Marked efficacy of combined three-drug therapy (Sodium Valproate, Topiramate and Stiripentol) in a patient with Dravet syndrome.

WHAT IS KNOWN AND OBJECTIVE: Dravet syndrome (DS) is an intractable epilepsy syndrome. The three-drug combination therapy of sodium valproate (VPA), clobazam (CLB) and stiripentol (STP) is recommended worldwide. CASE SUMMARY: We present a case of DS, in which treatment with CLB could not be continued because of the appearance of adverse reactions to it. Replacement with topiramate (TPM) proved to be markedly effective. WHAT IS NEW AND CONCLUSION: It is suggested that combination therapy with VPA, TPM and STP is for DS epilepsy.

Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hypertension were improved by continuous prostacyclin therapy.

BACKGROUND: Thrombosis in situ related to endothelial cell injury may contribute to the development of pulmonary hypertension (PH). P-selectin, a leukocyte adhesion receptor present in endothelial cells and platelets, reflects endothelial injury and platelet activation, and thrombomodulin (TM), a receptor for thrombin and a major anticoagulant proteoglycan on the endothelial membrane, reflects the anticoagulant activity of the endothelium. METHODS AND RESULTS: To assess abnormal coagulation due to endothelial injury in patients with PH, plasma levels of soluble P-selectin and TM were measured in 32 patients with primary PH (PPH), 25 with secondary pulmonary arterial hypertension (sPAH), 31 with pulmonary venous hypertension (PVH), and 17 healthy subjects (Control). These measurements were repeated after continuous infusion of prostacyclin in 15 patients with PPH and 3 with sPAH. P-selectin levels in both the sPAH and PPH groups were significantly higher than those in the Control and PVH groups (P<0.05). Plasma TM level in the PPH group was significantly lower than those in the other groups (P<0.01). After prostacyclin therapy, the lower TM level was increased and the higher P-selectin level was decreased (P<0.05). CONCLUSIONS: Decreased TM and increased P-selectin in PPH and sPAH may reflect in situ thrombosis due to endothelial injury. Prostacyclin may act not only as a vasodilator but also as an agent that improves endothelial injury and altered hemostasis in pulmonary arterial injury.

Improvement in exercise capacity with nitric oxide inhalation in patients with precapillary pulmonary hypertension.

BACKGROUND: Patients with precapillary pulmonary hypertension (PH) exhibit a poor exercise capacity due to an impaired vasodilatory response of their pulmonary arteries. By causing the pulmonary artery to dilate, inhaled nitric oxide (NO) may allow an increase in exercise capacity in patients with PH. METHODS AND RESULTS: On 2 separate days, 3 days apart, 14 patients with precapillary PH (10 primary PH, 4 residual PH after correction of an intracardiac shunt; age, 40+/-12 years; mean pulmonary artery pressure, 60+/-23 mm Hg) performed exercise, with and without inhalation of 20 ppm NO, on a cycle ergometer. The work rate was increased 15 W/min until their symptom-limited maximum, with breath-by-breath gas analysis. Patients were randomly and blindly selected to inhale NO on either their first or second test. Peak exercise load and anaerobic threshold tended to increase, but not significantly. Peak oxygen consumption (f1.gif" BORDER="0">O(2)) and Deltaf1.gif" BORDER="0">O(2)/DeltaW ratio increased significantly, by 18% and 22%, respectively (peak f1.gif" BORDER="0">O(2), 13.6+/-3.6 to 16.0+/-4. 1 mL. kg(-1). min(-1); Deltaf1.gif" BORDER="0">O(2)/DeltaW ratio, 5. 8+/-2.4 to 7.1+/-2.3 mL. kg(-1). min(-1). W(-1); both P<0.01). Peak f1.gif" BORDER="0">O(2) increased >10% in 12 of the 14 patients. However, respiratory quotient at peak exercise decreased from 1. 22+/-0.15 to 1.09+/-0.15 (P<0.01). CONCLUSIONS: Inhaled NO substantially increases oxygen consumption at the same workload during exercise. This finding supports the possibility of ambulatory NO inhalation therapy in patients with precapillary PH.

Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension.

BACKGROUND: Plasma brain natriuretic peptide (BNP) level increases in proportion to the degree of right ventricular dysfunction in pulmonary hypertension. We sought to assess the prognostic significance of plasma BNP in patients with primary pulmonary hypertension (PPH). METHODS AND RESULTS: Plasma BNP was measured in 60 patients with PPH at diagnostic catheterization, together with atrial natriuretic peptide, norepinephrine, and epinephrine. Measurements were repeated in 53 patients after a mean follow-up period of 3 months. Forty-nine of the patients received intravenous or oral prostacyclin. During a mean follow-up period of 24 months, 18 patients died of cardiopulmonary causes. According to multivariate analysis, baseline plasma BNP was an independent predictor of mortality. Patients with a supramedian level of baseline BNP (>/=150 pg/mL) had a significantly lower survival rate than those with an inframedian level, according to Kaplan-Meier survival curves (P<0.05). Plasma BNP in survivors decreased significantly during the follow-up (217+/-38 to 149+/-30 pg/mL, P<0. 05), whereas that in nonsurvivors increased (365+/-77 to 544+/-68 pg/mL, P<0.05). Thus, survival was strikingly worse for patients with a supramedian value of follow-up BNP (>/=180 pg/mL) than for those with an inframedian value (P<0.0001). CONCLUSIONS: A high level of plasma BNP, and in particular, a further increase in plasma BNP during follow-up, may have a strong, independent association with increased mortality rates in patients with PPH.

Gene transfer of human prostacyclin synthase ameliorates monocrotaline-induced pulmonary hypertension in rats.

BACKGROUND: Prostacyclin is a potent vasodilator that also inhibits platelet adhesion and cell growth. We investigated whether in vivo gene transfer of human prostacyclin synthase (PGIS) ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. METHODS AND RESULTS: The cDNA encoding PGIS was intratracheally transfected into the lungs of rats by the hemagglutinating virus of Japan-liposome method. Rats transfected with control vector lacking the PGIS gene served as controls. Three weeks after MCT injection, mean pulmonary arterial pressure and total pulmonary resistance had increased significantly; the increases were significantly attenuated in PGIS gene-transfected rats compared with controls [mean pulmonary arterial pressure, 31+/-1 versus 35+/-1 mm Hg (-12%); total pulmonary resistance, 0.087+/-0.01 versus 0.113+/-0.01 mm Hg x mL x min(-1) x kg(-1) (-23%), both P:<0.05]. Systemic arterial pressure and heart rate were unaffected. Histologically, PGIS gene transfer inhibited the increase in medial wall thickness of peripheral pulmonary arteries that resulted from MCT injection. PGIS immunoreactivity was intense predominantly in the bronchial epithelium and alveolar cells. Lung tissue levels of 6-keto-PGF(1alpha), a stable metabolite of prostacyclin, were significantly increased for >/=1 week after transfer of PGIS gene. The Kaplan-Meier survival curves demonstrated that repeated transfer of PGIS gene every 2 weeks increased survival rate in MCT rats (log-rank test, P:<0.01). CONCLUSIONS: Intratracheal transfer of the human PGIS gene augmented pulmonary prostacyclin synthesis, ameliorated MCT-induced pulmonary hypertension, and thereby improved survival in MCT rats.

Hemodynamic, renal, and hormonal effects of adrenomedullin infusion in patients with congestive heart failure.

BACKGROUND: Experimental studies have shown that adrenomedullin (AM) causes vasodilatation, diuresis, and a positive inotropic effect. In humans, however, whether infusion of AM has beneficial effects in congestive heart failure (CHF) remains unknown. METHODS AND RESULTS: Hemodynamic, renal, and hormonal responses to intravenous infusion of human AM (0.05 microg. kg(-1). min(-1)) were examined in 7 patients with CHF and 7 normal healthy subjects (NL). In NL group, AM significantly decreased mean arterial pressure (-16 mm Hg, P<0. 05) and increased heart rate (+12 bpm, P<0.05). In CHF group, AM also decreased mean arterial pressure (-8 mm Hg, P<0.05) and increased heart rate (+5 bpm, P<0.05), but to a much lesser degree (P<0.05 versus NL). AM markedly increased cardiac index (CHF, +49%; NL, +39%, P<0.05) while decreasing pulmonary capillary wedge pressure (CHF, -4 mm Hg; NL, -2 mm Hg, P<0.05). AM significantly decreased mean pulmonary arterial pressure only in CHF (-4 mm Hg, P<0.05). AM increased urine volume (CHF, +48%; NL, +62%, P<0.05) and urinary sodium excretion (CHF, +42%; NL, +75%, P<0.05). Only in CHF, plasma aldosterone significantly decreased during (-28%, P<0.05) and after (-36%, P<0.05) AM infusion. These parameters remained unchanged in 7 patients with CHF and 6 healthy subjects who received placebo. CONCLUSIONS: Intravenous infusion of AM has beneficial hemodynamic and renal effects in patients with CHF.

Pulmonary artery reflection for differentially diagnosing primary pulmonary hypertension and chronic pulmonary thromboembolism.

OBJECTIVES: The purpose of this investigation was to differentiate chronic pulmonary thromboembolism (CPTE) from primary pulmonary hypertension (PPH) by means of the indexes of pulmonary arterial reflection. BACKGROUND: These differences in the primary lesions would make pulmonary artery reflection occur earlier in CPTE than in PPH. Although the analysis of pulsatility of pulmonary arterial pressure is useful in the differential diagnosis of PPH and CPTE, it is not known whether the analysis of pulmonary artery reflection can differentiate CPTE from PPH. METHODS: Since CPTE predominantly involves the proximal arteries, whereas PPH involve the peripheral arteries, we hypothesized that patients with CPTE have a large augmentation index and a short inflection time. For this study, we enrolled 62 patients who had CPTE (31 patients) and PPH (31 patients). We measured pulmonary arterial pressure using a fluid filled system that included a balloon-tipped flow directed catheter. To quantify the pulmonary artery reflection, we used the augmentation index and inflection time. RESULTS: The augmentation index was markedly higher in CPTE than it was in PPH (27.4% +/- 15.2% [SD] and -25.1% +/- 26.9%, respectively, p < 0.001) and was diagnostic in separating the two groups. Inflection time separated the two groups reasonably well (97 +/- 20 ms and 210 +/- 49 ms, respectively, p < 0.001). CONCLUSIONS: The analysis of pulmonary arterial reflection is useful in the differential diagnosis of CPTE and PPH.

Characteristics of pulmonary artery pressure waveform for differential diagnosis of chronic pulmonary thromboembolism and primary pulmonary hypertension.

OBJECTIVES: The accurate diagnosis of chronic pulmonary thromboembolism (CPTE) is a prerequisite for life-saving surgical interventions. To help in the differential diagnosis of CPTE and primary pulmonary hypertension (PPH), we characterized the configuration of the pulmonary artery pressure waveform. BACKGROUND: Because CPTE predominantly involves the proximal arteries, whereas PPH involves the peripheral arteries, we hypothesized that patients with CPTE would have stiff or high resistance proximal arteries, whereas those affected by PPH would have high resistance peripheral arteries. These differences in the primary lesions would make arterial pulsatility relative to mean pressure larger in CPTE than in PPH. METHODS: In 34 patients with either CPTE (n = 22) or PPH (n = 12) whose pulmonary systolic pressure was > or = 50 mm Hg, we measured pulmonary artery pressure using a fluid-filled system that included a balloon-tipped flow-directed catheter. RESULTS: To quantify the magnitude of pulsatility relative to mean pressure, we normalized pulse pressure by mean pressure, hereinafter referred to as fractional pulse pressure (PPf). PPf was markedly higher in CPTE than in PPH (mean [+/-SD] 1.41 +/- 0.20 and 0.80 +/- 0.18, respectively, p < 0.001) and was diagnostic in separating the two groups without overlap. Similarly, the coefficient of variation of pulmonary artery pressure also separated the two groups without overlap (0.45 +/- 0.06 and 0.25 +/- 0.06, respectively, p < 0.001). Fractional time to half the area under the pressure curve separated the two groups reasonably well (0.35 +/- 0.02 and 0.43 +/- 0.03, respectively, p < 0.001). CONCLUSIONS: The analysis of pulsatility of pulmonary artery pressure is useful in the differential diagnosis of CPTE and PPH.

Effect of orally active prostacyclin analogue on survival of outpatients with primary pulmonary hypertension.

OBJECTIVES: This study sought to investigate the effect of beraprost sodium (BPS), an orally active prostacyclin analogue, on the survival of outpatients with primary pulmonary hypertension (PPH). BACKGROUND: Continuous intravenous administration of epoprostenol (prostacyclin) has been shown to improve survival in PPH. However, the effect of oral BPS on survival in PPH remains unknown. METHODS: Fifty-eight consecutive patients with PPH who could be discharged after the first diagnostic catheterization for PPH were retrospectively divided into two groups: patients treated with BPS (BPS group, n = 24) and those without BPS (conventional group, n = 34). The baseline demographic and hemodynamic data did not significantly differ between the two. RESULTS: Twenty-seven patients died of cardiopulmonary causes in the conventional group during a mean follow-up period of 44 +/- 45 months. In contrast, only 4 patients died of cardiopulmonary causes in the BPS group during a mean follow-up period of 30 +/- 20 months. In a subsample (n = 15) of patients in the BPS group, mean pulmonary arterial pressure and total pulmonary resistance significantly decreased, respectively, by 13% and 25% during a mean follow-up period of 53 days. Among the variables previously known to be associated with the mortality in PPH, the absence of BPS therapy and the reduced cardiac output were independently related to the mortality by a multivariate Cox proportional hazards regression analysis (both p < 0.05). The Kaplan-Meier survival curves demonstrated that the one-, two- and three-year survival rates for the BPS group were 96%, 86% and 76%, respectively, as compared with 77%, 47% and 44%, respectively, in the conventional group (log-rank test, p < 0.05). CONCLUSIONS: The oral administration of BPS may have beneficial effects on the survival of outpatients with PPH as compared with conventional therapy alone.

Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension.

OBJECTIVES: This study sought to investigate the influence of right ventricular (RV) hemodynamic variables and function on the secretion of brain natriuretic peptide (BNP) in patients with isolated RV overload. BACKGROUND: Plasma BNP is known to increase in proportion to the degree of left ventricular (LV) overload. However, whether BNP secretion is also regulated in the presence of RV overload remains unknown. METHODS: Plasma BNP and atrial natriuretic peptide (ANP) levels in the pulmonary artery were measured in 44 patients with RV overload: 18 with RV volume overload (RVVO) due to atrial septal defect and 26 with RV pressure overload (RVPO) due to primary or thromboembolic pulmonary hypertension. Right heart catheterization was performed in all patients. RV and LV ejection fraction, myocardial mass and volume of the four chambers were determined by using electron beam computed tomography. RESULTS: Although both plasma BNP and ANP levels were significantly elevated in patients with RV overload compared with values in control subjects, plasma BNP and the BNP/ANP ratio were significantly higher in patients with RVPO than with RVVO (BNP 294 +/- 72 vs. 48 +/- 14 pg/ml; BNP/ANP 1.6 +/- 0.2 vs. 0.8 +/- 0.2, both p < 0.05). Plasma BNP correlated positively with mean pulmonary artery pressure (r = 0.73), total pulmonary resistance (r = 0.79), mean right atrial pressure (r = 0.79), RV end-diastolic pressure (r = 0.76) and RV myocardial mass (r = 0.71); it correlated negatively with cardiac output (r = -0.33) and RV ejection fraction (r = -0.71). Plasma BNP significantly decreased from 315 +/- 120 to 144 +/- 54 pg/ml with long-term vasodilator therapy (total pulmonary resistance decreased from 23 +/- 4 to 15 +/- 3 Wood U). CONCLUSIONS: Plasma BNP increases in proportion to the extent of RV dysfunction in pulmonary hypertension.

Intracoronary endothelin-1 increases coronary retrograde pressure by constricting arterioles.

STUDY OBJECTIVE: The aim was to determine the site of coronary vasoconstriction induced by endothelin, by investigating the response in terms of retrograde pressure and reactive hyperaemia. EXPERIMENTAL MATERIAL: Twelve anaesthetised mongrel dogs, 12-14 kg, were used for the studies. DESIGN: The left anterior descending coronary artery was cannulated and perfused with blood through an extracorporeal bypass. The effects of intracoronary endothelin-1 (1-500 pmol) on coronary blood flow, coronary flow reserve (the peak reactive flow and the repayment after 15 s coronary occlusion), and retrograde coronary pressure during coronary occlusion were studied (n = 7). The retrograde coronary flow was collected from the bypass at each dose (n = 5). MEASUREMENTS AND MAIN RESULTS: At doses of greater than 20 pmol the coronary flow decreased dose dependently and reached almost zero flow at 500 pmol. The coronary flow reserve also decreased; however, the retrograde pressure was raised dose dependently at doses of greater than 10 pmol. At a dose of 500 pmol, the retrograde pressure was increased to 61 mm Hg [82(SEM 12)% of the coronary perfusion pressure]. Retrograde flow remained unchanged throughout the experiment. CONCLUSIONS: The endothelin-1 induced rise in retrograde pressure is in accordance with a dose dependent reduction in coronary flow reserve, and collateral flow was not augmented by endothelin. It is concluded that the effect of endothelin-1 on coronary circulation in situ was mainly due to the constriction of small resistant vessels.

Correlation between severity of pulmonary arterial hypertension and 123I-metaiodobenzylguanidine left ventricular imaging.

UNLABELLED: It remains unclear whether cardiac sympathetic nervous function is disturbed in patients with pulmonary arterial hypertension (PH) and how sympathetic dysfunction is related to PH. METHODS: In this study, (123)I-metaiodobenzylguanidine (MIBG) imaging of the heart, which reveals the sympathetic innervation of the left ventricle, was performed in 7 healthy volunteers without cardiopulmonary disease (control subjects); 55 patients with PH, including 27 with chronic thromboembolic pulmonary hypertension (CTEPH) of major vessels; and 28 patients with primary pulmonary hypertension (PPH). RESULTS: Cardiac (123)I-MIBG uptake, assessed as the heart-to-mediastinum activity ratio (H/M), was significantly lower in the CTEPH and PPH groups compared with that in the control group (P < 0.01). Myocardial MIBG turnover, expressed as the washout rate (WR [%]) from 15 to 240 min, was significantly higher in the CTEPH and PPH groups than that in the control group (P < 0.01). In the PPH group, H/M and WR values of MIBG correlated with the severity of pulmonary hypertension (represented by total pulmonary vascular resistance determined by right heart catheterization), the right ventricular ejection fraction determined by electron beam CT, and other variables but did not correlate well in the CTEPH group. In both groups, patients with H/M > or = 2.0 showed better cumulative survival than did those with H/M < 2.0 (P < 0.05). CONCLUSION: Patients with PH have significant left ventricular myocardial sympathetic nervous alteration. (123)I-MIBG imaging of the heart is useful for assessing the severity of pulmonary hypertension caused by PPH or CTEPH.

Impaired regional fatty acid uptake and systolic dysfunction in hypertrophied right ventricle.

UNLABELLED: Little information is available regarding the determinants of systolic contractile function of the hypertrophied right ventricle (RV). The purpose of this study was to clarify the relationship between myocardial metabolism and contractile function in the hypertrophied RV due to pulmonary hypertension (PH). METHODS: Iodine-123-labeled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) and 99mTc-sestamibi (MIBI) SPECT were performed to calculate the RV-to-left ventricle (LV) tracer uptake ratio (RV/LV) in 21 patients with PH (6 with primary PH and 15 with chronic thromboembolic PH). The patients also underwent electron-beam CT to assess RV ejection function (RVEF) and percentage systolic wall thickening (%SWT) and right heart catheterization to measure mean pulmonary arterial pressure (mPAP). RESULTS: There were significant positive correlations between mPAP and MIBI-RV/LV (r = 0.89, p < 0.001) and between mPAP and BMIPP-RV/LV (r = 0.86, p < 0.001). However, 8 patients showed lower BMIPP-RV/LV than MIBI-RV/LV, indicating the impairment of myocardial fatty acid uptake in the RV. These patients had lower RVEF and %SWT compared to those with normal myocardial fatty acid uptake (RVEF = 28% +/- 10% compared to 40% +/- 9% and %SWT = 33% +/- 27% compared to 74% +/- 30%, respectively; p < 0.05 for both comparisons). Although mPAP did not differ between the groups, the RVEF-mPAP and %SWT-mPAP regression lines drawn from the patients with impaired myocardial fatty acid uptake were located below the lines from the patients with normal myocardial fatty acid uptake, suggesting disproportionately decreased RV myocardial contractility for a given mPAP in patients with impaired myocardial fatty acid uptake. The patients with the impaired fatty acid uptake in the RV had a significantly higher death rate (log-rank test, p < 0.05). CONCLUSION: The results from this preliminary study suggest that myocardial fatty acid uptake is impaired in the failing hypertrophied RV due to PH.

Shortening of Doppler-derived deceleration time of early diastolic transmitral flow in the presence of pulmonary hypertension through ventricular interaction.

Deceleration time (DT) of the early transmitral flow velocity has recently been highlighted as a simple, noninvasive indicator of pulmonary arterial wedge pressure. In patients with pulmonary hypertension without left-sided heart disease, however, increased right ventricular pressure may result in an abnormal ventricular septal motion, which may impact on left ventricular (LV) early diastolic filling. We sought to determine if DT may be influenced by the severity of pulmonary hypertension in patients without left-sided heart disease. Doppler-derived transmitral flow and hemodynamic parameters were simultaneously assessed in 26 patients with pulmonary hypertension (primary pulmonary hypertension = 11; chronic thromboembolism = 15). Transmitral Doppler variables including DT were correlated with hemodynamics and LV deformity index measured in early diastole with 2-dimensional echocardiography. DT significantly correlated with the total pulmonary resistance (r = -0.70, p <0.001). Multivariate analysis revealed that DT was independently determined by total pulmonary resistance, but not by pulmonary arterial wedge pressure, heart rate, or patient's age in our study population. DT showed a correlation with LV deformity index (r = -0.74, p <0.001). These results indicate that DT may shorten in association with the severity of pulmonary hypertension and that the shortened DT in pulmonary hypertension may be attributable to right ventricular pressure overload which causes geometric changes.

Abnormality of left ventricular sympathetic nervous function assessed by (123)I-metaiodobenzylguanidine imaging in patients with COPD.

BACKGROUND: Cardiac and systemic autonomic nervous function may be impaired in patients with COPD. Few reports, however, have described sympathetic nervous function of the left ventricle (LV) in COPD patients. STUDY OBJECTIVE: To assess the LV sympathetic nervous function in patients with COPD using (123)I-metaiodobenzylguanidine (MIBG) imaging of the heart. DESIGN: Prospective comparison of (123)I-MIBG imaging results in COPD patients and normal subjects. PARTICIPANTS: Twenty-eight patients with COPD without manifest right ventricular overload and 7 volunteers without cardiopulmonary disease (control subjects). MEASUREMENTS: (123)I-MIBG imaging results and plasma norepinephrine concentration were compared between the COPD and control groups. In the COPD group, pulmonary function tests were performed and all subjects were interviewed about their symptoms. RESULTS: (123)I-MIBG uptake, assessed as the cardiac to mediastinal activity ratio in the delayed image, was significantly lower in the COPD group than in the control group (p < 0.05). (123)I-MIBG turnover, expressed as the washout rate (WR) of (123)I-MIBG from 15 to 240 min, was significantly higher in the COPD group than in the control group (p < 0.01). In the COPD group, patients with dyspnea showed lower cardiac to mediastinal activity ratios and higher WRs compared with patients who had mild dyspnea. The WR correlated negatively with the vital capacity/predicted value ratio, correlated negatively with the maximal voluntary ventilation volume/predicted value ratio, and correlated positively with the residual volume/total lung capacity ratio in the COPD group. The plasma norepinephrine concentration in COPD patients was higher than that in the control subjects. CONCLUSION: Patients with COPD have significant sympathetic nervous impairment of the LV myocardium as a result of generalized sympathetic overactivity.

Noninvasive quantitative evaluation of early atherosclerosis and the effect of monatepil, a new antihypertensive agent. An interim report.

In two studies on the same group of patients we evaluated noninvasive methods of assessing atherosclerosis and determined the effect of the new calcium channel-blocking agent monatepil on the progression of early atherosclerosis in humans. Computed tomography (CT) of the lower abdominal aorta and ultrasonography of the carotid arteries were used as noninvasive methods to determine the extent of atherosclerosis. To evaluate the CT images, we developed a new medical image analysis program. This enabled aortic calcification volume (ACV) to be quantified using plain CT images, and aortic wall volume (AWV) and aortic wall and calcification volume (AWCV) to be quantified from contrast CT images. Interobserver coefficients of variation of ACV, AWV, and AWCV (n = 8) were 4.7, 2.4, and 5.0%, respectively. In the monatepil study, the effect of the drug on serum lipid profiles was evaluated. Preliminary results show that shortly after monatepil administration, total serum cholesterol levels decreased significantly from 253.8 +/- 35.6 to 244.8 +/- 38.6 mg/dL (P < .009) and triglyceride levels tended to decrease. A positive correlation between the change in total cholesterol and changes in mean platelet volume was found (P = .028). Fasting immunoreactive insulin levels decreased in the four patients in which they were determined. Although this is a preliminary study, results indicate that CT of the lower abdominal aorta in combination with our new analysis program may be a precise, reproducible means of assessing early atherosclerosis. We have also shown that monatepil significantly decreases total cholesterol levels. However, the long-term effects of monatepil on the progression of atherosclerosis remain to be determined.

Operation for chronic pulmonary thromboembolism accompanied by thrombophilia in 8 patients.

BACKGROUND: Medical therapy for chronic pulmonary thromboembolism is limited, and surgical treatment has become more frequent recently. We have performed pulmonary thromboendarterectomy on 8 patients with chronic pulmonary thromboembolism accompanied by thrombophilia. METHODS: The patients were 6 men and 2 women aged 21 to 56 years (mean, 35 years). Five patients had antiphospholipid syndrome, 2 had protein C deficiency, and 1 had congenital antithrombin III deficiency. The preoperative condition was New York Heart Association functional class III in 5 and class IV in 3. Hypoxemia, marked pulmonary hypertension (mean pulmonary artery pressure, 47+/-6.7 mm Hg), and low cardiac output were observed in all patients. After a median sternotomy, deep hypothermia was induced using a cardiopulmonary bypass, and pulmonary thromboendarterectomy in the bilateral pulmonary arteries was performed under intermittent circulatory arrest. RESULTS: There were no operative deaths. Long-term respiratory management was needed postoperatively by 3 patients. In the remaining 5 patients, no reperfusion injury was observed. The arterial blood oxygen concentration improved, and the mean pulmonary pressure decreased to 16+/-5.5 mm Hg. The cardiac output also increased, and New York Heart Association functional class improved to I in 4 and II in 4 patients. CONCLUSION: Pulmonary thromboendarterectomy under deep hypothermic intermittent circulatory arrest was effective for chronic pulmonary thromboembolism accompanied by thrombophilia for which medical treatment is of limited value.

Effect of endothelin as a coronary vasoconstrictor in the Langendorff-perfused rat heart.

The effects of endothelin on coronary circulation were studied in isolated rat heart using a constant-flow system. Endothelin (10 fmol to 20 pmol/g heart weight) elevated the coronary perfusion pressure in a dose-dependent manner. Nifedipine (100 nM) inhibited the vasoconstriction and shifted the dose-response curve to the right. These results indicate that endothelin is a potent coronary vasoconstrictor and that its action is possibly mediated by the nifedipine-dependent Ca2+ channel.

K(ATP) channels predominantly regulate conduit vessel tone in normoxic cat pulmonary arteries in vivo.

Through our investigations of the intact pulmonary circulation, we aimed to find out whether K(ATP) channels contribute to regulating basal vascular tone and to clarify which vascular segments dilate during K(ATP) channel activation under basal tone conditions. Using an X-ray television system on anesthetized cat lungs, we measured internal diameter (ID) responses to two K(ATP) channel inhibitors (glibenclamide and 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl-hydrochloride (U-37883A)) and to an activator (levcromakalim) in normoxic pulmonary arteries. In conduit arteries (800-3000 microm ID), the inhibitors and activator induced larger ID constrictions (14-17%) and dilatations (29-32%), respectively. However, in resistance arteries (<500 microm), the constriction response was negligible and the dilatation response relatively small (5-10%). The data suggest that K(ATP) channels are active and capable of regulating basal vascular tone primarily within conduit pulmonary arteries even though these channels are present in all pulmonary arteries.

Impaired left ventricular myocardial metabolism in patients with pulmonary hypertension detected by radionuclide imaging.

To assess whether left ventricular myocardial metabolism is affected by the presence of right ventricular pressure overload, we performed 123I-beta-methyl-iodophenyl pentadecanoic acid (123I-BMIPP) and 99Tc(m)-sestamibi (99Tc(m)-MIBI) single photon emission tomography in 24 patients with pulmonary hypertension and in 10 control subjects. The left ventricle was divided into six regions using a short-axis tomogram at the mid-ventricular level. The relative regional uptake (RRU, %) was determined for each region as the ratio of the regional uptake per pixel to the maximum uptake in the six regions. Right heart catheterization was performed to obtain mean pulmonary arterial pressure. 123I-BMIPP uptake in the septum and the adjacent myocardium of the left ventricle was lower in patients with pulmonary hypertension than in control subjects (septal RRU, 75 +/- 6 vs 85 +/- 4%; anteroseptal RRU, 76 +/- 6 vs 86 +/- 3%; posteroseptal RRU, 75 +/- 4 vs 84 +/- 4%; P < 0.001). The reduction in 99Tc(m)-MIBI uptake was confined to the septum in patients with pulmonary hypertension (79 +/- 5 vs 85 +/- 5%; P < 0.05). Interestingly, the septal RRU of 123I-BMIPP and the sum of the septal, anteroseptal and posteroseptal RRUs of 123I-BMIPP were negatively correlated with mean pulmonary arterial pressure (r = -0.70 and -0.55, respectively; P < 0.01). In conclusion, myocardial metabolism in the interventricular septum and the adjacent regions of the left ventricle may be impaired in proportion to the degree of pulmonary hypertension.