Sustained pulmonary hypertension and right ventricular hypertrophy after chronic hypoxia in mice with congenital deficiency of nitric oxide synthase 3.

Chronic hypoxia induces pulmonary hypertension and right ventricular (RV) hypertrophy. Nitric oxide (NO) has been proposed to modulate the pulmonary vascular response to hypoxia. We investigated the effects of congenital deficiency of endothelial NO synthase (NOS3) on the pulmonary vascular responses to breathing 11% oxygen for 3-6 wk. After 3 wk of hypoxia, RV systolic pressure was greater in NOS3-deficient than in wild-type mice (35+/-2 vs 28+/-1 mmHg, x+/-SE, P < 0.001). Pulmonary artery pressure (PPA) and incremental total pulmonary vascular resistance (RPI) were greater in NOS3-deficient than in wild-type mice (PPA 22+/-1 vs 19+/-1 mmHg, P < 0.05 and RPI 92+/-11 vs 55+/-5 mmHg.min.gram.ml-1, P < 0.05). Morphometry revealed that the proportion of muscularized small pulmonary vessels was almost fourfold greater in NOS3-deficient mice than in wild-type mice. After 6 wk of hypoxia, the increase of RV free wall thickness, measured by transesophageal echocardiography, and of RV weight/body weight ratio were more marked in NOS3-deficient mice than in wild-type mice (RV wall thickness 0.67+/-0.05 vs 0.48+/-0.02 mm, P < 0.01 and RV weight/body weight ratio 2.1+/-0.2 vs 1.6+/-0.1 mg. gram-1, P < 0.05). RV hypertrophy produced by chronic hypoxia was prevented by breathing 20 parts per million NO in both genotypes of mice. These results suggest that congenital NOS3 deficiency enhances hypoxic pulmonary vascular remodeling and hypertension, and RV hypertrophy, and that NO production by NOS3 is vital to counterbalance pulmonary vasoconstriction caused by chronic hypoxic stress.

A murine model of myocardial microvascular thrombosis.

Disorders of hemostasis lead to vascular pathology. Endothelium-derived gene products play a critical role in the formation and degradation of fibrin. We sought to characterize the importance of these locally produced factors in the formation of fibrin in the cardiac macrovasculature and microvasculature. This study used mice with modifications of the thrombomodulin (TM) gene, the tissue-type plasminogen activator (tPA) gene, and the urokinase-type plasminogen activator (uPA) gene. The results revealed that tPA played the most important role in local regulation of fibrin deposition in the heart, with lesser contributions by TM and uPA (least significant). Moreover, a synergistic relationship in fibrin formation existed in mice with concomitant modifications of tPA and TM, resulting in myocardial necrosis and depressed cardiac function. The data were fit to a statistical model that may offer a foundation for examination of hemostasis-regulating gene interactions.

Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects.

BACKGROUND: Data in normal human subjects on the factors affecting pulmonary artery systolic pressure (PASP) are limited. We determined the correlates of and established a reference range for PASP as determined by Doppler transthoracic echocardiography (TTE) from a clinical echocardiographic database of 102 818 patients, of whom 15 596 (15%) had a normal Doppler TTE study. METHODS AND RESULTS: A normal TTE was based on normal cardiac structure and function during complete Doppler TTE studies. The PASP was calculated by use of the modified Bernoulli equation, with right atrial pressure assumed to be 10 mm Hg. Among TTE normal subjects, 3790 subjects (2432 women, 1358 men) from 1 to 89 years old had a measured PASP. The mean PASP was 28.3+/-4.9 mm Hg (range 15 to 57 mm Hg). PASP was independently associated with age, body mass index (BMI), male sex, left ventricular posterior wall thickness, and left ventricular ejection fraction (P<0.001). The estimated upper 95% limit for PASP among lower-risk subjects was 37.2 mm Hg. A PASP >40 mm Hg was found in 6% of those >50 years old and 5% of those with a BMI >30 kg/m(2). CONCLUSIONS: Among 3790 echocardiographically normal subjects, PASP was associated with age, BMI, sex, wall thickness, and ejection fraction. Of these subjects, 28% had a PASP >30 mm Hg, and the expected upper limit of PASP may include 40 mm Hg in older or obese subjects. These findings support the use of age- and BMI-corrected values in establishing the expected normal range for PASP.

Congenital deficiency of nitric oxide synthase 2 protects against endotoxin-induced myocardial dysfunction in mice.

BACKGROUND: Sepsis can be complicated by severe myocardial dysfunction and is associated with increased nitric oxide (NO) production by inducible NO synthase (NOS2). To investigate the role of NOS2 in endotoxin-induced myocardial dysfunction in vivo, we studied wild-type and NOS2-deficient mice. METHODS AND RESULTS: Serial echocardiographic parameters of myocardial function were measured before and at 4, 7, 16, and 24 hours after an endotoxin challenge. Seven hours after challenge with either endotoxin or saline, systemic and left ventricular pressures were measured, and the first derivative of left ventricular developed pressure (dP/dt), slope of the end-systolic pressure-dimension relationship (Slope(LVESPD)), and time constant of isovolumic relaxation (tau) were calculated. Endotoxin challenge in wild-type mice decreased left ventricular fractional shortening, velocity of circumferential shortening, dP/dt(max), Slope(LVESPD), and dP/dt(min) and increased time constant tau. Endotoxin-induced myocardial dysfunction was associated with increased ventricular NOS2 gene expression and cGMP concentrations. Seven hours after endotoxin challenge, NOS2-deficient mice had greater fractional shortening, dP/dt(max), and Slope(LVESPD) than did endotoxin-challenged wild-type mice. Measures of diastolic function, dP/dt(min) and time constant tau, were preserved in endotoxin-challenged NOS2-deficient mice. After endotoxin challenge in wild-type mice, early (3-hour) inhibition of NOS2 with L-N:(6)-(1-iminoethyl)lysine hydrochloride prevented, whereas later (7-hour) inhibition could not reverse, endotoxin-induced myocardial dysfunction. CONCLUSIONS: These results suggest that NOS2 is required for the development of systolic and diastolic dysfunction in murine sepsis.

Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice.

BACKGROUND: To test whether deficiency in endothelial nitric oxide synthase (eNOS) affects atherosclerosis development, we compared lesion formation in apolipoprotein E (apoE)/eNOS-double knockout (DKO) and apoE-knockout (KO) control animals. METHODS AND RESULTS: After 16 weeks of "Western-type" diet, apoE/eNOS-DKO males and females showed significant increases in lesion area of 93.6% and 59.2% compared with apoE-KO mice. All apoE/eNOS-DKO animals studied developed peripheral coronary arteriosclerosis, associated with perivascular and myocardial fibrosis, whereas none of the apoE-KO mice did. Transthoracic echocardiography showed a significantly increased left ventricular wall thickness and decreased fractional shortening in DKO animals. Mean arterial pressure was increased in DKO mice and was comparable in degree to eNOS-KO animals. Male DKO animals developed atherosclerotic abdominal aneurysms and aortic dissection. CONCLUSIONS: eNOS deficiency increases atherosclerosis in Western-type diet-fed apoE-KO animals and introduces coronary disease and an array of cardiovascular complications, including spontaneous aortic aneurysm and dissection. This phenotype constitutes the first murine model to demonstrate distal coronary arteriosclerosis associated with evidence of myocardial ischemia, infarction, and heart failure. Hypertrophy and reduced left ventricular function cannot be explained by increased blood pressure alone, because eNOS-KO animals do not develop these complications.

Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice.

Background- To investigate the role of endothelial nitric oxide synthase (NOS3) in left ventricular (LV) remodeling after myocardial infarction (MI), the impact of left anterior descending coronary artery ligation on LV size and function was compared in 2- to 4-month-old wild-type (WT) and NOS3-deficient mice (NOS3(-/-)). Methods and Results- Two days after MI, both strains of mice had a similar LV size, fractional shortening, and ejection fraction by echocardiography. Twenty-eight days after MI, both strains had dilated LVs with decreased fractional shortening and lower ejection fractions. Although the infarcted fraction of the LV was similar in both strains, LV end-diastolic internal diameter, end-diastolic volume, and mass were greater, but fractional shortening, ejection fraction, and the maximum rate of developed LV pressure (dP/dt(max)) were lower in NOS3(-/-) than in WT mice. Impairment of diastolic function, as measured by the time constant of isovolumic relaxation (tau) and the maximum rate of LV pressure decay (dP/dt(min)), was more marked in NOS3(-/-) than in WT mice. Mortality after MI was greater in NOS3(-/-) than in WT mice. Long-term administration of hydralazine normalized blood pressure in NOS3(-/-) mice, but it did not prevent the LV dilatation, impaired systolic and diastolic function, and increased LV mass that followed MI. In WT mice, capillary density and myocyte width in the nonischemic portion of the LV did not differ before and 28 days after MI, whereas in NOS3(-/-) mice, capillary density decreased and myocyte width increased after MI, whether or not hydralazine was administered. Conclusions- These results suggest that the presence of NOS3 limits LV dysfunction and remodeling in a murine model of MI by an afterload-independent mechanism, in part by decreasing myocyte hypertrophy in the remote myocardium.

Improvement of transthoracic pulmonary venous flow Doppler signal with intravenous injection of sonicated albumin.

OBJECTIVES: This study was performed to determine whether intravenous injection of a sonicated albumin echocardiographic contrast agent (Albunex) improved the quality of the transthoracic pulmonary venous flow Doppler signal. BACKGROUND: Previous studies have shown that transesophageal echocardiography provides pulmonary venous flow Doppler signals superior in quality to those seen with transthoracic echocardiography, which are of limited quality in up to 25% of patients. METHODS: Twenty-one patients underwent transthoracic pulsed wave Doppler examination of pulmonary venous flow before, during and after two doses of Albunex ranging from 0.08 ml/kg (low dose) to 0.22 ml/kg (high dose). In addition, five patients underwent transesophageal examination of pulmonary venous flow before and after a 0.08-ml/kg dose of Albunex. The efficacy of the contrast injection was determined using a score that graded the quality of the three components of the pulmonary venous Doppler signal from 0 to 3 (0 = no visible signal; 3 = optimal signal). RESULTS: Albunex enhanced the quality of the pulmonary venous Doppler signal from baseline (score 3.9 +/- 1.8 [mean +/- SD]) and at both low (score 5.1 +/- 2.2, p < 0.05) and high doses (score 5.6 +/- 2, p < 0.001). Transthoracic pulmonary venous flow velocities were increased, and peak flow velocity ratios were unchanged, after injection of contrast agent. The contrast-enhanced variables showed good agreement with transesophageal flow velocities. CONCLUSIONS: Albunex improves the quality of the transthoracic pulmonary venous Doppler signal, thus allowing improved accuracy of measurement. This approach appears to be effective for increasing the quality of data obtained from the transthoracic examination.

Effects of prolonging peak dobutamine dose during stress echocardiography.

OBJECTIVES: This study sought to test whether the physiologic advantage of a prolonged dobutamine stage during stress echocardiography can be effectively combined with a clinically practical infusion protocol. BACKGROUND: Dobutamine has a half-life of 2 min and requires up to 10 min to achieve steady state. Despite these known pharmacodynamics, dobutamine stress echocardiography is routinely performed by advancing doses at 3-min intervals. Canine studies have shown that dobutamine stress echocardiography end points will occur at a lower dose if each stage is prolonged, but these findings have yet to be used in the clinical setting. METHODS: The standard 3-min dobutamine dose stage during stress echocardiography was modified by extending the peak dose (40 micrograms/kg body weight per min) for an additional 2 min. Consecutive patients underwent this modified protocol to test whether the requirement for atropine could be reduced. According to this modified protocol, if a dobutamine stress echocardiographic end point (85% of maximal predicted heart rate, new wall motion abnormalities, hypotension, arrhythmia or intolerable symptoms) was not reached at 3 min of the peak dose, this dose was prolonged for an additional 2 min. If a doubtamine stress echocardiographic end point was still not attained, atropine (up to 1.0 mg intravenously) was administered. RESULTS: The study included 84 patients, 22 of whom (26.2%) achieved a dobutamine stress echocardiographic end point using the standard 3-min stage. Of the 62 patients who did not reach an end point in the initial 3 min of peak dobutamine dose, the additional 2 min of dobutamine increased heart rate (from 99.6 +/- 23.8 to 107.2 +/- 23.2 beats/min, p < 0.01) and allowed 20 patients (32.3%, p < 0.01) to attain an end point. Of the remaining 42 patients, 23 never achieved a stress echocardiographic end point, despite 1.0 mg of atropine. One patient developed supraventricular tachycardia during the additional 2 min of dobutamine, and one developed nonsustained ventricular tachycardia after receiving atropine. CONCLUSIONS: These data demonstrate that a significant number of patients (32%) who do not reach a dobutamine stress echocardiographic end point with the standard protocol can safely attain an end point solely by extending the duration of the peak dose. Adoption of this strategy may reduce the need for supplemental atropine and its potential adverse effects.

Prevalence and timing of regional myocardial dysfunction after rotational coronary atherectomy.

OBJECTIVES: This study aimed to evaluate the prevalence and time course of wall motion abnormalities associated with rotational coronary atherectomy. BACKGROUND: Although initial clinical studies found evidence of transient wall motion abnormalities after rotational coronary atherectomy, the prevalence and duration of these wall motion abnormalities are unknown. METHODS: Using simultaneous echocardiography, we prospectively evaluated 22 patients undergoing rotational atherectomy and compared their wall motion abnormalities with those of 10 patients undergoing coronary angioplasty alone. The extent of wall motion abnormality was quantified and plotted against time to produce curves of abnormal wall motion development and recovery for the two groups. RESULTS: The cumulative ischemic time was similar for the two groups ([mean +/- SD] 10.3 +/- 6 min for rotational atherectomy vs. 9.6 +/- 4.2 min for coronary angioplasty, p = 0.73). The rate of return to baseline function was significantly lower in the rotational atherectomy group than in the coronary angioplasty group (rotational atherectomy rate constant 0.069 +/- 0.079/min vs. coronary angioplasty rate constant 1.250 +/- 0.47/min, p = 0.0001). The mean time to recovery of baseline wall motion in the rotational atherectomy group (153 min, 95% confidence interval [CI] 6.5 to 3,600) was significantly longer than in the coronary angioplasty group (2.6 min, 95% CI 1.3 to 5.5, p = 0.0001). Rotational atherectomy burr time was longer in the patients who developed myocardial infarction than in those without myocardial infarction (4.7 +/- 2.4 vs. 3 +/- 1.4 min, p = 0.045). CONCLUSIONS: Transient wall motion abnormalities are common after rotational coronary atherectomy and have a longer duration than those observed after coronary angioplasty. This disparity may be a consequence of differences in the mechanisms by which rotational coronary atherectomy and coronary angioplasty produce their effect.

Optimal stage duration in dobutamine stress echocardiography.

OBJECTIVES: This study attempted to determine the benefit of a 5-min dobutamine stress echocardiographic stage versus a 3-min stage in a canine model. BACKGROUND: Dobutamine stress echocardiography, as currently performed, uses a variety of different protocols. Among the many aspects of dobutamine stress echocardiographic protocols that vary is stage duration. Because dobutamine has specific pharmacodynamics, it is possible that stages of different durations may have different cardiovascular effects. METHODS: Paired dobutamine stress echocardiograms were obtained in 10 open chest instrumented dogs. The stage duration for the initial dobutamine stress echocardiogram was randomly allocated to either 3 or 5 min, and all hemodynamic and echocardiographic variables were allowed to return to baseline before the second dobutamine stress echocardiogram was obtained using the alternative stage duration. At each stage, heart rate, systolic blood pressure, coronary flow, myocardial wall thickness and left ventricular cavity area were recorded. Cavity obliteration, hypotension, ventricular tachycardia or a maximal dose of 40 micrograms/kg body weight per min served as the dobutamine stress echocardiographic end point. RESULTS: At baseline, no difference was detected between the 3- or 5-min protocols for heart rate, systolic blood pressure, rate-pressure product, coronary blood flow, wall thickness or percent area change. Heart rate, systolic blood pressure and coronary flow increased more by the 10-micrograms/kg per min dose with the 5-min protocol than with the 3-min protocol. The dobutamine stress echocardiographic end points were achieved at a lower dobutamine dose (15.0 +/- 4.1 vs. 11.0 +/- 2.1 micrograms/kg per min [mean +/- SD], p = 0.01) with the longer stage duration. CONCLUSIONS: In this canine model, a longer stage produced a greater hemodynamic effect at a lower peak dose. Thus, extending stage duration in clinical dobutamine stress echocardiography may achieve equivalent physiologic stress at lower doses and contribute to the optimization of dobutamine stress echocardiographic protocols.

Quantitative relation between increased intrapericardial pressure and Doppler flow velocities during experimental cardiac tamponade.

To establish whether a quantitative relation exists between pericardial pressure and respiratory variation in intracardiac blood flow velocities, a spontaneously breathing closed chest canine model of pericardial tamponade was created. In seven dogs, pericardial pressure was sequentially increased in stages from a mean of -4 +/- 1 to 10 +/- 2 mm Hg while aortic and pulmonary Doppler flow velocities, pleural pressure changes (respiratory effort), blood pressure and cardiac output were measured. The variation in the Doppler-detected peak transaortic velocity (AV) during inspiration (IV) increased linearly from -5 +/- 3% at baseline (pericardial pressure -4 mm Hg) to -32 +/- 9% at a pericardial pressure of 10 mm Hg [IVAV = -2 (pericardial pressure)--13.1; r = 0.78, p less than 10(-6)]. The inspiratory variation in the peak transpulmonary velocity increased from 13 +/- 3% at baseline to 71 +/- 19% at a pericardial pressure of 10 mm Hg. The inspiratory variation in the pulmonary Doppler peak velocity (IVPV) was dependent on both pericardial pressure and degree of respiratory effort [IVPV = 3.8 (pericardial pressure) + 2.6 (respiratory effort) + 10.9; r = 0.88, p less than 10(-8)]. Thus, quantitative relations exist between increases in intrapericardial pressure and increases in inspiratory variation of peak aortic and pulmonary flow velocities. Additionally, pulmonary artery flow velocity is influenced more than aortic velocity by intrathoracic pressure.

Benefit of late coronary reperfusion on ventricular morphology and function after myocardial infarction.

OBJECTIVES: This study was designed to examine the relation between the timing and adequacy of perfusion of the infarct bed and changes in ventricular size and the extent of abnormal wall motion after acute myocardial infarction. METHODS: A validated echocardiographic mapping technique was used to measure the left ventricular endocardial surface area index and the extent of abnormal wall motion over a 3-month period in 91 patients who had either 1) no anterograde or collateral flow to the infarct bed (n = 14), 2) only collateral flow to the infarct bed (n = 18), 3) restoration of anterograde flow to the infarct bed within hours of chest pain (early [n = 43]), or 4) restoration of anterograde flow to the infarct bed within a mean of 5 days after acute myocardial infarction (late [n = 16]). RESULTS: Over the follow-up period, a progressive and significant increase in endocardial surface area index was observed only in the group of patients without anterograde or collateral flow to the infarct bed (entry 64 +/- 3.4 cm2/m2 vs. 3 months 75.9 +/- 6.4 cm2/m2, p < 0.005). In contrast, a progressive reduction in the extent of abnormal wall motion was evident in the group of patients in whom anterograde flow to the infarct bed was restored within hours (entry 26.7 +/- 2.5 cm2 vs. 3 months 11.8 +/- 2.9 cm2, p < 0.001) or days (entry 22.1 +/- 3.6 cm2 vs. 3 months 11.8 +/- 3.3 cm2, p < 0.001) of coronary occlusion. Multiple stepwise linear regression analysis confirmed that by 3 months, 1) ventricular size was independently related to endocardial surface area index and abnormal wall motion at entry (p < 0.0001) and to the change in abnormal wall motion over the follow-up period (p < 0.0001), and 2) the change in abnormal wall motion was related to the presence of anterograde flow to the infarct bed (p < 0.0001) independent of the timing of reperfusion, infarct site or the extent of abnormal wall motion on admission. CONCLUSIONS: After myocardial infarction, the process of ventricular remodeling is influenced by changes in the extent of abnormal wall motion, which in turn are related to the adequacy rather than the timing of perfusion of the infarct bed.

Echocardiographic assessment of patients with infectious endocarditis: prediction of risk for complications.

To enhance the echocardiographic identification of high risk lesions in patients with infectious endocarditis, the medical records and two-dimensional echocardiograms of 204 patients with this condition were analyzed. The occurrence of specific clinical complications was recorded and vegetations were assessed with respect to predetermined morphologic characteristics. The overall complication rates were roughly equivalent for patients with mitral (53%), aortic (62%), tricuspid (77%) and prosthetic valve (61%) vegetations, as well as for those with nonspecific valvular changes but no discrete vegetations (57%), although the distribution of specific complications varied considerably among these groups. There were significantly fewer complications in patients without discernible valvular abnormalities (27%). In native left-sided valve endocarditis, vegetation size, extent, mobility and consistency were all found to be significant univariate predictors of complications. In multivariate analysis, vegetation size, extent and mobility emerged as optimal predictors and an echocardiographic score based on these factors predicted the occurrence of complications with 70% sensitivity and 92% specificity in mitral valve endocarditis and with 76% sensitivity and 62% specificity in aortic valve endocarditis.

Determination of aortic valve area in valvular aortic stenosis by direct measurement using intracardiac echocardiography: a comparison with the Gorlin and continuity equations.

OBJECTIVES: This study sought to 1) show that intracardiac echocardiography can allow direct measurement of the aortic valve area, and 2) compare the directly measured aortic valve area from intracardiac echocardiography with the calculated aortic valve area from the Gorlin and continuity equations. BACKGROUND: Intracardiac echocardiography has been used in the descriptive evaluation of the aortic valve; however, direct measurement of the aortic valve area using this technique in a clinical setting has not been documented. Despite their theoretical and practical limitations, the Gorlin and continuity equations remain the current standard methods for determining the aortic valve orifice area. METHODS: Seventeen patients underwent intracardiac echocardiography for direct measurement of the aortic valve area, including four patients studied both before and after valvuloplasty, for a total of 21 studies. Immediately after intracardiac echocardiography, hemodynamic data were obtained from transthoracic echocardiography and cardiac catheterization. RESULTS: Adequate intracardiac echocardiographic images were obtained in 17 (81%) of 21 studies. The average aortic valve area (mean +/- SD) determined by intracardiac echocardiography for the 13 studies in the Gorlin analysis group was 0.59 +/- 0.18 cm2 (range 0.37 to 1.01), and the average aortic valve area determined by the Gorlin equation was 0.62 +/- 0.18 cm2 (range 0.31 to 0.88). The average aortic valve area determined by intracardiac echocardiography for the 17 studies in the continuity analysis group was 0.66 +/- 0.23 cm2 (range 0.37 to 1.01), and that for the continuity equation was 0.62 +/- 0.22 cm2 (range 0.34 to 1.06). There was a significant correlation between the aortic valve area determined by intracardiac echocardiography and the aortic valve area calculated by the Gorlin (r = 0.78, p = 0.002) and continuity equations (r = 0.82, p < 0.0001). CONCLUSIONS: In the clinical setting, intracardiac echocardiography can directly measure the aortic valve area with an accuracy similar to the invasive and noninvasive methods currently used. This study demonstrates a new, quantitative use for intracardiac echocardiographic imaging with many potential clinical applications.

Evidence of reduced resting blood flow in viable myocardial regions with chronic asynergy.

OBJECTIVES: We tested the hypothesis in patients (n = 24) with ischemic heart disease that chronic contractile dysfunction occurs in myocardial regions with true reduction in rest blood flow. BACKGROUND: Whether viable myocardial regions with chronic contractile dysfunction have true reduction in rest myocardial blood flow is controversial. METHODS: Positron emission tomography (PET) 13N-ammonia was used to measure myocardial blood flow in combination with 18F-fluorodeoxyglucose (18FDG) to assess myocardial viability. Viability also was assessed by dobutamine echo and recovery of function after coronary artery bypass grafting (CABG). Segments (n = 252) were selected based on PET measured reduced resting blood flow and rest asynergy on echo. RESULTS: Regional myocardial viability was present in 20 of 23 patients by PET, 13 of 23 by dobutamine echo and 10 of 11 by postrevascularization criteria. Rest blood flow in normal regions was 1.14+/-0.52 ml/min/g and by definition exceeded (p < 0.005) that in both viable (0.48+/-0.15; n = 8 patients) and nonviable (0.45+/-0.14; n = 8 patients) regions (post-CABG criteria), which did not differ. Correction of rest myocardial blood flow in viable asynergic segments, only, for fibrosis and incomplete tracer recovery raised the level to 0.67+/-0.21 (p < 0.005 vs. normal). Finally, evidence of both stunning (rest asynergy with normal flow) and hibernation was present in 15 of 23 (65%) patients. CONCLUSIONS: Reduced rest blood flow in viable myocardial regions with chronic asynergy is common and cannot be accounted for by partial volume effect. Thus, hypotheses concerning physiologic mechanisms underlying chronic contractile dysfunction should consider the role played by chronic reduction of basal myocardial blood flow.

Transmitral Doppler: a new transthoracic contrast method for patent foramen ovale detection and quantification.

OBJECTIVES: This study compared a new transthoracic echocardiographic (TTE) method for detection of right to left bubble passage, transmitral Doppler (TMD), against two-dimensional (2D) TTE contrast study and the gold standard, of transesophageal echocardiography (TEE), and assessed its utility in quantitative assessment of patent foramen ovales (PFO). BACKGROUND: Current TTE methods are relatively insensitive in PFO detection and do not allow quantitative assessment of right to left shunt. METHODS: In 44 patients (59 years, range 34 to 76 years) saline contrast and color Doppler studies were performed in three conditions--TTE TMD, TTE 2D and TEE. Bubble transit on the TMD was measured semiquantitatively by a visual bubble score and objectively by integrating the acoustic power within the mitral velocity envelope. RESULTS: By TEE it was determined that 17 patients (39%) had PFOs; 16 had right to left contrast passage, and only 1 had left to right flow by color Doppler. Against TEE contrast study, the sensitivity of TMD and 2D contrast studies were 100% and 75%, respectively, with specificity of 96% and 100%. Greater than 10 bubbles on a single beat of the resting contrast TMD identified patients with a maximum resting TEE PFO opening diameter >2 mm with 78% sensitivity and 100% specificity. There was a strong correlation (r2 = 0.72, p<0.01) between the TMD acoustic power and PFO opening diameter. CONCLUSIONS: Transmitral Doppler is a sensitive and specific method for TTE PFO detection that allows quantification of right to left bubble passage and may obviate the need for TEE in many patients after stroke.

New perspectives in the assessment of cardiac chamber dimensions during development and adulthood.

The use of body surface area to assess the normalcy of cardiac dimensions has several limitations. To determine whether cardiac dimensions can be assessed by other indexes of body size and growth, this study evaluated the relations between cardiac dimensions assessed by two-dimensional echocardiography and age, height, weight and body surface area. The study group included 268 normal persons aged 6 days to 76 years of age. The dimensions examined included the aortic anulus, left atrium and left ventricular end-diastolic diameter, each measured in the parasternal long-axis plane, and left ventricular length measured from the apical two-chamber view. The analysis confirmed that the heart and great vessels grow in unison and at a predictable rate after birth, reaching 50% of their adult dimensions at birth, 75% by 5 years and 90% by 12 years. Although each cardiac dimension related linearly with height (aortic anulus, r = 0.96; left atrium, r = 0.91; left ventricular diameter, r = 0.94; left ventricular length, r = 0.93), the relations among age, weight and body surface area were best expressed by quadratic equations. Multiple regression confirmed that after adjustment for height, other indexes including age, gender, weight and body surface area had no independent effect on the prediction of each dimension. Therefore, because height is a nonderived variable that relates linearly with cardiac dimensions independent of age, it offers a simple yet accurate means of assessing the normalcy of cardiac dimensions in children and adults.

A new integrated system for three-dimensional echocardiographic reconstruction: development and validation for ventricular volume with application in human subjects.

OBJECTIVES: The purpose of this study was to improve three-dimensional echocardiographic reconstruction by developing an automated mechanism for integrating spark gap locating data with corresponding images in real time and to validate use of this mechanism for the measurement of left ventricular volume. BACKGROUND: Initial approaches to three-dimensional echocardiographic reconstruction were often limited by inefficient reconstructive processes requiring manual coordination of two-dimensional images and corresponding spatial locating data. METHODS: In this system, a single computer overlays the binary-encoded positional data on the two-dimensional echocardiographic image, which is then recorded on videotape. The same system allows images to be digitized, traced, analyzed and displayed in three dimensions. This system was validated by using it to reconstruct 11 ventricular phantoms (19 to 271 ml) and 11 gel-filled excised ventricles (21 to 236 ml) imaged in intersecting long- and short-axis views and by apical rotation. To measure cavity volume, a surface was generated by an algorithm that takes advantage of the full three-dimensional data set. RESULTS: Reconstructed cavity volumes agreed well with actual values: y = 0.96x + 2.2 for the ventricular phantoms in long- and short-axis views (r = 0.99, SEE = 2.7 ml); y = 0.95x + 2.9 for the phantoms, reconstructed by apical rotation (r = 0.99, SEE = 2.7 ml); and y = 0.99x + 0.11 ml for the excised ventricles (reconstructed in long- and short-axis views; r = 0.99, SEE = 5.9 ml). The mean difference between three-dimensional and actual volumes was 3% of the mean (3.0 ml) for the phantoms and 6% (4.6 ml) for the excised ventricles. Observer variability was 2.3% for the phantoms and 5.6% for the excised ventricles. Application to 14 normal subjects demonstrated feasibility of left ventricular reconstruction, which provided values for stroke volume that agreed well with an independent Doppler measure (y = 0.97x + 0.94; r = 0.95, SEE = 3.2 ml), with an observer variability of 4.9% (2.4 ml). CONCLUSIONS: A system has therefore been developed that automatically integrates locating and imaging data in no more time than the component two-dimensional echocardiographic scans. This system can accurately reconstruct ventricular volumes in vitro over a wide range and is feasible in vivo, thus laying the foundation for further applications. It has increased the efficiency of three-dimensional reconstruction and enhanced our ability to address clinical and research questions with this technique.

Quantification of pericardial effusions by three-dimensional echocardiography.

OBJECTIVES: The purpose of this study was to examine the accuracy of three-dimensional echocardiography for the quantification of asymmetric pericardial effusion volume and to compare this new technique with two-dimensional echocardiography. BACKGROUND: Quantification of pericardial effusion by two-dimensional echocardiography relies on a symmetric distribution of the fluid. Three-dimensional echocardiography can quantitate volume without these limitations, but its accuracy for pericardial effusion volume has not yet been assessed. METHODS: In six open chest dogs, 41 different asymmetrically distributed pericardial effusions of known volume were created by serial infusions of fluid through a pericardial catheter. The hearts were imaged using an automated echocardiographic method that integrates three-dimensional spatial and imaging data. The surfaces of the pericardial sac and heart were then reconstructed, and the volumes of pericardial effusions were calculated. Two-dimensional echocardiography was performed simultaneously, and volumes were calculated using the prolate ellipsoid method. Asymmetric distribution of the fluid was obtained by applying localized hydrostatic pressure to the pericardium. RESULTS: The volumes of pericardial effusion quantified using three-dimensional echocardiography correlated well with actual volumes (y = 1.0x - 1.4, SEE = 7.7 ml, r = 0.98). Two-dimensional echocardiography had an acceptable correlation (y = 1.0x + 2.3, SEE = 23 ml, r = 0.84), but a marked degree of variation from the true value was observed for any individual measurement. CONCLUSIONS: Three-dimensional echocardiography accurately quantifies pericardial effusion volume in vivo, even when the fluid is distributed asymmetrically, whereas two-dimensional echocardiography is less reliable. This new technique may be of clinical value in quantitating pericardial effusion, especially in the serial evaluation of asymmetric or loculated effusions.

Phase III multicenter trial comparing the efficacy of 2% dodecafluoropentane emulsion (EchoGen) and sonicated 5% human albumin (Albunex) as ultrasound contrast agents in patients with suboptimal echocardiograms.

OBJECTIVES: This study was performed to compare the safety and efficacy of intravenous 2% dodecafluoropentane (DDFP) emulsion (EchoGen) with that of active control (sonicated human albumin [Albunex]) for left ventricular (LV) cavity opacification in adult patients with a suboptimal echocardiogram. BACKGROUND: The development of new fluorocarbon-based echocardiographic contrast agents such as DDFP has allowed opacification of the left ventricle after peripheral venous injection. We hypothesized that DDFP was clinically superior to the Food and Drug Administration-approved active control. METHODS: This was a Phase III, multicenter, single-blind, active controlled trial. Sequential intravenous injections of active control and DDFP were given 30 min apart to 254 patients with a suboptimal echocardiogram, defined as one in which the endocardial borders were not visible in at least two segments in either the apical two- or four-chamber views. Studies were interpreted in blinded manner by two readers and the investigators. RESULTS: Full or intermediate LV cavity opacification was more frequently observed after DDFP than after active control (78% vs. 31% for reader A; 69% vs. 34% for reader B; 83% vs. 55% for the investigators, p < 0.0001). LV cavity opacification scores were higher with DDFP (2.0 to 2.5 vs. 1.1 to 1.5, p < 0.0001). Endocardial border delineation was improved by DDFP in 88% of patients versus 45% with active control (p < 0.001). Similar improvement was seen for duration of contrast effect, salvage of suboptimal echocardiograms, diagnostic confidence and potential to affect patient management. There was no difference between agents in the number of patients with adverse events attributed to the test agent (9% for DDFP vs. 6% for active control, p = 0.92). CONCLUSIONS: This Phase III multicenter trial demonstrates that DDFP is superior to sonicated human albumin for LV cavity opacification, endocardial border definition, duration of effect, salvage of suboptimal echocardiograms, diagnostic confidence and potential to influence patient management. The two agents had similar safety profiles.