The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect.

BACKGROUND: PAH trials traditionally use 6MW as the primary endpoint. Concerns regarding a "ceiling effect" masking efficacy have led to exclusion of patients with milder disease from most trials (BL 6MW>450 m). STRIDE I evaluated the selective endothelin A receptor antagonist, sitaxsentan (SITAX), in a 12-week randomized, double-blind, trial (178 patients) employing placebo (PBO), 100 mg or 300 mg SITAX orally once daily in PAH and included patients with NYHA class II, congenital heart disease and a BL 6MW>450 m, groups often excluded from previous trials. METHODS: We analyzed 6MW effects For All Pts (intention-to treat) and those meeting Traditional enrollment criteria, defined as patients with NYHA class III or IV and 6MW< or =450 m at BL with idiopathic PAH or PAH related to connective tissue disease. The 100 mg and 300 mg SITAX arms are pooled based on similar treatment effects on 6MW. CONCLUSION: Existence of a "ceiling effect" is supported by these data. The magnitude of the treatment effect and statistical power when using 6MW as the endpoint. Comparisons between PAH trials that do not adjust for the effects of differing enrollment criteria require caution.

Effect of electrocardiogram triggering on reproducibility of coronary artery calcium scoring.

PURPOSE: To test the hypothesis that computed tomographic (CT) scanning during early rather than middle diastole can significantly reduce the interscan variability of coronary artery calcium (CAC) scores. MATERIALS AND METHODS: Five hundred thirty-eight patients were initially enrolled; 282 of them were found to have CAC at electron-beam CT and underwent repeat scanning to measure interscan variability with different electrocardiogram (ECG) triggers. Eight patients were excluded owing to respiratory motion; thus, 274 asymptomatic patients were examined. Patients were randomly assigned to different ECG trigger interval groups: 40% (group 1), 50% (group 2), 60% (group 3), and 80% (group 4). Patients in whom more than one-third of sections had greater than 10% ECG trigger variability were classified in the untriggered group (group 5). Interscan variation was compared among all five groups. RESULTS: Interscan variabilities in CAC groups 1-5 were 11.5%, 15.3%, 20.3%, 17.4%, and 33.1%, respectively, for total calcium area, and 15.0%, 23.3%, 25.6%, 24.0%, and 42.4%, respectively, for total calcium score. CAC score variability was reduced by 34%; and calcium area variability, by 38% in group 1, as compared with the reduced variabilities in group 4 (P <.01 for both measures). Breath holding was adequate in 812 cases, and ECG triggering was correct in 790 of cases. CONCLUSION: Study results strongly support the use of an ECG trigger of 40% rather than 80% of the R-R interval in electron-beam CT calcium studies.

Exercise pathophysiology in patients with primary pulmonary hypertension.

BACKGROUND: Patients with primary pulmonary hypertension (PPH) have a pulmonary vasculopathy that leads to exercise intolerance due to dyspnea and fatigue. To better understand the basis of the exercise limitation in patients with PPH, cardiopulmonary exercise testing (CPET) with gas exchange measurements, New York Heart Association (NYHA) symptom class, and resting pulmonary hemodynamics were studied. METHODS AND RESULTS: We retrospectively evaluated 53 PPH patients who had right heart catheterization and cycle ergometer CPET studies to maximum tolerance as part of their clinical workups. No adverse events occurred during CPET. Reductions in peak O(2) uptake (VO(2)), anaerobic threshold, peak O(2) pulse, rate of increase in VO(2), and ventilatory efficiency were consistently found. NYHA class correlated well with the above parameters of aerobic function and ventilatory efficiency but less well with resting pulmonary hemodynamics. CONCLUSIONS: Patients with PPH can safely undergo noninvasive cycle ergometer CPET to their maximal tolerance. The CPET abnormalities were consistent and characteristic and correlated well with NYHA class.

Diabetes and the associated incidence of subclinical atherosclerosis and coronary artery disease: Implications for management.

BACKGROUND: We sought to examine the prevalence, sensitivity, and specificity of coronary calcium (CC), a marker of atherosclerosis, in a population of symptomatic and asymptomatic diabetic persons. METHODS: We used electron beam tomography (EBT) to quantitate CC in 168 symptomatic (chest pain or anginal equivalent) persons with diabetes who underwent coronary angiography and then compared this with a cohort of 155 asymptomatic persons with diabetes. RESULTS: In the 168 symptomatic diabetic persons, 124 (74%) had obstructive coronary artery disease (CAD) by angiography. Receiver-operator characteristic curve analysis was used to maximize sensitivity and specificity for obstructive CAD (>50% stenosis), which established a CC score of 102 as optimal. With use of this cut point, EBT has a sensitivity of 77% and a specificity of 77% for detecting obstructive CAD. Of the 155 asymptomatic diabetic persons, 72% had CC and 48% had a CC score >102. The presumed prevalence of obstructive disease (on the basis of EBT scores and prevalence of CC) among asymptomatic diabetic persons is quite high (as high as symptomatic persons without diabetes). Analyzing the 323 diabetic patients demonstrated no significant age difference in CC scores between women and men. CONCLUSIONS: This study confirms that higher CC scores should be used in diabetic patients to improve the specificity of CC to determine obstructive disease. EBT can allow a noninvasive diagnosis of CAD before clinical presentation, allowing for more therapy for those in which CC is detected. These results suggest that asymptomatic diabetic persons have the same atherogenic burden of those patients with CAD without diabetes. The high prevalence of CC in asymptomatic persons with diabetes supports the need for aggressive management of diabetes and associated risk factors.

Comparison of spiral and electron beam tomography in the evaluation of coronary calcification in asymptomatic persons.

Recently, investigators have begun evaluating the ability of spiral computed tomography (sequence scan mode-SEQ) to measure coronary calcium. Electron Beam Tomography (EBT) and SEQ studies were performed in 10 women and 23 men, with a mean age of 54+/-9 years. The EBT study was performed within 4 weeks (mean 11+/-4 days) of the SEQ with no clinical interval event (MI, revascularization). The mean EBT calcium score (Agatston method) was 52.1+/-58.6, with a range of 0 to 175. The SEQ mean score was 60.1+/-71.1 (range 0 to 253). There were 7 persons with scores of 0 on both scans, and 9 persons with scores of zero on either EBT or spiral CT, but not both. Three persons had negative EBT studies where SEQ detected calcium, and 6 persons had EBT detected calcium and negative SEQ studies. The six patients with negative SEQ and positive EBT studies had a mean score of 47+/-25.7 (range 9 to 99). The remaining sixteen persons had coronary calcium detected on both studies. As compared to EBT, spiral CT had a sensitivity of 74% and a specificity of 70%, for an overall diagnostic accuracy of 73%. The positive and negative predictive values were 85 and 54%, respectively for SEQ in this study. The absolute difference in scores between the two tests was 29.1+/-28.5 (mean+/-S.D.). The inter-test variability, defined as the mean values of the differences between the calcium scores in the two scans on the same subjects divided by the mean of the two scores (Absolute Difference between tests/mean), was 84.5% in this study. In asymptomatic persons, spiral CT (using SEQ) provides a limited sensitivity (74%) and specificity (70%) for coronary calcium when compared to EBT. Caution should be used when evaluating the results of spiral CT coronary calcium especially in patients with relatively low calcium scores (<200).

A simple single slice method for measurement of left and right ventricular enlargement by electron beam tomography.

RATIONALE AND OBJECTIVE: We devised to test the feasibility of measuring the left and right ventricular sizes by non-contrast electron beam tomographic images. METHODS: Ventricular sizes consist of the sum of the intracavitary cavity and myocardial mass for each ventricle. A total of 50-image studies from subjects undergoing contrast-enhanced studies were used to develop the measurement methodology. About 20 contrast studies were used to test the measure. The methodology was then prospectively tested on 75 patients with non-contrast studies to estimate the intra-observer, inter-observer and inter-study reproducibility. RESULTS: Multiple linear regression analysis was completed and the correct regression formulas to calculate ventricular volumes were acquired by using the area and span from the contrast studies. There was excellent correlation between the estimate of LV (r > 0.97, p < 0.001) and RV (r > 0.93, p < 0.001) sizes between measured and calculated (contrast, single slice) left and right ventricular volumes. The intra-observer, inter-observer and inter-study reproducibility demonstrated excellent results with < 7% difference in absolute values and a high correlation (r > 0.89, p < 0.001). CONCLUSION: We conclude that the left and right ventricular sizes can be accurately estimated from a single mid-ventricular slice on non-contrast electron beam tomographic images.

Safety of EBCT contrast injection studies in severe pulmonary hypertension.

PURPOSE: There is considerable literature published on noninvasive contrast-enhanced techniques to diagnose pulmonary vascular abnormalities, however little data exists on the safety of contrast injections in patients with elevated pulmonary arterial pressures. We studied the safety of contrast-enhanced electron beam computed tomography (EBCT) in 29 patients with severe pulmonary hypertension. The mean dose of intravenous contrast used was 124 +/- 39 cc. MATERIALS AND METHODS: Subjects underwent EBCT using contrast injected at a rate of 2-4 ml/s. All patients were watched closely for at least 15 min post-procedure prior to being released. Patients had Doppler echocardiograms to estimate pulmonary artery pressure. Right heart catheterization data was collected for patients in which echocardiographic data was unavailable. RESULTS: A total of 29 patients with pulmonary arterial hypertension were studied. There were 17 patients with primary pulmonary hypertension (PPH), and 12 patients with secondary forms of pulmonary hypertension. None of the patients developed complications from their study. CONCLUSION: There is a paucity of data on the safety of contrast injections in patients with severely elevated pulmonary arterial pressures. Contrast-enhanced EBCT was well-tolerated in our diverse series of patients with severely elevated pulmonary arterial pressures. Clinicians concerned about invasive pulmonary angiography should consider contrast-enhanced EBCT as a safe alternative to angiography.

Coronary artery motion in electron beam tomography.

PURPOSE: The purpose of this work was to evaluate coronary artery motion characteristics and determine optimal electron beam tomography (EBT) scan time during the cardiac cycle to image the coronary arteries. METHOD: This study evaluated the movement of coronary arteries in 20 EBT cine studies, at rest and during stress, obtained for evaluating coronary artery disease. The proximal, middle, and distal segments of each coronary artery were measured at multiple times during the cardiac cycle. The motion distance (mm) and velocity (mm/s) of each segment of the coronary arteries were then measured to establish the motion that occurs in the x and y axes during different times in the cardiac cycle. RESULTS: Coronary artery velocity ranged from 22.4 to 108.6 mm/s. The least motion (and slowest speed) occurred between 30-50 and 40-60% of the R-R interval at rest and stress, respectively. The right coronary artery moved the greatest in the x and y planes (highest speed and spatial change), followed in decreasing order by the circumflex, left main, and left anterior descending arteries. The phase of the cardiac cycle with the greatest coronary artery motion was between 0 and 20% of the R-R interval. CONCLUSION: Coronary artery motion varies greatly throughout the cardiac cycle. To minimize cardiac motion during tomographic imaging of the coronary arteries, we recommend 40-50% R-R interval as an electrocardiographic trigger time and avoiding the use of image acquisition times of >100 ms.

Effect of exercise on left and right ventricular ejection fraction and wall motion.

OBJECTIVE: We evaluated the diagnostic value of response of left and right ventricular ejection fraction and wall motion to exercise using electron beam computed tomography. METHODS AND RESULTS: We attempted to determine the value of exercise electron beam computed tomography for detecting coronary artery disease, including evaluation of the right ventricular ejection fraction and wall motion abnormalities. A study of 35 patients undergoing electron beam tomography exercise cine studies and coronary artery angiography for the evaluation of chest pain was performed. Of the 18 patients with significant coronary disease (> or = 50% luminal diameter stenosis in at least one coronary artery), 17 (94%) had failure to increase global left ventricular ejection fraction with exercise. Fourteen of 18 (78%) developed a wall motion abnormality during peak exercise, and eight (44%) developed a regional right ventricular wall motion abnormality during peak exercise. Of the 17 patients without obstructive disease, 14 (82%) had a increase in ejection fraction > or = 5% and none had an abnormal response in left ventricular wall motion during peak exercise (specificity = 100%). The change in right ventricular ejection fraction with exercise was not a significant predictor of obstructive coronary disease in this study (P=NS). Using different criteria during stress to predict coronary disease, the accuracy was 89% (31/35) using an increase of <5% in ejection fraction, 89% (31/35) using the development of a new or worsened wall motion abnormality, and 91% (32/35) using both left ventricular criteria. CONCLUSION: Our study suggests that exercise electron beam computed tomography appears to be a useful tool for the detection of coronary disease. A increase of <5% in ejection fraction and abnormal left ventricular response to exercise were important predictors, while the exercise induced changes of right ventricular ejection fraction was not a significant predictor of obstructive disease. Both left and right ventricular wall motion abnormalities are useful and important parameters in identifying patients with obstructive disease from those with normal coronary arteries.

Nitrate-enhanced thallium 201 single-photon emission computed tomography imaging in hibernating myocardium.

OBJECTIVES: This study tested the usefulness of nitrate-enhanced thallium 201 imaging for detecting myocardial viability. BACKGROUND: Previous work suggests that nitrates enhance the ability of (201)Tl imaging to detect viable myocardium. METHODS: Eighteen patients with coronary artery disease underwent (201)Tl imaging at rest, after 4 hours of redistribution, and during intravenous nitroglycerine infusion (mean dose = 5.96 +/- 5.37 microgram/kg/min). Twelve patients had their echocardiograms repeated after revascularization. Perfusion and wall motion were scored from 0 to 2 (absent to normal). RESULTS: All the regions identified as viable by the rest/redistribution pair of scans were identified as viable by the rest/nitroglycerine pair of scans. Ninety-one percent of these regions were identified as viable by the single nitroglycerine scan alone. In patients who underwent revascularization, the total (201)Tl perfusion score improved from 193 to 214 after revascularization (P =.009). Wall motion score improved from 151 to 168 after revascularization (P =.09). Both the rest/nitroglycerine and rest/redistribution studies correctly predicted 14 (88%) of 16 regions that improved after revascularization. Most importantly, the rest/nitroglycerine and rest/redistribution studies were able to predict postrevascularization myocardial viability (absence of akinesis or dyskinesis after revascularization), with a sensitivity of 95% and 92%, respectively, and a predictive accuracy of 84.4%. CONCLUSIONS: Nitroglycerine infusion during (201)Tl imaging is a useful technique for detecting underperfused, viable myocardium, requires less time to perform than rest/redistribution imaging, and may allow detection of viable myocardium with a single (201)Tl single-photon emission computed tomographic study.

Intravenous three-dimensional coronary angiography using contrast enhanced electron beam computed tomography.

Coronary angiography remains the diagnostic standard for establishing the presence, site, and severity of coronary artery disease (CAD). Electron beam computed tomography (EBCT), with its 3-dimensional capabilities, is an emerging technology with the potential for obtaining essentially noninvasive coronary arteriograms. The purpose of this study was to (1) test the accuracy of intravenous coronary arteriography using the EBCT to conventional coronary arteriographic images; (2) establish the inter-reader variability of this procedure; (3) determine the limitations due to location within the coronary tree; and (4) identify factors that contributed to improved image quality of the 3-dimensional EBCT angiograms. Fifty-two patients underwent both EBCT angiography and coronary angiography within 2 weeks. The coronary angiogram and the EBCT 3-dimensional images were analyzed by 2 observers blinded to the results of the other techniques. EBCT correctly identified 43 of 55 significantly stenosed arteries (sensitivity 78%), and correctly identified 118 of 130 of the nonobstructed arteries, yielding a specificity of 91% (p <0.001, chi-square analysis). The overall accuracy for EBCT angiography was 87%. Significantly more left main and anterior descending coronary arteries were adequately visualized than the circumflex and right coronary vessels (p = 0.003). Overall, 23 of 208 (11%) major epicardial vessels were noninterpretable by the blinded EBCT readers, primarily due to motion artifacts caused by cardiac and respiratory motion and poor electrocardiographic gating. The inter-reader variability was similar to that of angiography, and its high accuracy makes this a clinically useful test. This study demonstrates, by using intravenous contrast enhancement, that EBCT can clearly depict the coronary artery anatomy and can permit identification of coronary artery stenosis.

Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion.

OBJECTIVES: This study sought to determine the long-term effects of continuous infusion of epoprostenol (epo) therapy on survival and pulmonary artery pressure in patients with primary pulmonary hypertension (PPH). BACKGROUND: PPH is a progressive disease for which there are few effective therapies. METHODS: Patients with PPH and New York Heart Association functional class III or IV symptoms of congestive heart failure underwent right heart catheterization and Doppler-echocardiography to measure the maximal systolic pressure gradient between the right ventricle and right atrium (delta P) and cardiac output (CO). Doppler-echocardiography and catheterization data were compared. Patients were followed up long term with Doppler-echocardiography. RESULTS: Of 69 patients who went on to receive epo, 18 were followed up for > 330 days (range 330 to 700). During long-term follow-up, there was a significant reduction in delta P, which decreased from 84.1 +/- 24.1 to 62.7 +/- 18.2 (mean +/- SD, p < 0.01). A Kaplan-Meier plot of survival of our study patients demonstrated improved survival compared with that of historical control subjects. The 1-, 2- and 3-year survival rates for our patients were 80% (n = 36), 76% (n = 22) and 49% (n = 6) compared with 10- (88%, n = 31), 20- (56%, n = 27) and 30-month (47%, n = 17) survival rates in historical control subjects. CONCLUSIONS: Patients receiving continuous infusion of epo for treatment of PPH experience a decrease in pulmonary artery pressure. Long-term follow-up of this single-center patient group demonstrated improved long-term survival during epo therapy compared with that in historical control subjects and confirms predicted improved outcomes based on shorter follow-up periods.

Variation of heart rate and electrocardiograph trigger interval during ultrafast computed tomography.

OBJECTIVES: Electrocardiographic (ECG) trigger records obtained during cardiac ultrafast computed tomography (UFCT) scanning were analyzed to estimate the variability in heart rate and ECG trigger interval to develop a protocol that would allow the development of better ECG triggering software. METHODS: One-hundred-eighteen patients underwent cardiac UFCT imaging for diagnostic purposes. All subjects were divided into three groups according to the heart rate and ECG trigger condition. Thirty slices were obtained in the high-resolution volume mode for each patient. RESULTS: A decrease in heart rate and ECG trigger interval was found during image acquisition of the first four slices in all three groups. The nadir of the heart rate occurred during acquisition of the 4th slice, 5.3, 3.5, and 5.6 beats per minute less than the initial heart rate in groups 1, 2, and 3 respectively, with a 6.9%, 2.8%, and 5.0% shorter ECG trigger interval (p < .001, p = .08, p < .05, respectively). From the 4th to the 30th slices, heart rate and ECG trigger interval progressively increased, but less variability was found in the last 20 slices in all three groups. CONCLUSIONS: Significant variation in heart rate and ECG trigger interval was seen during 30-level cardiac UFCT imaging, especially during image acquisition of the first four slices (approximately 1-6 seconds after breatholding). This can result in scanning during the suboptimal phase of the cardiac cycle by the current UFCT triggering software. A delay in the initiation of scanning to approximately 6 to 10 seconds after breatholding would result in imaging during a time when the heart rate is relatively stable, and a smaller variability in ECG trigger interval occurs. Recalculation of the required delay before each heart beat may improve the precision of ECG triggering.

Disseminated coccidioidomycosis with rapid progression to effusive-constrictive pericarditis.

This case reports coccidiomycosis presenting as pericarditis with tamponade rapidly progressing to effusive-constrictive pericarditis and death over 72 hours. Coccidiomycosis pericarditis is a rapidly progressing disease requiring early and complete pericardiectomy to avoid the hemodynamics of constriction. We illustrate the use of echocardiography in this case and demonstrate the histopathology. We review the literature and discuss therapy and management. Coccidiomycosis is often clinically unsuspected and unrecognized by the health care worker unfamiliar with the disease process.

Minimal alpha 1- and alpha 2-adrenoceptor-mediated coronary vasoconstriction in the anaesthetized swine.

alpha-Adrenoceptor-mediated coronary vasoconstriction contributes to the initiation and aggravation of experimental and clinical myocardial ischaemia. However, the extent of alpha 1- and alpha 2-adrenoceptor-mediated constriction has not been characterized in the porcine coronary circulation despite the frequent use of this experimental model. Fifteen swine were anaesthetized with either alpha-chloralose, enflurane or isoflurane to determine the amount of alpha-adrenoceptor-mediated coronary constriction elicited by either the selective alpha 1-adrenoceptor agonist methoxamine or the selective alpha 2-adrenoceptor agonist azepexole. The left anterior descending coronary artery was cannulated and perfused by an external pump delivering constant blood flow from the carotid artery. Following bilateral cervical vagotomy and beta-adrenoceptor blockade with propranolol (2 mg kg-1), graded dosages of either one of the alpha-adrenoceptor agonists (9-45 micrograms kg-1 min-1) were infused into the coronary perfusion line while coronary arterial pressure (CAP) was measured through a distal side arm of the cannula to detect changes in coronary vascular resistance. Infusion of the alpha-adrenoceptor agonists was terminated when systemic arterial pressure increased. Sonomicrometers were used to measure anterior left ventricular wall thickening for the assessment of regional contractile function. During methoxamine infusion, no increase in vascular resistance was observed during alpha-chloralose, enflurane or isoflurane anaesthesia, whereas the infusion of azepexole increased CAP from 103 +/- 31 mmHg to 120 +/- 35 mmHg (alpha-chloralose), from 101 +/- 16 mmHg to 122 +/- 11 mmHg (enflurane) and from 84 +/- 20 mmHg to 94 +/- 19 mmHg (isoflurane), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)