Pulmonary Vascular Resistance Is Associated With Brachial-Ankle Pulse-Wave Velocity and Adverse Clinical Outcomes in Patients With Heart Failure With Preserved Ejection Fraction

BackgroundThe precise mechanisms underlying the high prevalence of pulmonary hypertension (PH) with increased pulmonary vascular resistance (PVR) in heart failure with preserved ejection fraction (HFpEF) remain largely unknown. Measurements of brachial-ankle pulse wave velocity (baPWV) have been shown to be useful for risk assessment in HF patients. Thus, this study sought to define the association of PVR with baPWV and clinical outcomes in HFpEF.Methods and ResultsPatients with HFpEF (n = 198) had measurements of baPWV and PVR by right heart catheterization, and were prospectively followed-up for <96 months or until the occurrence of a composite of all-cause death, hospitalization with worsening HF, and nonfatal acute coronary syndrome.ResultsMultivariate logistic analysis showed that baPWV was independently associated with PH with increased PVR (P < .001). During the follow-up period, 46 clinical events occurred. Multivariate Cox proportional hazards analysis showed that PH with increased PVR was a significant predictor of adverse outcomes after adjustment for conventional risk factors (HR 1.96, 95% CI 1.03–3.76, P = .04).ConclusionsPH with increased PVR was associated with increased baPWV and adverse clinical outcomes in HFpEF. Thus, increased arterial stiffness may contribute to increased risk predictability of PVR for patients with HFpEF.     

Clinical course of patients with nonclassical 21-hydroxylase deficiency (21-OHD) diagnosed in infancy and childhood

We report four cases of nonclassical 21-hydroxylase deficiency (21-OHD) diagnosed in neonate or early childhood. The four patients comprised a 6-year, 5-month-old male (case 1); a 3-year, 10-month-old female (case 2); a 13-year, 11-month-old female (case 3) and a 17-year, 1-month-old male (case 4). Cases 3 and 4 were siblings. None had any signs of virilization or salt wasting at birth. 21-OHD was diagnosed using ACTH loading test and other adrenal steroid evaluations. Mutations of the CYP21 gene were detected in all patients. Three patients (cases 1, 3 and 4) had positive results in neonatal mass screening. Cases 1 and 2 showed no apparent signs of virilization and were observed without conventional treatment. In cases 3 and 4, because of increased growth velocity and accelerated bone maturation, hydrocortisone administration was initiated from their late infantile period. In spite of hydrocortisone treatment, in case 4, the final height of 159.7 cm was less than his predicted final height. Besides he revealed adrenal insufficiency at the age of 9 years and 2 months old caused by viral infection. Hydrocortisone supplementation therapy may cause adrenal insufficiency in nonclassical patients due to suppression of the hypothalamus-pituitary-adrenal axis. The clinical courses in these cases were various, and it was difficult to predict the appearance of any symptoms of virilization. Careful observation is necessary.     

Angiotensin II type 1 receptor blocker telmisartan suppresses superoxide production and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice

Angiotensin II is involved in the process of atherosclerosis and stimulates superoxide production from cardiovascular cells. We examined the effect of telmisartan, an angiotensin II type 1 receptor blocker, on atherosclerosis. We chronically treated apolipoprotein E-deficient mice with two different doses of telmisartan dissolved in drinking water (0.3 and 3 mg/kg) starting from 4 weeks of age for 12 weeks. Lipid contents were not different in both telmisartan-treated groups compared with control group. Systolic blood pressure was significantly reduced with 3 mg/kg, but unchanged with 0.3 mg/kg. The total atherosclerotic lesion size at the aortic sinus was reduced with 0.3 mg/kg compared with control, and additional reduction was proved with 3 mg/kg. The fibrotic change was not different among three groups, but MOMA-2-, malondialdehyde-, 4-hydroxy-2-nonenal-immunostained areas were reduced by telmisartan. As the mechanism, we revealed that both doses of telmisartan markedly reduced superoxide production from in situ vessels assessed by lucigenin-enhanced chemiluminescence and dihydroethidium staining. And NAD(P)H dependent oxidase activity in vessels was reduced by telmisartan. Further, 8-iso-prostaglandin F2alpha level, a systemic oxidative stress marker, obtained from urine and plasma samples were significantly reduced by telmisartan. Telmisartan reduced atherosclerosis in apolipoprotein E-deficient mice at least partly via the suppression of oxidative stress.     

Cardiac electrophysiologic effects of parathyroid hormone in the guinea pig

Summary The cardiac electrophysiologic effects of parathyroid hormone (PTH) were studied in three different experimental models. Purified synthetic human parathyroid hormone (hPTH 1–84), at a dose of 30 ng/g body weight (BW), prolonged the QT interval of surface ECGs in intact guinea pigs. To further clarify the mechanisms of the QT prolongation caused by hPTH, the action potentials of guinea pig papillary muscle were recorded by conventional microelectrode techniques. hPTH (10^–7 M) prolonged the action potential duration without changing the action potential amplitude, resting potential, maximal upstroke velocity of the action potential, or maximal repolarization rate. hPTH affected only the plateau phase, in a concentration-dependent fashion. The half-maximum concentration was 6.8 × 10^–8M for action potential duration at 30% repolarization (APD₃₀), 3.2 × 10^–8M for APD₅₀, and 2.1 × 10^–8M for APD₉₀. In isolated single guinea pig ventricular cells, the patch clamp method was used to record the slow inward calcium current (I_Ca) and delayed rectifier potassium current (I_K) responsible for the action potential plateau phase. hPTH increased the peak amplitude of I_Ca at +10mV by an average of 42%, and increased I_K at +10mV by 85%. These results indicate that, in ventricular muscle, hPTH prolongs the action potential duration and QT interval by the balance of the prolongation effect on APD by enhancing the slow inward calcium current and the shortening effect on APD by enhancing the delayed rectifier potassium current.     

Ontogeny of the transplantation immunity of mice for rejecting ascitic allogeneic tumors

Ontogeny of the murine transplantation immunity for rejecting ascitic allogeneic tumors (chemically-induced RG lymphoma and L1210 leukemia) as a model of $\text{in vivo}$ cytotoxic T cell immunity was studied. challenge by 10⁶ to 10⁷ allogeneic tumor cells per 20 g body weight (b.w.) of the mouse was fatal to 1–3 day-old mice, whereas 7–30 day-old mice rejected the tumor. In newborn mice however some yet undetermined mechanism worked to temporally depress the initial tumor growth. Injection of low (10⁶ cells per 20 g b.w.) to moderate (10⁷) doses of semiallogeneic spleen cells into newborn mice prepared for second set rejection of the tumor carrying the same alloantigens as the spleen cells, although injection of high dose (3 × 10⁸) cells reduced the tumor rejecting immunity. This second set rejection occurred even against the allogeneic tumor inoculated as early as 3 days old, if the mice had been primed with the alloantigens at birth. It appears therefore that newborn and early suckling mice are protected from tumor invasion by cytotoxic immunity more powerfully than expected from earlier $\text{in vitro}$ works.     

Bronchiolitis obliterans with allogeneic hematopoietic cell transplantation: a 10-year experience of the Okayama BMT Group

Bronchiolitis obliterans (BO) is a devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT). We retrospectively studied 465 patients who underwent HSCT in the Okayama BMT Group between 2000 and 2009, and describe the detailed clinical features of 13 patients with BO. The 5-year cumulative incidence of BO was 3.43 %. The median time from transplantation to onset of BO was 15 months. In seven of the 13 patients, the primary symptom was only cough, indicating that cough was an important initial symptom for early diagnosis. The median duration from the onset of BO to the requirement of O₂ supplementation was 13 months and the main cause of death was respiratory failure. History of chronic graft-versus-host disease was a significant risk factor. Furthermore, female recipients were at greater risk of BO than male recipients; however, no other previously reported risk factors were detected. It is currently difficult to prevent BO on the basis of the reported risk factors. A novel strategy for the early diagnosis and treatment of BO is required.     

A small-angled thin edge of the placenta predicts abnormal placentation at delivery.

OBJECTIVE: This study was intended to determine the relationship between the angle of the lower placental edge in early pregnancy and the previa/low-lying placenta at delivery. METHODS: We used transvaginal sonography to consecutively screen 2543 singleton pregnancies. All subjects were scanned during the period of gestation between 12 weeks 0 days and 15 weeks 6 days. The angle of the lower placental edge was measured when the placenta covered the internal cervical os. These cases were followed sonographically until term. RESULTS: Of 168 cases in which the internal cervical os was covered at screening, 9 showed previa/low-lying placenta at delivery (previa/low-lying group). The remaining 159 showed no abnormal placentation (nonprevia group). There were significantly fewer degrees of angle in the previa/low-lying group than in the nonprevia group (P < .05). For the previa/low-lying group, the arithmetic mean, median, and SD values of the angles were 60.8 degrees , 50.0 degrees , and 9.8 degrees , respectively. For the nonprevia group, those values were 103.4 degrees , 103.0 degrees , and 31.8 degrees , respectively. Data based on the cutoff number of the angle of 74 degrees indicated the following: sensitivity of placenta previa or low-lying placenta at term, 100% (9 of 9); false-positive rate, 23% (36 of 159); positive predictive value, 20% (9 of 45); and negative predictive value, 100% (123 of 123). CONCLUSIONS: The angle between the placental-uterine interface and fetal placental surface can be evaluated during early pregnancy. It appears to accurately predict placenta previa or low-lying placenta at term gestation with a sensitivity of 100%, a false-positive rate of 23%, and a high negative predictive value of 100%, which would allow for elimination of some of the multiple scans.     

Microscopic polyangiitis histologically confirmed by biopsy from nasal cavity and paranasal sinuses: a case report

Microscopic polyangiitis (MPA) is a systemic necrotizing vasculitis affecting small vessels without necrotizing granulomatous inflammation and is commonly associated with necrotizing glomerulonephritis. Diagnosis is based on typical clinical features, the presence of antimyeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCA), and histopathologic findings. Cases of pathologically proven small-vessel vasculitis in nasal biopsy specimens are sparse. Here we report a patient with MPA that was histopathologically confirmed by nasal and paranasal biopsy. A 67-year-old man presented with fever and general fatigue. Laboratory examinations showed severe inflammation and acute progressive renal failure. The serum MPO-ANCA level was elevated. The patient also had nasal polyps that seemed to be nonspecific chronic sinusitis. To obtain a pathologic diagnosis, bilateral ethmoidectomy and nasal polypectomy were performed. Pathological findings revealed vasculitis of small vessels in the mucosal surface. MPA was diagnosed on the basis of clinical symptoms, elevated MPO-ANCA and the pathological findings of the nasal and paranasal surgical specimen.     

Polydisperse low-density lipoproteins in hyperalphalipoproteinemic chronic alcohol drinkers in association with marked reduction of cholesteryl ester transfer protein activity

Long-term heavy alcohol intake is well known to increase serum high-density lipoprotein (HDL) cholesterol concentrations. Epidemiologic studies have shown that the protective effect of alcohol intake against coronary heart disease (CHD) is observed in moderate alcohol drinkers, but not in heavy ones. To clarify whether heavy alcohol intake may cause abnormalities in lipoprotein metabolism, we analyzed the plasma lipoproteins in eight male chronic heavy alcohol drinkers with marked hyperalphalipoproteinemia. Although their serum HDL cholesterol levels were remarkably high, ranging from 2.67 to 3.58 mmol/L, three patients had CHD and corneal arcus was present in seven patients. Cholesteryl ester transfer protein (CETP) activity was reduced in all subjects (7.3% +/- 4.2%/10 microL/18 h in alcohol drinkers v 20.5% +/- 2.4%/10 microL/18 h in control; mean +/- SD, P < .001). The CETP mass levels were also markedly reduced in these subjects. The analysis of low-density lipoprotein (LDL) on nondenaturing polyacrylamide gradient gel electrophoresis revealed that four subjects with severely low CETP activity (< 25% of control) had polydisperse LDLs, similar to those observed in genetic CETP deficiency. The other four subjects with approximately half the normal CETP activity had homogeneous but smaller-sized LDLs, as compared with control subjects. Particle size of HDL was larger than that of normal control HDL in all subjects. After cessation of alcohol intake, plasma HDL cholesterol levels were decreased and LDLs became more homogeneous and normal in size, in parallel with elevation of CETP activity.(ABSTRACT TRUNCATED AT 250 WORDS)