Vδ1 Effector and Vδ2 γδ T-Cell Subsets Shift in Frequency and Are Linked to Plasma Inflammatory Markers During Antiretroviral Therapy-Suppressed HIV Infection.

BACKGROUND: Chronic inflammation is prevalent with antiretroviral therapy (ART)-suppressed human immunodeficiency virus (HIV) infection and one immune cell subset putatively driving this phenomenon is TIGIT+ γδ T cells. METHODS: To elucidate γδ T-cell phenotypic diversity, spectral flow cytometry was performed on blood lymphocytes from individuals of a HIV and aging cohort and data were analyzed using bioinformatic platforms. Plasma inflammatory markers were measured and correlated with γδ T-cell subset frequencies. RESULTS: Thirty-nine distinct γδ T-cell subsets were identified (22 Vδ1+, 14 Vδ2+, and 3 Vδ1-Vδ2-Vγ9+) and TIGIT was nearly exclusively found on the Vδ1+CD45RA+CD27- effector populations. People with ART-suppressed HIV infection (PWH) exhibited high frequencies of distinct clusters of Vδ1+ effectors distinguished via CD8, CD16, and CD38 expression. Among Vδ2+ cells, most Vγ9+ (innate-like) clusters were lower in PWH; however, CD27+ subsets were similar in frequency between participants with and without HIV. Comparisons by age revealed lower 'naive' Vδ1+CD45RA+CD27+ cells in older individuals, regardless of HIV status. Plasma inflammatory markers were selectively linked to subsets of Vδ1+ and Vδ2+ cells. CONCLUSIONS: These results further elucidate γδ T-cell subset complexity and reveal distinct alterations and connections with inflammatory pathways of Vδ1+ effector and Vδ2+ innate-like subsets during ART-suppressed HIV infection.

B cells in the pneumococcus-infected lung are heterogeneous and require CD4+ T cell help including CD40L to become resident memory B cells.

Recovery from respiratory pneumococcal infections generates lung-localized protection against heterotypic bacteria, mediated by resident memory lymphocytes. Optimal protection in mice requires re-exposure to pneumococcus within days of initial infection. Serial surface marker phenotyping of B cell populations in a model of pneumococcal heterotypic immunity revealed that bacterial re-exposure stimulates the immediate accumulation of dynamic and heterogeneous populations of B cells in the lung, and is essential for the establishment of lung resident memory B (BRM) cells. The B cells in the early wave were activated, proliferating locally, and associated with both CD4+ T cells and CXCL13. Antagonist- and antibody-mediated interventions were implemented during this early timeframe to demonstrate that lymphocyte recirculation, CD4+ cells, and CD40 ligand (CD40L) signaling were all needed for lung BRM cell establishment, whereas CXCL13 signaling was not. While most prominent as aggregates in the loose connective tissue of bronchovascular bundles, morphometry and live lung imaging analyses showed that lung BRM cells were equally numerous as single cells dispersed throughout the alveolar septae. We propose that CD40L signaling from antigen-stimulated CD4+ T cells in the infected lung is critical to establishment of local BRM cells, which subsequently protect the airways and parenchyma against future potential infections.

GL7 ligand expression defines a novel subset of CD4+ TRM cells in lungs recovered from pneumococcus.

Streptococcus pneumoniae is the most common etiology of bacterial pneumonia, one of the leading causes of death in children and the elderly worldwide. During non-lethal infections with S. pneumoniae, lymphocytes accumulate in the lungs and protect against reinfection with serotype-mismatched strains. Cluster of differentiation CD4+ resident memory T (TRM) cells are known to be crucial for this protection, but the diversity of lung CD4+ TRM cells has yet to be fully delineated. We aimed to identify unique subsets and their contributions to lung immunity. After recovery from pneumococcal infections, we identified a distinct subset of CD4+ T cells defined by the phenotype CD11ahiCD69+GL7+ in mouse lungs. Phenotypic analyses for markers of lymphocyte memory and residence demonstrated that GL7+ T cells are a subset of CD4+ TRM cells. Functional studies revealed that unlike GL7- TRM subsets that were mostly (RAR-related Orphan Receptor gamma T) RORγT+, GL7+ TRM cells exhibited higher levels of (T-box expressed in T cells) T-bet and Gata-3, corresponding with increased synthesis of interferon-γ, interleukin-13, and interleukin-5, inherent to both T helper 1 (TH1) and TH2 functions. Thus, we propose that these cells provide novel contributions during pneumococcal pneumonia, serving as important determinants of lung immunity.

Novel ELISA Protocol Links Pre-Existing SARS-CoV-2 Reactive Antibodies With Endemic Coronavirus Immunity and Age and Reveals Improved Serologic Identification of Acute COVID-19 via Multi-Parameter Detection.

The COVID-19 pandemic has drastically impacted work, economy, and way of life. Sensitive measurement of SARS-CoV-2 specific antibodies would provide new insight into pre-existing immunity, virus transmission dynamics, and the nuances of SARS-CoV-2 pathogenesis. To date, existing SARS-CoV-2 serology tests have limited utility due to insufficient reliable detection of antibody levels lower than what is typically present after several days of symptoms. To measure lower quantities of SARS-CoV-2 IgM, IgG, and IgA with higher resolution than existing assays, we developed a new ELISA protocol with a distinct plate washing procedure and timed plate development via use of a standard curve. Very low optical densities from samples added to buffer coated wells at as low as a 1:5 dilution are reported using this 'BU ELISA' method. Use of this method revealed circulating SARS-CoV-2 receptor binding domain (RBD) and nucleocapsid protein (N) reactive antibodies (IgG, IgM, and/or IgA) in 44 and 100 percent of pre-pandemic subjects, respectively, and the magnitude of these antibodies tracked with antibody levels of analogous viral proteins from endemic coronavirus (eCoV) strains. The disease status (HIV, SLE) of unexposed subjects was not linked with SARS-CoV-2 reactive antibody levels; however, quantities were significantly lower in subjects over 70 years of age compared with younger counterparts. Also, we measured SARS-CoV-2 RBD- and N- specific IgM, IgG, and IgA antibodies from 29 SARS-CoV-2 infected individuals at varying disease states, including 10 acute COVID-19 hospitalized subjects with negative serology results by the EUA approved Abbott IgG chemiluminescent microparticle immunoassay. Measurements of SARS-CoV-2 RBD- and N- specific IgM, IgG, IgA levels measured by the BU ELISA revealed higher signal from 9 of the 10 Abbott test negative COVID-19 subjects than all pre-pandemic samples for at least one antibody specificity/isotype, implicating improved serologic identification of SARS-CoV-2 infection via multi-parameter, high sensitive antibody detection. We propose that this improved ELISA protocol, which is straightforward to perform, low cost, and uses readily available commercial reagents, is a useful tool to elucidate new information about SARS-CoV-2 infection and immunity and has promising implications for improved detection of all analytes measurable by this platform.

Airway-Associated Macrophages in Homeostasis and Repair.

There is an increasing appreciation for the heterogeneity of myeloid lineages in the lung, but relatively little is known about populations specifically associated with the conducting airways. We use single-cell RNA sequencing, flow cytometry, and immunofluorescence to characterize myeloid cells of the mouse trachea during homeostasis and epithelial injury/repair. We identify submucosal macrophages, similar to lung interstitial macrophages, and intraepithelial macrophages. Following injury, there are early increases in neutrophils and submucosal macrophages, including M2-like macrophages. Intraepithelial macrophages are lost after injury and later restored by CCR2+ monocytes. We show that repair of the tracheal epithelium is impaired in Ccr2-deficient mice. Mast cells and group 2 innate lymphoid cells are sources of interleukin-13 (IL-13) that polarize macrophages and directly influence basal cell behaviors. Their proximity to the airway epithelium establishes these myeloid populations as potential therapeutic targets for airway disease.

Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation.

Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4+ T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in autophagy and mitochondrial bioenergetics that associate with redox imbalance. Metformin ameliorated the Th17 inflammaging profile by increasing autophagy and improving mitochondrial bioenergetics. By contrast, autophagy-targeting siRNA disrupted redox balance in T cells from young subjects and activated the Th17 profile by activating the Th17 master regulator, STAT3, which in turn bound IL-17A and F promoters. Mitophagy-targeting siRNA failed to activate the Th17 profile. We conclude that metformin improves autophagy and mitochondrial function largely in parallel to ameliorate a newly defined inflammaging profile that echoes inflammation in diabetes.

Multivariate Computational Analysis of Gamma Delta T Cell Inhibitory Receptor Signatures Reveals the Divergence of Healthy and ART-Suppressed HIV+ Aging.

Even with effective viral control, HIV-infected individuals are at a higher risk for morbidities associated with older age than the general population, and these serious non-AIDS events (SNAEs) track with plasma inflammatory and coagulation markers. The cell subsets driving inflammation in aviremic HIV infection are not yet elucidated. Also, whether ART-suppressed HIV infection causes premature induction of the inflammatory events found in uninfected elderly or if a novel inflammatory network ensues when HIV and older age co-exist is unclear. In this study we measured combinational expression of five inhibitory receptors (IRs) on seven immune cell subsets and 16 plasma markers from peripheral blood mononuclear cells (PBMC) and plasma samples, respectively, from a HIV and Aging cohort comprised of ART-suppressed HIV-infected and uninfected controls stratified by age (≤35 or ≥50 years old). For data analysis, multiple multivariate computational algorithms [cluster identification, characterization, and regression (CITRUS), partial least squares regression (PLSR), and partial least squares-discriminant analysis (PLS-DA)] were used to determine if immune parameter disparities can distinguish the subject groups and to investigate if there is a cross-impact of aviremic HIV and age on immune signatures. IR expression on gamma delta (γδ) T cells exclusively separated HIV+ subjects from controls in CITRUS analyses and secretion of inflammatory cytokines and cytotoxic mediators from γδ T cells tracked with TIGIT expression among HIV+ subjects. Also, plasma markers predicted the percentages of TIGIT+ γδ T cells in subjects with and without HIV in PSLR models, and a PLS-DA model of γδ T cell IR signatures and plasma markers significantly stratified all four of the subject groups (uninfected younger, uninfected older, HIV+ younger, and HIV+ older). These data implicate γδ T cells as an inflammatory driver in ART-suppressed HIV infection and provide evidence of distinct "inflamm-aging" processes with and without ART-suppressed HIV infection.

Mdm2 overexpression and p73 loss exacerbate genomic instability and dampen apoptosis, resulting in B-cell lymphoma.

Many human tumors express high levels of the p53 inhibitor Mdm2, resulting from amplification of the Mdm2 locus or aberrant post-translational regulation of the Mdm2 protein. While the importance of Mdm2 in regulating p53 is clear, Mdm2 also has p53-independent roles. For example, overexpression of Mdm2 results in genomic instability in a p53-independent manner. In addition, Mdm2 has many additional binding partners, some of which, such as the tumor suppressor p73, have also been implicated in genomic instability. In this study, cells and tumors with Mdm2 overexpression and p73 loss exhibit increased genomic instability as compared with either alteration alone and cooperate in development of B-cell lymphomagenesis. Cytogenetic analysis of mouse embryonic fibroblasts and pre-malignant B cells demonstrates that loss of p73 exacerbates the chromosome breaks and fusions observed in Mdm2(Tg) cells. B-cell lymphomas from Mdm2(Tg);p73(+/-) mice retain the remaining p73 allele, exhibit elevated levels of the antiapoptotic protein Bcl2 and thus dampen apoptosis. In summary, Mdm2 overexpression and p73 loss cooperate in genomic instability and tumor development, indicating that the oncogenic function of Mdm2 is a combined effect of inhibiting p53 and p73 functions. Given that p73 is lost or silenced in human B-cell lymphomas, the Mdm2(Tg);p73(+/-) mouse serves as a model for human disease and may provide additional insight into the pathways that contribute to B-cell lymphomagenesis.

Echocardiographic assessment of aortic valve area in elderly patients with aortic stenosis and of changes in valve area after percutaneous balloon valvuloplasty.

Echocardiographic studies, adequate for analysis of aortic valve area using the continuity equation, were obtained in 31 patients aged greater than or equal to 60 years who were undergoing catheterization for assessment of suspected aortic stenosis. Catheterization-determined aortic valve area was 0.74 +/- 0.30 cm2 (mean +/- SD) and Doppler-determined aortic valve areas were 0.68 +/- 0.27 and 0.65 +/- 0.27 cm2, depending on whether peak or mean velocities, respectively, were entered into the continuity equation. There were significant correlations between both of the Doppler-derived and the catheterization-determined aortic valve areas (r = 0.86, p less than 0.001 for both the continuity equation employing peak velocities and the continuity equation employing mean velocities) which were demonstrated to be linear by F test (catheterization area = -0.03 + 1.13 X Doppler area determined using peak velocities, SEE = 0.163 cm2, p less than 0.001; and catheterization area = -0.02 + 1.16 X Doppler area determined using mean velocities, SEE = 0.165 cm2, p less than 0.001). Both sets of correlations had linear regression parameters meeting the conditions for identity. Significant linear correlations were also noted between the non-invasive measurements of aortic valve excursion, ventricular ejection time, time to one-half carotid upstroke, maximal Doppler velocity and maximal Doppler gradient and catheterization aortic valve area, but the correlations were less tight than those between valve areas determined by catheterization and by Doppler continuity equation. Ten of the patients underwent percutaneous balloon aortic valvuloplasty. There were significant linear correlations between aortic valve areas determined by Doppler and catheterization methods both before valvuloplasty (r = 0.77, p = 0.01; p less than 0.001 by F test, SEE = 0.134 cm2) and after valvuloplasty (r = 0.85, p less than 0.01; p = 0.0001 by F test, SEE = 0.161 cm2). Linear regression parameters met the conditions for identity. There was also a significant linear correlation between catheterization and Doppler measurements of absolute change in aortic valve area (r = 0.79, p less than 0.01; p less than 0.001 by F test, SEE = 0.11 cm2). Aortic valve area can be determined reliably by continuity equation in elderly patients. In addition, results of balloon valvuloplasty, measured by changes in catheterization-determined aortic valve area, are accurately reflected by changes in aortic valve area determined using the continuity equation.

Pulsed Doppler echocardiographic evaluation of valvular regurgitation in patients with mitral valve prolapse: comparison with normal subjects.

Pulsed Doppler echocardiography was used to determine prospectively the prevalence of mitral, aortic, tricuspid and pulmonary regurgitation in 80 consecutive patients with mitral valve prolapse and 85 normal subjects with similar age and sex distribution. Mitral valve prolapse was defined by posterior systolic displacement of the mitral valve on M-mode echocardiography of 3 mm or more (40 patients), the presence of one or more mid- or late systolic clicks (61 patients), or both. Mitral regurgitation, detected by pulsed Doppler techniques in 53 patients with prolapse, was holosystolic in 24, early to mid-systolic in 6, late systolic in 15 and both holosystolic and late systolic behind different portions of the valve in 8. Definitive M-mode findings were present in only 27 of the 53 patients, and only 21 had mitral regurgitation audible on physical examination. Tricuspid regurgitation was evident by pulsed Doppler echocardiography in 15 patients (holosystolic in 9, early to mid-systolic in 1, late systolic in 4 and both holosystolic and late systolic in 1); 12 of these 15 patients, including all with an isolated late systolic pattern, had an echocardiographic pattern of tricuspid prolapse, but none had audible tricuspid regurgitation. A Doppler pattern compatible with aortic regurgitation was recorded in seven patients, all without echocardiographic aortic valve prolapse and only two with audible aortic insufficiency. A Doppler shift in the right ventricular outflow tract in diastole, suggestive of pulmonary regurgitation, was recorded in 16 of the 78 patients with an adequate Doppler examination: only 1 of the 16 had audible pulmonary insufficiency. Of the 85 normal subjects without audible regurgitation, pulsed Doppler examination detected mitral regurgitation in 3 subjects (holosystolic in 1 and early to mid-systolic in 2), aortic regurgitation in none, tricuspid regurgitation in 9 (holosystolic alone in 8 and both holosystolic and late systolic in 1) and right ventricular outflow tract turbulence compatible with pulmonary insufficiency in 15. The prevalence of valvular regurgitation, detected by pulsed Doppler echocardiography, is high in patients with mitral valve prolapse. Regurgitation may involve any of the four cardiac valves and is clinically silent in the majority of patients. The prevalence rates of mitral and aortic regurgitation are significantly higher in patients with mitral prolapse than in normal subjects, suggesting that alterations in underlying valve structure in the prolapse syndrome may indeed be responsible for this regurgitation.(ABSTRACT TRUNCATED AT 400 WORDS)

Two-dimensional and Doppler echocardiographic diagnosis of an aortic to right atrial fistula complicating aortic dissection.

A 60 year old woman presented with massive aortic root dilation and sudden cardiovascular collapse 10 years after aortic valve replacement. An aortic to right atrial fistula was diagnosed by echocardiographic imaging and Doppler ultrasound. At operation, the patient was found to have chronic aortic dissection with aneurysm formation. Rupture of the aneurysm into the right atrium was confirmed.

Importance of imaging method over imaging modality in noninvasive determination of left ventricular volumes and ejection fraction: assessment by two- and three-dimensional echocardiography and magnetic resonance imaging.

OBJECTIVES: This study sought to determine the concordance between biplane and volumetric echocardiography and magnetic resonance imaging (MRI) strategies and their impact on the classification of patients according to left ventricular (LV) ejection fraction (EF) (LVEF). BACKGROUND: Transthoracic echocardiography and MRI are noninvasive imaging modalities well suited for serial evaluation of LV volume and LVEF. Despite the accuracy and reproducibility of volumetric methods, quantitative biplane methods are commonly used, as they minimize both scanning and analysis times. METHODS: Thirty-five adult subjects, including 25 patients with dilated cardiomyopathies, were evaluated by biplane and volumetric (cardiac short-axis stack) cine MRI and by biplane and volumetric (three-dimensional) transthoracic echocardiography. Left ventricular volume, LVEF and LV function categories (LVEF > or =55%, >35% to <55% and < or =35%) were then determined. RESULTS: Biplane echocardiography underestimated LV volume with respect to the other three strategies (p < 0.01). There were no significant differences (p > 0.05) between any of the strategies for quantitative LVEF. Volumetric MRI and volumetric echocardiography differed by a single functional category for 2 patients (8%). Six to 11 patients (24% to 44%) differed when comparing biplane and volumetric methods. Ten patients (40%) changed their functional status when biplane MRI and biplane echocardiography were compared; this comparison also revealed the greatest mean absolute difference in estimates of EF for those subjects whose EF functional category had changed. CONCLUSIONS: Volumetric MRI and volumetric echocardiographic measures of LV volume and LVEF agree well and give similar results when used to stratify patients with dilated cardiomyopathy according to systolic function. Agreement is poor between biplane and volumetric methods and worse between biplane methods, which assigned 40% of patients to different categories according to LVEF. The choice of imaging method (volumetric or biplane) has a greater impact on the results than does the choice of imaging modality (echocardiography or MRI) when measuring LV volume and systolic function.

Serial assessment of mitral regurgitation by pulsed Doppler echocardiography in patients undergoing balloon aortic valvuloplasty.

Mitral regurgitation was serially assessed by pulsed Doppler echocardiography in 144 patients undergoing balloon aortic valvuloplasty for symptomatic aortic stenosis. Regurgitant scores of 0, 1, 2 and 3 were assigned to pulsed Doppler patterns corresponding to no, mild, moderate and severe mitral regurgitation, respectively. Before balloon aortic valvuloplasty, mitral regurgitant score correlated significantly (p less than 0.005) but weakly with aortic valve area (r = -0.24), left ventricular ejection fraction (r = -0.34) and left ventricular systolic pressure (r = 0.23). There was no significant correlation between mitral regurgitation and either mean catheterization or mean Doppler aortic valve gradient. Balloon aortic valvuloplasty produced significant decreases in both catheterization and Doppler mean transvalvular aortic valve gradients (56 +/- 19 to 31 +/- 12 and 60 +/- 19 to 48 +/- 16 mm Hg, respectively; both p less than 0.0001) and a significant increase (p less than 0.0001) in aortic valve area assessed by catheterization (0.6 +/- 0.2 to 0.9 +/- 0.3 cm2). Left ventricular ejection fraction did not change, but cardiac output increased (p less than 0.001) and pulmonary capillary wedge pressure decreased (p less than 0.0001). Pulsed Doppler findings of mitral regurgitation were present in 102 of the 144 patients. Eighty-eight patients had a score compatible with mild or more severe degrees of mitral regurgitation, and 49 had a score indicative of moderate or severe valvular insufficiency. In the entire group of 144 patients, mitral regurgitant score decreased significantly from 1.1 +/- 1.0 to 1.0 +/- 1.0 (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired left atrial mechanical function after cardioversion: relation to the duration of atrial fibrillation.

OBJECTIVES: We hypothesized that the time course of the recovery of atrial systolic function may be related to the duration of atrial fibrillation before cardioversion and sought to study noninvasively the recovery of left atrial mechanical function utilizing serial transthoracic Doppler studies. BACKGROUND: Recovery of atrial mechanical function may be delayed for several weeks after successful cardioversion of atrial fibrillation to sinus rhythm. METHODS: After successful cardioversion, 60 patients with atrial fibrillation of brief (< or = 2 weeks, 17 patients), moderate (> 2 to 6 weeks, 22 patients) or prolonged (> 6 weeks, 21 patients) duration were followed up with serial transmitral pulsed Doppler echocardiography immediately (60 patients) and at 24 h (45 patients), 1 week (41 patients), 1 month (31 patients) and > 3 months (30 patients) after cardioversion. RESULTS: Atrial mechanical function is greater immediately and at 24 h and 1 week after cardioversion in patients with "brief" compared with "prolonged" atrial fibrillation. In all groups, atrial mechanical function increases over time, ultimately achieving similar levels. Full recovery of atrial mechanical function, however, is achieved within 24 h in patients with brief atrial fibrillation, within 1 week in patients with moderate-duration atrial fibrillation and within 1 month in patients with prolonged atrial fibrillation. CONCLUSIONS: Recovery of left atrial mechanical function is related to the duration of atrial fibrillation before cardioversion. These findings have important implications for assessing the early hemodynamic benefit of successful cardioversion.

Prediction of severity of aortic stenosis: accuracy of multiple noninvasive parameters.

PURPOSE: As newer non-medical techniques are developed to treat older patients with severe aortic stenosis, reliable noninvasive diagnosis of the condition will become increasingly important. For this reason, the accuracy of multiple noninvasive indexes for quantitation of the severity of aortic stenosis was evaluated, relative to catheterization-determined aortic valve area. PATIENTS AND METHODS: To evaluate the accuracy of multiple noninvasive parameters in assessing the presence and extent of aortic valve narrowing, noninvasive and catheterization correlations of the severity of aortic stenosis were obtained on 121 occasions in 81 patients (mean age, 76 +/- 11 years). Forty patients had studies performed before and after valvuloplasty. Noninvasive studies included the time to one-half carotid upstroke and carotid ejection time, corrected for heart rate, measured from a carotid pulse tracing; M-mode echocardiographic aortic valve excursion; mean pressure gradient across the aortic valve assessed by Doppler technique; the ratio of the peak to mean pressure gradient by Doppler; and Doppler aortic valve area assessed using the following continuity equation: aortic valve area = A X V/V1, where A = left ventricular outflow tract area, V = peak left ventricular outflow tract velocity, and V1 = peak velocity in the aortic stenotic jet. Mean aortic valve gradients and area (calculated using the Gorlin formula) were also assessed at cardiac catheterization. RESULTS: The correlations between the catheterization measurement of aortic valve area and the various noninvasive measurements were as follows: time to one-half carotid upstroke (r = -0.32, p less than 0.001); corrected left ventricular ejection time (r = -0.24, p less than 0.05); aortic valve excursion (r = 0.51, p less than 0.001); mean gradient by Doppler study (r = -0.44, p less than 0.001); mean gradient by catheterization analysis (r = -0.55, p less than 0.001); peak to mean gradient ratio measured by continuous wave Doppler (r = 0.38, p less than 0.001); and aortic valve area assessed using the Doppler continuity equation (r = 0.85, p less than 0.001). CONCLUSION: Noninvasive determination of aortic valve area using the continuity equation is an accurate means of assessing the severity of aortic stenosis. Although multiple other noninvasive parameters also correlate with aortic valve area measured at catheterization, there is too much scatter of data points to permit accurate prediction of catheterization aortic valve area in any given patient.

M mode and cross-sectional echocardiographic recognition of fibrosis and calcification of the mitral valve chordae and left ventricular papillary muscles.

The echocardiographic appearance of fibrotic thickening and calcification of mitral valve chordae tendineae and left ventricular papillary muscles in 17 patients is described. Pathologic proof of excessive fibrosis or calcification was obtained in five patients. In a sixth patient, calcium was demonstrated on angiography to extend from the chordae into papillary muscle. The characteristic feature of chordal and papillary muscle fibrosis and calcification is the presence of highly echogenic densities best visualized within the left ventricle at a level below the mitral valve leaflets. The more inferior location of these densities, within the body of the left ventricle, enables them to be easily differentiated from densities indicating fibrosis and calcification of the mitral valve anulus. The pattern of chordal and papillary muscle fibrosis and calcification was frequently associated with mitral anular calcification, aortic valve fibrosis or calcification and left atrial enlargement. One patient had rheumatic mitral valve disease. Many patients had mitral regurgitation and most had a history, physical examination and radiologic findings compatible with congestive heart failure. Although the origin and importance of the chordal and papillary muscle changes reported are not known, their frequent association with mitral regurgitation and with congestive heart failure suggests possible interrelations.

Limitations of echocardiographic techniques in evaluation of left atrial masses.

Four patients with large left atrial masses documented angiographically or pathologically, or both, were studied with M mode echocardiography (four patients) and two dimensional echocardiography (three patients) within 2 to 5 days of angiographic or pathologic diagnosis. The left atrium appeared clear of echos in two patients subsequently documented to have a left atrial thrombus weighing 35 and 100 g, respectively, and located within the body of the left atrium. Definitely abnormal echoes were visualized in a third patient only in the inferior aspect of the left atrium immediately beneath the posterior root of the aorta. Subsequently, a 70 g left atrial myxoma filling almost the entire left atrium was found. In the fourth patient, who had a 125 g left atrial myxoma, the two dimensional four chamber apical view demonstrated tumor filling almost the entire left atrium. Long axis cross-sectional and M mode echocardiograms less clearly demonstrated the extent of the mass. Even large left atrial tumors located within the body of the left atrium may not be apparent or may be underestimated in size by currently available ultrasonic techniques. The relatively homogenous nature of certain masses may be, in part, responsible for the inability to visualize some of them adequately with echocardiography.

Echocardiographic mimicry of pericardial effusion.

Echocardiography is a sensitive technique for the detection of pericardial effusion, but the abnormal echocardiographic patterns seen with effusions are not, however, entirely specific for that diagnosis. This study describes four patients in whom anatomic structures, a coronary artery to coronary sinus fistula (one case) and tumors metastatic to pericardium (three cases), produced posterior and, in two cases, anterior spaces compatible with pericardial fluid. Echocardiographic patterns mimicking pericardial effusion have previously been reported in patients with anatomic abnormalities such as mitral anular calcification, pleural effusions, left atrial enlargement, anterior mediastinal or pericardial tumors, foramen of Morgagni hernia and pseudoaneurysm of the left ventricle. It appears that structures of fluid or tissue density, interposed between the heart and the airfilled lung, can produce echocardiographic patterns simulating pericardial effusion.

Evaluation of left atrial appendage anatomy and function in recent-onset atrial fibrillation by transesophageal echocardiography.

Data regarding left atrial (LA) and LA appendage anatomy and function among patients with newly recognized atrial fibrillation (AF) who have not received long-term warfarin are currently unknown. To identify echocardiographic indexes which characterize those at increased risk for thrombus formation, we analyzed transesophageal echocardiographic studies in 100 consecutive patients with newly recognized AF (duration 2.6 +/- 0.3 week) who had not received long-term warfarin. Fourteen percent of patients had LA thrombi. LA thrombi were associated with larger LA appendages, more depressed LA appendage outflow velocities, and a higher prevalence of severe spontaneous LA contrast. Patients with spontaneous contrast had larger LA and LA appendage anatomy and lower LA appendage ejection velocity. Among patients presenting with their first episode of AF, greater LA appendage ejection and filling velocities and smaller LA and LA appendage sizes were seen among those with AF of <2 weeks duration compared with those with AF of >2 weeks. Thus, patients with recent onset AF and LA thrombi or spontaneous echo contrast have more dilated LA and LA appendage anatomy, and more depressed LA appendage systolic function. Data from patients with their first episode of AF suggests that AF is associated with rapid LA remodeling.

Noninvasive assessment of mitral stenosis before and after percutaneous balloon mitral valvuloplasty.

Thirty-seven patients with symptomatic mitral stenosis underwent balloon dilatation of the mitral valve. Significant increases (p less than 0.001) were noted in both catheterization- and Doppler-determined valve area (0.9 +/- 0.3 to 1.8 +/- 0.8 and 0.9 +/- 0.2 to 1.7 +/- 0.5 cm2). However, catheterization and Doppler areas before and after valvuloplasty correlated less well (r = 0.51, p less than 0.002 and r = 0.47, p less than 0.005, respectively) than the catheterization-Doppler area correlation in a previous study of 59 consecutive patients with varying degrees of mitral stenosis (r = 0.84, p less than 0.001). Mitral valve area increases were independent of valve thickness estimated using 2-dimensional echocardiography. Flail mitral leaflet movement was not observed and the degree of mitral regurgitation qualitatively assessed using pulsed Doppler mapping techniques increased by greater than 1 of 4 grades in only 1 patient. The lateral mitral valve orifice diameter increased more than the anteroposterior diameter, suggesting commissural splitting as the mechanism of successful valvuloplasty. Increases (all p less than 0.0001) were noted in mitral valve EF slope (7 +/- 5 to 18 +/- 10 mm/s), excursion (11 +/- 5 to 13 +/- 4 mm), S20S interval (0.07 +/- 0.02 to 0.08 +/- 0.02 s) and cardiac output (4.2 +/- 1.3 to 5.3 +/- 2.0 liters/min). There were significant decreases (all p less than 0.001) in left atrial diameter (5.4 +/- 1.0 to 5.1 +/- 1.0 cm), mean catheterization gradient (15 +/- 5 to 8 +/- 4 mm Hg) and mean Doppler gradient (10 +/- 4 to 6 +/- 3 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)