Potential complications in patients undergoing an ethanol injection into the vein of Marshall.

BACKGROUND: Ethanol injections into the vein of Marshall (VOM) (EIM) are considered to be a good therapeutic option for atrial tachyarrhythmias, however, the safety remains to be determined. To elucidate what would affect the safety and potential complications of an EIM, we investigated the anatomical features of the VOM and patient background. METHODS: We performed the EIM before the conventional pulmonary vein isolation for drug-resistant atrial fibrillation in 88 patients and evaluated the anatomical features of the VOM and their background. RESULTS: All procedures were completed, however, other than myocardial staining, trivial contrast medium leaked out of the VOM into the pericardial space, that is, extravasation of contrast medium with capillary rupture, during the EIM in 20 patients (22.7%) regardless of the features of the VOM. No pericardial effusions requiring further intervention developed after the extravasation, which resolved by the next day on echocardiography in 18 of those patients. However, two patients who had extravasation other than during the initial contrast injection required additional therapeutic intervention for nonnegligible pericardial effusions. Their body weights were significantly lower and the latter two patients were also small lean women with heart failure and a preserved ejection fraction. CONCLUSIONS: The physical constitution, regardless of the characteristics of the VOM, could be strongly associated with adverse events during the EIM. We must take extreme care in smaller patients with poor compliant hearts during the EIM.

Hypertrophic Cardiomyopathy Accompanied by Spinocerebellar Atrophy With a Novel Mutation in Troponin I Gene.

We report the case of a 66 year-old woman with chronic atrial fibrillation, hypertrophic cardiomyopathy (HCM), and spinocerebellar atrophy (SCA). Her mother and first-born son had died of heart disease at the ages of 65 and 16 years, respectively. Four of her 8 siblings had died suddenly of unknown cause or of heart disease, and 2 others of cerebral infarction by the 7th decade. Genetic testing revealed that she had a novel mutation (c. 482C > A, p. Ala161Asp) in the troponin I gene (TNNI3), and no abnormality of the GAA repeat in the frataxin gene. Her older brother with SCA but without HCM was also analyzed, with no abnormality noted in either gene. The Ala161Asp mutation in TNNI3 was implicated in the pathogenesis of her HCM, though an association between HCM and SCA was not revealed.

Low dose of hydrochlorothiazide, in combination with angiotensin receptor blocker, reduces blood pressure effectively without adverse effect on glucose and lipid profiles.

Previous studies have shown highly effective lowering of blood pressure with thiazide diuretics in combination with angiotensin receptor blockers. However, thiazide diuretics may cause the development of diabetes and abnormal lipid metabolism. Little is known as to whether dysmetabolic potential of thiazide diuretics could be neutralized when adding angiotensin receptor blockers. This study consisted of 26 patients with essential hypertension. Patients were randomized to 24 weeks of treatment with either candesartan, 12 mg monotherapy (n = 13, group A), or hydrochlorothiazide (HCTZ), 6.25 mg in combination with candesartan, 8 mg (n = 13, group B). Before and after treatment, we assessed glucose and lipid profiles including adiponectin, resistin, and active glucagon-like peptide-1 (GLP-1) levels. At baseline, there were no differences in age, body mass index, systolic blood pressure (SBP), and diastolic blood pressure (DBP), as well as plasma levels of hemoglobin A1c, insulin, low-density lipoprotein cholesterol, triglycerides, adiponectin, resistin, and active GLP-1 between the two groups. There were significant reductions in SBP (from 152 ± 10 mmHg at baseline to 134 ± 12 mmHg after treatment) and DBP (from 84 ± 5 mmHg at baseline to 71 ± 8 mmHg after treatment) in group A. There were also significant reductions in SBP (from 148 ± 10 at baseline to 128 ± 7 mmHg after treatment) and DBP (from 90 ± 9 at baseline to 74 ± 12 mmHg after treatment) in group B. There were no differences in reduction of SBP or DBP after 24 weeks of treatment between the two groups. There were no changes of the glucose and lipid profiles, including adiponectin, resistin, insulin, and active GLP-1 levels after 24 weeks of treatment in both groups. A low dose of HCTZ in combination with candesartan reduces blood pressure effectively without adverse effects on the glucose and lipid profiles. Therefore, the combination of thiazide diuretics and angiotensin receptor blockers could assist patients in achieving long-term control of blood pressure with good tolerability.

Serum angiotensin-converting enzyme levels indicating early sarcoidosis diagnosis and immunosuppressive therapy efficacy.

AIMS: This study aimed to determine the new cut-off value of serum angiotensin-converting enzyme (ACE) levels for detecting patients with sarcoidosis and to examine the change in ACE levels after the initiation of immunosuppressive therapy. METHODS AND RESULTS: We retrospectively examined patients in whom serum ACE levels were measured for suspected sarcoidosis between 2009 and 2020 in our institution. For patients diagnosed with sarcoidosis, changes in ACE levels were also observed. Of the 3781 patients (51.1% men, 60.1 ± 17.0 years old), 477 were excluded for taking ACE inhibitors and/or immunosuppression agents or those with any diseases affecting serum ACE levels. In 3304 patients including 215 with sarcoidosis, serum ACE levels were 19.6 IU/L [interquartile range, 15.1-31.5] in patients with sarcoidosis and 10.7 [8.4-16.5] in those without sarcoidosis (P < 0.01), and the best cut-off value was 14.7 IU/L with 0.865 of the area under the curves. Compared with the current ACE cut-off of 21.4, the sensitivity improved from 42.3 to 78.1 at the new cut-off, although specificity slightly decreased from 98.6 to 81.7. The ACE level significantly decreased more in those with immunosuppression therapy than in those without it (P for interaction <0.01), although it decreased in both groups (P < 0.01). CONCLUSIONS: Because the sensitivity for detecting sarcoidosis is comparatively low at the current standard value, further examinations are needed for patients suspected of sarcoidosis with relatively high ACE levels in the normal range. In patients with sarcoidosis, ACE levels decreased after the initiation of immunosuppression therapy.

Lack of association between IL10 polymorphisms and sarcoidosis in Japanese patients.

PURPOSE: To investigate whether interleukin 10 (IL10) gene polymorphisms are associated with the development of sarcoidosis in Japanese patients. METHODS: Two hundred and eighty-eight Japanese sarcoidosis patients and 310 Japanese healthy controls were recruited. We genotyped 9 single-nucleotide polymorphisms in IL10 and assessed the allelic diversity between cases and controls. RESULTS: No significant differences in the frequency of IL10 alleles, genotypes, and haplotypes in the sarcoidosis cases compared to the controls were detected. CONCLUSIONS: Our results suggest that IL10 polymorphisms are not significantly related to the pathogenesis of sarcoidosis in the Japanese population.

Identification and characterization of a ferritin gene and its product from the multicellular green alga Ulva pertusa.

Iron is an essential element for virtually all kingdoms of life, and especially for primary producers in ocean ecosystems. To date, the molecular mechanism of iron utilization by macroalgae remains largely unknown. To elucidate the strategy of iron acquisition and storage in macroalgae, we focused on the function of the iron storage protein ferritin in the sea lettuce, Ulva pertusa, which has abundant iron content. Judging from the primary structure, U. pertusa ferritin (UpFer) can be classified as a land-plant-type ferritin, which is usually found in plastids. The gene of UpFer was expressed in the peripheral, central and rhizoid parts. Western blot analysis showed that UpFER was present and functioned in processed 26- and 22-kDa forms. Furthermore, recombinant UpFER had iron incorporation activity comparable to other ferritins. These results suggest that ferritin also functions as an iron storage protein as in unicellular algae and land plants.

The characteristics of Japanese guidelines on diagnosis and treatment of cardiac sarcoidosis compared with the previous guidelines.

Sarcoidosis in Japanese sarcoidosis is characterized by a high prevalence of cardiac involvement. In this regard, cardiac sarcoidosis (CS) continues to be an important focus of study among physicians caring for sarcoidosis in Japan. The Japanese Ministry of Health, Labor and Welfare (MHLW) and Japan Society of Sarcoidosis and other Granulomatous Disorders (JSSOG) have published clinical guidelines aiming to assist clinical practices. Recently, the Japanese Circulation Society (JCS) has published new clinical guidelines for the diagnosis and treatment of CS that contain several new insights compared to previously published guidelines in Japan and other countries.

Histology of Cardiac Sarcoidosis with Novel Considerations Arranged upon a Pathologic Basis.

Sarcoidosis is a rare disease of isolated or diffuse granulomatous inflammation. Although any organs can be affected by sarcoidosis, cardiac sarcoidosis is a fatal disorder, and it is crucial to accurately diagnose it to prevent sudden death due to dysrhythmia. Although endomyocardial biopsy is invasive and has limited sensitivity for identifying granulomas, it is the only modality that yields a definitive diagnosis of cardiac sarcoidosis. It is imperative to develop novel pathological approaches for the precise diagnosis of cardiac sarcoidosis. Here, we aimed to discuss commonly used diagnostic criteria for cardiac sarcoidosis and to summarize useful and novel histopathologic criteria of cardiac sarcoidosis. While classical histologic observations including noncaseating granulomas and multinucleated giant cells (typically Langhans type) are the most important findings, others such as microgranulomas, CD68+ CD163- pro-inflammatory (M1) macrophage accumulation, CD4/CD8 T-cell ratio, Cutibacterium acnes components, lymphangiogenesis, confluent fibrosis, and fatty infiltration may help to improve the sensitivity of endomyocardial biopsy for detecting cardiac sarcoidosis. These novel histologic findings are based on the pathology of cardiac sarcoidosis. We also discussed the principal histologic differential diagnoses of cardiac sarcoidosis, such as tuberculosis myocarditis, fungal myocarditis, giant cell myocarditis, and dilated cardiomyopathy.

An autopsy case report of fulminant myocarditis: Following mRNA COVID-19 vaccination.

There have been few case reports on fatal outcomes in patients with acute myocarditis after mRNA coronavirus disease 2019 (COVID-19) vaccination. In most cases of myocarditis after mRNA COVID-19 vaccination, the myocarditis is mild, and the prognosis is good. Here we report an autopsy case of fulminant myocarditis following mRNA COVID-19 vaccination. Learning objective: The global distribution of the mRNA coronavirus disease 2019 vaccine requires consideration of appropriate treatment for postvaccination myocarditis. Eosinophil-mediated immunological injury to cardiomyocytes can be involved in the cause of fulminant inflammation from the pathological findings of postvaccination myocarditis.

Toll-like receptor 2 (TLR2) gene polymorphisms are not associated with sarcoidosis in the Japanese population.

PURPOSE: Sarcoidosis is a systemic inflammatory disease characterized by the formation of non-caseating granulomas, with varied clinical manifestations. The common etiology of sarcoidosis is uncertain, but it is thought to be triggered by an exogenous antigenic stimulus, such as some bacterial proteins. Toll-like receptors (TLRs) recognize microbial components and elicit innate as well as adaptive immune responses. It has been reported that polymorphisms in TLR2 might be important in a small group of Caucasian sarcoidosis patients. The present study aimed to establish whether these findings are relevant to the Japanese population. METHODS: We genotyped 5 single-nucleotide polymorphisms (SNPs) in TLR2 and assessed the allelic diversity between 257 Japanese sarcoidosis patients and 193 Japanese healthy controls. RESULTS: No significant differences in the frequency of TLR2 alleles and haplotypes in the sarcoidosis cases were found in comparison with the controls. However, marginal associations were observed for TLR2 at rs3804099 and rs3804100 in sarcoidosis patients with cutaneous manifestations. CONCLUSIONS: Our results suggest that TLR2 polymorphisms are not significantly related to the pathogenesis of sarcoidosis in the Japanese population.

Histopathological aspects of cardiac biopsy in pediatric patients with dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is a heart muscle disease with cardiac dysfunction and a heterogeneous disorder. This disease may show various histopathological aspects of the myocardium, but little is known about these in children. METHODS: Histopathological findings of endomyocardial biopsy from 20 pediatric patients with DCM were analyzed and compared with those in adult patients. RESULTS: Advanced histopathology, including myocytolysis and/or fragmentation of muscle bundles, was frequently observed in patients with poor prognosis. Patchy fibrosis was predominantly demonstrated in the pediatric patients, whereas perivascular fibrosis was mostly observed in the older adults. The myocarditic index, assessed in terms of the findings of fibrosis, size variation of myocytes, disarrangement of muscle bundles and mononuclear cell infiltration was higher in the pediatric patients than in the older adults (P < 0.05). Bizarre myocardial hypertrophy with disorganization, which tends to be frequently demonstrated in hypertrophic cardiomyopathy, was revealed in 30% of the pediatric patients, whereas it was disclosed in none of the older adult patients (P < 0.05). CONCLUSION: These results suggest that the major pathogenetic factors of DCM in children may be different from those in adults.

Coexistence of amyloidosis and light chain deposition disease in the heart.

There are few reports on the coexistence of cardiac amyloid light-chain (AL) amyloidosis and light chain deposition disease (LCDD), despite their similar pathophysiologies caused by plasma-cell dyscrasia. Herein, we report the coexistence of these diseases. A 59-year-old man was referred to our hospital because of exertional dyspnea and hypotension. Renal dysfunction of unknown etiology had been present for 4 years and hemodialysis had been introduced. Severe systolic and diastolic cardiac dysfunction was apparent, accompanied with dilatation and granular sparkling, but not with left ventricular hypertrophy. The plasma-free light chain κ was found to be extremely high, with a κ/λ ratio of 1,919. Light microscopic examination of the endomyocardial biopsy revealed spotty and homogenous deposits, which positively stained with Congo red, and exhibited a blazing apple-green color under polarized light. Based on these results, cardiac amyloidosis was diagnosed. In specimens prepared for electron microscopy, no amyloid fibrils could be found. Instead, we observed amorphous nonfibrillar deposits around several small vessels including capillaries and small arteries, which were consistent with light-chain deposits. LCDD was diagnosed based on the systemic increase in κ light chain and the ultrastructural findings of the endomyocardial biopsy specimens. Coexistence of cardiac amyloidosis and LCDD was thus confirmed in our patient. An electron microscopic assessment in addition to Congo red staining may be useful to diagnose latent LCDD in patients with suspected cardiac light-chain amyloidosis.

Prognosis and Outcomes of Clinically Diagnosed Cardiac Sarcoidosis Without Positive Endomyocardial Biopsy Findings.

Background: Diagnosis of cardiac sarcoidosis (CS) is sometimes difficult due to a low positive rate of epithelioid granulomas by endomyocardial biopsy (EMB). Accordingly, Japanese guidelines can allow the CS diagnosis using clinical data alone without EMB results (clinical CS) since 2006. However, little is known about prognosis and outcome of clinical CS. Objectives: Purpose of this study was to analyze the prognosis, outcomes, and response to corticosteroid of clinical CS using large-scale cohort survey. Methods: Overall, 422 CS patients (mean age 60 ± 13 years, 68% female, median follow-up period of 5 years), including 345 clinical CS and 77 EMB-positive patients, histologically diagnosed CS (histological CS) by Japanese guidelines, were enrolled and examined. Results: Clinical profile (age, sex, initial cardiac arrhythmias, and abnormal uptake of gallium-67 scintigraphy or 18F-fluorodeoxyglucose positron emission tomography in heart) was similar in both groups. Although clinical CS had better prognosis (P = 0.018) and outcome (all-cause death, appropriate defibrillator therapy, and heart transplantation; P = 0.008), multivariate Cox hazard analysis revealed that left ventricular ejection fraction (LVEF) and sustained ventricular tachycardia history were independently associated with outcome (P < 0.001 and P = 0.002, respectively), but not with the diagnosed CS category. Moreover, similar LVEF recovery after corticosteroid was observed in both groups with low LVEF (≤35%) at the 1-year follow-up period (P < 0.001). Conclusions: In clinical CS according to the Japanese guideline, prophylactic implantable-cardioverter-defibrillator and immunosuppressive therapy are important in patients with low LVEF or ventricular tachycardia history, similar to histological CS.

Cardio-renal interaction: impact of renal function and anemia on the outcome of chronic heart failure.

The purpose of this study is to investigate the effects of renal function and anemia on the outcome of chronic heart failure (CHF). We targeted 711 consecutive patients who were hospitalized at the Division of Cardiology of Fujita Health University Hospital during a 5-year period. The subjects were divided into four groups according to their estimated glomerular filtration rate (e-GFR) calculated using the Modification of Diet in Renal Disease (MDRD) formula. Intergroup comparisons were conducted for underlying heart diseases, clinical findings at the time of hospitalization, treatment, and outcome. Moreover, the patients were divided into two groups according to their serum hemoglobin concentration at the time of hospitalization, using 12.0 g/dl as the dividing point, to study the effects of anemia on the outcome. In the group with decreased renal function, the average age was higher, and ischemic heart disease and associated conditions such as hypertension and diabetes mellitus were observed in most of the patients. In addition, the rate of anemia development and the plasma B-type natriuretic peptide concentration were also high. The greater the deterioration in renal function, the poorer the outcome became (P < 0.0001). Chronic heart failure complicated by anemia showed an especially poor outcome (P < 0.0001). As this study showed that renal function and anemia significantly affected the outcome of CHF, it is clear that the preservation of renal function and the management of anemia are important in addition to the conventional treatments for CHF.

Diagnosis of isolated cardiac sarcoidosis based on new guidelines.

AIMS: In the updated guidelines for cardiac sarcoidosis (CS) proposed by the Japanese Circulation Society (JCS), the definition of isolated CS (iCS) was established for the first time. This prompted us to examine the characteristics of patients with CS including iCS according to them by reviewing patients undergoing 18 F-fluoro-2-deoxyglucose positron-emission tomography/computerized tomography (FDG-PET/CT), compared with those with CS determined by the conventional international criteria. METHODS AND RESULTS: From 2013 to 2019, 94 patients (61 ± 15 years, 50 female patients) with suspected CS underwent whole-body and cardiac FDG-PET/CT scanning. In contrast to 22 patients with CS based on the international criteria, 34 [27 with systemic sarcoidosis including cardiac involvement (sCS) and 7 with definitive iCS] were diagnosed with CS according to the new JCS guidelines (P = 0.012), and 60 were not (4 suspected iCS, 13 systematic sarcoidosis without cardiac involvement, and 43 no sarcoidosis). In addition to 26 of 34 patients with CS, corticosteroids were also started in 6 of 60 without CS according to clinical need. CONCLUSIONS: Diagnostic yield with the new JCS guidelines was higher, with approximately 1.5-fold of the patients diagnosed with CS compared with the previous international criteria and definitive iCS accounting for approximately 20% of the whole CS cohort. In addition to 75% of the patients with sCS or definitive iCS in the updated guidelines, 10% in whom CS was not documented were also started on corticosteroids for clinical indications such as reduced cardiac function or arrhythmia.

Genetic control of CCL24, POR, and IL23R contributes to the pathogenesis of sarcoidosis.

Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10-8) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.

Lack of association between toll-like receptor 4 gene polymorphisms and sarcoidosis-related uveitis in Japan.

PURPOSE: Toll-like receptors (TLRs) are pattern-recognition receptors that play an important role in innate and adaptive immune responses to microbial pathogens. Among TLRs, TLR4 recognizes lipopolysaccharides of Gram-negative bacteria. Genetic polymorphisms within the TLR4 gene have been reported to be associated with various inflammatory diseases; therefore, TLR4 appears to be a susceptibility gene for sarcoidosis. Although sarcoidosis has various clinical manifestations, its association with uveitis is more common in Japan than in other countries. The aim of this study was to investigate whether TLR4 polymorphisms were associated with sarcoidosis-related uveitis in a Japanese population. METHODS: Two hundred twenty-three patients with sarcoidosis and 206 healthy control subjects were recruited at seven sites in Japan. Eight single-nucleotide polymorphisms (SNPs) in TLR4 were genotyped with a TaqMan assay, and allelic and phenotypic diversity were assessed in affected and control subjects. RESULTS: We found no association with susceptibility to sarcoid-related uveitis for any of the SNPs analyzed. Strong linkage disequilibrium was observed among all the SNPs analyzed (D'>/=0.78), which were located in one haplotype block. CONCLUSION: TLR4 polymorphisms do not play an important role in the development of uveitis in Japanese patients with sarcoidosis.

Management of severe heart failure.

Patients admitted to the hospital with heart failure (HF) include those with new-onset of acute HF and those with acute exacerbation of chronic HF (CHF). In therapy for new-onset acute HF associated with acute myocardial infarction, therapy to inhibit left ventricular (LV) remodeling in the convalescent phase is required in addition to that needed to overcome the acute phase. Hitherto, CHF therapy was aimed at improving LV contractability, whereas more recently the aim has shifted to resting the heart. Most patients with HF should be routinely managed with a combination of 3 types of drugs: a diuretic; an angiotensin converting enzyme inhibitor and/or an angiotensin II receptor blocker; and a beta-blocker. The administration of beta-blockers is of particular importance. For HF unresponsive to medical therapy, non-pharmacological therapies are considered. When a HF patient fails to respond to all available therapies, heart transplantation becomes necessary. Of the 1,000 HF patients admitted to our hospital, two cases received heart transplants. 11 cases were indicated for heart transplantation but died before registration. It should be remembered that although in Japan the possibility of receiving a heart transplant is very low, it is by no means entirely impossible.

Ethanol injection into the Marshall vein provoking a pericardial effusion resulting in a fatal complication in a patient with persistent atrial fibrillation.

An EIM (ethanol infusion into the vein of Marshall [VOM]) provoked a fatal complication in a chronic hemodialysis patient. Autopsy revealed a lacerated VOM covered with thrombi as the only potential cause. The EIM caused vascular damage and clots resulting in myocardial necrosis and interstitial bleeding around the lacerated VOM.