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Background: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. Methods: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion ( Conclusions: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

During postischemic reperfusion, free radicals are produced and have deleterious effects in isolated rat hearts. We investigated whether melatonin (MEL) reduces the production of hydroxyl radical (*OH) in the effluent and aids in recovery of left ventricular (LV) function. Hearts were subjected to 30 min of ischemia followed by 30 min of reperfusion. Salicylic acid (SAL) was used as the probe for *OH, and its derivatives 2,5- and 2,3-dihydroxybenzoic acid (DHBA) were quantified using HPLC. In addition, thiobarbituric acid reactive substances (TBARS) in the myocardium was measured. Plateaus in the measurement of 2,5- and 2,3-DHBA were seen from 3 to 8 min after reperfusion in each group. The group that received 100 microM MEL+ SAL had significantly reduced amounts of 2,5- and 2,3-DHBA by multiple folds, compared to the SAL group. TBARS was significantly decreased in the 100 microM MEL group (1.20+/-0.36 vs 1.85+/-0.10 micromol/g of drug-free group, p

Our objective was 1) to assess postischemic vasodilatation using simultaneous intravascular two-dimensional and Doppler ultrasound, and 2) to clarify whether plasma nitrite and nitrate (NOx-) levels change during postischemic vasodilatation. The vascular cross-sectional area (GSA) was evaluated in 18 mongrel dogs, and the average instantaneous peak velocity (APV) in the iliac arteries after the 5-min occlusion of blood flow was determined. Plasma NOx- levels were measured at the baseline, during the occlusion of blood flow, and 1.5, 3, and 10min after recanalization. The %CSA significantly increased from 30s to 7 min after the recanalization, and maximal vasodilatation was observed at 1.5min after the recanalization (14.1±0.9 to 15.8±1.0mm2, p

We investigated whether the apolipoprotein E (apoE) and the angiotensin-converting enzyme (ACE) genotypes contribute to the variance in low-density lipoprotein (LDL) particle size in Japanese subjects (n = 136; M/F= 106/30). ACE polymorphism was associated with neither LDL size nor individual lipid levels. In contrast, the subjects with the epsilon2 allele of the apoE genotype had significantly lower levels of total cholesterol (P = 0.002) and LDL cholesterol (P = 0.004) compared with those without the epsilon2 allele. The subjects with the epsilon4 allele had a significantly smaller LDL particle size than those without the epsilon4 allele (P = 0.012). Separate analyses of the male subjects showed similar associations. A stepwise regression analysis revealed the epsilon4 allele to be an independent contributing variable that could affect LDL particle size. Our results suggest that the apoE genotype is associated with the development of atherosclerotic disease, since the epsilon2 and epsilon4 alleles relate to a decrease in LDL cholesterol levels and a decrease in LDL particle size, respectively.

This study was performed to clarify the mechanism of vasoconstriction induced by oxygen-derived free radicals in spontaneously hypertensive rats. The isometric tension of aortic rings from spontaneously hypertensive rats and Wistar-Kyoto rats was measured in Krebs-Henseleit solution. Oxygen-derived free radicals were generated by mixing xanthine and xanthine oxidase. The removal of endothelium enhanced the contractions induced by oxygen-derived free radicals. The inhibition of nitric oxide production with N G -nitro-L-arginine methyl ester (10 -4 M) enhanced the contractions. Treatment with the thromboxane A 2 (TXA 2 ) synthetase inhibitor OKY-046 (10 -4 M) or RS-5186 (10 -4 M) markedly reduced the contractions. Treatment with the cyclooxygenase inhibitor indomethacin (10 -5 M) and a TXA 2 /prostaglandin H 2 (PGH 2 ) receptor antagonist. ONO-3708 (10 -6 M), completely abolished the oxygen-derived free radical-induced contractions. In contrast, treatment with the PGI 2 synthetase inhibitor tranylcypromine (10 -4 M) did not attenuate the oxygen-derived free radical-induced contractions. Whether endothelium was present or not, the release of TXB 2 , PGE 2 , and 6-keto-PGF 1α . but not PGF 2α . was increased by the production of oxygen-derived free radicals. Catalase and the hydroxyl radical scavenger deferoxamine plus mannitol markedly inhibited the oxygen-derived free radical-induced contractions. These results suggest that oxygen-derived free radical-induced vasoconstriction in spontaneously hypertensive rat aorta is caused by TXA 2 and PGH 2 released in smooth muscle.

This study was undertaken to clarify factors other than nitric oxide involved in reactive hyperemia after a short (30 sec) and a long (300 sec) coronary global no-flow ischemia in isolated rat hearts perfused at a constant pressure (90 mmHg) with special focuses on the contribution of various K channels including large and small conductance Ca-activated K (KCa) channels as well as ATP-sensitive K (KATP) channels. Reactive hyperemia was induced following 30 sec and 300 sec of no-flow ischemia of the heart. Coronary reactive hyperemia was observed even after the inhibition of nitric oxide synthase by N(omega)-nitro-L-arginine methylester (L-NAME). Selected K channel blockers, none of which affected the basal flow, were used to evaluate contribution of K channels to this L-NAME-resistant reactive hyperemia. After 30-sec ischemia, tetraethylammonium (TEA: a non-selective K channel blocker), glibenclamide (Gli: a KATP channel blocker) and alpha,beta-methylene adenosine 5'-diphosphonate (AOPCP: an inhibitor of ecto 5'-nucleotidase) all suppressed both peak flow/basal flow (%PF) and repayment of flow debt (%RFD). After 300-sec ischemia, TEA and charybdotoxin (ChTX: a large conductance KCa channel blocker) decreased %PF and %RFD; AOPCP decreased both %RFD and duration, 4-aminopyridine (a voltage-dependent K channel blocker) decreased only duration. Neither apamin (a small conductance KCa channel blocker) nor indomethacin (a cyclooxygenase inhibitor) affected the both types of reactive hyperemia. These findings suggest that opening of KATP channel contributes to coronary vasodilation in reactive hyperemia after short 30-sec ischemia, and that opening of KCa, but not KATP, channel contributes to it after long 300-sec ischemia. These results also suggest that adenosine may partly be involved in both types of reactive hyperemia.

The clinical significance of the angiographic no-reflow phenomenon was evaluated in 93 patients with acute myocardial infarction treated by percutaneous transluminal coronary angioplasty (PTCA). On the basis of the post-PTCA angiograms, patients were divided into three groups: normal angiogram (group 1, n = 65), slight no-reflow (group 2, n = 13), and severe no-reflow (group 3, n = 15). Regional wall motion in the chronic phase was depressed in groups 2 and 3 compared with group 1. The proportion of the area of the transmural infarction to that of the total infarction determined by scintigraphy was higher in groups 2 and 3 than in group 1. A significantly higher incidence of myocardial rupture and of death resulting from cardiac causes was observed in group 3 compared with group 1. The severity of this phenomenon immediately after an emergency PTCA correlated well with the severity of myocardial damage, with patients having severe no-reflow showing the poorest prognosis.

Few studies have reported on the association of viscosity with coronary circulation. We evaluated the change in coronary flow after dextran was added to a perfusion solution to increase viscosity in isolated rat hearts. We also measured NOx– production induced by the change in shear stress in the coronary effluent, as a marker of NO synthesis. The baseline coronary flow was not influenced by the presence of either the cyclooxygenase inhibitor indo metha cin, the thromboxane A2 (TXA2)–prostaglandin H2 (PGH2) receptor antagonist ONO-3708, or the TXA2 synthase inhibitor OKY-046. After exposure to solution containing 0.5% dextran, the coronary flow first decreased and then gradually increased until 10 min. The initial decrease in coronary flow was inhibited by indomethacin, ONO-3708, and OKY-046 individually. The gradual increase was completely inhibited by the NO inhibitor L-NAME, but not by indomethacin or ONO-3708. OKY-046 partially inhibited the increase. NOx– levels in the effluent were higher after the dextran solution was administered, and the increased NOx– levels were inhibited by L-NAME. The increased NOx- levels were not inhibited by inhibitors of the cyclooxygenase pathway. It appears that a higher viscosity of perfusion solution induced a gradual increase in NO production and was associated with increased production of indomethacin-sensitive contracting factor.Key words: coronary flow, indomethacin, nitric oxide, viscosity.

In the current study, we investigated the NO-generation pathway in response to mechanical stimuli in SHR at the prehypertensive stage. To examine the role of NO in coronary autoregulation, we evaluated the effects of L-NAME on the coronary flow in SHR at both the prehypertensive and hypertensive stages. Isolated perfused hearts from 5- and 15-week-old SHR and from age-matched Wistar-Kyoto rats (WKY) were used. After stabilization at 60 mmHg, perfusion pressure was immediately raised to 90 mmHg to record the change in coronary flow for 10 min without (control) or with NO synthesis blockade by Nω-nitro-L-arginine methyl ester (L-NAME). NOx- (nitrite/nitrate) was measured in coronary effluent. At 5 weeks of age, SHR did not have hypertension, while the coronary autoregulation was enhanced. L-NAME did not affect this enhanced autoregulation in 5-week-old SHR. At perfusion pressures of both 60 and 90 mmHg, 5-week-old SHR showed less coronary NOx- production than age-matched WKY. At 15 weeks, SHR showed a higher blood pressure than WKY. The coronary autoregulation in SHR remained higher than that in WKY, but was below that in 5-week-old SHR. NOx- production in 15-week-old SHR recovered to the level of age-matched WKY. These results indicate that NOx- production induced by mechanical stimulation was markedly reduced in 5-week-old SHR at the prehypertensive stage, which may have enhanced coronary autoregulation. An impaired nitric oxide production may precede the onset of hypertension in SHR. (Hypertens Res 2001; 24: 395-401)

We pharmacologically investigated the potential involvement of nitric oxide (NO), prostacyclin, adenosine, adenosine triphosphate (ATP)-sensitive K (K(ATP)) channel opening and Ca2+-activated K (K(Ca)) channel opening in coronary vasodilatation during 15 min of hypoxia in isolated rat hearts perfused at a constant pressure of 70 mm Hg. The coronary flow suppressed by 10(-4) M Nomega-nitro-L-arginine methyl ester (L-NAME), which corresponds to the NO-dependent flow, decreased to almost zero during hypoxia. In contrast, the NO-dependent coronary flow amounted to approximately 40% of the total coronary flow during normoxia. The suppression of coronary flow by 10(-5) M 8-phenyltheophylline (8-PT), which corresponds to the adenosine-dependent flow, was remarkable in the middle and the late phases of a 15-min hypoxia. The coronary flow suppressed by 2 x 10(-6) M glibenclamide, which corresponds to the K(ATP) channel opening-dependent flow, depended on the agents added to the perfusate. However, there was a marked increase in coronary flow in the early phase of hypoxia in the heart perfused with the combination of 8-PT, 10(-2) M tetraethylammonium (TEA) and L-NAME. During hypoxia, the coronary flow suppressed by TEA, which corresponds mainly to the K(Ca) channel opening-dependent flow, also depended on the agents added to the perfusate. However, during reoxygenation, there was a transient significant increase in any combination of the agents. Our study suggests that hypoxia almost completely inhibits NO production, and that K(ATP) channel opening immediately after hypoxia and subsequent enhanced adenosine production cause a marked hypoxic coronary vasodilatation. It also suggests that K(Ca) channel opening causes vasodilatation during reoxygenation.

We have recently reported that melatonin protects against adriamycin-induced cardiomyopathy whose pathogenesis may involve free radicals and lipid peroxidation. Melatonin has also been shown to affect zinc turnover. Since zinc may act as an antioxidant, we investigated the role of zinc in the pathogenesis of adriamycin-induced cardiomyopathy as well as in the treatment of melatonin against this disorder. Sprague-Dawley rats were given adriamycin (cumulative dose, 15 mg/kg); melatonin (cumulative dose, 84 mg/kg); adriamycin plus melatonin; adriamycin plus probucol, another antioxidant (cumulative dose, 90 mg/kg); or vehicle alone, according to previously-used regimens. Cardioprotective effects of both antioxidants (melatonin and probucol) were confirmed by the parameters of fractional shortening, heart weight, heart/body weight ratio, ascites volume, and mortality. Adriamycin increased both the myocardial and plasma levels of thiobarbituric acid reactive substances (TBARS) and myocardial zinc levels, and decreased plasma zinc levels. The significant negative correlation observed between the myocardial and plasma zinc levels (r = 0.73, P < 0.01) among the samples of adriamycin-treated and control rats suggested an internal redistribution of zinc. Melatonin and probucol were equally effective in inhibiting the increase in myocardial TBARS as well as zinc levels, suggesting that myocardial zinc accumulation might be a protective response against adriamycin-induced oxidative stress. Melatonin also inhibited the adriamycin-induced decrease in plasma zinc levels; probucol was not as effective in doing so. In addition to melatonin's antioxidative effect, it may have the effect of maintaining the plasma zinc levels.

Abstract —Prostacyclin (PGI 2 ), a metabolite of arachidonic acid, has the vasoprotective effects of vasodilation, anti-platelet aggregation, and inhibition of smooth muscle cell proliferation. We hypothesized that an overexpression of endogenous PGI 2 may accelerate the recovery from endothelial damage and inhibit neointimal formation in the injured artery. To test this hypothesis, we investigated in vivo transfer of the PGI 2 synthase (PCS) gene into balloon-injured rat carotid arteries by a nonviral lipotransfection method. Seven days after transfection, a significant regeneration of endothelium was observed in the arteries transfected with a plasmid carrying the rat PCS gene (pCMV-PCS), but little regeneration was seen in those with the control plasmid carrying the lacZ gene (pCMV-lacZ) (percent luminal circumference lined by newly regenerated endothelium: 87.1±6.9% in pCMV-PCS-transfected vessels and 6.9±0.2% in pCMV-lacZ vessels, P P 1α , the main metabolite of PGI 2 , compared with the segments transfected with pCMV-lacZ (10.2±0.55 and 2.1±0.32 ng/mg tissue for pCMV-PCS and pCMV-placZ, P 2 and markedly inhibited neointimal formation with accelerated reendothelialization in rat carotid arteries after balloon injury.

Some acute myocarditis is refractory to conventional therapies including IASP and is rapidly culminating in death without extracorporeal circulatory support. In order to study possible effectiveness of PCPS against this subgroup, acute fulminant myocarditis (AFM), we have reviewed our experiences and have examined the clinical outcome following PCPS treatment. Since 1986, we have applied emergency PCPS to 10 AFM pts (mean 38 years) with rapidly progressive cardiac dysfunction and sustained wide GRS VT/vf with hemodynamic collapse. The average interval from the onset of the very early signs of AFM (common cold like symptoms) to the induction of PCPS was 5.2 days. IASP was routinely applied before, during and after PCPS. Nafamostat mesilate (1 mg/kg/hr,iv) was also administered in combination with Heparin (ACT g 200 sec) as prophylaxis for bleeding complications. Histological examinations obtained from 12 endomyocardial biopsies and 2 autopsies revealed various inflamatory changes in myocardium in all of the 8 pts examined. Although the courses and degree of recovery varied among the pts, PCPS could be eventually weaned in all pts after a mean of 167 hours (ranging 37–302 hours). After the removal of PCPS, 2 old pts ( g 70 years) expired within 1 week due to sepsis and 1 pt expired 4 months later due to multiple organ failure. Seventy percent of pts (7 of 10) survived, 6 pts recovered to show normal cardiac function (mean EF = 0.62) and 1 pt showed DCM like chronic heart failure (EF = 0.321 Although nonsustained VT was observed in 3 of 7 survivors. they have been experiencing an event free follow-up period (mean 4.8 years). Conclusion Hemodynamic support by PCPS in the acute phase of AFM was shown to be an effective treatment and the long-term outcome of the survivors was shown to be excellent in the majority of the cases.