Predictive Value of the Cardio-Ankle Vascular Index for Cardiovascular Events in Patients at Cardiovascular Risk.

Background Arterial stiffness is an important predictor of cardiovascular events; however, indexes for measuring arterial stiffness have not been widely incorporated into routine clinical practice. This study aimed to determine whether the cardio-ankle vascular index (CAVI), based on the blood pressure-independent stiffness parameter ß and reflecting arterial stiffness from the origin of the ascending aorta, is a good predictor of cardiovascular events in patients with cardiovascular disease risk factors in a large prospective cohort. Methods and Results This multicenter prospective cohort study, commencing in May 2013, with a 5-year follow-up period, included patients (aged 40‒74 years) with cardiovascular disease risks. The primary outcome was the composite of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. Among 2932 included patients, 2001 (68.3%) were men; the mean (SD) age at diagnosis was 63 (8) years. During the median follow-up of 4.9 years, 82 participants experienced primary outcomes. The CAVI predicted the primary outcome (hazard ratio, 1.38; 95% CI, 1.16‒1.65; P<0.001). In terms of event subtypes, the CAVI was associated with cardiovascular death and stroke but not with myocardial infarction. When the CAVI was incorporated into a model with known cardiovascular disease risks for predicting cardiovascular events, the global χ2 value increased from 33.8 to 45.2 (P<0.001), and the net reclassification index was 0.254 (P=0.024). Conclusions This large cohort study demonstrated that the CAVI predicted cardiovascular events. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01859897.

Effect of acute aerobic exercise on arterial stiffness and thyroid-stimulating hormone in subclinical hypothyroidism.

Acute exercise has been reported to increase thyroid hormone levels and decrease arterial stiffness in healthy young subjects. However, the effect of acute aerobic exercise on circulating thyroid hormone levels and arterial stiffness in patients with subclinical hypothyroidism remains unclear. The aim of this study was to investigate the effects of acute aerobic exercise on arterial stiffness and thyroid hormone levels, and any relationship between these endpoints, in patients with subclinical hypothyroidism. We studied patients with untreated subclinical hypothyroidism (n = 53, 65 ± 12 years old) compared with euthyroid subjects (n = 55, 64 ± 10 years old). Exercise analysis was performed with a ramp cycle ergometer test. Arterial stiffness (cardio-ankle vascular index, CAVI) was measured at baseline and 5 min after exercise. We collected participant blood samples for serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) measurements before and 5 min after exercise. The CAVI and serum TSH levels significantly decreased after exercise in the subclinical hypothyroidism group (CAVI; 8.1 ± 1.6 vs. 8.5 ± 1.5, p < 0.001, TSH; 6.7 ± 1.4 vs. 7.6 ± 1.2 µIU/ml, p < 0.001) and euthyroid group (CAVI; 7.6 ± 1.0 vs. 8.3 ± 0.9, p < 0.001, TSH; 2.2 ± 1.1 vs. 2.4 ± 1.2 µIU/ml, p = 0.005). The changes in CAVI from baseline compared with after exercise were lower, in absolute values, in the subclinical hypothyroidism group than in the euthyroid group (subclinical hypothyroidism group vs euthyroid group; ΔCAVI: - 0.4 ± 0.6 vs. - 0.7 ± 0.7, p = 0.012). The changes in serum TSH from baseline to after exercise were higher, in absolute values, in the subclinical hypothyroidism group than in the euthyroid group (subclinical hypothyroidism group vs euthyroid group; Δ serum TSH: - 1.3 ± 1.4 vs. - 0.3 ± 0.5, p < 0.001). The changes in CAVI from baseline to after exercise were negatively correlated with changes in TSH (r = - 0.32, p = 0.038) in the subclinical hypothyroidism group. In conclusion, acute aerobic exercise decreased both arterial stiffness and serum TSH levels in patients with subclinical hypothyroidism and euthyroid subjects. While the absolute change in arterial stiffness decreased, the absolute change in serum TSH levels increased in patients with subclinical hypothyroidism compared with euthyroid subjects. These data suggest that subclinical hypothyroidism reduces CAVI during acute aerobic exercise. Further changes in absolute levels of serum TSH in subclinical hypothyroidism may result in reduced CAVI improvement by acute aerobic exercise.

Long-term effects of L- and N-type calcium channel blocker on uric acid levels and left atrial volume in hypertensive patients.

Left ventricular (LV) diastolic dysfunction is associated with hypertension and hyperuricemia. However, it is not clear whether the L- and N-type calcium channel blocker will improve LV diastolic dysfunction through the reduction of uric acid. The aim of this study was to investigate the effects of anti-hypertensive therapy, the L- and N-type calcium channel blocker, cilnidipine or the L-type calcium channel blocker, amlodipine, on left atrial reverse remodeling and uric acid in hypertensive patients. We studied 62 patients with untreated hypertension, randomly assigned to cilnidipine or amlodipine for 48 weeks. LV diastolic function was assessed with the left atrial volume index (LAVI), mitral early diastolic wave (E), tissue Doppler early diastolic velocity (E') and the ratio (E/E'). Serum uric acid levels were measured before and after treatment. After treatment, systolic and diastolic blood pressures equally dropped in both groups. LAVI, E/E', heart rate and uric acid levels decreased at 48 weeks in the cilnidipine group but not in the amlodipine group. The % change from baseline to 48 weeks in LAVI, E wave, E/E' and uric acid levels were significantly lower in the cilnidipine group than in the amlodipine group. Larger %-drop in uric acid levels were associated with larger %-reduction of LAVI (p < 0.01). L- and N-type calcium channel blocker but not L-type calcium channel blocker may improve LV diastolic function in hypertensive patients, at least partially through the decrease in uric acid levels.

The association between left ventricular twisting motion and mechanical dyssynchrony: a three-dimensional speckle tracking study.

Left ventricular (LV) dyssynchrony is a causal factor in LV dysfunction and thought to be associated with LV twisting motion. We tested whether three-dimensional speckle tracking (3DT) can be used to evaluate the relationship between LV twisting motion and dyssynchrony. We examined 25 patients with sick sinus syndrome who had received dual chamber pacemakers. The acute effects of ventricular pacing on LV wall motion after the switch from atrial to ventricular pacing were assessed. LV twisting motion and dyssynchrony during each pacing mode were measured using 3DT. LV dyssynchrony was calculated from the time to the minimum peak systolic area strain of 16 LV imaging segments. Ventricular pacing increased LV dyssynchrony and decreased twist and torsion. A significant correlation was observed between changes in LV dyssynchrony and changes in torsion (r = -0.65, p < 0.01). Evaluation of LV twisting motion can potentially be used for diagnosing LV dyssynchrony.

Changes in collagen metabolism account for ventricular functional recovery following beta-blocker therapy in patients with chronic heart failure.

While beta blockade improves left ventricular (LV) function in patients with chronic heart failure (CHF), the mechanisms are not well known. This study aimed to examine whether changes in myocardial collagen metabolism account for LV functional recovery following beta-blocker therapy in 62 CHF patients with reduced ejection fraction (EF). LV function was echocardiographically measured at baseline and 1, 6, and 12 months after bisoprolol therapy along with serum markers of collagen metabolism including C-terminal telopeptide of collagen type I (CITP) and matrix metalloproteinase (MMP)-2. Deceleration time of mitral early velocity (DcT) increased even in the early phase, but LVEF gradually improved throughout the study period. Heart rate (HR) was reduced from the early stage, and CITP gradually decreased. LVEF and DcT increased more so in patients with the larger decreases in CITP (r = -0.33, p < 0.05; r = -0.28, p < 0.05, respectively), and HR (r = -0.31, p < 0.05; r = -0.38, p < 0.05, respectively). In addition, there were greater decreases in CITP, MMP-2 and HR from baseline to 1, 6, or 12 months in patients with above-average improvement in LVEF than in those with below-average improvement in LVEF. Similar results were obtained in terms of DcT. There was no significant correlation between the changes in HR and CITP. In conclusion, improvement in LV systolic/diastolic function was greatest in patients with the larger inhibition of collagen degradation. Changes in myocardial collagen metabolism are closely related to LV functional recovery somewhat independently from HR reduction.

Postprandial Hemodynamics in Hypertrophic Cardiomyopathy.

OBJECTIVES: Prior analysis at our institution found that patients with hypertrophic cardiomyopathy (HCM) who experience postprandial symptoms (PPS) are more likely to have resting left ventricular outflow tract (LVOT) obstruction and reduced quality of life. Our objective was to determine whether PPS in patients with HCM vs healthy subjects occur as a result of measurable hemodynamic alterations in the postprandial hemodynamic response. METHODS: We conducted a prospective cross-sectional study examining 45 patients with HCM and 10 controls who underwent fasting and postprandial 2-dimensional Doppler echocardiography. Postprandial echocardiographic measurements were obtained at symptom onset or 30 minutes after consumption of a standardized meal, whichever occurred first. RESULTS: The HCM population included 18 (40%) patients with PPS and 27 (60%) without PPS. Compared to controls, mean resting peak LVOT gradient was 23.4 ± 17.6 mmHg in HCM patients with PPS and 25.1 ± 33.1 mmHg in those without PPS (P = 0.10). The mean change in peak LVOT gradient after a meal was 0.7 ± 1.1 mmHg for controls, 5.0 ± 8.3 mmHg for HCM patients with PPS, and 1.5 ± 18.2 mmHg for HCM patients without PPS (P = 0.64). CONCLUSION: Although the ability to provoke an increased LVOT gradient with a postprandial, upright exercise study protocol was recently reported, the current study suggests that a resting, supine, postprandial protocol does not elicit evidence of LVOT obstruction. Therefore, future investigations should consider whether simply performing an upright postprandial study in HCM patients with PPS will provide evidence of dynamic LVOT or if the addition of an exercise component is necessary.

Outcome prediction in sepsis: speckle tracking echocardiography based assessment of myocardial function.

INTRODUCTION: Speckle tracking echocardiography (STE) is a relatively novel and sensitive method for assessing ventricular function and may unmask myocardial dysfunction not appreciated with conventional echocardiography. The association of ventricular dysfunction and prognosis in sepsis is unclear. We sought to evaluate frequency and prognostic value of biventricular function, assessed by STE in patients with severe sepsis or septic shock. METHODS: Over an eighteen-month period, sixty patients were prospectively imaged by transthoracic echocardiography within 24 hours of meeting severe sepsis criteria. Myocardial function assessment included conventional measures and STE. Association with mortality was assessed over 12 months. RESULTS: Mortality was 33% at 30 days (n = 20) and 48% at 6 months (n = 29). 32% of patients had right ventricle (RV) dysfunction based on conventional assessment compared to 72% assessed with STE. 33% of patients had left ventricle (LV) dysfunction based on ejection fraction compared to 69% assessed with STE. RV free wall longitudinal strain was moderately associated with six-month mortality (OR 1.1, 95% confidence interval, CI, 1.02-1.26, p = 0.02, area under the curve, AUC, 0.68). No other conventional echocardiography or STE method was associated with survival. After adjustment (for example, for mechanical ventilation) severe RV free wall longitudinal strain impairment remained associated with six-month mortality. CONCLUSION: STE may unmask systolic dysfunction not seen with conventional echocardiography. RV dysfunction unmasked by STE, especially when severe, was associated with high mortality in patients with severe sepsis or septic shock. LV dysfunction was not associated with survival outcomes.

[Verification of complete blood cell count (CBC) data from heparinized blood gas samples].

Complete blood cell count (CBC) data from heparinized blood gas (H-Gas) samples were verified with primary focus on the platelet count (PLT). When a part of H-Gas sample was taken to a separation tube from the blood collection syringe and CBC of the sample in the separation tube was repeatedly measured (Procedure 1), the PLT from 5 samples relative to that obtained immediately after the separation was gradually reduced to 72.6-94.2% during serial measurements (every 5 minutes, up to 30 minutes). The change in the scattergram pattern suggested that this PLT decrease was due to the formation of platelet clumps. The white blood cell count (WBC), red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Ht) values did not significantly change during the repeated measurements. On the other hand, PLT was significantly improved to 96.8-99.8% when the H-Gas sample was kept in the blood collection syringe so as to minimizing the exposure to the air, and the sample for the measurement from H-Gas was taken every time to separation tube from the syringe, followed by CBC measurement without delay (Procedure 2). In addition, while there were significant variations (CV: 11.8-18.2%) in PLT reproducibility among H-Gas samples by Procedure 1, measurements utilizing the Procedure 2 resulted in much smaller variations (CV: 2.2-3.7%). Thus the CBC data obtained from H-Gas samples were equivalent to those from EDTA samples when the Procedure 2 was applied. These data suggest that H-Gas samples can be used for the accurate CBC measurement, including PLT, by applying the Procedure 2.

Elevated arterial stiffness and diastolic dysfunction in subclinical hypothyroidism.

BACKGROUND: Thyroid hormone is associated with arterial stiffness and left ventricular diastolic function in hypothyroid disease. The relationship of thyroid hormone level to cardio-ankle vascular index (CAVI) and left ventricular diastolic function, however, remains unclear in subjects with subclinical hypothyroidism. METHODS AND RESULTS: We conducted a cross-sectional study of 83 patients with untreated subclinical hypothyroidism and compared them with 83 randomly selected controls from health check-ups. Log N-terminal prohormone of brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), and arterial stiffness were measured. In addition, we measured early diastolic mitral annular velocity (E') in 43 participants with subclinical hypothyroidism and in 40 controls. When compared with the control group, patients with subclinical hypothyroidism had higher logNT-proBNP (1.9±0.5 vs. 1.7±0.3pg/ml, P<0.05), CRP (0.22±0.04 vs. 0.09±0.06mg/dl, P<0.05), and CAVI (8.8±1.7 vs. 7.8±1.4, P<0.001) and lower E' (5.8±1.7 vs. 7.5±2.1cm/s, P<0.001). CAVI was significantly associated with logNT-proBNP, CRP and E' in the subclinical hypothyroidism group. CONCLUSIONS: High logNT-proBNP was associated with a raised CAVI in patients with subclinical hypothyroidism. Subclinical hypothyroidism may be a risk factor for cardiovascular events related to arterial stiffening and left ventricular diastolic dysfunction.

Beta-blocker stress echocardiography in an aortic stenosis patient with associated left ventricular outflow tract obstruction.

An 80-year-old man visited our hospital because of dyspnea on exertion from 6 months ago. Echo Doppler study showed severe calcification in the aortic valve with restricted movement and the sigmoid septum causing obstruction at the LV outflow tract (LVOT). Considering the aortic valve area (AVA) might have been inaccurately estimated, we carried out beta-blocker stress echocardiography. The transaortic pressure gradient and AVA were respectively calculated as 52 mmHg and 0.90 cm(2) before propranolol administration and as 64 mmHg and 0.86 cm(2) after propranolol administration. Thus, beta-blocker stress echocardiography may provide an accurate assessment of AS if the LVOT obstruction is concomitant.

The impairment of the parasympathetic modulation is involved in the age-related change in mitral E/A ratio.

The mitral early to late diastolic flow velocity ratio (E/A ratio) is age-dependent. It has been considered that its age dependency reflects the age-related lengthening of left ventricular (LV) relaxation; however, the change in E/A ratio is far larger than that expected from those in LV relaxation. We hypothesized that an age-related reduction of the parasympathetic activity increases left atrial (LA) contractility, and that this accounts for the age-related change in E/A ratio. (1) Exercise stress test was performed in 61 normal subjects (age range, 8-80 years, mean, 40 years) to assess heart rate (HR) recovery because slowed HR recovery indicates lowered parasympathetic activity. There were good interrelations among age, E/A ratio, and HR recovery. Among those aged ≤30 years, the age no longer correlated with E/A ratio or HR recovery, but there was a significant correlation between HR recovery and E/A ratio (r = 0.44, p < 0.05). (2) Pulsed Doppler and two-dimensional speckle tracking echocardiography (2DSTE) were performed before and after administration of parasympathetic blockade (atropine) in ten young healthy subjects. LA booster pump function was assessed with LA emptying index calculated by 2DSTE. LA emptying index was calculated from ([LA volume before the atrial contraction - minimal LA volume]/LA volume before the atrial contraction) × 100. Atropine increased mitral A velocity (p < 0.001) and LA emptying index (p < 0.05) along with a decrease in E/A ratio (p < 0.001). Parasympathetic withdrawal enhances LA contraction and increases mitral A velocity, which likely cause a reciprocal decrease in mitral E velocity and E/A ratio. Thus, parasympathetic deactivation with aging should be closely involved in the age-related change in mitral E/A ratio.

Long-term effects of irbesartan on plasma aldosterone concentration and left atrial volume in hypertensive patients.

BACKGROUND: Plasma aldosterone concentration (PAC) is related to cardiac remodeling in patients with hypertension. However, we do not know the detailed relationship between changes in PAC and regression of left atrial (LA) volume following long-term treatment with angiotensin II receptor blocker (ARB) or calcium-channel blocker (CCB). OBJECTIVE: The aim of this study was to investigate the effects of anti-hypertensive monotherapy, an ARB irbesartan or a CCB amlodipine, on PAC and LA reverse remodeling in hypertensive patients. METHODS: A total of 48 patients with untreated hypertension were randomly assigned to irbesartan (ARB group, n=26) and amlodipine (CCB group, n=22). We examined the correlation between LA volume index (LAVI) and other echocardiographic parameters or PAC (n=40) at the baseline and after 12 months of treatment. RESULTS: After 12 months, blood pressure (BP) decreased similarly in both groups. LAVI and PAC significantly decreased in the ARB group, but not in the CCB group (-16±8% vs. 22±9%, p<0.01, -16±9% vs. 11±9%, p<0.05). Larger %-decrease in PAC was associated with larger %-reduction of LAVI in the ARB group (r=0.54, p<0.05), but not in the CCB group. CONCLUSIONS: While BP reduction was similar between the two groups, decrease in LA volume was larger in the ARB group than in the CCB group. Decrease in LA volume was larger in patients with a greater decrease in PAC than in those with smaller decrease in PAC. ARB may facilitate reverse remodeling of LA through decreases in PAC in hypertensive patients.

[Comments on routine laboratory data that are of practical use for physicians].

In the reversed clinicopathological conference (R-CPC), we analyzed a patient's pathosis using only the results of routine laboratory tests. R-CPC is one of the most effective training methods to acquire the abil- ity to interpret such data logically and reasonably. At the same time, we can know the limits of laboratory data, even though they can be analyzed in detail. In this R-CPC, three specialists in laboratory medicine discussed routine laboratory data of a patient with a ruptured abdominal aortic aneurysm. Then, they and moderators fielded a question-and-answer session with an audience in a hall. It was difficult for us to decide on the correct diagnosis, but we were able to analyze the data logically and reasonably in order to understand the patient's actual condition. It has been revealed that the Department of Laboratory Medicine can support physicians by adding comments to laboratory data that are of practical use to follow a patient.

[Comments on routine laboratory data that are of practical use for physicians].

Routine laboratory data are not adequately used to follow a patient because medical students are not educated to comprehend them with time series analysis. The Department of Laboratory Medicine can support physicians by adding comments to laboratory data that are of practical use for following a patient. At Shinshu University School of Medicine, routine laboratory data are discussed by time series analysis in a reversed clinicopathological conference(R-CPC). The general status is checked and then the state of each organ is examined using routine laboratory data, and we can obtain much more information about the patient than from physical examinations. In this R-CPC, several specialists in laboratory medicine discussed routine laboratory data of a patient with severe inflammation. It was difficult to diagnose him with a bacterial infection. Elevation of white blood cell count and high C-reactive protein suggested bacterial infection, and decreased platelets showed the possibility of bacteremia. However, he was clinically diagnosed as having multiple trauma without bacterial infection after falling down a mountainside. If routine laboratory data are finely analyzed by specialists in laboratory medicine, physicians can obtain useful information for patient treatment from the Department of Laboratory Medicine.

Clinical spectrum, frequency, and significance of myocardial dysfunction in severe sepsis and septic shock.

OBJECTIVE: To determine the frequency and spectrum of myocardial dysfunction in patients with severe sepsis and septic shock using transthoracic echocardiography and to evaluate the impact of the myocardial dysfunction types on mortality. PATIENTS AND METHODS: A prospective study of 106 patients with severe sepsis or septic shock was conducted from August 1, 2007, to January 31, 2009. All patients underwent transthoracic echocardiography within 24 hours of admission to the intensive care unit. Myocardial dysfunction was classified as left ventricular (LV) diastolic, LV systolic, and right ventricular (RV) dysfunction. Frequency of myocardial dysfunction was calculated, and demographic, hemodynamic, and physiologic variables and mortality were compared between the myocardial dysfunction types and patients without cardiac dysfunction. RESULTS: The frequency of myocardial dysfunction in patients with severe sepsis or septic shock was 64% (n=68). Left ventricular diastolic dysfunction was present in 39 patients (37%), LV systolic dysfunction in 29 (27%), and RV dysfunction in 33 (31%). There was significant overlap. The 30-day and 1-year mortality rates were 36% and 57%, respectively. There was no difference in mortality between patients with normal myocardial function and those with left, right, or any ventricular dysfunction. CONCLUSION: Myocardial dysfunction is frequent in patients with severe sepsis or septic shock and has a wide spectrum including LV diastolic, LV systolic, and RV dysfunction types. Although evaluation for the presence and type of myocardial dysfunction is important for tailoring specific therapy, its presence in patients with severe sepsis and septic shock was not associated with increased 30-day or 1-year mortality.

Electrophysiological and hemodynamic characteristics associated with obesity in patients with atrial fibrillation.

OBJECTIVES: The authors sought to characterize the left atrial (LA) and pulmonary vein (PV) electrophysiological and hemodynamic features in obese patients with atrial fibrillation (AF). BACKGROUND: Obesity is associated with increased risk for AF. METHODS: A total of 63 consecutive patients with AF who had normal left ventricular (LV) ejection fraction and who underwent catheter ablation were studied. Atrial and PV electrophysiological studies were performed at the time of ablation with hemodynamic assessment by cardiac catheterization, and LA/LV structure and function by echocardiography. Patients were compared on the basis of body mass index (BMI): <25 kg/m(2) (n = 19) and BMI ≥30 kg/m(2) (n = 44). RESULTS: At a 600-ms pacing cycle length, obese patients had shorter effective refractory period (ERP) in the left atrium (251 ± 25 ms vs. 233 ± 32 ms, p = 0.04), and in the proximal (207 ± 33 ms vs. 248 ± 34 ms, p < 0.001) and distal (193 ± 33 ms vs. 248 ± 44 ms, p < 0.001) PV than normal BMI patients. Obese patients had higher mean LA pressure (15 ± 5 mm Hg vs. 10 ± 5 mm Hg, p < 0.001) and LA volume index (28 ± 12 ml/m(2) vs. 21 ± 14 ml/m(2), p = 0.006), and lower LA strain (5.5 ± 3.1% vs. 8.8 ± 2.8%; p < 0.001) than normal BMI patients. CONCLUSIONS: Increased LA pressure and volume, and shortened ERP in the left atrium and PV are potential factors facilitating and perpetuating AF in obese patients with AF.

Carbacyclin induces carnitine palmitoyltransferase-1 in cardiomyocytes via peroxisome proliferator-activated receptor (PPAR) delta independent of the IP receptor signaling pathway.

Prostacyclin (PGI2) and its analogues exert cardioprotective effects via the rhodopsin type membrane PGI2 receptor, IP. Peroxisome proliferator-activated receptor (PPAR) delta is a nuclear receptor abundantly expressed in cardiomyocytes and plays a pivotal role in maintaining constitutive mitochondrial fatty acid beta-oxidation (FAO). Recently, a novel signaling pathway of PGI2 via PPARdelta has been demonstrated in non-cardiac tissues. We therefore examined whether carbacyclin (cPGI2), a PGI2 analogue, up-regulates transcriptional expression of carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting enzyme in mitochondrial FAO, via PPARdelta in cardiomyocytes. Intraperitoneal injection of cPGI2 increased CPT-1 mRNA expression in murine hearts. Transcriptional activity was evaluated by PPAR responsive element (PPRE)-luciferase reporter gene assay in cultured neonatal rat cardiomyocytes. CPT-1 mRNA expression and PPRE promoter activity were significantly increased by cPGI2 in a concentration-dependent manner, where PPRE has been mapped to the promoter region of the CPT-1 gene. Moreover, the elevation of CPT-1 mRNA expression and PPRE promoter activity by cPGI2 was not abolished by H-89, a potent protein kinase A inhibitor, but was significantly inhibited in cardiomyocytes over-expressing a dominant-negative type of PPARdelta. Furthermore, electrophoretic mobility shift assays demonstrated that binding of PPARdelta to PPRE in the CPT-1 gene promoter is enhanced in response to cPGI2 stimulation. In addition, down-regulation of CPT-1 mRNA expression in cardiomyocytes subjected to hypoxia was attenuated by cPGI2. These results indicate that cPGI2 induces CPT-1 mRNA expression through PPARdelta, independent of the IP receptor signaling pathway, suggesting a possibility that cPGI2 modulates cardiac energy metabolism by activating FAO via PPARdelta.

Effect of bosentan on plasma endothelin-1 concentration in patients with pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease with high mortality. An orally active dual endothelin (ET) receptor antagonist, bosentan, has been reported to improve exercise capacity and survival in patients with PAH. Plasma ET-1 concentration is known to be increased in PAH patients; however, the effect of bosentan on ET-1 concentration has not yet been investigated. METHODS AND RESULTS: The concentration of ET-1 after bosentan administration was examined in 7 PAH patients, including 2 primary and 5 secondary cases. They were clinically assessed by pulmonary artery pressure (PAP), 6-min walk distance (6MWD) and plasma brain natriuretic peptide (BNP) concentration. Baseline ET-1 concentration was significantly higher in patients with PAH than in normal individuals (2.19+/-0.71 pg/ml vs 1.45+/-0.10 pg/ml, p<0.05) and was significantly correlated with 6MWD and BNP. A single dose of 62.5 mg bosentan in patients with PAH significantly increased plasma ET-1 concentration to 2.04 times the basal concentration (p<0.01) with a peak at 8.1 h. The peak to base ratio of ET-1 after bosentan administration correlated negatively with severity of PAH as assessed by PAP. CONCLUSIONS: The present study is the first study to show that bosentan administration increases plasma ET-1 in patients with PAH. The response of plasma ET-1 to bosentan administration might be useful for determining the severity of PAH.

Sildenafil as adjunct therapy to high-dose epoprostenol in a patient with pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease is refractory to medical treatment and is generally associated with a poor prognosis. Treatment with vasodilators, such as prostacyclin, of patients with PVOD is controversial because of concerns regarding hemodynamic deterioration. Although a preferential pulmonary vasodilatory effect of a specific phosphodiesterase-5 inhibitor, sildenafil, has recently been reported in patients with primary pulmonary hypertension, little information is available regarding the effect of sildenafil on patients with pulmonary veno-occlusive disease. In the present case, remarkable improvement of hemodynamics and of clinical course was produced by adjunctive use of oral sildenafil in association with intravenous high-dose epoprostenol. These findings suggest that sildenafil may be a therapeutic option in the medical treatment of pulmonary veno-occlusive disease.