Immune-related adverse event-myocarditis with marked ST-segment elevation requiring differentiation from COVID-19-induced myocarditis: a case report.

Background: Immunotherapy with immune checkpoint inhibitors (ICIs) enhances the host immune reaction against tumour cells by inhibiting intrinsic down-regulators of the T cell-mediated immune response. Although the advent of ICIs has dramatically changed oncology, ICIs may also trigger an overactivation of T cells against non-cancerous tissues, leading to off-target immune-related adverse events (irAEs). Case summary: A 64-year-old man with a history of seven courses of atezolizumab, an ICI, for small-cell lung cancer and coronavirus disease 2019 (COVID-19) was admitted to the hospital complaining of acute chest pain. Transthoracic echocardiography showed preserved ejection fraction (EF), but electrocardiography indicated precordial ST-elevations and marked increases in biomarkers for myocardial injury were observed. Emergent cardiac catheterization showed no significant coronary stenosis. On the fifth hospital day, EF decreased to 25% and pericardial effusion occurred. Endomyocardial biopsy was immediately performed, and prednisolone (60 mg/day) was administered. Troponin I level rapidly reduced, ST changed, and EF improved. Histological examinations demonstrated CD8-predominant T lymphocytic infiltration with myocardial cell injury, consistent with irAE-myocarditis. Discussion: In irAEs, myocarditis is the most common and severe cardiac manifestation with a high mortality. Even at 20 weeks after the initial ICI treatment, irAE-myocarditis occurs and the clinical presentation may mimic ST-elevation myocardial infarction. The histopathological findings suggested the high possibility of irAE-myocarditis rather than COVID-19-induced myocarditis, but COVID-19 has possibly played a role in the development of late-onset irAE-myocarditis. This educational case implies the importance of immediate recognition of irAE even after stable ICI treatment.

A woman with a dual genetic diagnosis of autosomal dominant tubulointerstitial kidney disease and KBG syndrome.

We present a female patient with a dual genetic diagnosis of autosomal dominant tubulointerstitial kidney disease and KBG syndrome. The proband was an 18-year-old woman presenting with intellectual disability, renal insufficiency, and hyperuricemia. Abdominal ultrasonography did not reveal any abnormalities. The patient's father had been diagnosed with chronic kidney disease and hyperuricemia in his twenties; however, he had no intellectual disability. Her mother and two younger siblings were not affected. Next generation sequencing (NGS) identified mutations in UMOD (c.796T > C) of the proband and her father, and in ANKRD11 (c.1903_1907del) of the proband. Renal insufficiency and intellectual disability were attributed to mutations in UMOD and ANRKD11, respectively. When making genetic diagnoses, the presence of multiple mutations in an individual should be considered, particularly when not all symptoms could be attributed to a single disease. The number of patients with dual genetic diagnosis is expected to increase as NGS becomes more readily available; thus, making it necessary to undertake a careful and robust assessment of the clinical symptoms and the related genotypes, to ensure an accurate diagnosis.

Increasing effects of S-methyl-L-cysteine on the extracellular D-serine concentrations in the rat medial frontal cortex.

In an in vivo dialysis experiment, the intra-medial frontal cortex infusion of a system A and Asc-1 transporter inhibitor, S-methyl-L-cysteine, caused a concentration-dependent increase in the dialysate contents of an endogenous coagonist for the N-methyl-D-aspartate (NMDA) type glutamate receptor, D-serine, in the cortical portion. These results suggest that these neutral amino acid transporters could control the extracellular D-serine signaling in the brain and be a target for the development of a novel threapy for neuropsychiatric disorders with an NMDA receptor dysfunction.

Impact of NAD(P)H oxidase-derived reactive oxygen species on coronary arterial remodeling: a comparative intravascular ultrasound and histochemical analysis of atherosclerotic lesions.

BACKGROUND: Coronary arterial remodeling, which is a response to the growth of atherosclerotic plaques, is associated with plaque vulnerability. Oxidative stress induced by reactive oxygen species (ROS) via NAD(P)H oxidase in the vasculature also plays a crucial role in the pathogenesis of atherosclerosis-based cardiovascular disease. In this study, the relationship between coronary arterial remodeling and ROS generation was examined by comparing preinterventional intravascular ultrasound findings of atherosclerotic lesions to the histochemical findings of corresponding specimens obtained by directional coronary atherectomy. METHODS AND RESULTS: Predirectional coronary atherectomy intravascular ultrasound images of 49 patients were analyzed. The remodeling index was calculated by dividing the target-lesion external elastic membrane cross-sectional area by the reference-segment external elastic membrane cross-sectional area. Expansive remodeling was defined as a remodeling index of >1.0. ROS generation and NAD(P)H oxidase p22(phox) expression in directional coronary atherectomy specimens were evaluated using the dihydroethidium staining method and immunohistochemistry as the ratio of the positive area to the total surface area in each specimen, respectively. ROS generation and p22(phox) expression were significantly greater in lesions with expansive remodeling than in lesions without remodeling (0.18+/-0.12 versus 0.03+/-0.02, P<0.0001, 0.10+/-0.08 versus 0.04+/-0.05, P=0.0039, respectively). Both ROS generation and p22(phox) expression significantly correlated with the intravascular ultrasound-derived remodeling index (r=0.77, P<0.0001, r=0.53, P<0.0001, respectively). CONCLUSIONS: Simultaneous examination with intravascular ultrasound and immunohistochemistry analyses suggests that NAD(P)H oxidase-derived ROS is related to the coronary arterial remodeling process associated with plaque vulnerability.

Effect of culprit-lesion remodeling versus plaque rupture on three-year outcome in patients with acute coronary syndrome.

To investigate intravascular ultrasound predictors of long-term clinical outcome in patients with acute coronary syndrome, 94 patients with a first acute coronary syndrome with both preintervention intravascular ultrasound imaging and long-term follow-up were enrolled in this study. Remodeling index was defined as external elastic membrane cross-sectional area at the target lesion divided by that at the proximal reference. Arterial remodeling was defined as either positive (PR: remodeling index >1.05) or intermediate/negative remodeling (remodeling index < or =1.05). Clinical events were death, myocardial infarction, and target-lesion revascularization. Patients were followed up for a mean of 3 years. PR was observed in 50 (53%), and intermediate/negative remodeling, in 44 (47%). During the 3-year follow-up, there were 20 target-lesion revascularization events and 5 deaths (2 cardiac and 3 noncardiac), but no myocardial infarctions. Patients with PR showed significantly lower major adverse cardiac event (MACE; death, myocardial infarction, and target-lesion revascularization)-free survival (log-rank p = 0.03). However, patients with plaque rupture showed a nonsignificant trend toward lower MACE-free survival (p = 0.13), but there were no significant differences in MACE-free survival between those with single versus multiple plaque ruptures. Using multivariate logistic regression analysis, only culprit lesion PR was an independent predictor of MACEs (p = 0.04). In conclusion, culprit-lesion remodeling rather than the presence or absence of culprit-lesion plaque rupture was a strong predictor of long-term (3-year) clinical outcome in patients with acute coronary syndrome.

Relationship between coronary plaque formation and NAD(P)H oxidase-derived reactive oxygen species - comparison of intravascular ultrasound finding of atherosclerotic lesions with histochemical characteristics-.

BACKGROUND: Oxidative stress induced by reactive oxygen species (ROS) in the vessel wall plays an essential role in atherogenesis. Recently, we demonstrated that the generation of ROS via NAD(P)H oxidase was correlated with plaque instability using coronary specimens obtained by directional coronary atherectomy (DCA). In this study, the relation between plaque formation and ROS generation was studied based on pre-interventional examination with intravascular ultrasound (IVUS) and histological analysis of the corresponding DCA specimens. METHODS: Pre-interventional IVUS images of 29 patients were analyzed. Vessel cross-sectional area (CSA), lumen CSA, plaque CSA and % plaque area were obtained at the minimal lumen site. ROS generation and expression of NAD(P)H oxidase p22phox in DCA specimens were evaluated by the dihydroethidium method and immunohistochemistry as the ratio of positive area versus total surface area in each specimen. RESULTS: ROS positive area ratio in DCA specimens was correlated positively with vessel CSA, plaque CSA, and % plaque area (r = 0.51, p = 0.0046; r = 0.62, p = 0.0004; r = 0.60, p = 0.0006, respectively). Further, p22phox positive area ratio in DCA specimens was also correlated with vessel CSA and plaque CSA (r = 0.47, p = 0.0095; r = 0.47, p = 0.0103, respectively). CONCLUSIONS: This in vivo study clearly demonstrates that NAD(P)H oxidase-derived ROS plays a significant role in the development of atherosclerosis.

[Repeated percutaneous transluminal septal myocardial ablation leads to reduction of left ventricular outflow-tract pressure gradient in hypertrophic obstructive cardiomyopathy: a case report].

A 61-year-old man with hypertrophic obstructive cardiomyopathy was treated twice with percutaneous transluminal septal myocardial ablation (PTSMA). The first procedure improved the left ventricular outflow tract pressure gradient (LVOTG) from 148 to 48 mmHg and the New York Heart Association (NYHA) class from III to II in a week. However, the LVOTG increased to 197 mmHg and the NYHA class worsened to III within 3 months. In spite of medical treatment with beta-blocker, syncope attack occurred suddenly. Repeated PTSMA was performed. Just after the second procedure, the LVOTG did not decrease. However, the LVOTG decreased to 81 mmHg and the NYHA class improved to II with 3 months. The different response of pressure gradient in the acute and chronic phase with repeated PTSMA was interesting.

Soluble CD40 ligand and interleukin-6 in the coronary circulation after acute myocardial infarction.

BACKGROUND: Inflammation, operated by blood, vascular and immune cells interaction, is implicated in plaque disruption and CD40 ligand (CD40L) was identified on activated T cells and platelets. We sought to investigate the roles of local inflammation in acute myocardial infarction (AMI). METHODS: Coronary sinus (CS) and arterial (A) levels of interleukin (IL)-6 and soluble CD40L (sCD40L) and matrix metalloproteinase (MMP)-9 activity in serial blood samples obtained until 48 h after percutaneous coronary intervention (PCI) were determined. In tissue specimens obtained by aspirating thrombectomy and directional coronary atherectomy, CD40L was immunohistochemically stained. RESULTS: Trans-cardiac gradient (CS-A) of IL-6, indicating cardiac release into the coronary circulation, significantly increased at 24 h after PCI in patients with AMI (group MI, n=17) in contrast with angina pectoris (n=10). Soluble CD40L levels in CS showed earlier peak, yielding trans-cardiac gradient, at 9 h in both groups. The maximum (max) release of IL-6 in MI, but not sCD40L, positively correlated with end-diastolic volume index (R=0.84) and negatively with ejection fraction (R=-0.66) by contrast ventriculography at 6-month follow up. Immunohistological study revealed the expression of CD40L in intra-coronary occlusive and mural thrombi. Aspirating thrombectomy significantly reduced the increase in both sCD40L levels and MMP-9 activity, but not max IL-6 release in MI. CONCLUSIONS: In contrast with myocardial injury represented by IL-6 release, acute rise in sCD40L levels with the MMP-9 activation in the coronary circulation may possibly reflect local inflammation with platelet activation and be a novel marker of plaque damage by PCI.

[Impact of metabolic syndrome and diabetes mellitus on cardiovascular events in coronary artery disease without ischemia on stress thallium-201 single photon emission computed tomography after percutaneous coronary intervention].

OBJECTIVES: The metabolic syndrome defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) is a predictor of cardiovascular events. However, the significance of metabolic syndrome for cardiovascular events has been not clarified in Japan. The impact of metabolic syndrome and diabetes mellitus on cardiovascular events was investigated, especially in the high risk group after percutaneous coronary intervention. METHODS: We studied 456 patients (mean age 63 +/- 10 years, range 36-88 years) without ischemia on stress thallium-201 single photon emission computed tomography after percutaneous coronary intervention. The diagnosis of metabolic syndrome was made according to the modified NCEP ATP III criteria. Cardiovascular events were examined for mean 3.7 +/- 1.8 years (range 2.0-8.7 years). There were 196 patients without diabetes mellitus or metabolic syndrome (Group D - M -), 89 patients without diabetes mellitus but with metabolic syndrome (Group D - M +), 61 patients with diabetes mellitus but without metabolic syndrome (Group D + M -), and 110 patients with both diabetes mellitus and metabolic syndrome (Group D + M +). RESULTS: The event-free survival curve in Group D - M + was significantly lower than that in Group D - M - (p < 0.05), but not different from that in Group D + M -. The survival curve was markedly lower in Group D + M + than that in Group D - M + (p < 0.005). The Cox proportional hazard model revealed that diabetes mellitus and metabolic syndrome were independent significant risk factors for events. CONCLUSIONS: The diagnosis of metabolic syndrome was helpful for identification of patients with high cardiovascular event rate even in patients after percutaneous coronary intervention. The combination of metabolic syndrome and diabetes mellitus markedly increases the risk for cardiovascular events.

Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease.

BACKGROUND: The neurotrophin (NT) family, including nerve growth factor NT-3 and brain-derived neurotrophic factor (BDNF), has a critical role in the survival, growth, maintenance, and death of central and peripheral neurons. NTs and their receptors are expressed in atherosclerotic lesions; however, their significance in cardiovascular disease remains unclear. METHODS AND RESULTS: To clarify the role of NTs in the pathogenesis of coronary artery disease, NT plasma levels in the aorta, coronary sinus, and peripheral veins of patients with unstable angina (n=38), stable effort angina (n=45), and non-coronary artery disease (n=24) were examined. In addition, regional expression of BDNF in coronary arteries was examined in autopsy cases and patients with angina pectoris by directional coronary atherectomy. The difference in BDNF levels, but not NT-3, between the coronary sinus and aorta was significantly greater in the unstable angina group compared with the stable effort angina and non-coronary artery disease groups. Immunohistochemical investigations demonstrated BDNF expression in the atheromatous intima and adventitia in atherosclerotic coronary arteries. BDNF expression was enhanced in macrophages and smooth muscle cells in atherosclerotic coronary arteries. Stimulation with recombinant BDNF significantly enhanced NAD(P)H oxidase activity and the generation of reactive oxygen species in cultured human coronary artery smooth muscle cells. CONCLUSIONS: BDNF has an important role in atherogenesis and plaque instability via the activation of NAD(P)H oxidase.

Interaction of oxidative stress and inflammatory response in coronary plaque instability: important role of C-reactive protein.

OBJECTIVE: C-reactive protein (CRP), a predictor of cardiovascular events, localizes in atherosclerotic arteries and exerts proinflammatory effects on vascular cells. Reactive oxygen species (ROS) have been implicated in atherogenesis and plaque instability. METHODS AND RESULTS: Expressional pattern of CRP in directional coronary atherectomy specimens from 39 patients was examined. Characteristics of histological plaque instability and higher levels of serum CRP and fibrinogen were associated with the CRP immunoreactivity. In situ hybridization revealed the presence of CRP mRNA in coronary vasculature. Furthermore, the expression of CRP mRNA and protein was detected in cultured human coronary artery smooth muscle cells (CASMCs) by reverse transcriptase-polymerase chain reaction and Western blotting. In addition, CRP was frequently colocalized with p22phox, an essential component of NADH/NADPH oxidase, which is an important source of ROS in vasculature. Moreover, the incubation of cultured CASMCs with CRP resulted in the enhanced p22phox protein expression and in the generation of intracellular ROS. CONCLUSIONS: The expression of CRP in coronary arteries was associated with histological and clinical features of vulnerable plaque, and it had a prooxidative effect on cultured CASMCs, suggesting that it might play a crucial role in plaque instability and in the pathogenesis of acute coronary syndrome via its prooxidative effect.

Superoxide generation in directional coronary atherectomy specimens of patients with angina pectoris: important role of NAD(P)H oxidase.

OBJECTIVE: NADH/NADPH oxidase is an important source of reactive oxygen species (ROS) in the vasculature. Recently, we demonstrated that p22(phox), an essential component of this oxidase, was expressed in human coronary arteries and that its expression was enhanced with the progression of atherosclerosis. The present study was undertaken to investigate its functional importance in the pathogenesis of coronary artery disease. For this aim, the expression of p22(phox), the distribution of oxidized low density lipoprotein (LDL), and the generation of ROS in directional coronary atherectomy (DCA) specimens were examined. METHODS AND RESULTS: DCA specimens were obtained from patients with stable or unstable angina pectoris. The distribution of p22(phox) and of oxidized LDL was examined by immunohistochemistry. The generation of superoxide in DCA specimens was assessed by the dihydroethidium method and lucigenin-enhanced chemiluminescence. ROS were closely associated with the distribution of p22(phox) and oxidized LDL. Not only inflammatory cells but also smooth muscle cells and fibroblasts generated ROS. There was a correlation between ROS and the expression of p22(phox) or oxidized LDL. The generation of ROS was significantly higher in unstable angina pectoris compared with stable angina pectoris. CONCLUSIONS: ROS generated by p22(phox)-based NADH/NADPH oxidase likely mediate the oxidative modification of LDL and might play a major role in pathogenesis of atherosclerotic coronary artery disease.

Overexpression of endothelial nitric oxide synthase attenuates cardiac hypertrophy induced by chronic isoproterenol infusion.

Endogenous nitric oxide (NO) inhibits the contractile response to beta-adrenergic stimulation, but its effect on cardiac hypertrophy mediated by beta-adrenoceptors remains unclear. The present study was designed to determine whether overproduction of endothelial NO synthase (eNOS) could inhibit cardiac hypertrophy induced by chronic isoproterenol (ISO) infusion (30mg/kg per day) using eNOS overexpressing (eNOS-Tg) mice and wild-type (WT) mice. In a separate group, WT mice were treated with ISO and hydralazine to decrease blood pressure to the same levels in eNOS-Tg mice. The eNOS expression, NOS activity, and cGMP levels in the heart were remarkably higher in eNOS-Tg mice than in WT mice. ISO increased both heart weight and the heart/body weight ratio, which were significantly attenuated in eNOS-Tg mice compared with WT or hydralazine-treated WT mice. Histological examination revealed that the extent of fibrosis was not significantly different among the 3 groups, and that the increase in myocyte size was more than 10% lower in eNOS-Tg than in the other groups. In addition, up-regulated expression of atrial natriuretic peptide mRNA associated with cardiac hypertrophy was significantly inhibited in eNOS-Tg mice during ISO infusion. These results indicate that endogenous NO might act as a negative modulator for the hypertrophic response to beta-adrenergic stimulation.