (SPECT) imaging at baseline and after an interval of 2 to 3 months. Echocardiographic measures of LV size and function, including speckle tracking-derived circumferential strain, were compared between ambulatory and reduced LVAD support at baseline and between baseline and follow-up at reduced LVAD support. The extent of myocardial viability by SPECT was compared between baseline and follow-up at reduced LVAD support. RESULTS With reduction in LVAD speeds (6,600 rpm; interquartile range: 6,200, 7,400 rpm), LV size increased, LV systolic function remained stable, and filling pressures nominally worsened. After a median 2.1 months, cardiac structure, function, and the extent of viable myocardium, globally and regionally, was unchanged on repeat imaging while at reduced LVAD speed. CONCLUSIONS In clinically stable chronically supported LVAD patients, intrinsic cardiac structure, function, and myocardial viability did not significantly change over the pre-specified time frame. Echocardiographic circumferential strain and (99m)Tc-sestamibi SPECT myocardial viability imaging may provide useful non-invasive end points for the assessment of cardiac structure and function, particularly for phase II studies of novel therapies aimed at promoting reverse remodeling and myocardial recovery in LVAD patients.

Providing Initial Transthoracic Echocardiography Training for Anesthesiologists: Simulator Training Is Not Inferior to Live Training

OBJECTIVE Transthoracic echocardiography (TTE) is finding increased use in anesthesia and critical care. Efficient options for training anesthesiologists should be explored. Simulator mannequins allow for training of manual acquisition and image recognition skills and may be suitable due to ease of scheduling. The authors tested the hypothesis that training with a simulator would not be inferior to training using a live volunteer. DESIGN Prospective, randomized trial. SETTING University hospital. PARTICIPANTS Forty-six anesthesia residents, fellows, and faculty. INTERVENTIONS After preparation with a written and video tutorial, study subjects received 80 minutes of TTE training using either a simulator or live volunteer. Practical and written tests were completed before and after training to assess improvement in manual image acquisition skills and theoretic knowledge. The written test was repeated 4 weeks later. MEASUREMENTS AND MAIN RESULTS Performance in the practical image-acquisition test improved significantly after training using both the live volunteer and the simulator, improving by 4.0 and 4.3 points out of 15, respectively. Simulator training was found not to be inferior to live training, with a mean difference of -0.30 points and 95% confidence intervals that did not cross the predefined non-inferiority margin. Performance in the written retention test also improved significantly immediately after training for both groups but declined similarly upon repeat testing 4 weeks later. CONCLUSIONS When providing initial TTE training to anesthesiologists, training using a simulator was not inferior to using live volunteers.

Left ventricular deformation at rest predicts exercise-induced elevation in pulmonary artery wedge pressure in patients with unexplained dyspnoea.

Impaired left ventricular (LV) deformation despite preserved LV ejection fraction (LVEF) is common and predicts outcomes in heart failure with preserved LVEF. We hypothesized that impaired LV deformation at rest is a marker of impaired cardiac systolic and diastolic reserve, and aimed to determine whether resting longitudinal (LS) and circumferential strain (CS) are associated with invasively measured haemodynamic response to exercise in patients with dyspnoea and a normal LVEF.

Impact of device selection and clip duration on lung ultrasound assessment in patients with heart failure.

OBJECTIVES Pulmonary edema is a common sign of heart failure and can be quantified by counting vertical artifacts (B-lines) on lung ultrasound (LUS). The primary aim of this study was to compare a pocket size ultrasound device to high-end ultrasound systems on the measured number of B-lines. We also compared the impact of different-length ultrasound clips on the measured number of B-lines. METHODS AND RESULTS We studied 21 hospitalized patients with heart failure (81% men; median age, 73; 71% Caucasian) who underwent concurrent 8- and 4-zone LUS using both a pocket ultrasound device and a high-end ultrasound system. For the 4-zone scanning method, the median B line number was 2 (interquartile range, 1-4) for the pocket device and 3 (1-5) for the high-end system (P = .67). For the 8-zone method, the median B-line number was 4 (2-7) for the pocket device and 5 (3-7) for the high-end system (P = .18). A higher number of B-lines was identified on the 4- vs 2-second LUS clips (P < .001 for 4 zones, P = .001 for 8 zones), and on the 6- vs 4-second LUS clips (P=0.057 for 4 zones, P=0.018 for 8 zones). CONCLUSIONS Our findings suggest significant differences based on LUS clip duration rather than the type of ultrasound device used, with respect to the number of B-lines detectable in patients with heart failure. These factors should be considered in the design and reporting of LUS studies and in longitudinal assessments of heart failure patients.

Accuracy of Echocardiography to Estimate Pulmonary Artery Pressures With ExerciseCLINICAL PERSPECTIVE: A Simultaneous Invasive–Noninvasive Comparison

Background— Exercise echocardiography is often applied as a noninvasive strategy to screen for abnormal pulmonary hemodynamic response, but it is technically challenging, and limited data exist regarding its accuracy to estimate pulmonary arterial pressure during exercise. Methods and Results— Among 65 patients with exertional intolerance undergoing upright invasive exercise testing, tricuspid regurgitation (TR) Doppler estimates and invasive measurement of pulmonary arterial pressure at rest and peak exercise were simultaneously obtained. TR Doppler envelopes were assessed for quality. Correlation, Bland–Altman, and receiver-operating characteristic curve analyses were performed to evaluate agreement and diagnostic accuracy. Mean age was 62±13 years, and 31% were male. High-quality (grade A) TR Doppler was present in 68% at rest and 34% at peak exercise. For grade A TR signals, echocardiographic measures of systolic pulmonary arterial pressure correlated reasonably well with invasive measurement at rest (r=0.72, P<0.001; bias, −2.9±8.0 mm Hg) and peak exercise (r=0.75, P<0.001; bias, −1.9±15.6 mm Hg). Lower quality TR signals (grade B and C) correlated poorly with invasive measurements overall. In patients with grade A TR signals, mean pulmonary arterial pressure-to-workload ratio at a threshold of 1.4 mm Hg/10 W was able to identify abnormal pulmonary hemodynamic response during exercise (>3.0 mm Hg/L per minute increase), with 91% sensitivity and 82% specificity (area under the curve, 0.90; 95% confidence interval, 0.77–1.0; P=0.001). Conclusions— Agreement between echocardiographic and invasive measures of pulmonary pressures during upright exercise is good among the subset of patients with high-quality TR Doppler signal. While the limits of agreement are broad, our results suggest that in those patients, sensitivity is adequate to screen for abnormal pulmonary hemodynamic response during exercise.