Yutaka Takeda

Bilirubin as a prognostic marker in patients with pulmonary arterial hypertension

BackgroundLiver dysfunction reflects the status of heart failure, with congestion and low perfusion of the liver serving as causative mechanisms. Previous studies demonstrated relationship between the results of liver function test and the prognosis in patients with heart failure. However, few studies have examined this relationship in patients with pulmonary arterial hypertension (PAH).MethodsThe subjects were 37 patients with PAH (8 men and 29 women; 18 with idiopathic PAH and 19 with connective tissue disease-associated PAH). A blood test was performed after a 3-month period free from hospitalization and without changes in functional class, treatment, heart sounds, body weight, or heart rate.ResultsIn a mean follow-up period of 635 ± 510 days, 12 patients died due to heart failure, 2 died due to pulmonary hemorrhage, and 23 patients survived. Cox proportional hazard analyses identified functional class (p < 0.001), plasma concentration of brain natriuretic peptide (BNP) (p = 0.001), and hyperbilirubinemia (serum total bilirubin > 1.2 mg/dL; p < 0.001; hazard ratio = 13.31) as predictors of mortality. Patients with hyperbilirubinemia had a worse functional class (P = 0.003), a higher right atrial pressure (p < 0.001), a higher plasma concentration of BNP (p = 0.004), and a larger Doppler right ventricular index of the right ventricle (p = 0.041).ConclusionElevated serum bilirubin is a risk factor for death in patients with PAH.

High density lipoprotein cholesterol and apolipoprotein A-I are persistently elevated during long-term treatment with pitavastatin, a new HMG-CoA reductase inhibitor

Although a low level of high density lipoprotein-cholesterol (HDL-C) is an important risk factor for coronary heart disease, few available agents are capable of significantly increasing HDL-C. This multicenter study demonstrated that administration of pitavastatin, a new HMG-CoA reductase inhibitor, significantly and persistently increased HDL-C (from 36.0+/-5.9 to 40.5+/-9.1 mg/dL: p<0.001) and apolipoprotein A-I levels (from 108.4+/-18.0 to 118.7+/-19.3 mg/dL: p<0.01) in 43 hypercholesterolemic patients with low HDL-C over the course of 12 months of treatment. This suggests that pitavastatin may contribute to reduction in coronary heart disease.

Within-person variation of the plasma concentration of B-type natriuretic peptide : Safety range in stable patients with heart failure

BACKGROUND The plasma concentration of B-type natriuretic peptide (BNP) in outpatients is hard to interpret because of the lack of knowledge of the natural within-person variation of BNP. In this study, we estimated the safety range of within-person variation in the plasma concentration of BNP in outpatients with stable heart failure. METHODS In a prospective historical cohort study, 6 consecutive measurements of the plasma concentration of BNP were made at 4-week intervals in 131 consecutive patients with strictly stable heart failure. The reference change values at the 95% CI and the 95% limits of agreement of the peptide concentration were calculated with a log-normal approach, and the results were back-transformed to a normal scale. RESULTS The within-person distribution of BNP was right-skewed, and a Gaussian distribution was achieved by log transformation. In all of 15 combinations of paired measurements randomly selected from 6 measurements, the correlations were significant (P < .001) with correlation coefficients ranging from 0.615 to 0.835. The up and down reference change values at the 95% confidence level for all measurements were 240.4% and -70.6% of the geometric means, respectively, and the median values of the upper and lower 95% limits of agreements were 219.7% and -71.8% of the geometric mean, respectively. CONCLUSION The plasma concentration of BNP may triple or fall by one third without a change in the status of heart failure. In monitoring of patients with heart failure, BNP should be interpreted in the context of the skewed within-person distribution.

Efficacy and Safety of Inhaled Iloprost in Japanese Patients With Pulmonary Arterial Hypertension – Insights From the IBUKI and AIR Studies –

BACKGROUND Inhaled iloprost is approved for pulmonary arterial hypertension (PAH) in many countries. IBUKI was a phase III, non-randomized, open-label study of the efficacy and safety of inhaled iloprost in Japanese patients with PAH. METHODSANDRESULTS Adults with PAH who were treatment-naïve or administered endothelin receptor antagonists (ERAs) and/or phosphodiesterase type 5 inhibitors (PDE5-Is) and in NYHA/WHO functional class (FC) III/IV had inhaled iloprost (2.5 µg, increased to 5.0 µg if tolerated) 6-9 times daily for 12 weeks. Eligible patients entered a 40-week extension phase. Endpoints included change from baseline to week 12 in pulmonary vascular resistance (PVR; primary endpoint), other efficacy parameters, and safety. Data were compared with new subgroup analyses of treatment-naïve Western PAH patients from the global phase III AIR study. 27 patients received iloprost: 89% were treated with an ERA and/or PDE5-I; 70% with both. At week 12, PVR improved from baseline by -124 dyn·sec·cm(-5)(95% CI, -177 to -72) and 6-min walking distance increased by 36.0 m (95% CI, 14.9 to 57.1). NYHA/WHO FC improved in 62%; none worsened. Common drug-related adverse events were headache (37%) and cough (15%); 1 patient experienced hypotension; none reported syncope or hemoptysis. There were no deaths and no unexpected long-term safety findings. AIR PAH subgroup analyses showed similar results. CONCLUSIONS Inhaled iloprost appeared effective and safe in Japanese PAH patients, including ERA- and PDE5-I-treated patients, consistent with findings of the AIR PAH subpopulation and previous iloprost studies.

Effect of carvedilol on atrioventricular conduction in the ischemic heart.

We compared the effects of carvedilol on atrial-His and His-ventricular conduction with those of propranolol in isolated rat hearts. Hearts were perfused retrograde, and atrial-His and His-ventricular intervals were measured. The effective doses that increased conduction times by 25% were 10(-6) M for atrial-His and 3x10(-6) M for His-ventricular for propranolol, and 8x10(-8) M for atrial-His and 10(-8) M for His-ventricular for carvedilol. Prazosin did not affect the atrial-His and His-ventricular intervals. After ischemia-reperfusion, atrial-His and His-ventricular intervals increased to a greater extent with 10(-6) M carvedilol. To determine the direct membrane effect, we examined the transmembrane action potential in guinea pig papillary muscle. Both drugs decreased the maximum upstroke velocity equally. Our data indicate that carvedilol had a greater effect on atrioventricular conduction in the setting of ischemia-reperfusion than did propranolol. This effect of carvedilol was not due to its alpha-adrenoceptor blocking property or to a direct membrane effect.

Excessive blood pressure elevation upon awakening involves an exaggerated cardiac response to slight physical activity: a possible mechanism underlying the risk of 'morning surge'.

ObjectiveAn exaggerated elevation in blood pressure around waking potentially increases the risk of cardiovascular events, even in individuals with normal blood pressure at other-fold of day. The impact of such a transient blood pressure elevation is disproportionate to its short duration, and the reason has not been elucidated. We hypothesize that individuals with such a blood pressure abnormality receive a cardiovascular overload, even from slight physical activities that are frequently undertaken in daily life. MethodsA total of 16 patients with essential hypertension (52±15 years) staying at hospital for lifestyle education participated in this study. Morning blood pressure elevation was assessed with 24 h ambulatory blood pressure monitoring. Cardiovascular responses to unloaded pedaling, including blood pressure changes, were assessed in a limited maximum exercise test using an electronically braked bicycle ergometer. ResultsChanges in the systolic blood pressure caused by unloaded pedaling correlated positively with the elevation in systolic blood pressure around waking (r=0.52, P=0.05). Moreover, waking elevation of the systolic blood pressure correlated with changes in all of the following cardiovascular variables during unloaded pedaling: heart rate (r=0.69, P=0.003), oxygen consumption (r=0.73, P=0.001), oxygen pulse (r=0.62, P=0.001), and rate pressure product (r=0.64, P=0.008), respectively. ConclusionThese observations indicate that individuals with prominent blood pressure elevation upon awakening also experience cardiovascular overload from slight physical activities.

Conservative therapy with a gonadotropin-releasing hormone agonist for a uterine arteriovenous malformation in a patient with congenital heart disease.

Uterine arteriovenous malformation (AVM) is rare but it can cause life‐threatening genital bleeding. Conservative therapy with GnRHa can be a useful option for treating a uterine AVM presenting with a congenital heart disease shunt in hemodynamically stable patients.

Pulmonary venous occlusion and death in pulmonary arterial hypertension: survival analyses using radiographic surrogates

BackgroundRecent studies find that a considerable number of patients with pulmonary arterial hypertension (PAH) develop fibrous obstruction of the pulmonary veins. Such obstruction more commonly accompanies connective tissue disorder (CTD)-associated PAH than idiopathic PAH. However, few researchers have gauged the risk of death involving obstruction of the pulmonary veins.MethodsThirty-seven patients with PAH were enrolled (18 patients, idiopathic PAH; 19 patients, CTD-associated PAH). The patients were 49 ± 18 years and had a World Health Organization functional class of 3.2 ± 0.6. Thickening of the interlobular septa, centrilobular ground-glass attenuation, and mediastinal adenopathy were surrogates for obstruction of the pulmonary veins, and were detected by a 16-row multidetector computed tomography scanner.ResultsThe follow-up period was 714 ± 552 days. Fifteen deaths occurred. Thickening of the interlobular septa, centrilobular ground-glass attenuation, and mediastinal adenopathy were found in 37.8%, 24.3%, and 16.2% of patients, respectively. Cox proportional hazard analysis revealed an increased risk of death with each radiographic surrogate (mediastinal adenopathy: p < 0.0001, hazard ratio = 13.9; thickening of interlobular septa: p < 0.001, hazard ratio = 12.0; ground-glass attenuation: p = 0.02, hazard ratio = 3.7). The statistical significance of these relationships was independent of the cause of PAH and plasma concentration of brain natriuretic peptide.ConclusionsThe results of this study imply that obstruction of the pulmonary veins is associated with an increased risk of death in patients with PAH.

Efficacy and safety of an orally administered selective prostacyclin receptor agonist, selexipag, in Japanese patients with pulmonary arterial hypertension

BACKGROUND Selexipag is an orally available prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. In this open-label Phase II trial, the efficacy and safety of selexipag in Japanese patients with pulmonary arterial hypertension (PAH) is examined.Methods and Results:Selexipag was administered at 200 μg twice daily and titrated up to 1,600 μg by increments of 200 μg in 37 subjects to reach the individual maximum tolerated dose. At 16 weeks, in 33 patients comprising the per-protocol set, the pulmonary vascular resistance (PVR; primary endpoint) decreased from 683.2±237.3 to 560.3±238.7 dyn·s/cm5(P<0.0001). For the secondary endpoint, the 6-min walk distance (6MWD) increased from 445.0±102.2 to 459.1±112.8 m (P=0.0324); World Health Organization functional class improved in 4 patients (12.1%), and was maintained in 29 patients (87.9%). A decrease in PVR was also shown in patients treated with selexipag, on top of a phosphodiesterase inhibitor and endothelin receptor antagonist. Most of the commonly reported adverse events were consistent with those reported for other PGI2formulations. Thirty-four patients attained the individual maximum tolerated dose (maintenance dose). CONCLUSIONS The efficacy and tolerability of selexipag in Japanese PAH patients was confirmed by improvement in pulmonary hemodynamics, exercise capacity, symptoms. Selexipag is an efficacious treatment option for Japanese PAH patients. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111532].).

High-amplitude QRS complex in the electrocardiograms of normotensive people and risk of subsequent hypertension

BACKGROUND Left ventricular hypertrophy sometimes develops in normotensive people with a genetic background for hypertension. The aim of this case-control study was to test the hypothesis that a high-amplitude QRS complex (high-QRS) is indicative of risk of eventual hypertension. METHODS We reviewed medical charts that included blood pressure data obtained every 6 months from 7011 Japanese workers. The cases were all of 24 normotensive people showing an electrocardiogram with SV1+RV5>4.0 mV (high-QRS). The 24 controls chosen presented normal electrocardiograms and were matched for blood pressure, body mass index, age, gender, glycated hemoglobin A1c fraction, and parental occurrence of hypertension. The incidence of hypertension and change in blood pressure during a 5-year study period were compared in the two groups. RESULTS The cases were more likely than the controls to have a parent with hypertension (18/24 [75.0%] and 686/5704 [12.0%], respectively; P<0.01, odds ratio=21.8 [95% CI: 8.6-55.2]). At the end of the study period, hypertension was more frequent (18/24 [75.0%] and 3/24 [12.5%], respectively; P<0.01, odds ratio=21.0 [95% CI; 4.6-96.2]) and both systolic and diastolic blood pressures were higher (149.0+/-17.1 mmHg vs. 139+/-17.1 mmHg, P<0.01; and 89.5+/-9.2 mmHg vs. 81.7+/-11.5 mmHg, P=0.01, respectively) in the cases than in the controls. CONCLUSIONS High-QRS may be indicative of risk of eventual hypertension, and may therefore be useful for screening purposes.