Expression of the familial cardiac valvular dystrophy gene, filamin-A, during heart morphogenesis.

Myxoid degeneration of the cardiac valves is a common feature in a heterogeneous group of disorders that includes Marfan syndrome and isolated valvular diseases. Mitral valve prolapse is the most common outcome of these and remains one of the most common indications for valvular surgery. While the etiology of the disease is unknown, recent genetic studies have demonstrated that an X-linked form of familial cardiac valvular dystrophy can be attributed to mutations in the Filamin-A gene. Since these inheritable mutations are present from conception, we hypothesize that filamin-A mutations present at the time of valve morphogenesis lead to dysfunction that progresses postnatally to clinically relevant disease. Therefore, by carefully evaluating genetic factors (such as filamin-A) that play a substantial role in MVP, we can elucidate relevant developmental pathways that contribute to its pathogenesis. In order to understand how developmental expression of a mutant protein can lead to valve disease, the spatio-temporal distribution of filamin-A during cardiac morphogenesis must first be characterized. Although previously thought of as a ubiquitously expressed gene, we demonstrate that filamin-A is robustly expressed in non-myocyte cells throughout cardiac morphogenesis including epicardial and endocardial cells, and mesenchymal cells derived by EMT from these two epithelia, as well as mesenchyme of neural crest origin. In postnatal hearts, expression of filamin-A is significantly decreased in the atrioventricular and outflow tract valve leaflets and their suspensory apparatus. Characterization of the temporal and spatial expression pattern of filamin-A during cardiac morphogenesis is a crucial first step in our understanding of how mutations in filamin-A result in clinically relevant valve disease.

When staplers misfire: endoscopic rescue of low pelvic anastomoses.

The end-to-end stapler has made it possible for colorectal surgeons to construct deeper anastomoses. Although complications associated with the device are mainly postoperative, very serious intraoperative complications, such as stapler misfire, can occur. The authors report their experience with two cases of stapler misfire, describing their method for the extraction of the device and the entrapped tissue using a flexible sigmoidoscope and a hot biopsy forceps. There were no immediate or long-term problems. The technique appears to be safe and effective.

Tetrahydrobiopterin in striatum: localization in dopamine nerve terminals and role in catecholamine synthesis.

The hydroxylase cofactor, tetrahydrobiopterin, and its biosynthetic system are localized in dopaminergic nerve terminals in the striatum. This conclusion is based on the nearly equivalent loss of tyrosine hydroxylase and tetrahydrobiopterin and its initial biosynthetic enzyme, guanosine triphosphate cyclohydrolase, after injection of 6-hydroxydopamine into the substantia nigra. The role of the hydroxylase cofactor in the regulation of dopamine synthesis is reassessed.

Hydroxylase cofactor activity in cerebrospinal fluid of normal subjects and patients with Parkinson's disease.

A method for measuring hydroxylase cofactor activity in human cerebrospinal fluid is described. The hydroxylase cofactor content of cerebrsopinal fluid from Parkinsonian patients is approximately 50 percent that of normal subjects. A significant correlation between hydroxylase cofactor and the concentration of homovanillic acid in the cerebrospinal fluid was observed.

Hypoxia induces a specific set of stress proteins in cultured endothelial cells.

Vascular endothelial cells (EC) are the initial cells within the vascular wall exposed to decreases in blood ambient oxygen concentration. The mechanisms by which they tolerate low levels of oxygen are unknown, but may parallel the response to other cellular stresses, such as heat shock. After 4-8 h of hypoxia, we found a decrease in total protein synthesis in both cultured bovine aortic and pulmonary arterial EC. SDS-PAGE and autoradiographic analysis of [35S]methionine-labeled proteins demonstrated the concomitant induction of a specific set of proteins (Mr 34, 36, 47, and 56 kD) in both cell types. These hypoxia-associated proteins (HAPs) were cell-associated and up-regulated in a time- and oxygen concentration-dependent manner. Comparison of these proteins with heat shock proteins (HSPs) demonstrated that HAPs were distinct from HSPs. EC maintained chronically in 3% O2 continued to synthesize elevated levels of HAPs, yet further up-regulated these proteins when exposed to 0% O2. The presence of five times the normal media glucose concentration did not alter the appearance of HAPs. Hypoxia sensitive renal tubular epithelial cells up-regulated no proteins corresponding to HAPs and were irreversibly damaged within 8 h of exposure to 0% O2. In vitro translation experiments demonstrated that the steady-state level of several mRNAs was higher in the anoxic EC than in normoxic EC and encoded for proteins of Mr 32, 35, 37, 40, and 48 kD that were different from proteins encoded by HSP mRNAs. The induction of HAPs during acute hypoxia and their continued synthesis in chronic hypoxia suggest that HAPs may be important in the maintenance of endothelial cell integrity under conditions of decreased ambient oxygen.

Aspirin potentiates prestimulated acid secretion and mobilizes intracellular calcium in rabbit parietal cells.

The effects of aspirin on gastric acid secretion were studied in isolated rabbit parietal cells (PC). Aspirin (10(-5) M) potentiated histamine-, dibutyryl cyclic AMP (dbcAMP)-, forskolin- and 3-isobutyl-1-methylxanthine-stimulated acid secretion without affecting basal acid secretion. Augmentation of secretagogue-stimulated acid secretion by aspirin was dependent on calcium (Ca2+) since potentiation was blocked by removal of extracellular Ca2+ ([Ca2+]o) or addition of the calcium antagonist lanthanum chloride. Using the Ca2+ probe fura-2, aspirin (10(-6) - 2 X 10(-5) M) rapidly increased intracellular free Ca2+ concentration ([Ca2+]i) in a dose-dependent manner. The source of released Ca2+ was intracellular as demonstrated by depletion of intracellular Ca2+ and [Ca2+]o with EGTA washing. Aspirin did not affect several other signal transduction sites involved in stimulus-secretion coupling, including the H2 receptor, intracellular cyclic AMP (cAMP), inositol 1,4,5, triphosphate (IP3) and H+,K(+)-ATPase. Aspirin decreased PC prostaglandin E2 (PGE2) content by 98%. Exogenous dimethyl PGE2 (dmPGE2) inhibited both histamine-stimulated acid secretion and its enhancement by aspirin. In contrast, dmPGE2 abolished aspirin-induced potentiation of dbcAMP-stimulated acid secretion by augmenting the dbcAMP-stimulated response. These results indicate that aspirin acts at a site beyond the adenylate cyclase/cAMP system and before the proton pump, presumably by releasing Ca2+ from an IP3-independent intracellular storage pool and by inhibiting PGE2 generation.

Evidence for a tinnitus subgroup responsive to somatosensory based treatment modalities.

Studies have established that the somatosensory system of the upper cervical region and head can be intimately involved in tinnitus. Tinnitus can arise directly from a disorder of the head and upper neck through activation of the somatosensory system. "Somatic testing" (a series of strong muscle contractions of the head and neck) can (1) modulate the tinnitus percept of approximately 80% of people with ongoing tinnitus, and (2) elicit a sound percept in approximately 50% of people with no tinnitus. These somatic phenomena are equally prevalent among people with or without functioning cochlea. Likely neural pathways underlying both the induction and modulation of tinnitus have been revealed in animal studies. Because somatic influences are fundamental to the operation of the auditory system, in general, and to tinnitus, in particular, somatic testing should be incorporated into all evaluations of tinnitus (1) to improve understanding of the role of the somatosensory system in any individual and (2) to identify subgroups of tinnitus patients who may respond to a particular treatment modality (as has already been shown for the tinnitus associated with temporomandibular disorder). Our clinical experience and review of reports of treatment modalities directed toward the somatosensory system supports the hypothesis that these modalities can benefit individuals with symmetric hearing thresholds but asymmetric widely fluctuating tinnitus. Treatment modalities involving the somatosensory system should be re-assessed by targeting this tinnitus subgroup.

c-myc regulation during retinoic acid-induced differentiation of F9 cells is posttranscriptional and associated with growth arrest.

We have shown that c-myc mRNA levels decrease more than 20-fold when F9 teratocarcinoma stem cells are induced to arrest growth and terminally differentiate to parietal endoderm after exposure to retinoic acid and cyclic AMP (Campisi et al., Cell 36:241-247, 1984). Here, we demonstrate that although growth arrest and full expression of the differentiated phenotype required about 3 days, c-myc mRNA declined abruptly between 8 and 16 h after the addition of retinoic acid and cyclic AMP. The decline was independent of cyclic AMP. We found little or no change in the level of c-myc transcription during differentiation, although two other genes showed marked transcriptional regulation. Thus, decreased c-myc mRNA is a consequence of very early posttranscriptional regulation directed by retinoic acid. Differentiation was not fundamental to this regulation. We have shown that sodium butyrate blocks expression of the differentiated phenotype if added within 8 h of retinoic acid and cyclic AMP (Levine et al., Dev. Biol. 105:443-450, 1984). However, butyrate did not inhibit the decrease in c-myc mRNA. Furthermore, F9 cells partially arrested growth without differentiating when grown in isoleucine-deficient medium. Under these conditions, c-myc mRNA levels also declined. Our results suggest that induction of differentiation-specific genes may be under retinoic acid-mediated control dissimilar from that responsible for the decay of c-myc mRNA. In addition, they raise the possibility that growth arrest may be initiated by reduced c-myc expression.

c-ras-Ha gene expression is regulated by insulin or insulinlike growth factor and by epidermal growth factor in murine fibroblasts.

Although much is known about the structure of ras-encoded proteins, little is known about how expression is regulated. In serum-stimulated murine fibroblasts, c-ras-Ha mRNA levels fluctuated with the growth state but not with the position in the cell cycle. Two types of growth factors regulated c-ras-Ha expression: insulin (IN) or insulinlike growth factor I, each apparently acting through its cognate receptor, and epidermal growth factor (EGF). In quiescent cells, IN or insulinlike growth factor I induced c-ras-Ha mRNA three- to fivefold within 4 h, but thereafter the mRNA declined. By contrast, EGF had little effect in 4 h but induced the mRNA after 4 to 6 h. When quiescent cells were given serum or IN and EGF simultaneously, c-ras-Ha mRNA rose steadily, beginning 1 to 2 h after stimulation, and reached a stable five- to sevenfold elevation in 16 h. Thus, c-ras-Ha gene expression was sequentially regulated by two growth factors, one of which (IN) does not induce expression of other growth-regulated protooncogenes. A transformed derivative cell line that does not require IN for G1 progression has lost early IN-dependent but not late serum-dependent regulation. The results support the possibility that c-ras-Ha and IN action are functionally linked.

Isolation of cDNA clones for genes exhibiting reduced expression after differentiation of murine teratocarcinoma stem cells.

In the absence of retinoic acid, PSA-G teratocarcinoma stem cells spontaneously differentiate at a moderate frequency into fibroblast-like cells. In the presence of retinoic acid and dibutyryl cyclic AMP, PSA-G stem cells differentiate into parietal endoderm cells. We prepared a cDNA library from undifferentiated PSA-G teratocarcinoma stem cells; this cDNA library was then screened for gene sequences which exhibit a reduction in expression during the differentiation of these stem cells. From ca. 1,000 clones screened, eight independent sequences were isolated. The level of expression of these cloned genes decreases by 3.0-fold to more than 10-fold after differentiation of PSA-G cells into fibroblast-like cells. After treatment of either PSA-G or F9 teratocarcinoma cells with retinoic acid and dibutyryl cyclic AMP for 72 h, the expression of seven genes is inhibited by two- to fourfold. This decrease of clone-specific transcripts can be detected within 12 h after the addition of retinoic acid. Hybridization-selection and in vitro translation experiments identified the proteins encoded by three of the cloned genes: pST 6-23 codes for a 89,000-dalton protein, pST 7-105 codes for a 41,000-dalton protein, and pST 9-31 codes for a 34,000-dalton protein. The 89,000-dalton protein encoded by pST 6-23 is a heat shock protein. In vitro transcription experiments demonstrate that the retinoic acid-mediated decrease in pST 6-135- and pST 1-68-specific RNA occurs at the transcriptional level and that dibutyryl cyclic AMP acts posttranscriptionally to further depress the levels of these RNAs.

Transcriptional and posttranscriptional control of c-myc gene expression in WEHI 231 cells.

Incubation of WEHI 231 cells, derived from a murine B-cell lymphoma, with antisera directed against its surface immunoglobulin results in the inhibition of growth within 24 h. Previously, we demonstrated that this treatment selectively affects cytoplasmic levels of c-myc mRNA (J. E. McCormack, V. H. Pepe, R. B. Kent, M. Dean, A. Marshak-Rothstein, and G. E. Sonenshein, Proc. Natl. Acad. Sci. USA 81:5546-5550, 1984). An initial increase in the cytoplasmic mRNA level is followed by a precipitous drop. We now show that the early increase results from a dramatic increase in the rate of c-myc gene transcription, as well as from partial stabilization of the mRNA in the cytoplasm. The later decrease results from a shutdown in transcription of the c-myc gene and a return to the normal lability of the cytoplasmic c-myc mRNA. Treatment with phorbol ester, like treatment with anti-immunoglobulin sera, inhibited WEHI 231 cell growth and caused similar changes in cytoplasmic c-myc mRNA levels, which can also be related to alterations in c-myc gene transcription. These results indicate that the control of c-myc gene expression in B cells is effected through regulation at multiple levels.

Independent regulation of transcription of the two strands of the c-myc gene.

Previously we demonstrated the existence of transcripts from the noncoding strand of a rearranged, truncated c-myc gene in murine plasmacytomas in which this oncogene is translocated to an immunoglobulin constant-region gene element (M. Dean, R. B. Kent, and G. E. Sonenshein, Nature [London] 305:443-446, 1983). Here we report on the transcription of the two strands of a normal, unrearranged c-myc gene. We examined the effects of gene rearrangements, growth state transitions, and differentiation on the relative levels of usage of the two strands. Transcription from intron 1 to exon 3 of the murine c-myc gene was studied in in vitro nuclear runoff assays. The level of transcription of the noncoding strand across this region of a germ line c-myc gene in a murine B-cell lymphoma line was comparable to the level observed in plasmacytomas with translocated c-myc genes. Rapid changes in transcription of the coding strand of the c-myc gene could be seen during growth arrest of WEHI 231 cells and during activation of splenic T lymphocytes. Transcription of the noncoding strand was constitutive during these growth state transitions and during activation of primary cultures of quiescent calf aortic smooth muscle cells as well. In contrast, differentiation of murine erythroleukemia cells was accompanied by an early drop in transcription of the two strands of this gene. The ramifications of these findings with respect to measurements of c-myc gene transcription and to the regulation of this gene are discussed.

Alternative modes of c-myc regulation in growth factor-stimulated and differentiating cells.

We have analysed the regulation of c-myc expression in murine fibroblasts and F9 teratocarcinoma cells. The initiation of c-myc transcription is induced to similar levels after serum stimulation of confluent and subconfluent Balb/c A31 fibroblasts while intragenic pausing within the gene's first exon remains unaffected. Sense c-myc transcription continues unabated for at least 18 hours in subconfluent cells, whereas in confluent cells it rapidly falls to pre-induced levels. Cytoplasmic c-myc mRNAs accumulate within 1-2 hours of serum addition to subconfluent cells and reach a higher level than expected from the degree of induction of sense transcription. However, c-myc mRNA levels fall close to pre-induced levels by 18 hours demonstrating that c-myc expression is initially subject to strong positive and then eventually strong negative post-transcriptional control. Anti-sense transcription within the c-myc locus was found to be constitutive under all these physiological states, thereby demonstrating that c-myc transcriptional control is strand specific. Epidermal growth factor stimulates c-myc transcription in a way different from that of serum: (1) initiation of transcription is not significantly enhanced, but intragenic pausing is significantly abrogated; and (2) post-transcriptional mechanisms do not enhance the degree of c-myc mRNA accumulation. In contrast to our results in fibroblastic cells, differentiating F9 teratocarcinoma cells down-regulate c-myc expression entirely at the post-transcriptional level. Our findings indicate that different cell types preferentially employ different modes of myc control depending on their physiological status.

Proton nuclear magnetic resonance spectroscopy of isolated rabbit fundic glands.

1H-nuclear magnetic resonance spectroscopy (NMR) was adapted to isolated rabbit fundic glands and identification made of compounds responsible for several observed spectral resonances. A minimum gland concentration of 0.5 mg dry weight or 5 mg wet weight per 0.5 ml was needed for adequate signal-to-noise ratio. At physiological temperature and pH, the glands demonstrated reproducible spectra, stability for accumulation times greater than 30 min and responsiveness to histamine stimulation, as measured by oxygen consumption and aminopyrine uptake. The relatively anaerobic conditions favored use of proton compared to phosphorus NMR, since 1H-NMR allowed significantly shorter spectral accumulation times and therefore did not compromise glandular viability to the same extent as 31P-NMR. The most conspicuous resonance in the gland spectrum was assigned to the -N+(CH3)3 protons of choline and related compounds. In membrane-free lysates, several components of the signal were resolvable and assigned to choline, phosphatidylcholine, phosphocholine and L-alpha-glycerophosphocholine. Thin-layer chromatography verified that phosphatidylcholine and phosphatidylethanolamine were the major phospholipids present in gland lipid. Presumably, they represent the source of the surface-active phospholipids present in gastric juice, which may play a role in gastric cytoprotection.

The power-velocity integral at the vena contracta: A new method for direct quantification of regurgitant volume flow.

BACKGROUND: Noninvasive quantification of regurgitation is limited because Doppler measures velocity, not flow. Because backscattered Doppler power is proportional to sonified blood volume, power times velocity should be proportional to flow rate. Early studies, however, suggested that this held only for laminar flow, not for regurgitant jets, in which turbulence and fluid entrainment augment scatter. We therefore hypothesized that this Doppler power principle can be applied at the proximal vena contracta, where flow is laminar before entrainment, so that the power-times-velocity integral should vary linearly with flow rate and its time integral with stroke volume (SV). METHODS AND RESULTS: This was tested in vitro with steady and pulsatile flow through 0.07- to 0.8-cm(2) orifices and in 36 hemodynamic stages in vivo, replacing the left atrium with a rigid chamber and column for direct visual recording of mitral regurgitant SV (MRSV). In 12 patients, MRSV was compared with MRI mitral inflow minus aortic outflow and in 11 patients with 3D echo left ventricular ejection volume-Doppler aortic forward SV. Vena contracta power in the narrow high-velocity spectrum from a broad measuring beam was calibrated against that from a narrow reference beam of known area. Calculated and actual flow rates and SV correlated well in vitro (r=0.99, 0.99; error=-1.6+/-2.5 mL/s, -2. 4+/-2.9 mL), in vivo (MRSV: r=0.98, error=0.04+/-0.87 mL), and in patients (MRSV: r=0.98, error=-2.8+/-4.5 mL). CONCLUSIONS: The power-velocity integral at the vena contracta provides an accurate direct measurement of regurgitant flow, overcoming the limitations of existing Doppler techniques.

Design of a new surgical approach for ventricular remodeling to relieve ischemic mitral regurgitation: insights from 3-dimensional echocardiography.

BACKGROUND: Mechanistic insights from 3D echocardiography (echo) can guide therapy. In particular, ischemic mitral regurgitation (MR) is difficult to repair, often persisting despite annular reduction. We hypothesized that (1) in a chronic infarct model of progressive MR, regurgitation parallels 3D changes in the geometry of mitral leaflet attachments, causing increased leaflet tethering and restricting closure; therefore, (2) MR can be reduced by restoring tethering geometry toward normal, using a new ventricular remodeling approach based on 3D echo findings. METHODS AND RESULTS: We studied 10 sheep by 3D echo just after circumflex marginal ligation and 8 weeks later. MR, at first absent, became moderate as the left ventricle (LV) dilated and the papillary muscles shifted posteriorly and mediolaterally, increasing the leaflet tethering distance from papillary muscle tips to the anterior mitral annulus (P<0.0001). To counteract these shifts, the LV was remodeled by plication of the infarct region to reduce myocardial bulging, without muscle excision or cardiopulmonary bypass. Immediately and up to 2 months after plication, MR was reduced to trace-to-mild as tethering distance was decreased (P<0.0001). LV ejection fraction, global LV end-systolic volume, and mitral annular area were relatively unchanged. By multiple regression, the only independent predictor of MR was tethering distance (r(2)=0.81). CONCLUSIONS: Ischemic MR in this model relates strongly to changes in 3D mitral leaflet attachment geometry. These insights from quantitative 3D echo allowed us to design an effective LV remodeling approach to reduce MR by relieving tethering.

Paradoxic decrease in ischemic mitral regurgitation with papillary muscle dysfunction: insights from three-dimensional and contrast echocardiography with strain rate measurement.

BACKGROUND: Ischemic mitral regurgitation (MR) was first ascribed to papillary muscle (PM) contractile dysfunction. Current theories include apical leaflet tethering caused by left ventricular (LV) distortion, but PM dysfunction is still postulated and commonly diagnosed. PM contraction, however, parallels apical tethering, suggesting the hypothesis that PM contractile dysfunction can actually diminish MR due to ischemic distortion of the inferior base alone. METHODS AND RESULTS: We therefore occluded the proximal circumflex circulation in 7 sheep while maintaining PM perfusion, confirmed by contrast echocardiography. By 3D echocardiography, we measured the tethering distance between the ischemic medial PM tip and anterior annulus and LV ejection volume to give MR (by subtracting flowmeter LV outflow). In 6 sheep without initial MR, inferior ischemia alone produced PM tip retraction with restricted leaflet closure and mild-to-moderate MR (regurgitant fraction, 25.2+/-2.8%). Adding PM ischemia consistently decreased MR and tethering distance (5.2+/-0.3 to 1.4+/-0.3 mL; +3.8+/-0.5 mm to -2.2+/-0.7 mm axially relative to baseline; P<0.001) as PM strain rate decreased from +0.78+/-0.07 per second (contraction) to -0.42+/-0.06 per second (elongation, P<0.001) and leaflet tenting decreased. In one sheep, prolapse and MR resolved with inferior ischemia and recurred with PM ischemia. CONCLUSIONS: PM contractile dysfunction can paradoxically decrease MR from inferobasal ischemia by reducing leaflet tethering to improve coaptation. This emphasizes the role of geometric factors in ischemic MR mechanism and potential therapy.

Chordal cutting: a new therapeutic approach for ischemic mitral regurgitation.

BACKGROUND: Mitral regurgitation (MR) conveys adverse prognosis in ischemic heart disease. Because such MR is related to increased leaflet tethering by displaced attachments to the papillary muscles (PMs), it is incompletely treated by annular reduction. We therefore addressed the hypothesis that such MR can be reduced by cutting a limited number of critically positioned chordae to the leaflet base that most restrict closure but are not required to prevent prolapse. This was tested in 8 mitral valves: a porcine in vitro pilot with PM displacement and 7 sheep with acute inferobasal infarcts studied in vivo with three-dimensional (3D) echo to quantify MR in relation to 3D valve geometry. METHODS AND RESULTS: In all 8 valves, PM displacement restricted leaflet closure, with anterior leaflet angulation at the basal chord insertion, and mild-to-moderate MR. Cutting the 2 central basal chordae reversed this without prolapse. In vivo, MR increased from 0.8+/-0.2 to 7.1+/-0.5 mL/beat after infarction and then decreased to 0.9+/-0.1 mL/beat with chordal cutting (P<0.0001); this paralleled changes in the 3D leaflet area required to cover the orifice as dictated by chordal tethering (r(2)=0.76). CONCLUSIONS: Cutting a minimum number of basal chordae can improve coaptation and reduce ischemic MR. Such an approach also suggests the potential for future minimally invasive implementation.

Increased heart rate can cause underestimation of regurgitant jet size by Doppler color flow mapping.

OBJECTIVES: This study addressed the hypothesis that at a constant peak flow rate, an increasing heart rate could decrease the maximal apparent jet size by Doppler color flow mapping. BACKGROUND: Recent studies have attempted to predict the severity of regurgitation from maximal jet area by Doppler color flow mapping, which correlates with flow rate for free jets at constant driving pressure and steady flow. In patients, however, maximal jet area exists for only a limited time per beat and the likelihood of visualizing it by Doppler color flow mapping depends on its duration relative to the color frame sampling rate. Increased heart rate could potentially diminish apparent jet size, particularly at slow frame rates that may not permit visualization of the maximal jet area in all beats. METHODS: This interaction was examined in pulsatile flow, holding orifice size and peak flow rate constant and varying pump pulse rate (70 to 180 beats/min) and frame rate (three rates) for jets of low and high momentum. Maximal jet area was measured in 10 consecutive beats at each pulse rate and frame rate and averaged. RESULTS: For the low momentum jet, the 10-beat average of peak jet area decreased progressively with increasing pulse rate. As pulse rate increased from 70 to 180 beats/min, maximal jet area decreased 23% at the fastest frame rate and 42% at the slowest frame rate, with prominent beat to beat variability. Jet area decreased 13% to 20% at pulse rates as low as 90 beats/min. In contrast, for the high momentum jet, maximal jet area decreased by < or = 9% from low to high pulse rate at any frame rate. CONCLUSIONS: Increased heart rate can cause underestimation of apparent jet size by Doppler color flow mapping for a given peak flow rate, particularly for jets with low momentum and delayed penetration into the receiving chamber. This observation may be relevant to acute severe regurgitation with increased heart rate in which such underestimation has been reported, as well as to right-sided lesions and children with rapid heart rates. It will also affect new techniques proposed to quantify regurgitation on the basis of velocities derived from Doppler color flow images. In practice, this effect can be reduced by increasing frame rate and selecting maximal apparent jet size at rapid heart rates and should be considered in relating jet size to the severity of regurgitation.

Adjacent solid boundaries alter the size of regurgitant jets on Doppler color flow maps.

Recent studies have attempted to predict the severity of regurgitant lesions from jet size on Doppler flow maps. Jet size is a function of both regurgitant volume and fluid entrained from the receiving chamber and, for a free jet, is a function of its momentum at the orifice. However, regurgitant jets often approach or attach to cardiac walls, potentially altering their momentum and ability to expand by entrainment. Therefore, this study addressed the hypothesis that adjacent walls influence regurgitant jet size as seen on Doppler flow maps. Steady flow was driven through circular orifices (0.02 to 0.05 cm2) at physiologic velocities of 2 to 5 m/s. At a constant flow rate and orifice velocity, orifice position was varied to produce three jet geometries: free jets, jets adjacent to a horizontal chamber wall lying 1 cm below the orifice and wall jets with the orifice at the level of the wall. Doppler color flow imaging was performed at identical instrument settings for all jets. Two long-axis views of the jet were obtained: a vertical view perpendicular to the wall, resembling that most commonly used in patients to image the length of the jet, and a horizontal view parallel to the chamber wall. Velocities along the jet were also measured by Doppler mapping.(ABSTRACT TRUNCATED AT 250 WORDS)