Roles of HAUSP-mediated p53 regulation in central nervous system development.

The deubiquitinase HAUSP (herpesvirus-associated ubiquitin-specific protease; also called USP7) has a critical role in regulating the p53-Mdm2 (murine double minute 2) pathway. By using the conventional knockout approach, we previously showed that hausp inactivation leads to early embryonic lethality. To fully understand the physiological functions of hausp, we have generated mice lacking hausp specifically in the brain and examined the impacts of this manipulation on brain development. We found that deletion of hausp in neural cells resulted in neonatal lethality. The brains from these mice displayed hypoplasia and deficiencies in development, which were mainly caused by p53-mediated apoptosis. Detailed analysis also showed an increase of both p53 levels and p53-dependent transcriptional activation in hausp knockout brains. Notably, neural cell survival and brain development of hausp-mutant mice can largely be restored in the p53-null background. Nevertheless, in contrast to the case of mdm2- and mdm4 (murine double minute 4)-mutant mice, inactivation of p53 failed to completely rescue the neonatal lethality of these hausp-mutant mice. These results indicate that HAUSP-mediated p53 regulation is crucial for brain development, and also suggest that both the p53-dependent and the p53-independent functions of HAUSP contribute to the neonatal lethality of hausp-mutant mice.

Inactivation of HAUSP in vivo modulates p53 function.

Hausp is a deubiquitinase that has been shown to regulate the p53-Mdm2 pathway. Cotransfection of p53 and Hausp stabilizes p53 through the removal of ubiquitin moieties from polyubiquitinated p53. Interestingly, knockout or RNA interference-mediated knockdown of Hausp in human cells also resulted in the stabilization of p53 due to the destabilization of Mdm2, suggesting a dynamic role of Hausp in p53 activation. To understand the physiological functions of Hausp, we generated hausp knockout mice. Hausp knockout mice die during early embryonic development between embryonic days E6.5 and E7.5. The hausp knockout embryos showed p53 activation, but no apparent increase in apoptosis. Embryonic lethality was caused by a dramatic reduction in proliferation and termination in development, in part due to p53 activation and/or abrogation of p53-independent functions. Although deletion of p53 did not completely rescue the embryonic lethality of the hausp knockout, embryonic development was extended in both hausp and p53 double knockout embryos. These data show that Hausp has a critical role in regulating the p53-Mdm2 pathway.

Does breastfeeding in the neonatal period influence the cognitive function of very-low-birth-weight infants at 5 years of age?

AIM: Breast milk is rich in docosahexaenoic acid (DHA), which is selectively concentrated in neuronal membranes and is thought to be necessary for optimal neurodevelopment. This study evaluated the relationship between breastfeeding, especially the resultant DHA level in the red blood cell (RBC) membranes of infants, and the cognitive function of very-low-birth-weight infants at 5 years of age. METHODS: Eighteen patients were classified into groups that were breastfed or formula-fed or both. We measured the DHA concentration in the RBC membranes of 18 preterm infants at 4 weeks of age. To evaluate cognitive function at the age of 5 years, we asked the children to perform five tests: the Kaufman Assessment Battery for Children, Day-Night Test, Kansas Reflection Impulsivity Scale for Preschoolers (KRISP), Motor Planning Test, and Strengths and Difficulties Questionnaire. RESULTS: The DHA level at 4 weeks after birth was significantly higher in the breastfed infants than in the formula-fed infants. The scores for the Day-Night Test, KRISP, and Motor Planning Test were significantly higher in the breastfed group. There were significant correlations between the scores for the Day-Night Test and for the KRISP and the level of DHA at 4 weeks of age. CONCLUSION: Breastfeeding in the neonatal periods increases the DHA level in preterm infants and may have an important influence on brain development not only during early infancy but also during the preschool years, especially in terms of cognitive function.

Dissecting roles of ubiquitination in the p53 pathway.

Posttranslational modification of proteins by mono- or polyubiquitination represents a central mechanism to modulate a wide range of cellular functions like protein stability, intracellular transport, protein interactions, and transcriptional activity. Analogous to other posttranslational modifications, ubiquitination is a reversible process counteracted by deubiquitinating enzymes (DUBs), which cleave the isopeptide linkage between protein substrate and the ubiquitin residue. The p53 tumor suppressor is a sequence-specific DNA-binding transcriptional factor that plays a central role in regulating growth arrest and apoptosis during the stress response. Notably, recent studies indicate that both the stability and the subcellular localization of p53 are tightly regulated by ubiquitination; p53 is mainly ubiquitinated by Mdm2 but other ubiquitin ligases such as ARF-BP1/HectH9/MULE are also involved in p53 regulation in vivo. Moreover, a deubiquitinase HAUSP was initially identified in p53 deubiquitination but more recent studies showed that both Mdm2 and Mdmx are also bona fide substrates of HAUSP. In this article, we review our latest understanding of ubiquitination in modulating the p53 tumor suppression pathway.

Benefit of glyceryl trinitrate on arterial stiffness is directly due to effects on peripheral arteries.

OBJECTIVE: To determine how the vasodilator glyceryl trinitrate (GTN) alters arterial stiffness and improves left ventricular afterload. METHODS: Ascending aortic pressure waves were measured with fluid filled catheters of high fidelity in 50 patients undergoing cardiac surgery, before cardiopulmonary bypass, both before and after intravenous infusion of GTN. In all 50 patients, wave reflection was identifiable as a secondary boost to late systolic pressure, permitting the pressure wave to be separated into a primary component, attributable to left ventricular ejection and properties of the proximal aorta, and a secondary component, attributable to reflection of the primary wave from the peripheral vasculature. RESULTS: GTN infusion caused no change in amplitude of the primary wave (mean (SD) 0.0 (1.4) mm Hg, not significant) but substantial reduction (14.6 (9.6) mm Hg, p < 0.0001) in amplitude of the secondary reflected wave. Fall in mean pressure was attributable to a mix of arteriolar and venous dilatation, with relative contributions unable to be separated. CONCLUSION: Favourable effects of GTN on arterial stiffness can be attributed to effects on peripheral muscular arteries, causing reduction in wave reflection. Results conform with previous invasive studies on vasodilator agents and their known effects on calibre and compliance of muscular arteries.

The second peak of the radial artery pressure wave represents aortic systolic pressure in hypertensive and elderly patients.

BACKGROUND: Simultaneous measurement of ascending aorta and radial artery pressure shows that mean and diastolic pressures (DP) are in close agreement in normotensive adults, while systolic pressures (SP) are not. However, in the aortic pressure wave, a second systolic peak appears with increasing age and increases to represent the SP by age 32 yr, while in the radial artery, a second systolic deflection appears by age 40 yr. We suggest that the second radial systolic wave, sometimes seen during radial arterial pressure monitoring in older hypertensives, represents the aortic SP. We set out to evaluate whether the aortic and radial second systolic peaks agree, and since doubts exist about the agreement between aortic and radial DP in elderly hypertensive patients, we also assessed that relationship. METHODS: We compared simultaneously recorded radial and aortic pressures from 21 anaesthetized adult patients using identical fluid-filled pressure measuring systems. CONCLUSIONS: The second radial pressure peak agreed with that in the aorta within a mean of 0.6 (SD 1.5) mm Hg. The difference between DP in the aorta and radial artery was -1.4 (2) mm Hg. The radial-aortic SP and pulse pressure differences were 5.9 (7.6) and 7.3 (7.6) mm Hg, respectively. These results confirm that when the radial artery pressure wave shows a first and second, or only a second systolic shoulder/peak (on the right side of the pressure wave), the second represents the maximal ascending aortic SP, and that the radial and aortic DP are equivalent, even in older hypertensive patients.

Prospective evaluation of a method for estimating ascending aortic pressure from the radial artery pressure waveform.

Pressure wave reflection in the upper limb causes amplification of the arterial pulse so that radial systolic and pulse pressures are greater than in the ascending aorta. Wave transmission properties in the upper limbs (in contrast to the descending aorta and lower limbs) change little with age, disease, and drug therapy in adult humans. Such consistency has led to use of a generalized transfer function to synthesize the ascending aortic pressure pulse from the radial pulse. Validity of this approach was tested for estimation of aortic systolic, diastolic, pulse, and mean pressures from the radial pressure waveform. Ascending aortic and radial pressure waveforms were recorded simultaneously at cardiac surgery, before initiation of cardiopulmonary bypass, with matched, fluid-filled manometer systems in 62 patients under control conditions and during nitroglycerin infusion. Aortic pressure pulse waves, generated from the radial pulse, showed agreement with the measured aortic pulse waves with respect to systolic, diastolic, pulse, and mean pressures, with mean differences <1 mm Hg. Control differences in Bland-Altman plots for mean+/-SD in mm Hg were systolic, 0.0+/-4.4; diastolic, 0.6+/-1.7; pulse, -0.7+/-4.2; and mean pressure, -0.5+/-2.0. For nitroglycerin infusion, differences respectively were systolic, -0.2+/-4.3; diastolic, 0.6+/-1.7; pulse, -0.8+/-4.1; and mean pressure, -0.4+/-1.8. Differences were within specified limits of the Association for the Advancement of Medical Instrumentation SP10 criteria. In contrast, differences between recorded radial and aortic systolic and pulse pressures were well outside the criteria (respectively, 15.7+/-8.4 and 16.3+/-8.5 for control and 14.5+/-7.3 and 15.1+/-7.3 mm Hg for nitroglycerin). Use of a generalized transfer function to synthesize radial artery pressure waveforms can provide substantially equivalent values of aortic systolic, pulse, mean, and diastolic pressures.

A study of C-F...M(+) interaction: metal complexes of fluorine-containing cage compounds.

The C-F...M(+) interaction was investigated by observation of the NMR spectroscopic changes and complexation studies between metal cations and the cage compounds 1 and 2 which have fluorobenzene units as donor atoms. As a result, the interaction was detected with all of the metal cations which form complexes with 1 and 2. The stability of the complexes of 1 and 2 was determined by the properties of the metal cations (ionic radii and degree of hydrolysis), not by the hard-soft nature of the cations. Crystallographic analyses of Tl(+) subset 1 and La(3+) subset 2 provided structural information (interatomic distances and bond angles), and the bond strengths, C-F...M(+), O...M(+), and N...M(+), were estimated by Brown's equation based on the structural data. Short C-F...Tl(+) (2.952-3.048 A) distances were observed in the complex Tl(+) subset 1. The C-F bond lengths in the complexes, Tl(+) subset 1 and La(3+) subset 2, are elongated compared to those of the metal-free compounds. Interestingly, no solvent molecules including water molecules were coordinated to La(3+) in the La(3+) subset 2. The stabilization energy of cation-dipole interaction was calculated on the basis of the data from X-ray crystallographic analysis, and it is roughly consistent with the (-)Delta H values estimated in solution. Thus, the C-F...M(+) interaction can be expressed by the cation-dipole interaction. This result explains the fact that compound 1 which has fluorine atom as hard donor strongly binds soft metals such as Ag(+) and Tl(+). Furthermore, it was concluded that the fluorobenzene unit has a poor electron-donating ability compared to that of ether oxygen or amine nitrogen, and thus the ratio of the coordination bond in C-F...M(+) is small. The specific and remarkable changes in the (1)H, (13)C, and (19)F NMR spectra were observed accompanied by the complexation between M(+) and the hosts 1 and 2. These spectral features are important tools for the investigation of the C-F...M(+) interaction. Furthermore, F.Tl(+) spin couplings were observed at room temperature in the Tl(+) subset 1, 2 (J(F-Tl) = 2914 Hz for Tl(+) subset 1 and 4558 Hz for Tl(+) subset 2), and these are clear and definitive evidence of the interaction.

Steroid-free maintenance immunosuppression after heart transplantation.

BACKGROUND: Steroids are routinely used in almost all immunosuppressive protocols after cardiac transplantation. The metabolic side effects of steroids are well known and could lead to significant morbidity and mortality in the posttransplant period. There is growing evidence to suggest that steroids may not be a requirement for adequate immunosuppression and that morbidity may be reduced by withdrawing steroids in select patients. We have reviewed our series of patients undergoing heart transplantation in whom steroids were weaned postoperatively. METHODS: We retrospectively reviewed all adult patients undergoing heart transplantation at our institution between November 1993 and April 2000 treated with a-triple-drug immunosuppressive regimen. Medications were recorded at discharge and at 6, 12, and 24 months posttransplant to determine the success of steroid weaning. Freedom from infection and rejection as well as overall survival was calculated using Kaplan-Meier methods. RESULTS: By 24 months posttransplant, almost 70% of patients were receiving double-drug therapy. Survival for the entire group was excellent with 1-, 3-, and 5-year survival of 98%+/-2.0%, 93.2%+/-3.8%, and 88.3%+/-6.0%, respectively. Freedom from rejection at 6 months was 60.7%+/-6.5%, at 1 year was 60.7%+/-6.5%, and at 2 years was 58.5%+/-6.7%. Infectious complications were low with freedom from infection at 6 months of 78.5+/-5.5%, at 1 year of 76.5%+/-5.7%, and at 2 years of 72.0%+/-6.2%. CONCLUSIONS: Our data suggest that an immunosuppressive regimen without long-term steroid administration results in excellent survival rates without an apparent increase in rejection or infectious complications.

A study of C-F.M+ interaction: alkali metal complexes of the fluorine-containing cage compound.

The C-F.M(+) interaction was investigated by employing a cage compound 1 that has four fluorobenzene units. The NMR ((1)H, (13)C, and (19)F) spectra and X-ray crystallographic analyses of 1 and its metal complexes showed clear evidence of the interaction. Short C-F.M(+) distances (C-F.K(+), 2.755 and 2.727 A; C-F.Cs(+), 2.944 and 2.954 A) were observed in the crystalline state of K(+) subset 1 and Cs(+) subset 1. Furthermore, the C-F bond lengths were elongated by the interaction with the metal cations. By calculating Brown's bond valence, it is shown that the contribution of the C-F unit to cation binding is comparable or greater than the ether oxygen in the crystalline state. Representative spectroscopic changes implying the C-F.M(+) interaction were observed in the NMR ((1)H, (13)C, and (19)F) spectra. In particular, (133)Cs-(19)F spin coupling (J = 54.9 Hz) was observed in the Cs(+) complex.

Impact of high transvalvular to subvalvular velocity ratio early after aortic valve replacement with Freestyle stentless aortic bioprosthesis.

Although stentless aortic bioprostheses are associated in general with excellent hemodynamics, a subset of patients exhibit high early postoperative gradients. The present study was performed to evaluate the prevalence and impact of suboptimal hemodynamics early after stentless tissue aortic valve replacement. The early postoperative peak transvalvular to peak left ventricular (LV) outflow tract velocity ratio was > or = 3.0 in 44 (6.7%) of 658 patients in the multicenter, long-term study of the Freestyle stentless aortic valve. Mean gradient, effective orifice area (EOA), and LV mass index were compared between these patients and a control group of 44 patients matched for age, sex, valve size, and implant technique. High velocity ratio was associated with female sex (63.6% v 42.8%, P =.01), smaller valve size (77.3% v 45.3%, < or = 23 mm, P =.0004), and use of the modified subcoronary rather than full root implant technique (90.9% v 70.2% modified subcoronary, P =.01). Mean gradient was significantly higher (P <.05) and EOA lower (P <.05) early postoperative and throughout follow-up among patients with high velocity ratio. LV mass index decreased across time among both groups; patients with high velocity ratio tended to have higher LV mass index with less complete LV mass regression, although the difference did not reach statistical significance. In conclusion, there was a 6.7% incidence of hemodynamics suggestive of significant aortic stenosis early after implantation of a Freestyle stentless aortic valve. Gradients decreased and EOA increased in the first months after surgery, although they remained less favorable. Multiple factors likely play a role in early suboptimal hemodynamics following stentless tissue aortic valve replacement, including factors related to patient population, valve size, implant modality, and implant technique.

Prophylactic nitroglycerin did not reduce myocardial ischemia during accelerated recovery management of coronary artery bypass graft surgery patients.

OBJECTIVE: To evaluate the use of a high dose of nitroglycerin (NTG) for prophylaxis against myocardial ischemia and infarction in patients undergoing coronary artery bypass graft (CABG) surgery with accelerated recovery. DESIGN: Prospective, double-blind, placebo-controlled randomized study. SETTING: A university-based medical center. PARTICIPANTS: Forty adult patients presenting for elective CABG surgery. INTERVENTIONS: Forty patients were divided into 2 blinded study groups. Twenty patients received 2 microg/kg/min of NTG starting before induction of anesthesia and continuing for 6 hours after extubation in the intensive care unit. The placebo group (n = 20) received normal saline during this same interval. MEASUREMENTS AND MAIN RESULTS: Hemodynamics, incidence and severity of myocardial ischemia, and myocardial infarction rates were determined. There were no differences in hemodynamic parameters between groups. The incidence of ischemia was approximately 35% in each group. Myocardial infarction (as determined by elevated creatine kinase-MB fraction, troponin I, and electrocardiogram criteria) was 10% in the placebo group and 5% in the NTG group (p = 0.234). CONCLUSIONS: This study shows a high incidence of myocardial ischemia and infarction in patients presenting for CABG surgery with an accelerated recovery management scheme. NTG was well tolerated clinically; however, it was not found to be protective against myocardial ischemia or infarction in this setting.

The C-F...cation interaction: an ammonium complex of a hexafluoro macrocyclic cage compound.

An ammonium complex of the hexafluoro cage compound 1 was isolated and its structure was elucidated by X-ray crystallographic analysis. The C-F bonds are elongated by the complexation, which is clear evidence of C-F...cation interaction. The driving force of NH4(+) inclusion is the C-F cation interaction, but the C-F...HN+ hydrogen bond does not contribute to this complexation. The crystal structure of the NH4+ complex 1 shows short C-F...HN+ contacts (2.286-2.662 A). Furthermore, it shows that closer F...H(+)(-N) distances give a larger F...H(+)-N angle. Although such structural features seem to indicate the existence of C-F...HN+ hydrogen bonds, the spectral data (1H NMR, 19F VT-NMR, and IR spectroscopy) did not support the existence of hydrogen bonds. Thermodynamic parameters, log K(s) (4.6 +/- 0.1, 298 K), deltaH (-5.3 +/- 0.1 kcal mol(-1)), and deltaS (3.2 +/- 0.3 cal mol(-1) K(-1)), of the complexation were obtained in CDCl3/CD3CN mixture.

Stentless aortic valve replacement with Freestyle or Toronto SPV: an early comparison.

BACKGROUND: Stentless aortic xenograft valves have been developed to overcome the disadvantages of conventional stented prostheses. We have implanted two new aortic bioprostheses: the Medtronic Freestyle and the St. Jude Toronto SPV. Early results are compared. METHODS: Forty-four Freestyle valves were implanted using a freestanding total root technique. Fourteen subcoronary Toronto SPV bioprostheses were implanted. Sixty-four percent of both groups (28 of 44 Freestyle and 9 of 14 Toronto SPV) underwent concurrent procedures. RESULTS: Ischemic time was 117 +/- 21 minutes for Freestyle and 124 +/- 19 minutes for Toronto SPV. There were no operative deaths or valve-related reoperations. Aortic valve area was 1.83 +/- 0.51 cm2 for Freestyle and 1.80 +/- 0.51 cm2 (p = 0.89) for Toronto SPV. Transvalvular gradient was 8.03 +/- 4.09 mm Hg for Freestyle and 12.4 +/- 1.82 mm Hg (p = 0.002) for the Toronto SPV. Aortic regurgitation was not experienced in any Freestyle patients, while Toronto SPV patients were graded as none to trace 79% (11 of 14), mild 14% (2 of 14), and moderate 7% (1 of 14). CONCLUSIONS: Aortic valve replacement with the Freestyle and Toronto SPV required equal time for implantation and had equal effective orifice areas. Freestyle had lower transvalvular gradient and less aortic insufficiency without increasing morbidity or mortality.

Synthesis of macrocyclic cage compounds by diamine-dihalide one-step coupling reaction

Macropolycyclic cage compounds were synthesized by a direct reaction between diamines and bis(bromomethyl) compounds. The procedure for constructing the polycyclic cage structure is simple and straightforward. The macropolycyclic compounds obtainable from this cyclization procedure are three-dimensional cage compounds, and any other isomers were not obtained except for two examples. Benzene, pyridine, and aliphatic units could be introduced into the cage structure. The macrocycles that have strong cation affinity were obtained as their potassium complexes.

Aortic root replacement with the freestyle stentless porcine aortic root bioprosthesis.

BACKGROUND: Stentless porcine prosthetic valves offer several advantages over traditional valves. Among these are superior hemodynamics, laminar flow patterns, lack of need for anticoagulation and perhaps improved durability. METHODS: One hundred and twelve patients were operated on from September 17, 1992 to April 13, 1998 as part of a multi-center worldwide investigation. All patients received a total aortic root replacement. Patients were evaluated postoperatively at discharge, 3 to 6 months, and yearly by clinical exam and color flow Doppler echocardiography. RESULTS: There were 4 deaths either in the hospital or within 30 days after surgery for an operative mortality of 3.6%. No patients experienced structural valve deterioration, non-structural valve deterioration, paravalvular leak, unacceptable hemodynamic performance, or postoperative endocarditis. The linearized rates for survival and thromboembolic complications at 5 years were 82.8% and 90.5% respectively. Excellent hemodynamic function is demonstrated by very low gradients, large EOA, and an exceedingly low incidence of any aortic regurgitation. CONCLUSIONS: The Medtronic Freestyle aortic root bioprosthesis can be used safely to replace the aortic root for aortic valve and aortic root pathology. Root replacement allows optimal hemodynamic performance with no significant aortic regurgitation. Early and intermediate results are encouraging, but further follow-up is needed to determine valve durability.

Aortic valve replacement with Medtronic Freestyle bioprosthesis: 5-year results.

The Medtronic Freestyle aortic root bioprosthesis has been implanted in patients since August 1992. This study reviews clinical and echocardiographic results at midterm (5 years) after implantation. The Freestyle bioprosthesis was implanted in 1,100 patients in a 21-center Food and Drug Administration clinical trial from August 1992 to October 1998. The device was implanted (1) as a subcoronary valve replacement, (2) as a complete aortic root replacement (full-root), or (3) as a root inclusion. Patients were followed annually by clinical examination and echocardiography. There were 47 deaths early after operation (7.1%). There were 2,478 patient-years of follow-up during which there were 99 deaths or 4.0/pt.-yr. Before implantation, 73% of patients were in New York Heart Association functional class III or IV. After operation, 95% were in class I or II. Transvalvular gradient 4 years after operation was low (7.5+/-5.3 mm Hg) for all valve sizes (subcoronary implant). Small valves (19 and 21 mm) had mean gradients (10.2+/-3.0, 9.1+/-4.4 mm Hg). There was no or mild valve insufficiency in 98% of patients. Actuarial analysis at 5 years showed the rate for freedom from thromboembolism of 86% in subcoronary implant and 93% in full root replacement. Freedom from endocarditis was 98%. Freedom from reoperation for explant of the valve highest in patients having full root replacement (98%) and lower with root inclusion (94%). There were 20 bioprostheses explanted; 10 for endocarditis, 8 for technical reasons, and 2 for structural deterioration. The Medtronic Freestyle bioprosthesis (1) has excellent hemodynamic performance, (2) techniques for insertion that result in a competent valve, (3) low rates of thromboembolism and endocarditis, and (4) a rare rate of structural deterioration at 5 years.

Comparison of results using "freestyle" stentless porcine aortic root bioprosthesis with cryopreserved aortic allograft.

Aortic valve replacement with natural heart valves offer the advantages of superior hemodynamics, laminar flow patterns, lack of need for anticoagulation, and perhaps improved durability. This study compares 5-year results for two stentless aortic valves. In 1992, two prospective clinical trials using two different stentless aortic valves were initiated at our center. The Freestyle stentless porcine aortic root bioprosthesis (SPB) was placed in 106 patients, and cryopreserved aortic allografts (CAA) were placed in 174 patients using a freestanding total root replacement technique in each series. The mean systolic gradient for the SPB was 7.5+/-4.4 mm Hg at discharge and 5.9+/-3.1 mm Hg at 5 years. The mean systolic gradient for the CAA was 6.4+/-3.3 mm Hg at discharge and 5.0+/-2.2 mm Hg at 5 years. At discharge 92.2% of SPB patients had no aortic insufficiency (AI) and 7.8% had trivial AI. In all, 92.9% of CAA patients had no AI at discharge, and 7.1% had mild AI. At 5-year follow-up, 100% of the SPB had no AI, and only 20% of the allograft patients had no AI. The remainder, 80%, had mild AI. Excellent hemodynamic function was seen with both SPB and CAA. A lower incidence of nonhemodynamically significant AI was observed in the SPB group. Preoperative factors such as chronic renal failure and endocarditis may have adversely affected durability in the allograft group, but long-term follow-up is still required to determine durability.

Three-dimensional surface area of the aortic valve orifice by three-dimensional echocardiography: clinical validation of a novel index for assessment of aortic stenosis.

BACKGROUND: A direct and accurate method of assessing aortic valve area (AVA) in patients with aortic stenosis (AS) is desirable because of the well-known theoretical and practical limitations of the currently available methods. We assessed the clinical feasibility and accuracy of a novel index, the 3-dimensional surface area (3-DSA) of the aortic valve orifice by 3-dimensional transesophageal echocardiography (3-DTEE) in patients with AS. METHODS: Intraoperative 3-DTEE was performed in 23 consecutive patients (mean age 58 +/- 15 years) with valvular AS using a Toshiba SSA-380A system with a multiplane TEE probe and a TomTec EchoScan system. The 3-DTEE acquisition, processing and reconstruction were conducted and the aortic valve orifice presented using a "surgeon's aortotomy view" (aortic valve orifice as if viewed through an open aortic root). The 3-D images were videotaped and calibrated and the 3-DSA measured by planimetry of the inner surface of the aortic valve leaflets at the maximal systolic opening using the dynamic 3-D images. For comparison, the 2-D cross sectional area (2-DCSA) of the aortic valve was also determined by 2-DTEE. The 3-DSA and 2-DCSA were compared with the AVA by the invasive Gorlin formula and the Doppler continuity equation method by transthoracic echocardiography. RESULTS: The 3-DSA and 2-DCSA measurements were feasible in all but one patient. Both 3-DSA and 2-DCSA correlated moderately well with the AVA by the Gorlin formula (n = 17, r = 0.66, standard error of the estimate [SEE] = 0.3 cm2, P <.05 for 3-DSA and r = 0.61, SEE = 0. 5 cm2 P <.05 for 2-DCSA, respectively). They also correlated well with the AVA by Doppler continuity equation method (n = 22, r = 0.90, SEE = 0.1 cm2, P <.05 for 3-DSA and r = 0.83, SEE = 0.3 cm2, P <.05 for 2-DCSA, respectively). There was no statistically significant difference between the 3-DSA and AVA by both the Gorlin formula (Delta = 0.1 +/- 0.3 cm2, P =.3) and the Doppler continuity equation (Delta = -0.0 +/- 0.3 cm2, P =.7). In contrast, the 2-DCSA significantly overestimated AVA by the Gorlin formula (Delta = 0.5 +/- 0.5 cm2, P <.005) and by the Doppler continuity equation (Delta = 0.5 +/- 0.6 cm2, P <.0001). CONCLUSIONS: Planimetry of 3-DSA of the aortic valve orifice by 3-DTEE is a clinically feasible and relatively accurate technique for assessment of AVA and is superior to 2-DCSA by 2-DTEE.