Interatrial septum pacing decreases atrial dyssynchrony on strain rate imaging compared with right atrial appendage pacing.

BACKGROUND: Interatrial septum pacing (IAS-P) decreases atrial conduction delay compared with right atrial appendage pacing (RAA-P). We evaluate the atrial contraction with strain rate of tissue Doppler imaging (TDI) during sinus activation or with IAS-P or RAA-P. METHODS: Fifty-two patients with permanent pacemaker for sinus node disease were enrolled in the study. Twenty-three subjects were with IAS-P and 29 with RAA-P. The time from end-diastole to peak end-diastolic strain rate was measured and corrected with RR interval on electrocardiogram. It was defined as the time from end-diastole to peak end-diastolic strain rate (TSRc), and the balance between maximum and minimum TSRc at three sites (ΔTSRc) was compared during sinus activation and with pacing rhythm in each group. RESULTS: There were no significant differences observed in general characteristics and standard echocardiographic parameters except the duration of pacing P wave between the two groups. The duration was significantly shorter in the IAS-P group compared with the RAA-P group (95 ± 34 vs 138 ± 41; P = 0.001). TSRc was significantly different between sinus activation and pacing rhythm (36.3 ± 35.7 vs 61.6 ± 36.3; P = 0.003) in the RAA-P group, whereas no significant differences were observed in the IAS-P group (25.4 ± 12.1 vs 27.7 ± 14.7; NS). During the follow-up (mean 2.4 ± 0.7 years), the incidence of paroxysmal atrial fibrillation (AF) conversion to permanent AF was not significantly different between the two groups. CONCLUSIONS: IAS-P decreased the contraction delay on atrial TDI compared to RAA-P; however, it did not contribute to the reduction of AF incidence in the present study.

The first clinical pilot study of intravenous adrenomedullin administration in patients with acute myocardial infarction.

Adrenomedullin (AM) is a 52-amino-acid vasodilator peptide that was originally isolated from human pheochromocytoma. In the previous experimental study with rat ischemia/reperfusion model, AM reduced infarct size and inhibited myocyte apoptosis. AM also suppressed the production of oxygen-free radicals. The present study was designed to evaluate the feasibility of intravenous administration of AM in patients with acute myocardial infarction. We studied 10 patients with first acute myocardial infarction [male to female ratio: 9 to 1, age: 65 ± 9 (mean ± SD) years, peak creatine phosphokinase level: 4215 ± 1933 (SD) U/L], who were hospitalized within 12 hours of symptom onset. Proceeding reperfusion therapy, AM infusion was initiated and continued at concentration of 0.0125-0.025 µg·kg·min for 12 hours. Follow-up coronary angiography and left ventriculography were performed at 3 months. Cardiac magnetic resonance was examined at 1 month and 3 months after AM therapy. During infusion of AM, hemodynamics kept stable except 2 patients. Wall motion index in the infarct area at 3 months was significantly improved compared with that at baseline, and infarct size evaluated by cardiac magnetic resonance was significantly decreased at 3 months. In conclusion, intravenous administration of AM, which possesses a variety of potential cardiovascular protective actions, can be adjunctive to percutaneous coronary intervention.

A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor-regulated channel.

Disruption of the dystrophin-glycoprotein complex caused by genetic defects of dystrophin or sarcoglycans results in muscular dystrophy and/or cardiomyopathy in humans and animal models. However, the key early molecular events leading to myocyte degeneration remain elusive. Here, we observed that the growth factor-regulated channel (GRC), which belongs to the transient receptor potential channel family, is elevated in the sarcolemma of skeletal and/or cardiac muscle in dystrophic human patients and animal models deficient in dystrophin or delta-sarcoglycan. However, total cell GRC does not differ markedly between normal and dystrophic muscles. Analysis of the properties of myotubes prepared from delta-sarcoglycan-deficient BIO14.6 hamsters revealed that GRC is activated in response to myocyte stretch and is responsible for enhanced Ca2+ influx and resultant cell damage as measured by creatine phosphokinase efflux. We found that cell stretch increases GRC translocation to the sarcolemma, which requires entry of external Ca2+. Consistent with these findings, cardiac-specific expression of GRC in a transgenic mouse model produced cardiomyopathy due to Ca2+ overloading, with disease expression roughly parallel to sarcolemmal GRC levels. The results suggest that GRC is a key player in the pathogenesis of myocyte degeneration caused by dystrophin-glycoprotein complex disruption.

Repolarization spatial-time current abnormalities in patients with coronary heart disease.

BACKGROUND: Magnetocardiography (MCG) is a new technique for visualizing a current distribution in the myocardium. In recent years, current distribution parameters (CDPs) have been developed based on the distribution. The CDPs reflect spatial-time current abnormalities in patients with coronary heart disease (CHD). However, the criteria and scoring method of the abnormalities using CDPs are still controversial. METHOD: We measured MCG signals for 101 normal controls and 56 CHD patients (single-, double-, and triple-vessel diseases) using a MCG system. The CDPs (maximum current vector [MCV], total current vector [TCV], current integral map, and current rotation) during ventricular repolarization were analyzed. To evaluate the CDPs that are effective in distinguishing between normal controls and CHD patients, the areas under the receiver operating characteristic curve (A(z)) are calculated. Furthermore, the total scores ("0" to "4") of four CDPs with high A(z) values are also calculated. RESULTS: MCV and TCV angles at the T-wave peak had the highest A(z) value. Furthermore, TCV angular differences between the ST-T segment also had high A(z) values. Using the four CDPs, the averaged total score for patients with triple-vessel disease was the highest ("2.67") compared to the other groups (normal controls: 0.53). Furthermore, based on the assumption that subjects with a total score over "1" were suspected of having CHD, sensitivity and specificity were 85.7% and 74.3%, respectively. CONCLUSION: We concluded that the score and criteria using MCV and TCV during repolarization in CHD patients can reflect lesion areas and time changes of electrical activation dispersion due to ischemia.

Right atrial spontaneous echo contrast indicates a high incidence of perfusion defects in pulmonary scintigraphy in patients with atrial fibrillation.

This study investigated the relationship between right atrial SEC (RA-SEC) and silent pulmonary embolism (PE) in patients with nonvalvular atrial fibrillation (NVAF). Spontaneous echo contrast (SEC) within the cardiac chambers is associated with an increased risk of thromboembolism. However, most studies have examined the relationship between left atrial SEC and systemic thromboembolic disease. Transesophageal echocardiography (TEE) was performed in 210 patients with NVAF to assess a risk of thromboembolism. Right atrial SEC was detected in 37 patients, and 35 of these patients with RA-SEC and 29 patients without RA-SEC were enrolled in this study. However, patients with a history of symptomatic PE or deep vein thrombosis were excluded. Spontaneous echo contrast was diagnosed by TEE as the presence of smoke-like echoes that swirled in a circular pattern. PE was diagnosed by pulmonary scintigraphy. Thrombotic and thrombolytic parameters, including serum concentrations of plasmin-alpha-plasmin inhibitor complex (PIC), thrombin-antithrombin complex (TAT), D-dimer, and fibrinogen were measured in all patients. Left ventricular dimension, cardiac function, and hematologic parameters were similar in the two groups. Nevertheless, the incidence of perfusion defects in pulmonary scintigraphy was significantly higher in the group with RA-SEC (40%) than in the group without RA-SEC (7%; chi-square, P=0.006). The increased incidence of perfusion defects in pulmonary scintigraphy in patients with RA-SEC indicates that right atrial SEC may be a predictable factor at a high risk of PE.

A case of Mikulicz's disease with Th2-biased cytokine profile: possible feature discriminable from Sjögren's syndrome.

This article concerns a male patient with Mikulicz's disease (MD) accompanied with marked elevation of serum immunoglobulin (Ig)G4 and IgE levels. His peripheral blood mononuclear cells (PBMC) showed markedly enhanced in vitro production of interleukin (IL)-4, IL-5, IL-13, but not interferon gamma (IFN-gamma) compared with patients with Sjögren's syndrome (SS) and healthy donors, suggesting distinct Th2 bias in this MD patient. Besides the prominent infiltration of IgG4-producing plasma cells, the enhanced expression of both CD40 and CD40 ligand (CD40L) were observed in the swollen salivary gland of the MD patient, suggesting enhanced signaling pathways for the induction of IgG4 and IgE switching. Possible differences between MD and SS in light of their underlying pathogenesis are discussed.

Comparison of the effects of telmisartan and olmesartan on home blood pressure, glucose, and lipid profiles in patients with hypertension, chronic heart failure, and metabolic syndrome.

We compared the effects of telmisartan and olmesartan in 20 patients with chronic heart failure and metabolic syndrome. The subjects underwent once-daily 40 mg telmisartan for at least 3 months before switching to once-daily 20 mg olmesartan for the next 3 months (post 1). They were then treated with 3 months of once-daily 40 mg telmisartan (post 2). Systolic and diastolic blood pressure in the early morning, plasma B-type natriuretic peptide, serum total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were increased at post 1 (p < 0.005, p < 0.05, p < 0.05, p < 0.05, p < 0.05, and p < 0.005 vs. baseline, respectively) before returning to their baseline values at post 2. The changes in plasma B-type natriuretic peptide levels correlated significantly with the shifts in systolic and diastolic blood pressure in the early morning at posts 1 and 2. Meanwhile, there were no fluctuations in either blood pressure in the late evening or in the outpatient room; nor were there fluctuations in heart rate. Simultaneously, neither serum high-density lipoprotein cholesterol nor fasting blood sugar levels differed significantly between posts. Moreover, telmisartan had more beneficial effects on glucose and lipid profiles in patients with relatively high HbA1c, serum total and low-density lipoprotein cholesterol, and triglyceride levels. Therefore, we concluded that telmisartan was more beneficial than olmesartan for controlling blood pressure in the early morning, as well as for improving glucose and lipid profiles in patients with hypertension, chronic heart failure, and metabolic syndrome.

Abundant expression of tetraspanin CD9 in activated osteoclasts in ovariectomy-induced osteoporosis and in bone erosions of collagen-induced arthritis.

Tetraspanin CD9 has been shown to be critically involved in multinucleation and cell fusion during osteoclastogenesis, however, its in vivo pathophysiological role in bone-resorbing disorders such as osteoporosis and rheumatoid arthritis, has not been elucidated. To investigate the involvement of tetraspanin CD9 in bone destruction in such diseases, we examined the expression and distribution of tetraspanin CD9 using murine experimental models of osteoporosis and arthritis. In results, CD9 protein is abundantly expressed on the activated osteoclasts in the bone tissues whose trabeculae are severely reduced in ovariectomy-induced osteoporosis. The expression of CD9 is also detected at the sites of bone erosion in arthritic lesions of collagen-induced arthritis (CIA), where tartate-resistant acid phosphatase (TRAP) staining-positive activated osteoclasts are present. These data suggest that tetraspanin CD9 play important roles in bone destructions in osteoporosis and arthritis, and therefore, functional alterations of tetraspanin CD9 may have therapeutic potential in such bone-resorptive disorders.

RGS18 acts as a negative regulator of osteoclastogenesis by modulating the acid-sensing OGR1/NFAT signaling pathway.

UNLABELLED: We showed that RGS18, a myeloid lineage-specific RGS protein that is inhibited after activation of the RANK/RANKL system, is a negative regulator of osteoclastogenesis. RGS18 acts through an external acidosis-sensing osteoclastogenic mechanism through the OGR1/NFAT pathway. INTRODUCTION: Osteoclasts are bone-resorbing multinuclear giant cells that are differentiated from mononuclear macrophage/monocyte lineage precursors stimulated by the RANK/RANKL system. The regulators of G-protein signaling (RGS) family is a diverse group of proteins that accelerate intrinsic GTP hydrolysis on heterotrimeric G-protein alpha subunits and play crucial roles in physiological regulation of G-protein-mediated cell signaling in various tissues and organs. We examined the expression and function of RGS18, a myeloid lineage-specific RGS protein, during osteoclastogenesis. MATERIALS AND METHODS: A macrophage/monocyte lineage cell line, RAW264.7, and primary osteoclast precursor monocytes derived from mouse bone marrow cultured with macrophage-colony stimulating factor (M-CSF) (bone marrow-derived monocytes [BMMs]) were used in this study. Both cell types differentiate into osteoclast-like cells on activation by RANKL. Expression of different RGS proteins, including RGS18, was assessed by gene-specific RT-PCR. The subcellular distribution of RGS18 on native osteoclasts in bone tissues, as well as in RAW264.7 cells, was examined by immunohistochemistry using a specific polyclonal antibody. Short interfering RNA against RGS18 was used to inhibit the function endogenous RGS18 in these cell types. Activation of NFATc1, an osteoclastogenic transcription factor, on external acidosis was assessed by visualizing the nuclear localization of NFATc1 visualized with anti-NFATc1 antibody. RESULTS: RAW264.7 and BMM cells both expressed mRNA for 10 different mammalian RGS proteins, including RGS18. Expression of RGS18 is significantly inhibited by RANKL both cell types, and inhibition of RGS18 function using RNA interference prominently enhanced osteoclastogenesis on stimulation with RANKL. The effect of RGS18 inhibition was reversed by blocking of proton-sensing OGR1 signaling, and overexpression of exogenous RGS18 inhibited extracellular acidosis-mediated NFATc1 activation. Immunohistochemical studies of mouse bone tissues revealed expression of RGS18 in osteoclasts in vivo. CONCLUSIONS: RGS18 acts as a negative regulator of the acidosis-induced osteoclastogenic OGR1/NFAT signaling pathway, and RANKL stimulates osteoclastogenesis by inhibiting expression of RGS18. Therefore, the results suggest a novel control mechanism of osteoclastogenesis by RGS proteins.

Autoantibodies to cyclic citrullinated peptide 2 (CCP2) are superior to other potential diagnostic biomarkers for predicting rheumatoid arthritis in early undifferentiated arthritis.

We evaluated the diagnostic value of anti-cyclic citrullinated peptide 2 (anti-CCP2) antibodies and other potential diagnostic biomarkers (IgM rheumatoid factor, anti-agalactosyl IgG antibodies, matrix metalloproteinase 3, C-reactive protein) for predicting early development of rheumatoid arthritis (RA). Patients were defined as having recent-onset undifferentiated arthritis (UA) if they had developed arthritis in two or more joints within the previous 2 years and could not be classified with a well-defined arthropathy. Baseline levels of biomarkers were measured in blood samples collected at the entry of the study and the patients were followed for 1 year to monitor development of RA. Diagnoses of RA and non-RA arthropathies were made according to individual standard diagnostic criteria. A total of 146 patients were enrolled in the study. In the follow-up year, 18 patients developed RA, 54 developed non-RA arthropathies, and 60 remained in the UA category. The sensitivity and specificity of the presence of anti-CCP2 antibodies for the diagnosis of RA were 83.3 and 93.0%, respectively. The positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of anti-CCP2 antibodies for RA (65.2, 97.2, and 91.7%, respectively) were higher than for any other biomarker. Combination of anti-CCP2 with any other biomarker only slightly improved each diagnostic value compared to the presence of anti-CCP2 alone. Among the anti-CCP2-positive patients, the average titer was significantly higher in those with RA than in non-RA or UA patients (163.7 +/- 138.4 vs 55.2 +/- 72.0 U/ml, p = 0.017). Anti-CCP2 antibodies are superior to any other single biomarker for predicting early development of RA in patients with recent-onset UA and the diagnostic value of anti-CCP2 alone is similar to that for biomarker combinations. Moreover, the anti-CCP2 antibody titer is useful to discriminate between patients at high risk for early developing RA from those at risk of developing non-RA arthropathies.

RANKL-induced expression of tetraspanin CD9 in lipid raft membrane microdomain is essential for cell fusion during osteoclastogenesis.

UNLABELLED: We showed that CD9, a member of tetraspanin superfamily proteins, is expressed in a specific membrane microdomain, called "lipid raft," and is crucial for cell fusion during osteoclastogenesis after activation of the RANK/RANKL system. INTRODUCTION: Osteoclasts are bone-resorbing multinuclear polykaryons that are essential for bone remodeling and are formed through cell fusion of mononuclear macrophage/monocyte lineage precursors. Although osteoclastogenesis has been shown to be critically regulated by the RANK/RANKL system, the mechanism how precursor cells fuse with each other remains unclear. We examined the function of CD9, a member of tetraspanin superfamily, which has previously been shown to form macromolecular membrane microdomains and to regulate cell-cell fusion in various cell types. MATERIALS AND METHODS: We used RAW264.7, a macrophage/monocyte lineage cell line, which can differentiate into osteoclast-like polykaryons on the application of RANKL. Expression and distribution of CD9 was assessed by Western blotting, fluorescence-assorted cell sorting (FACS) and immunohistochemistry with light and electron microscopy. A specific neutralizing antibody and RNA interference were used to inhibit the function of CD9, and green fluorescent protein (GFP)-CD9 was exogenously expressed to enhance the effect of CD9. The distribution of CD9 in lipid microdomain was examined by biochemical (sucrose density gradient) isolation and imaging technique. RESULTS: CD9 is expressed on cell surfaces of RAW264.7, which is enhanced by RANKL. Targeted inhibition of CD9 decreases the number of osteoclast-like cells. On the other hand, overexpression of CD9 promotes spontaneous cell fusion even in the absence of RANKL. CD9 is localized in detergent-insoluble "lipid raft" microdomain in RANKL stimulation, and disruption of lipid rafts markedly reduces the formation of osteoclast-like polykaryons. Immunohistochemical studies of bone tissues revealed the expression of CD9 in osteoclasts in vivo. CONCLUSIONS: These data suggest that function of tetraspanin CD9 and its expression in lipid rafts are crucial for cell fusion during osteoclastogenesis.

Adrenomedullin enhances angiogenic potency of bone marrow transplantation in a rat model of hindlimb ischemia.

BACKGROUND: Previous studies have shown that adrenomedullin (AM) inhibits vascular endothelial cell apoptosis and induces angiogenesis. We investigated whether AM enhances bone marrow cell-induced angiogenesis. METHODS AND RESULTS: Immediately after hindlimb ischemia was created, rats were randomized to receive AM infusion plus bone marrow-derived mononuclear cell (MNC) transplantation (AM+MNC group), AM infusion alone (AM group), MNC transplantation alone (MNC group), or vehicle infusion (control group). The laser Doppler perfusion index was significantly higher in the AM and MNC groups than in the control group (0.74+/-0.11 and 0.69+/-0.07 versus 0.59+/-0.07, respectively, P<0.01), which suggests the angiogenic potency of AM and MNC. Importantly, improvement in blood perfusion was marked in the AM+MNC group (0.84+/-0.08). Capillary density was highest in the AM+MNC group, followed by the AM and MNC groups. In vitro, AM inhibited MNC apoptosis, promoted MNC adhesiveness to a human umbilical vein endothelial cell monolayer, and increased the number of MNC-derived endothelial progenitor cells. In vivo, AM administration not only enhanced the differentiation of MNC into endothelial cells but also produced mature vessels that included smooth muscle cells. CONCLUSIONS: A combination of AM infusion and MNC transplantation caused significantly greater improvement in hindlimb ischemia than MNC transplantation alone. This effect may be mediated in part by the angiogenic potency of AM itself and the beneficial effects of AM on the survival, adhesion, and differentiation of transplanted MNCs.

Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy.

BACKGROUND: Pluripotent mesenchymal stem cells (MSCs) differentiate into a variety of cells, including cardiomyocytes and vascular endothelial cells. However, little information is available about the therapeutic potency of MSC transplantation in cases of dilated cardiomyopathy (DCM), an important cause of heart failure. METHODS AND RESULTS: We investigated whether transplanted MSCs induce myogenesis and angiogenesis and improve cardiac function in a rat model of DCM. MSCs were isolated from bone marrow aspirates of isogenic adult rats and expanded ex vivo. Cultured MSCs secreted large amounts of the angiogenic, antiapoptotic, and mitogenic factors vascular endothelial growth factor, hepatocyte growth factor, adrenomedullin, and insulin-like growth factor-1. Five weeks after immunization, MSCs or vehicle was injected into the myocardium. Some engrafted MSCs were positive for the cardiac markers desmin, cardiac troponin T, and connexin-43, whereas others formed vascular structures and were positive for von Willebrand factor or smooth muscle actin. Compared with vehicle injection, MSC transplantation significantly increased capillary density and decreased the collagen volume fraction in the myocardium, resulting in decreased left ventricular end-diastolic pressure (11+/-1 versus 16+/-1 mm Hg, P<0.05) and increased left ventricular maximum dP/dt (6767+/-323 versus 5138+/-280 mm Hg/s, P<0.05). CONCLUSIONS: MSC transplantation improved cardiac function in a rat model of DCM, possibly through induction of myogenesis and angiogenesis, as well as by inhibition of myocardial fibrosis. The beneficial effects of MSCs might be mediated not only by their differentiation into cardiomyocytes and vascular cells but also by their ability to supply large amounts of angiogenic, antiapoptotic, and mitogenic factors.

Circadian variation of endothelial function in idiopathic dilated cardiomyopathy.

This study measured flow-mediated dilation (FMD) of the brachial artery 3 times a day (6:30 a.m., 11:30 a.m., and 9 p.m.) in 7 normal subjects and 14 patients with idiopathic dilated cardiomyopathy (7 in New York Heart Association [NYHA] functional class I or II and 7 in NYHA functional class III or IV). FMD in normal subjects and patients in NYHA class I or II showed a circadian variation, being lowest in the morning and highest at night. Compared with them, FMD in patients in NYHA class III or IV was lower and almost constant during the day, showing loss of significant circadian variation in endothelial function in patients with congestive heart failure.

Determinants of rapid progression of aortic root dilatation and complications in Marfan syndrome.

BACKGROUND: Progressive aortic dilatation has prognostic significance in the Marfan syndrome. METHODS: To identify which patients were at high risk of rapid progression, we echocardiographically studied 43 patients (age 22 +/- 14 years) with the mean follow-up period of 5.2 +/- 3.2 years. Aortic diameters, left ventricular (LV) size, fractional shortening, and the severity of aortic and mitral regurgitation were assessed. Transmitral peak early and atrial flow velocities, their ratio and the deceleration time of peak early velocity were also obtained. RESULTS: Mean annual increases of aortic diameters were 0.4 +/- 0.3 mm at the annulus, 1.5 +/- 1.3 mm at the sinuses of Valsalva, 0.7 +/- 0.6 mm at the supraaortic ridge and 0.4 +/- 0.4 mm at the proximal ascending aorta. Patients were divided into 2 groups according to the aortic growth rate at the sinuses of Valsalva level: rapid (R, >3% per year, 15 patients) or slow (S, < or =3% per year, 28 patients) progression groups. Measured variables did not show significant differences between the 2 groups except older age, higher blood pressure and more severe aortic regurgitation in group R. Multiple regression analysis identified prolonged deceleration time as the most important variable predicting aortic complications. Aortic dissection occurred more frequently in group R (7 patients, 47%) than in group S (0%, P < 0.001). CONCLUSIONS: Marfan patients at older age, with higher blood pressure, and with significant aortic regurgitation were at high risk of progression of aortic dilatation, with the most remarkable increase at the sinuses of Valsalva. Prolonged deceleration time may relate to an increased risk for aortic complications.

Increase in cell adhesiveness on a poly(ethylene terephthalate) fabric by sintered hydroxyapatite nanocrystal coating in the development of an artificial blood vessel.

Nano-scaled sintered hydroxyapatite (HAp) crystals were covalently linked onto a poly(ethylene terephthalate) (PET) fabric substrate chemically modified by graft polymerization with gamma-methacryloxypropyl triethoxysilane (MPTS) for development of an artificial blood vessel. The weight gain of graft polymerization with poly(MPTS) on PET in benzyl alcohol containing H2O2 as an initiator increased as increasing the reaction time and finally reached a plateau value of about 3.5 wt%. The surface characterization of surface modification with poly(MPTS)-grafting was conducted by x-ray photoelectron spectroscopy. HAp nanocrystals of approximately 50 nm in diameter, monodispersed in pure ethanol, were coupled with alkoxysilyl groups of the poly(MPTS)-grafted PET substrate. The HAp nanocrystals were uniformly and strongly coated on the surface of the PET fabrics, although HAp particles adsorbed physically on the original PET without poly(MPTS) grafting were almost removed by ultrasonic wave treatment. More human umbilical vein endothelial cells adhered to the HAp/PET composite fabric compared with original PET after only 4 hours of initial incubation, and the same was observed on the collagen-coated PET. The coating of sintered HAp nanocrystals imparted bioactivity to the polyester substrate, which is a widely used biomedical polymer, without a coating of adhesion proteins derived from animals, such as collagen or gelatin. A prototype of an artificial blood vessel was finally fabricated by use of HAp/PET composite.

Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure.

BACKGROUND: Ghrelin is a novel growth hormone-releasing peptide that also induces vasodilation, inhibits sympathetic nerve activity, and stimulates feeding through growth hormone-independent mechanisms. We investigated the effects of ghrelin on left ventricular (LV) function, exercise capacity, and muscle wasting in patients with chronic heart failure (CHF). METHODS AND RESULTS: Human synthetic ghrelin (2 microg/kg twice a day) was intravenously administered to 10 patients with CHF for 3 weeks. Echocardiography, cardiopulmonary exercise testing, dual x-ray absorptiometry, and blood sampling were performed before and after ghrelin therapy. A single administration of ghrelin elicited a marked increase in serum GH (25-fold). Three-week administration of ghrelin resulted in a significant decrease in plasma norepinephrine (1132+/-188 to 655+/-134 pg/mL; P<0.001). Ghrelin increased LV ejection fraction (27+/-2% to 31+/-2%; P<0.05) in association with an increase in LV mass and a decrease in LV end-systolic volume. Treatment with ghrelin increased peak workload and peak oxygen consumption during exercise. Ghrelin improved muscle wasting, as indicated by increases in muscle strength and lean body mass. These parameters remained unchanged in 8 patients with CHF who did not receive ghrelin therapy. CONCLUSIONS: These preliminary results suggest that repeated administration of ghrelin improves LV function, exercise capacity, and muscle wasting in patients with CHF.

Failure to prevent progressive dilation of ascending aorta by aortic valve replacement in patients with bicuspid aortic valve: comparison with tricuspid aortic valve.

BACKGROUND: Patients with bicuspid aortic valve (BAV) have been frequently complicated with ascending aortic dilation possibly because of hemodynamic burdens by aortic stenosis (AS) or regurgitation (AR) or congenital fragility of the aortic wall. METHODS AND RESULTS: To clarify if the aortic dilation could be prevented by aortic valve replacement (AVR) in BAV patients, we studied 13 BAV (8 AR dominant, 5 AS dominant) and 14 tricuspid aortic valve (TAV) patients (7 AR, 7 AS) by echocardiography before and after AVR (9.7+/-4.8 years). We also studied 18 BAV (11 AR, 7 AS) without AVR. Diameters of the sinuses of Valsalva, sinotubular junction and the proximal aorta were measured. The annual dilation rate was calculated by dividing changes of diameters during the follow-up period by the body surface area and the observation interval. We found that aortic dilation in BAV patients tended to be faster than that in TAV patients, although a significant difference was found only at the proximal aorta (0.18+/-0.08 versus -0.08+/-0.08 mm/(m2/year), P=0.03). BAV patients with and without AVR showed similar progressive dilation. AR dominant group showed tendency of more progressive dilation than AS dominant group in BAV, although it did not reach statistical significance. TAV patients did not show further aortic dilation after AVR. CONCLUSIONS: AVR could not prevent progressive aortic dilation in BAV. Since the aorta did not dilate in TAV, progressive aortic dilation in BAV seems mainly due to the fragility of the aortic wall rather than hemodynamic factors.

Effects of adrenomedullin inhalation on hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension.

BACKGROUND: Adrenomedullin (AM) is a potent pulmonary vasodilator peptide. However, whether intratracheal delivery of aerosolized AM has beneficial effects in patients with idiopathic pulmonary arterial hypertension remains unknown. Accordingly, we investigated the effects of AM inhalation on pulmonary hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension. METHODS AND RESULTS: Acute hemodynamic responses to inhalation of aerosolized AM (10 microg/kg body wt) were examined in 11 patients with idiopathic pulmonary arterial hypertension during cardiac catheterization. Cardiopulmonary exercise testing was performed immediately after inhalation of aerosolized AM or placebo. The work rate was increased by 15 W/min until the symptom-limited maximum, with breath-by-breath gas analysis. Inhalation of AM produced a 13% decrease in mean pulmonary arterial pressure (54+/-3 to 47+/-3 mm Hg, P<0.05) and a 22% decrease in pulmonary vascular resistance (12.6+/-1.5 to 9.8+/-1.3 Wood units, P<0.05). However, neither systemic arterial pressure nor heart rate was altered. Inhalation of AM significantly increased peak oxygen consumption during exercise (peak o(2), 14.6+/-0.6 to 15.7+/-0.6 mL. kg(-1). min(-1), P<0.05) and the ratio of change in oxygen uptake to that in work rate (Deltao(2)/DeltaW ratio, 6.3+/-0.4 to 7.0+/-0.5 mL. min(-1). W(-1), P<0.05). These parameters remained unchanged during placebo inhalation. CONCLUSIONS: Inhalation of AM may have beneficial effects on pulmonary hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension.

Hybrid cell-gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) migrate to injured vascular endothelium and differentiate into mature endothelial cells. We investigated whether transplantation of vasodilator gene-transduced EPCs ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. METHODS AND RESULTS: We obtained EPCs from cultured human umbilical cord blood mononuclear cells and constructed plasmid DNA of adrenomedullin (AM), a potent vasodilator peptide. We used cationic gelatin to produce ionically linked DNA-gelatin complexes. Interestingly, EPCs phagocytosed plasmid DNA-gelatin complexes, which allowed nonviral, highly efficient gene transfer into EPCs. Intravenously administered EPCs were incorporated into the pulmonary vasculature of immunodeficient nude rats given MCT. Transplantation of EPCs alone modestly attenuated MCT-induced pulmonary hypertension (16% decrease in pulmonary vascular resistance). Furthermore, transplantation of AM DNA-transduced EPCs markedly ameliorated pulmonary hypertension in MCT rats (39% decrease in pulmonary vascular resistance). MCT rats transplanted with AM-expressing EPCs had a significantly higher survival rate than those given culture medium or EPCs alone. CONCLUSIONS: Umbilical cord blood-derived EPCs had a phagocytosing action that allowed nonviral, highly efficient gene transfer into EPCs. Transplantation of AM gene-transduced EPCs caused significantly greater improvement in pulmonary hypertension in MCT rats than transplantation of EPCs alone. Thus, a novel hybrid cell-gene therapy based on the phagocytosing action of EPCs may be a new therapeutic strategy for the treatment of pulmonary hypertension.