Natto (fermented soybeans)-induced anaphylaxis in a surfer with the possibility of sensitization to poly(γ-glutamic acid) from cutaneous exposure to jellyfish sting: a case report.

BACKGROUND: We report a case of anaphylaxis induced by natto (fermented soybeans) allergy that occurred following dermal sensitization from a jellyfish sting. CASE PRESENTATION: A 49-year-old male presented to the emergency room complaining of an acute onset of erythema with pruritis that appeared while he was surfing. Given that his heart rate dropped to ~ 40 bpm without a decline in blood pressure or oxygen saturation, we suspected anaphylaxis and administered 0.5 mg of adrenaline intramuscularly. Immediately after the muscular adrenaline injection, his heart rate recovered to ~ 60-70 bpm. CONCLUSIONS: The major allergen that induces natto allergy is poly(γ-glutamic acid) (PGA), which is present in its mucilage. Given that PGA is also produced by jellyfish tentacles, it can be inferred that the PGA sensitization occurred via dermal exposure to jellyfish PGA. This is an example of a food allergy induced by animal stings. As PGA is a high-molecular-weight polymer, natto allergy, despite being IgE-mediated, often presents with late-onset anaphylaxis, which typically develops half a day after digestion. PGA has a wide range of applications in pharmaceuticals, cosmetics, and foods. Patients may develop allergic symptoms and experience repeated anaphylaxis with no known cause. Therefore, it is important to obtain a detailed medical history and individually instruct patients suspected of being allergic to PGA to avoid PGA-containing products.

Relation between Oscillometric Measurement of Central Hemodynamics and Left Ventricular Hypertrophy in Hypertensive Patients.

INTRODUCTION: The augmentation index (AIx) or central systolic blood pressure (SBP), measured by radial applanation tonometry, has been reported to be independently associated with left ventricular hypertrophy (LVH) in Japanese hypertensive patients. Cuff-based oscillometric measurement of the AIx using Mobil-O-Graph® showed a low or moderate agreement with the AIx measurement with other devices. METHODS: The AIx measured using the Mobil-O-Graph was validated against the tonometric measurements of the radial AIx measured using HEM-9000AI in 110 normotensive healthy individuals (age, 21-76 years; 50 men). We investigated the relationship between the central hemodynamics assessed using the Mobil-O-Graph and LVH in 100 hypertensive patients (age, 54-75 years; 48 men), presenting a wall thickness of ≥11 mm and ≥10 mm in men and women, respectively. RESULTS: Although the Mobil-O-Graph-measured central AIx showed no negative values, it correlated moderately with the HEM-9000AI-measured radial AIx (r = 0.602, p < 0.001) in the normotensive individuals. The hypertensive patients did not show a significant difference in the central SBP between the sexes, but the central AIx was lower in men than in women. The independent determinants influencing left ventricle (LV) mass index (LVMI) (R2 = 0.362; adjusted R2 = 0.329, p < 0.001) were heart rate (ß = -0.568 ± 0.149, p < 0.001), central SBP (ß = 0.290 ± 0.100, p = 0.005), and aortic root diameter (ß = 1.355 ± 0.344, p = 0.001). Age (ß = -0.025 ± 0.124, p = 0.841) and the central AIx (ß = 0.120 ± 0.131, p = 0.361) were not independently associated with the LVMI. The area under the receiver operator characteristic curve to evaluate the diagnostic performance of the central AIx for the presence of LVH (LVMI >118 g/m2 in men or >108 g/m2 in women) was statistically significant in men (0.875, p < 0.001) but not in women (0.622, p = 0.132). In men, a central AIx of 28.06% had a sensitivity of 83.3% and specificity of 80.0% for detecting LVH. CONCLUSIONS: AIx measurement in men provided useful prognostic information for the presence of LVH. Pulse-wave analysis assessed using the Mobil-O-Graph may be a valuable tool for detecting LVH in hypertensive patients.

A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design.

BACKGROUND: Leakage of Ca2+ from the sarcoplasmic reticulum (SR) is a critical contributing factor to heart failure pathophysiology. Therefore, reducing SR Ca2+ leaks may provide significant additive benefits when used in combination with conventional therapies. Dantrolene, a drug routinely used to treat malignant hyperthermia, also stabilizes the cardiac isoform of the release channel (RyR2), thus decreasing SR Ca2+ leaks. The purpose of this study is to evaluate the effect of chronic administration of dantrolene on heart failure and lethal arrhythmia in patients with chronic heart failure and reduced ejection fraction in a multicenter, randomized, double-blind, controlled study. METHODS: Patients with chronic heart failure who had functional status of New York Heart Association class II and III and a left ventricular ejection fraction <40% were treated according to the Japanese Circulation Society, the European Society of Cardiology, and the American Heart Association/the American College of Cardiology guidelines for diagnosis and treatment of acute and chronic heart failure. Patients were randomized and divided into two groups in a double-blind fashion: dantrolene group and placebo group (target sample size: 300 cases). These drugs were administered for 96 weeks. The primary endpoint is cardiovascular death, first hospitalization for exacerbation of heart failure, or lethal arrhythmia [ventricular tachycardia (VT) storm, sustained VT, ventricular fibrillation] for 2 years after starting administration of dantrolene 1 cap (25mg) three times daily (if not tolerable, two times daily) or matching placebo. RESULTS: This paper presents the rationale and trial design of the study. Recruitment for the study started on 8 December 2017. CONCLUSIONS: The results of this trial will clarify the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction during guideline-directed medical treatment.

[Risk of Euglycemic Diabetic Ketoacidosis Due to Low-carbohydrate Diet While Taking Empagliflozin: a Case Report].

Empagliflozin reduces blood glucose levels independently of insulin secretion by reducing glucose reabsorption in the proximal renal tubules through inhibition of sodium-glucose cotransporter 2 (SGLT2). Because SGLT2 inhibitors have a different mechanism of action to conventional antidiabetic drugs, recommendations have been issued about the management of specific side effect such as ketoacidosis, urinary tract infection, and genital infection. There have been some reports of SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis (euDKA), but there have been few reports about euDKA in patients with type 2 diabetes using SGLT2 inhibitors while on a low-carbohydrate diet. Here we report a patient who developed euDKA after starting a very low-carbohydrate diet while taking empagliflozin. A 51-year-old man was hospitalized with nausea and vomiting, and investigations revealed metabolic acidosis. euDKA was diagnosed from the information about medications in his drug notebook and a history of eating a low-carbohydrate diet (1900 kcal, consisting of 5.7% carbohydrate, 21.1% protein, 47.3% fat and 25.9% alcohol) for 4 d. The patient improved after infusion of acetated Ringer's solution with 5% glucose and administration of regular insulin. It is necessary for physicians and pharmacists to thoroughly inform patients about the side effects of SGLT2 inhibitors such as ketoacidosis, urinary tract infection, and genital infection. Patients should also be advised about the higher risk of euDKA associated with a low-carbohydrate diet while taking SGLT2 inhibitors.

Cuff-Based Oscillometric Measurements of Central Hemodynamics: Factors Influencing Central Augmentation Pressure in Normotensive Japanese Individuals.

BACKGROUND: Recently, new devices using oscillometric cuff have been developed to derive central blood pressure (BP) waveform from brachial BP waveform. Late systolic pressure augmentation of central BP waveform is a marker of central hemodynamics. Mobil-O-Graph, a cuff-based oscillometric device, can assess central augmentation pressure (AP) together with central BP. Central AP measurement using the Mobil-O-Graph in the European population was reported to be associated with age and sex. However, factors influencing central AP in the Asian population have not been shown. OBJECTIVES AND METHODS: We enrolled 110 normotensive volunteers (50 men; age range, 21‒76 years). Central BP and AP were measured using the Mobil-O-Graph on the left arm with the subjects in the seated position after resting for at least 5 min. We compared central hemodynamics between the sexes. We investigated factors influencing central AP in uni- and multivariate linear regression analyses and age-related change in central AP using the Mobil-O-Graph in healthy Japanese individuals. RESULTS: Central AP were lower in men than in women (5.5 ± 2.8 vs. 11.0 ± 4.7 mm Hg, p < 0.001). The central AP in the total cohort was positively correlated with age (r = 0.325, p < 0.001) and inversely correlated with height (r = -0.601, p < 0.001) in the Pearson correlations. In multivariate regression analysis, the parameters influencing central AP (R>sup<2>/sup< = 0.467) were age (ß = 0.097, p < 0.001), sex (ß = -2.890, p = 0.010), and height (ß = -0.153, p = 0.031). The central AP (10.0 ± 4.8 mm Hg) in the ≥50-year-old group significantly increased compared with those in the 20- to 39-year-old group (6.7 ± 4.2 mm Hg, p < 0.05). CONCLUSIONS: Age, sex, and height influenced central AP, as assessed using the Mobil-O-Graph. Age-related increase in central AP was observed in normotensive Japanese individuals. Brachial cuff-based waveform recordings using the Mobil-O-Graph are feasible for the estimation of central AP in the Asian population.

Effects of therapy using the Celacade system on structural and functional cardiac remodelling in rats following myocardial infarction.

BACKGROUND: Immune modulation by the Celacade system (Vasogen Inc, Canada) decreases mortality and hospitalization in human heart failure. OBJECTIVES: To study the effects of Celacade in rats on acute cytokine expression after coronary artery ligation, cardiac dimensions following myocardial infarction (MI), and systolic and diastolic function of cardiac muscle in MI. METHODS: Celacade treatment was administered 14 days before coronary artery ligation and monthly after the surgery. Cytokine expression in cardiac tissue was measured on days 1 and 7 by ELISA in sham rats and in rats with MI (with or without Celacade treatment). Echocardiograms were obtained serially for 16 weeks. Force and sarcomere length (SL) were measured by strain gauge and laser diffraction in isolated right ventricle trabeculas at 16 weeks. The inotropic effect of pacing on force was quantified as F5 Hz/0.5 Hz. Diastolic dysfunction was quantified as the root mean square of spontaneous SL fluctuations. RESULTS: Celacade inhibited transforming growth factor beta-1 production in the infarct area on day 7 (191.6+/-22.6 pg/mg versus 275.4+/-30.1 pg/mg; P<0.05), but did not attenuate cardiac dilation in MI. Celacade restored positive inotropism of pacing in MI (F5 Hz/0.5 Hz in Celacade, 219.1+/-46.7%; MI, 148.1+/-27.1% [P<0.05 compared with 211.4+/-37.9% in sham]). Celacade reduced diastolic dysfunction in MI (root mean square of spontaneous SL fluctuations: 121+/-15% and 143+/-19% with Celacade versus 184+/-19% and 190+/-26% without Celacade at 26 degrees C and 36 degrees C, respectively) compared with sham (100%; P<0.05). CONCLUSIONS: Celacade reduces the increase of transforming growth factor beta-1 expression during the acute stage of MI in rats, but does not prevent chronic cardiac dilation. Celacade restores the positive inotropic effect of increased pacing rate in trabeculas from rat right ventricles with large MIs and reduces diastolic dysfunction.

AT1 receptor antagonist restores cardiac ryanodine receptor function, rendering isoproterenol-induced failing heart less susceptible to Ca2+ -leak induced by oxidative stress.

BACKGROUND: The Ca(2+) regulatory proteins in the sarcoplasmic reticulum (SR) play a key role in the pathogenesis of heart failure. In the present study the effect of chronic beta-receptor-stimulation on cardiac and SR functions was assessed, with or without angiotensin-II receptor antagonist treatment recently reported to have anti-beta-adrenergic activity. METHODS AND RESULTS: Rats were treated with isoproterenol with (+) or without (-) candesartan (CAN) and then SR vesicles were isolated from the left ventricular muscle. Both Ca(2+)-uptake and the amount of SR Ca(2+)-ATPase were significantly lower in the CAN (-) group than in the shams, but those were almost normally restored in the CAN (+). Although the level of the protein kinase A (PKA)-phosphorylation of the SR Ca(2+) release channel, known as the ryanodine receptor (RyR2), was elevated in the CAN (-), no Ca(2+)-leak was detected. However, SIN-1 (O(2) (-) donor) induced Ca(2+)-leak in the CAN (-) at a 10-fold lower dose than in the sham and CAN (+). In cardiomyocytes, SIN-1 decreased cell shortening and the peak Ca(2+) transient and prolonged time from peak to 70% decline in CAN (-), again at 10-fold lower dose than in the sham and CAN (+). CONCLUSION: Chronic beta-receptor-stimulation did not induce any Ca(2+)-leak from the SR, whereas Ca(2+)-leak was easily induced when oxidative stress was applied to the PKA-phosphorylated RyR2. Candesartan not only improved Ca(2+)-uptake, but also prevented PKA-phosphorylation, rendering the SR less susceptible to Ca(2+)-leak.

Ser-2030, but not Ser-2808, is the major phosphorylation site in cardiac ryanodine receptors responding to protein kinase A activation upon beta-adrenergic stimulation in normal and failing hearts.

We have recently shown that RyR2 (cardiac ryanodine receptor) is phosphorylated by PKA (protein kinase A/cAMP-dependent protein kinase) at two major sites, Ser-2030 and Ser-2808. In the present study, we examined the properties and physiological relevance of phosphorylation of these two sites. Using site- and phospho-specific antibodies, we demonstrated that Ser-2030 of both recombinant and native RyR2 from a number of species was phosphorylated by PKA, indicating that Ser-2030 is a highly conserved PKA site. Furthermore, we found that the phosphorylation of Ser-2030 responded to isoproterenol (isoprenaline) stimulation in rat cardiac myocytes in a concentration- and time-dependent manner, whereas Ser-2808 was already substantially phosphorylated before beta-adrenergic stimulation, and the extent of the increase in Ser-2808 phosphorylation after beta-adrenergic stimulation was much less than that for Ser-2030. Interestingly, the isoproterenol-induced phosphorylation of Ser-2030, but not of Ser-2808, was markedly inhibited by PKI, a specific inhibitor of PKA. The basal phosphorylation of Ser-2808 was also insensitive to PKA inhibition. Moreover, Ser-2808, but not Ser-2030, was stoichiometrically phosphorylated by PKG (protein kinase G). In addition, we found no significant phosphorylation of RyR2 at the Ser-2030 PKA site in failing rat hearts. Importantly, isoproterenol stimulation markedly increased the phosphorylation of Ser-2030, but not of Ser-2808, in failing rat hearts. Taken together, these observations indicate that Ser-2030, but not Ser-2808, is the major PKA phosphorylation site in RyR2 responding to PKA activation upon beta-adrenergic stimulation in both normal and failing hearts, and that RyR2 is not hyperphosphorylated by PKA in heart failure. Our results also suggest that phosphorylation of RyR2 at Ser-2030 may be an important event associated with altered Ca2+ handling and cardiac arrhythmia that is commonly observed in heart failure upon beta-adrenergic stimulation.

Spontaneous diastolic contractions and phosphorylation of the cardiac ryanodine receptor at serine-2808 in congestive heart failure in rat.

OBJECTIVE: The role of phosphorylation of the ryanodine receptor at serine-2808 (RyRS2808) in congestive heart failure (CHF) is controversial, and effects of RyRS2808 phosphorylation on contraction are unclear. It has been reported that diastolic sarcomere length (SL) fluctuations accompany propagating contractile waves due to propagating SR Ca2+ release in trabeculae from rats with CHF. Here, we studied the influence of RyR destabilization by FK506 and isoproterenol on twitch force (Ftw) and SL fluctuations in right ventricular (RV) trabeculae. We measured phosphorylation of RyRS2808 in rats with myocardial infarction (MI) with or without beta-blockade and in rats during isoproterenol stimulation in order to assess the role of RyRS2808 phosphorylation in SL fluctuations in failing hearts. METHODS: Five groups of male Lewis Brown-Norway rats were studied 3 months after MI: i) Sham; ii) MI with CHF (cMI); iii) MI without CHF; iv) metoprolol-treated MI, with and without CHF. The root mean square (RMSSL) of SL fluctuations in RV trabeculae was calculated. RESULTS: RMSSL increased strongly both following a short train of stimuli at 2.5 Hz and following catecholamine activation in trabeculae from MI with CHF, resulting in a decrease in Ftw in proportion to RMSSL. RyRS2808 phosphorylation was increased significantly in the left ventricle (LV; approximately 58%, P<0.05) but not in the RV (n.s.) in MI rats with CHF. FK506 tripled high frequency stimulation-induced RMSSL in nonfailing trabecula but did not further enhance RMSSL in failing trabecula. Isoproterenol increased RMSSL in nonfailing trabeculae only modestly despite a substantial increase in RyRS2808 phosphorylation in the RV (approximately 60%, P<0.05). Isoproterenol induced SL fluctuation without an increase in RV-RyRS2808 phosphorylation in failing trabeculae. Chronic beta-blockade decreased high frequency and catecholamine stimulation-induced RMSSL while RyRS2808 phosphorylation in the RV was indistinguishable from that in cMI. CONCLUSIONS: Acute RyRS2808 phosphorylation by itself does not cause spontaneous contractile waves owing to RyR2 destabilization. Spontaneous contractile waves in CHF are not caused by RyRS2808 phosphorylation alone, suggesting that factors other than RyRS2808 phosphorylation affect RyR function.

FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure.

BACKGROUND: The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury. METHODS AND RESULTS: Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts. CONCLUSIONS: During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.