良永 真隆

OBJECTIVES: MicroRNAs (miRNA) are functional RNAs that have emerged as pivotal gene expression regulators in cardiac disease. Although several cardiomyocyte miRNAs have been reported to play roles in heart failure progression among patients with idiopathic dilated cardiomyopathy (DCM), the role of circulating miRNAs has not yet been well-examined. METHODS: After total RNA extraction from the peripheral blood samples of three control participants and six patients with DCM, miRNA profiling was performed using miRNA arrays. Based on the results of this initial screening, real-time polymerase chain reaction (RT-PCR) was used to perform a quantitative analysis of blood samples from a larger number of matched patients (DCM, n=20; controls, n=5). Finally, the correlations between specific miRNA expression levels and hemodynamic parameters were analyzed. RESULTS: A primary screening of 2,565 miRNAs resulted in the identification of nine miRNA candidates. Quantitative RT-PCR results revealed significantly increased miR-489 expression levels in the DCM group. Moreover, there was a significant positive correlation between miR-489 expression level and left ventricular ejection fraction. CONCLUSIONS: Our results suggest that circulating miR-489 could be a potential noninvasive diagnostic biomarker for DCM. Additionally, the quantification of circulating miR-489 may have value as a potential prognostic marker for patients with DCM.

OBJECTIVES: There are benefits of exercise-based cardiac rehabilitation (CR) in patients with heart failure (HF), but their underlying molecular mechanisms remain elusive. The effect of CR on the expression profile of circulating microRNAs (miRNAs), which are short noncoding RNAs that regulate posttranscriptional expression of target genes, is unknown. If miRNAs respond to changes following CR for HF, then serum profiling of miRNAs may reveal cardioprotective mechanisms of CR. METHODS: This study enrolled three hospitalized patients with progressed systolic HF and three normal volunteer controls. In patients, CR was initiated after improvement of HF, which included 2 weeks of bicycle ergometer and resistance exercises. Genome-wide expression profiling of circulating miRNAs was performed using microarrays for the patients (mean±SD age, 60.0±12.2 years) and controls (58.7±0.58 years). Circulating miRNA expression profiles were compared between patients with HF before and after CR and the controls. RESULTS: Expression levels of two miRNAs were significantly different in patients before CR compared with controls and patients after CR. The expression of hsa-miR-125b-1-3p was significantly downregulated and that of hsa-miR-1290 was significantly upregulated in patients before CR. CONCLUSIONS: When performing CR, expression of certain circulating miRNAs in patients with HF is restored to nonpathological levels. The benefits of CR for HF may result from regulation of miRNAs through multiple effects of gene expression.

BACKGROUND: Although cardiac sarcoidosis is associated with poor prognosis, diagnosis of the disease is challenging and the sensitivity and specificity of diagnostic modalities are limited. This study was performed to evaluate the potential of serum microRNAs (miRNAs) as diagnostic biomarkers for cardiac sarcoidosis. METHODS: We performed genome-wide expression profiling for 2565 miRNAs (Human-miRNA ver.21) using peripheral blood samples from 5 patients with cardiac sarcoidosis (61±9 years) and 3 healthy controls (54±7 years). From this screening study, we selected 12 miRNAs that were significantly related to cardiac sarcoidosis. Next, we performed real-time polymerase chain reaction (PCR) on blood samples from 15 new patients with cardiac sarcoidosis and 4 healthy controls to quantify the expression of these 12 miRNAs. RESULTS: In the screening study, 12 miRNAs were differentially expressed (p<0.01) in all 5 patients with cardiac sarcoidosis, showing greater fold-change values (>4 or <0.25) compared with the expression in the 3 healthy controls. Analysis of the real-time PCR for blood samples from the other 15 patients and 4 controls using Mann-Whitney U tests revealed that the expression of miR-126 and miR-223 was significantly higher in the patients than in the healthy individuals. However, there were no differences in the expressions of miRNA-126 and miR-223 between patients with only cardiac lesions and those with extra-cardiac lesions. CONCLUSIONS: Our results demonstrate the potential of serum miR-126 and miR-223 as new-generation biomarkers for the differential diagnosis of cardiac sarcoidosis in patients with heart failure.

Although the renin-angiotensin system (RAS) is counter-balanced by a salt-sensitive mechanism in the hypertensive state, both are reported to be up-regulated in chronic kidney disease (CKD) patients. We conducted this study to evaluate the associations among the RAS, renal function, hypertension, and atherosclerosis, as well as to identify markers for salt-sensitivity. A total of 213 pre-dialysis CKD patients with preserved cardiac function (EF >50 %) were enrolled. Their renal and cardiac biochemical markers and plasma renin activity (PRA) were measured, and echocardiography and carotid artery ultrasound were performed. Their salt intake was estimated by the NaCl excretion from a 24-h collected urine sample. The PRA was higher in patients with hypertension (p = 0.018), and had a significant negative correlation with the eGFR (r = -0.23, p = 0.0067). Importantly, the PRA had a strong negative correlation with the brain natriuretic peptide (BNP) level (r = -0.28, p = 0.017) regardless of whether the patients were being treated with RAS inhibitors. The BNP level was related to the renal functions (eGFR: p = 0.001, ACR: p = 0.009). There was a significant positive correlation between the BNP level and carotid intima-media thickness (p < 0.001). A multivariate analysis revealed that older age and an excess of NaCl excretion were independent predictors of BNP elevation (p = 0.02 and 0.003, respectively). Our analysis revealed details of the counterbalance between BNP and PRA, as well as identifying that excess salt intake is a predictor of BNP elevation. These results indicate that the BNP could be a possible valuable marker for salt sensitivity, and that high salt sensitivity could facilitate atherosclerosis in CKD patients.

OBJECTIVES: The number of elderly patients with hypertension has been steadily increasing. However, there are limited data on the safety and efficacy of the new angiotensin type 1 receptor blocker (ARB) azilsartan in elderly patients with hypertension. We investigated the clinical efficacy and safety of azilsartan in this population. METHODS: The study population comprised 56 ambulatory patients with essential hypertension. We evaluated the reduction in blood pressure and safety after 12 weeks of treatment with azilsartan in 29 hypertensive patients ≥65 years of age (aged group) in comparison with the findings in 27 patients <65 years of age (non-aged group). RESULTS: Systolic blood pressure in the aged group declined significantly from 155 ± 18 mmHg at baseline to 138 ± 11 mmHg after 12 weeks of treatment with azilsartan, and that in the non-aged group also declined significantly from 152 ± 20 mmHg at baseline to 142 ± 13 mmHg after 12 weeks of treatment with azilsartan. There were no significant differences in the magnitude of change in blood pressures from pre-treatment to post-treatment with azilsartan between the non-aged and aged groups. There were no changes in clinical laboratory findings, including serum levels of creatinine, potassium, lipids, and other metabolic variables, after 12 weeks of treatment with azilsartan in both groups. CONCLUSIONS: Our findings suggest that azilsartan is effective in lowering blood pressure in elderly patients and may be safe. Therefore, azilsartan could be a valuable option for treating hypertension in elderly and non-elderly patients.

New oral anticoagulants (NOACs) are now clinically available. However, few studies have demonstrated which patients with non-valvular atrial fibrillation (NVAF) actually receive NOACs in a clinical setting. We analyzed 182 NVAF patients who received oral anticoagulants. Clinical backgrounds and the risk of stroke, systemic embolism, and bleeding associated with oral anticoagulants were investigated. Seventy-three (40 %) patients were treated with NOACs and 109 (60 %) patients were treated with warfarin. A significantly lower mean number of bleeding risk factors was observed among the patients treated with NOACs than among those treated with warfarin (P = 0.010). Of the bleeding risk factors, NOACs were significantly less frequently prescribed in patients with a bleeding history and elderly subjects (>65 years) than in those who received warfarin (P < 0.001 and P = 0.029). A multivariate logistic regression analysis revealed that CHF and bleeding history were independently and significantly associated with the administration of NOACs (P = 0.047 and P = 0.003). The rate of a history of intracranial hemorrhage was comparable between the patients treated with NOACs and those treated with warfarin (P = 1.000). Significantly lower rates of a history of gastrointestinal and other minor bleeding were observed in the patients who received NOACs versus those who received warfarin (P = 0.001 and P = 0.026). NOACs were less frequently prescribed in patients with a history of bleeding, especially those with a history of gastrointestinal bleeding in a clinical setting.

ビタミンB1欠乏症、特に衝心脚気は現代では非常に稀な病態であるが、1990年代から食生活の変化に伴い若年者に加え、高齢者の症例も散見されるようになった。症例は意識障害にて救急搬送された中年男性で、胸水・腹水含め、全身性の著明な浮腫を伴っていた。心臓超音波検査では重度のび漫性左室収縮低下を認めたが、生活歴・食事歴よりビタミン欠乏を疑い、ビタミン補充治療を施行するも改善に乏しかった。ビタミン利用障害の可能性も考慮し、大量補充療法を施行したところ、速やかな意識状態の正常化を認め、浮腫も改善した。最終的には心機能も正常範囲に回復し、社会生活への復帰が可能となった。改善後、ビタミンB1負荷検査にて、ビタミンB1の利用障害が認められた。本症例のような偏食を伺わせる生活歴を持った原因不明の循環不全においては、高拍出性心不全の病態でなくても、脚気心の可能性を念頭に置く必要がある。通常のビタミン補充療法で改善を認めない場合でも、ビタミンB1の利用障害が存在している可能性を考慮し、典型的なWernicke脳症の症状を呈さなくても、心不全に意識障害を併発している場合には、早期から高用量のビタミンB1投与も検討する必要があると考えられた。(著者抄録)

<p> ビタミンB1欠乏症, 特に衝心脚気は現代では非常に稀な病態であるが, 1990年代から食生活の変化に伴い若年者に加え, 高齢者の症例も散見されるようになった.</p><p> 症例は意識障害にて救急搬送された中年男性で, 胸水・腹水含め, 全身性の著明な浮腫を伴っていた. 心臓超音波検査では重度のび漫性左室収縮低下を認めたが, 生活歴・食事歴よりビタミン欠乏を疑い, ビタミン補充治療を施行するも改善に乏しかった. ビタミン利用障害の可能性も考慮し, 大量補充療法を施行したところ, 速やかな意識状態の正常化を認め, 浮腫も改善した. 最終的には心機能も正常範囲に回復し, 社会生活への復帰が可能となった. 改善後, ビタミンB1負荷検査にて, ビタミンB1の利用障害が認められた.</p><p> 本症例のような偏食を伺わせる生活歴を持った原因不明の循環不全においては, 高拍出性心不全の病態でなくても, 脚気心の可能性を念頭に置く必要がある. 通常のビタミン補充療法で改善を認めない場合でも, ビタミンB1の利用障害が存在している可能性を考慮し, 典型的なWernicke脳症の症状を呈さなくても, 心不全に意識障害を併発している場合には, 早期から高用量のビタミンB1投与も検討する必要があると考えられた.</p>

Takotsubo cardiomyopathy is a disorder characterized by left ventricular apical ballooning with preceding emotional and/or physical stressors. This condition is also an important differential diagnosis of acute coronary syndrome. We herein describe a case of Takotsubo cardiomyopathy, a significant clinical phenomenon, triggered by delayed-onset rhabdomyolysis following the administration of long-term statin treatment, without any preceding stressors or changes in the patient's medical condition, in association with complaints of non-specific muscle-related symptoms. Although an electrocardiogram showed remarkable ST-segment elevation, a careful reading of the electrocardiogram findings revealed the features of Takotsubo cardiomyopathy. Withdrawing the statin therapy improved the patient's cardiac function.

Hypertrophic cardiomyopathy (HCM) has various morphological and clinical features. A decade has passed since the previous survey of the epidemiological and clinical characteristics of Japanese HCM patients. The Aichi Hypertrophic Cardiomyopathy (AHC) Registry is based on a prospective multicenter observational study of HCM patients. The clinical characteristics of 42 ambulant HCM patients followed up for up to 5 years were investigated. The primary endpoint was major adverse cardiac events (MACE), defined as death, non-fatal stroke, admission due to congestive heart failure (CHF), or episodes of sustained ventricular tachycardia/fibrillation. The MACE-free survival during the 5-year follow-up period was 76% according to Kaplan-Meier analysis. HCM-related death occurred in 3 (7%) patients and SCD occurred in 2 (5%) patients. Additionally, 3 (7%) patients were admitted to the hospital due to CHF. Meanwhile, sustained VT was detected in one (2%) of the patients who received ICD implantation and subsequently terminated with antitachycardia pacing using an ICD. The patients with HCM exhibiting left ventricular outflow obstruction (HOCM) had a slightly lower MACE-free survival rate than those with neither HOCM nor dilated-HCM (dHCM) (71% versus 81%, log-rank P = 0.581). Furthermore, the patients with dHCM demonstrated a significantly lower MACE-free survival rate than those with neither HOCM nor dHCM (33% versus 81%, log-rank P = 0.029). In the AHC Registry targeting current Japanese HCM patients, we demonstrated that many HCM patients continue to suffer from MACE despite the development of various treatments for HCM.

目的:サルコイドーシスは一般的には自然寛解する予後良好な疾患と考えられているが、心病変は本症による死亡原因の1位であり、特に早期の心病変にはステロイドの有効性が認められているため的確な診断が必要とされる。18F-FDG PETはその診断能が注目されており、89%の症例で心臓サルコイドーシスが診断可能であったという報告もある。われわれはサルコイドーシスと診断した症例に対し18F-FDG PET/CTを用い心臓サルコイドーシスの検出も試み、さらに201TI心筋血流シンチグラフィと比較し、18F-FDG PET/CTの心臓サルコイドーシスの診断における有用性を検討した。方法:サルコイドーシスと診断された患者のうち、18F-FDG PET/CTを施行した7症例につき検討した。結果・考察:診断基準にて心臓サルコイドーシスと診断された3例において18F-FDGの集積が心臓に認められた。心臓サルコイドーシスではないと判定された残り4例には心臓に集積は認めなかった。201TI心筋血流シンチグラフィと比較してもより鋭敏に病変をとらえることができた。結論:18F-FDG PET/CTは疾患特異性が高く、鋭敏に炎症像もとらえることができることから、心臓サルコイドーシスの早期診断に有用であると考えられた。(著者抄録)

目的 : サルコイドーシスは一般的には自然寛解する予後良好な疾患と考えられているが, 心病変は本症による死亡原因の1位であり, 特に早期の心病変にはステロイドの有効性が認められているため的確な診断が必要とされる. ¹⁸F-FDG PETはその診断能が注目されており, 89%の症例で心臓サルコイドーシスが診断可能であったという報告もある. われわれはサルコイドーシスと診断した症例に対し¹⁸F-FDG PET/CTを用い心臓サルコイドーシスの検出を試み, さらに²⁰¹Tl心筋血流シンチグラフィと比較し, ¹⁸F-FDG PET/CTの心臓サルコイドーシスの診断における有用性を検討した. 方法 : サルコイドーシスと診断された患者のうち, ¹⁸F-FDG PET/CTを施行した7症例につき検討した. 結果・考察 : 診断基準にて心臓サルコイドーシスと診断された3例において¹⁸F-FDGの集積が心臓に認められた. 心臓サルコイドーシスではないと判定された残り4例には心臓に集積は認めなかった. ²⁰¹Tl心筋血流シンチグラフィと比較してもより鋭敏に病変をとらえることができた. 結論 : ¹⁸F-FDG PET/CTは疾患特異性が高く, 鋭敏に炎症像もとらえることができることから, 心臓サルコイドーシスの早期診断に有用であると考えられた.

BACKGROUND: Mechanisms of the pseudonormalization (PN) of the transmitral flow (TMF) velocity pattern have been mainly attributed to left ventricular diastolic function. PURPOSE: To assess the influence of left atrial (LA) function on the PN with two-dimensional tissue tracking technique. METHODS: The subjects consisted of 21 healthy volunteers and 70 patients with various cardiac diseases. Images of one cardiac cycle in the apical four-chamber view were stored by the HIVISION 900 (Hitachi Medico, Chiba, Japan). The LA volume (LAV) loop was created using two-dimensional tissue tracking technique and LAV index (LAVI) at a given cardiac phase was calculated. A preload of 90mmHg was applied using a customized lower body positive pressure (LBPP) system. Patients were divided into the PN group (n=18) with their early diastolic TMF velocity (E) increased and late diastolic TMF velocity (A) decreased, and the non-(N)-PN group (n=52) with both E and A wave velocities increased by LBPP. RESULTS: (1) During LBPP, the LAVImax in both the groups increased significantly. (2) In the N-PN group, the LAVIpass (p<0.001), LAVIact (p<0.01), and LAVItotal (p<0.0001) increased significantly. The dV/dts (p<0.0001) and dV/dtE (p<0.0001) increased significantly with an increase in the dV/dtA. On the other hand, there was no change in those parameters except LAVIpass (p<0.05) and dV/dtE (p<0.05) significantly increased in the PN group. (3) As a result, the LAVImin was significantly greater in the PN group than in the N-PN group (p<0.0001) during LBPP. The ratio of E velocity to early diastolic mitral annular velocity (E/E') during LBPP was significantly greater in the PN group than in the N-PN group (p<0.0001). CONCLUSIONS: The lack of an increase in active LA emptying volume in response to an increase of preload leads to elevated LA pressure and the pseudonormalization of the TMF velocity pattern in patients with various cardiac diseases.