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Hayabuchi, Y., N. B. Standen, and N. W. Davies. Angiotensin II inhibits and alters kinetics of voltage-gated [K.sup.+] channels of rat arterial smooth muscle. Am J Physiol Heart Circ Physiol 281: H2480-H2489, 2001.--The vasoconstrictor angiotensin II (ANG II) inhibits several types of [K.sup+] channels. We examined the inhibitory mechanism of ANG II on voltage-gated [K.sup.+] ([K.sub.v) currents (I.sub.Kv]) recorded from isolated rat arterial smooth muscle using patch-clamp techniques. Application of 100 nM ANG II accelerated the activation of [I.sub.Kv] but also caused inactivation. These effects were abolished by the A[T.sub.1] receptor antagonist losartan. The protein kinase A (PKA) inhibitor Rp-cyclic 3',5'-hydrogen phosphothioate adenosine (100 [micro]M) and an analog of diacylglycerol, 1,2dioctanyoyl-rac-glycerol (2 [micro]M), caused a significant reduction of [I.sub.Kv] Furthermore, the combination of 5 [micro]M PKA inhibitor peptide 5-24 (PKA-IP) and 100 [micro]M protein kinase C (PKC) inhibitor peptide 19-27 (PKC-IP) prevented the inhibition by ANG II, although neither alone was effective. The ANG II effect seen in the presence of PKA-IP remained during addition of the [Ca.sup.2+]-dependent PKC inhibitor Go6976 (1 [micro]M) but was abolished in the presence of 40 [micro]M PKC-[epsilon] translocation inhibitor peptide. These results demonstrate that ANG II inhibits Ky channels through both activation of PKC-[epsilon] and inhibition of PKA. potassium channel; activation; inactivation; protein kinase A; protein kinase C Received 22 May 2001; Accepted in Final Form 7 August 2001

We evaluated regional right ventricular wall motion during systole in patients with surgically repaired tetralogy of Fallot (TOF) using color kinesis imaging. Color kinesis images were obtained in a subcostal sagittal view from 19 patients with repaired TOF (TOF group), aged 3 to 5 years, and 20 age-matched normal subjects (control group). For regional wall motion analysis, the endocardial motion distance and the fractional area change (FAC) were calculated for 6 segments obtained from color kinesis images. The endocardial inward excursion distances and the FACs in the upper, middle, and lower posterior segments of the TOF group were significantly greater than those of the control group (p <0.01 for each segment). The upper anterior segment showed significantly reduced inward excursion distance and FAC in the TOF group than in the control group (p <0.01, both). The dyskinetic outward excursion distances of the middle and lower posterior segments were significantly lower in the TOF group than in the control group (p <0.01, both). In the upper and middle anterior segments, the endocardial outward excursion distances were significantly higher in the TOF group than in the control group (p <0.01 and 0.05). Correlation between right ventriculographic and color kinesis measurements was excellent (y = 1.14x - 1.30, r = 0.87 for the endocardial inward excursion, and y = 1.03x +/- 0.56, r = 0.91 for the FAC). In conclusion, color kinesis is a useful method for assessing regional right ventricular wall motion. Segmental analysis of color kinesis images provides accurate, automated, and quantitative diagnosis of regional right ventricular wall motion abnormalities in patients with surgically repaired TOF. [ABSTRACT FROM AUTHOR]

Abstract: Since, in addition to its growth-promoting actions, insulin-like growth factor-I (IGF-I) has rapid vasoactive actions, we investigated the effects of IGF-I on whole-cell ATP-sensitive K+ (KATP) currents of rat mesenteric arterial smooth muscle cells. IGF-I (10 or 30nM) reduced KATP currents activated by pinacidil or a membrane permeant cAMP analogue. Inhibition of phospholipase C, protein kinase C, protein kinase A, mitogen-activated protein kinase or mammalian target of rapamycin (mTOR) did not prevent the action of IGF-I. However, inhibition of KATP currents by IGF-I was abolished by the tyrosine kinase inhibitor genistein or the phosphoinositide 3-kinase inhibitors, LY 294002 and wortmannin. Intracellular application of either phosphatidylinositol 4,5-bisphosphate (PIP2) or phosphatidylinositol 3,4,5-trisphosphate (PIP3) increased the KATP current activated by pinacidil and abolished the inhibitory effect of IGF-I. Thus, we show regulation of arterial KATP channels by polyphosphoinositides and report for the first time that IGF-I inhibits these channels via a phosphoinositide 3-kinase-dependent pathway. [Copyright &y& Elsevier]

Examines the inhibitory mechanism of angiotensin II (ANG II) on voltage-gated K[sup +] channels of rat arterial smooth muscle. Use of patch-clamp techniques; Description of ANG II; Role of changes in intracellular [Ca[sup 2+]] in the control of vascular smooth muscle tone.

Presents information on a study which examined the inhibitory mechanism of angiotensin II on voltage-gated potassium currents from isolated rat arterial smooth muscle. Preparation of vascular smooth muscle cells; Technique used in recording single channel currents from smooth muscle cells; Properties of potassium channel currents of rat arterial smooth muscle.

Aims/hypothesis: Sulphonylureas stimulate insulin secretion by closing ATP-sensitive potassium (KATP) channels in the pancreatic beta-cell membrane. KATP channels are also found in other tissues, including heart and smooth muscle, where they link cellular metabolism to electrical activity. The sulphonylurea gliclazide blocks recombinant beta-cell KATP channels (Kir6.2/SUR1) but not heart (Kir6.2/SUR2A) or smooth muscle (Kir6.2/SUR2B) KATP channels with high potency. In this study, we examined the specificity of gliclazide for the native (as opposed to recombinant) KATP channels in beta cells, heart and smooth muscle. Methods: The action of the drug was studied by whole-cell current recordings of native KATP channels in isolated pancreatic beta-cells and myocytes from heart and smooth muscle. Results: Gliclazide blocked whole-cell beta-cell KATP currents with an IC50 of 184 ± 30 nmol/l (n = 6–10) but was much less effective in cardiac and smooth muscle (IC50s of 19.5 ± 5.4 μmol/l (n = 6–12) and 37.9 ± 1.0 μmol/l (n = 5–10), respectively). In all three tissues, the action of the drug on whole-cell KATP currents was rapidly reversible. In inside-out patches on beta-cells, gliclazide (1 μmol/l) produced a maximum of 66 ± 13 % inhibition (n = 5), compared with more than 98 % block in the whole-cell configuration. Conclusion/interpretation: Gliclazide is a high-potency sulphonylurea which shows specificity for the pancreatic beta-cell KATP channel over heart and smooth muscle. In this respect, it differs from glibenclamide. The difference in the maximal block observed in the excised patch and whole-cell recordings from beta-cells, may be due to the absence of intracellular Mg-nucleotides in the excised patch experiments. [Diabetologia (2001) 44: 1019–1025] [ABSTRACT FROM AUTHOR]

Unlabelled: Retrograde holodiastolic flow in the abdominal aorta (retrograde flow) detected by pulsed Doppler echocardiography is usually noted in patients with aortic regurgitation or patent ductus arteriosus. Similar abnormal flow often is present in patients with acute phase Kawasaki Disease (KD). In 21 patients with acute phase KD, 15 had a retrograde flow. Retrograde flow was recognised in only 3 of patients with acute infection (n = 31) and in no healthy controls (n = 10). The ratio of the time velocity integral for diastolic retrograde flow to that for antegrade flow (regurgitant fraction) was significantly greater in patients with KD (median value 23%) than in patients with acute infection (1%) or healthy individuals (1%) (P < 0.001 for both). Four patients with coronary arterial involvement (one with an aneurysm and three with transient dilation of the coronary arteries) had a greater regurgitant fraction than the 17 patients without coronary arterial involvement (median values: 31% versus 18%, P < 0.05). The C-reactive protein was increased for a longer period of time in patients with KD with a greater regurgitant fraction (P < 0.01). Plasma nitric oxide (NO) metabolite concentrations were significantly greater in patients with KD than in those with acute infection or in healthy controls (P < 0.001 for both). There was a positive correlation between plasma NO metabolite concentrations and the regurgitant fraction in patients with KD (r = 0.69).Conclusion: Retrograde flow in the abdominal aorta is increased in patients with Kawasaki disease. Further studies are needed to clarify the causal relationship between the abnormal flow and the overproduction of nitric oxide. [ABSTRACT FROM AUTHOR]

Although acidosis induces vasodilation, the vascular responses mediated by large-conductance Ca2+-activated K+ (KCa) channels have not been investigated in coronary artery smooth muscle cells. We therefore investigated the response of porcine coronary arteries and smooth muscle cells to acidosis, as well as the role of KCa channels in the regulation of muscular tone. Acidosis (pH 7.3–6.8), produced by adding HCl to the extravascular solution, elicited concentration-dependent relaxation of precontracted, endothelium-denuded arterial rings. Glibenclamide (20 µM) significantly inhibited the vasodilatory response to acidosis (pH 7.3-6.8). Charybdotoxin (100 nM) was effective only at pH 6.9–6.8. When we exposed porcine coronary artery smooth muscle cells to a low-pH solution, KCa channel activity in cell-attached patches increased. However, pretreatment of these cells with 10 or 30 µM O, O′-bis(2-aminophenyl)ethyleneglycol- N, N, N′, N′-tetraacetic acid tetrakis(acetoxymethyl)ester (BAPTA-AM), a Ca2+ chelator for which the cell membrane is permeable, abolished the H+-mediated activation of KCa channels in cell-attached patches. Under these circumstances H+ actually inhibited KCa channel activity. When inside-out patches were exposed to a [Ca2+] of 10–6 M [adjusted with ethyleneglycolbis(β-aminoethylester)- N, N, N′, N′-tetraacetic acid (EGTA) at pH 7.3], KCa channels were activated by H+ concentration dependently. However, when these patches were exposed to a [Ca2+] of 10–6 M adjusted with BAPTA at pH 7.3, H+ inhibited KCa channel activity. Extracellular acidosis had no significant direct effect on KCa channels, suggesting that extracellular H+ exerts its effects after transport into the cell, and that KCa channels are regulated by intracellular H+ and by cytosolic free Ca2+ modulated by acute acidosis. These results indicate that the modulation of KCa channel kinetics by acidosis plays an important role in the determination of membrane potential and, hence, coronary arterial tone. [ABSTRACT FROM AUTHOR]

Background: Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy characterized by prominent trabeculations. Detailed characteristics of biventricular noncompaction (BiVNC) remain unknown. This study aimed to elucidate the clinical characteristics and genetic landscape of BiVNC., Methods and Results: We recruited children with left ventricular noncompaction from Japanese multi-institutional centers from 2013 to 2021. Left ventricular noncompaction was classified as BiVNC, congenital heart disease, arrhythmia, dilated cardiomyopathy, or normal function. In these patients, cardiomyopathy-associated genes were screened. A total of 234 patients (127 male; mean age, 4 months [range, 0-6.6 years]) were enrolled in this study, of whom 25 had BiVNC; 55, normal function; 84, dilated cardiomyopathy; 38, congenital heart disease; and 32, arrhythmia. BiVNC was diagnosed during the perinatal period in 10 patients, in whom the prevalence was higher than that in other patients. A total of 14 patients in the group with BiVNC had congenital heart disease, but not necessarily right heart lesions. Left ventricular dyskinesis was frequently observed in the lateral wall (24%) and apex (28%). Eleven pathogenic variants were found in 11 patients with BiVNC (44.0%). The group with BiVNC had a higher ratio of mitochondrial and developmental gene variants than the other groups. Among all groups, the group with BiVNC had the worst survival rate ( P =0.0009)., Conclusions: Pediatric patients with BiVNC had a high rate of ventricular dyskinesis and poor outcome. A comprehensive and careful screening for disease-causing genes and phenotype may help identify specific patients with left ventricular noncompaction and mortality-related cardiac phenotypes.

Aims: Limited data exist on risk factors for the long-term outcome of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). We focused on the index of pulmonary vascular disease (IPVD), an assessment system for pulmonary artery pathology specimens. The IPVD classifies pulmonary vascular lesions into four categories based on severity: (1) no intimal thickening, (2) cellular thickening of the intima, (3) fibrous thickening of the intima, and (4) destruction of the tunica media, with the overall grade expressed as an additive mean of these scores. This study aimed to investigate the relationship between IPVD and the long-term outcome of CHD-PAH., Methods: This retrospective study examined lung pathology images of 764 patients with CHD-PAH aged <20 years whose lung specimens were submitted to the Japanese Research Institute of Pulmonary Vasculature for pulmonary pathological review between 2001 and 2020. Clinical information was collected retrospectively by each attending physician. The primary endpoint was cardiovascular death., Results: The 5-year, 10-year, 15-year, and 20-year cardiovascular death-free survival rates for all patients were 92.0%, 90.4%, 87.3%, and 86.1%, respectively. The group with an IPVD of ≥2.0 had significantly poorer survival than the group with an IPVD <2.0 ( P  = .037). The Cox proportional hazards model adjusted for the presence of congenital anomaly syndromes associated with pulmonary hypertension, and age at lung biopsy showed similar results (hazard ratio 4.46; 95% confidence interval: 1.45-13.73; P  = .009)., Conclusions: The IPVD scoring system is useful for predicting the long-term outcome of CHD-PAH. For patients with an IPVD of ≥2.0, treatment strategies, including choosing palliative procedures such as pulmonary artery banding to restrict pulmonary blood flow and postponement of intracardiac repair, should be more carefully considered., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Chida-Nagai, Masaki, Maeda, Sasaki, Sato, Muneuchi, Ochiai, Murayama, Tahara, Shiono, Shinozuka, Kono, Machida, Toyooka, Sugimoto, Nakamura, Akagi, Kondo, Kasahara, Kotani, Koizumi, Oda, Harada, Nakajima, Murata, Nagata, Yatsunami, Kobayashi, Matsunaga, Inoue, Yamagishi, Nakagawa, Ohtani, Yamamoto, Ito, Hokosaki, Kuwahara, Masutani, Nomura, Wada, Sawada, Abiko, Takahashi, Ishikawa, Okada, Naitoh, Toda, Ando, Masuzawa, Hoshino, Kawada, Nomura, Ueno, Ohashi, Tachibana, Cao, Ueda, Yanagi, Koide, Mitsushita, Higashi, Minosaki, Hayashi, Okamoto, Kuraishi, Ehara, Ishida, Horigome, Murakami, Takei, Ishii, Harada, Hirata, Maeda, Tatebe, Ota, Hayabuchi, Sakazaki, Sasaki, Hirono, Suzuki, Yasuda, Takeda, Sawai, Miyaji, Kitagawa, Nakai, Kakimoto, Agematsu, Manabe and Saiki.)

Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia that is characterized by thoracic hypoplasia, polydactyly, oral abnormalities, and congenital heart disease. It is caused by pathogenic variants in the EVC or EVC2 genes. We report a case of a newborn with a compound heterozygous variant comprising NM&#95;147127.5: c.1991dup:[p.Lys665Glufs*10] in the EVC2 gene and a novel large deletion involving exon 1 in EVC and exons 1-7 in EVC2., (© 2022. The Author(s).)

Costello syndrome (CS) is an autosomal-dominant disorder characterized by distinctive facial features, hypertrophic cardiomyopathy, skeletal abnormalities, intellectual disability, and predisposition to cancers. Germline variants in HRAS have been identified in patients with CS. Intragenic HRAS duplications have been reported in three patients with a milder phenotype of CS. In this study, we identified two known HRAS variants, p.(Glu63&#95;Asp69dup), p.(Glu62&#95;Arg68dup), and one novel HRAS variant, p.(Ile55&#95;Asp57dup), in patients with CS, including a patient with craniosynostosis. These intragenic duplications are located in the G3 domain and the switch II region. Cells expressing cDNA with these three intragenic duplications showed an increase in ELK-1 transactivation. Injection of wild-type or mutant HRAS mRNAs with intragenic duplications in zebrafish embryos showed significant elongation of the yolk at 11 h postfertilization, which was improved by MEK inhibitor treatment, and a variety of developmental abnormalities at 3 days post fertilization was observed. These results indicate that small in-frame duplications affecting the G3 domain and switch II region of HRAS increase the activation of the ERK pathway, resulting in developmental abnormalities in zebrafish or patients with CS., (© 2021 Wiley Periodicals LLC.)

Aims: We evaluated pulmonary arterial (PA) vasa vasorum (VV) in Fontan candidate patients with a novel three-dimensional (3D) imaging technique using optical coherence tomography (OCT)., Methods and Results: This prospective study assessed the development of adventitial VV in the distal PA of 10 patients with bidirectional Glenn circulation (BDG group, 1.6 ± 0.3 years) and Fontan circulation (Fontan group, 3.3 ± 0.3 years), and in 20 children with normal PA haemodynamics and morphology (Control group, 1.5 ± 0.3 years). We assessed the PA VV with two-dimensional (2D) cross-sectional, multi-planar reconstruction (MPR), and volume rendering (VR) imaging. VV development was evaluated by the VV area/volume ratio, defined as the VV area/volume divided by the adventitial area/volume. Compared to the control group, the observed VV number and diameter on 3D images of MPR and VR were significantly higher, and curved and torturous-shaped VV were more frequently observed in the BDG and Fontan groups (P < 0.001, all). The median VV volume ratio was significantly greater in the BDG than in the control group (3.38% vs. 0.61%; P < 0.001). Although the VV volume ratio decreased significantly after the Fontan procedure (2.64%, P = 0.005 vs. BDG), the ratio remained higher than in the control group (P < 0.001 vs. control)., Conclusion: 3D OCT imaging is a novel method that can be used to evaluate adventitial PA VV and may provide pathophysiological insight into the role of the PA VV in these patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

A disintegrin and metalloprotease 17 (ADAM17) is the major sheddase that processes more than 80 substrates, including tumour necrosis factor-α (TNFα). The homozygous genetic deficiency of ADAM17 causing a complete loss of ADAM17 expression was reported to be linked to neonatal inflammatory skin and bowel disease 1 (NISBD1). Here we report for the first time, a family with NISBD1 caused by functionally confirmed compound heterozygous missense variants of ADAM17, namely c.1699T>C (p.Cys567Arg) and c.1799G>A (p.Cys600Tyr). Both variants were detected in two siblings with clinical features of NISBD1, such as erythroderma with exudate in whole body, recurrent skin infection and sepsis and prolonged diarrhoea. In a cell-based assay using Adam10/17 double-knockout mouse embryonic fibroblasts (Adam10/17 -/- mEFs) exogenously expressing each of these mutants, phorbol 12-myristate 13-acetate-stimulated shedding was strongly reduced compared with wild-type ADAM17. Thus, in vitro functional assays demonstrated that both missense variants cause the loss-of-function of ADAM17, resulting in the development of NISBD1. Our study further expands the spectrum of genetic pathology underlying ADAM17 in NISBD1 and establishes functional assay systems for its missense variants.

Under a warming climate and urban heat island effects, cooling behaviours are increasingly important for city dwellers. Cooling actions, especially air conditioning, receive increasing scrutiny in social science, as does engagement and communication on behaviours spanning adaptation and mitigation. In response, this paper evaluates the relation between residents' adaptation and mitigation behaviours around cooling in Fukuoka, Japan, and draws lessons for communication on encouraging adaptation and mitigation actions. A survey distributed to residents in six areas of Fukuoka, Japan, assessed perceptions of global warming and urban heat island effects, frequency of mitigation and adaptation behaviours, use of air conditioning, electricity bills and evaluation of green spaces. We observe a difference between respondents using air conditioning with an energy-saving (i.e. mitigation) focus, versus those using air conditioning with an adaptation (i.e. cooling) focus. We also note residents emphasising mitigation behaviours may use shade in parks or cooling centres as alternative cooling strategies, but that awareness of effective air conditioning use may be lacking. Our findings build on existing literature by reinforcing - in a subtropical context - the need to reconsider practices around air conditioner use; and illustrate the value of a breadth of messages to promote joint mitigation and adaptation actions., Competing Interests: The authors report no declarations of interest., (© 2020 The Authors.)

Background: Although advances in cardiac surgery have led to an increased number of survivors with congenital heart disease (CHD), epidemiological data regarding the pregnancies and deliveries of patients with repaired CHD are scarce., Methods and results: In this study, we retrospectively reviewed the clinical outcomes of pregnancies and deliveries of women with repaired CHD. Overall, 131 women with repaired CHD were enrolled and there were 269 gestations. All patients were classified as New York Heart Association (NYHA) Class I or II. The prevalence of cesarean sections was higher in patients with (CyCHD) than without (AcyCHD) a past history of cyanosis (51% vs. 19%, respectively; P<0.01). There were 228 offspring from 269 gestations and the most prevalent neonatal complication was premature birth (10%), which was more frequent in the CyCHD than AcyCHD group (15.7% vs. 5.6%, respectively; P<0.01). Five maternal cardiac complications during delivery were observed only in the CyCHD group (8%); these were classified as NYHA Class II and none was fatal., Conclusions: Delivery was successful in most women with repaired CHD who were classified as NYHA Class I or II, although some with CyCHD and NYHA Class II required more attention. Cesarean sections were more common in the CyCHD than AcyCHD group, and CyCHD may be a potential risk for preterm deliveries.

A 13-year-old girl with a single ventricle and bilateral systemic-to-pulmonary shunts developed hypoxia due to shunt stenosis, which was caused by a methicillin-sensitive Staphylococcus aureus abscess. Stent implantation associated with appropriate antibiotic administration was crucial to dilate and maintain shunt patency.

A 1-month-old Japanese infant with cardiac rhabdomyoma was diagnosed with TSC2 / PKD1 contiguous gene syndrome by targeted panel sequencing with subsequent quantitative polymerase chain reaction that revealed gross monoallelic deletion, including parts of two genes: exons 19-42 of TSC2 and exons 2-46 of PKD1 . Early molecular diagnosis can help to detect bilateral renal cyst formation and multidisciplinary follow-up of this multisystem disease., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) 2020.)

Right ventricle (RV) has frequently been described as the forgotten ventricle in the circulation. However, its importance in various cardiac diseases is now unquestioned. This recognition has led to improved risk stratification and development of algorithms for intervention, which incorporate measurements of RV function as key components of the assessment of many conditions. The diastolic function plays an important role in determining ventricular filling and stroke volume. Abnormal left ventricular (LV) diastolic function has been recognized in many cardiovascular diseases and is associated with worse outcomes, including total mortality and hospitalizations due to heart failure. In this review, we define what global RV diastolic function is, and how to measure it. This article indicates the validation of kinematic model parameters for assessing RV diastolic function. J. Med. Invest. 67 : 11-20, February, 2020.