Among the several independent risk factors for atrial fibrillation (AF), hyperuricemia has been widely accepted as associated with the incidence of paroxysmal or persistent AF, as well as with the risk of AF in patients undergoing cardiovascular surgery. The electrophysiological mechanism of AF involves electrical remodeling of the arrhythmogenic substrate and abnormal automaticity as trigger. Both electrical and structural remodeling mediated by oxidative stress derived from either xanthine oxidoreductase (XOR), soluble uric acid (UA) or monosodium urate (MSU) crystals might be plausible explanations for the association of AF with hyperuricemia. XOR generates reactive oxygen species (ROS) that lead to atrial structural remodeling via inflammation. Soluble UA accumulates intracellularly through UA transporters (UAT), shortening the atrial action potential via enhanced expression and activity of Kv1.5 channel proteins. Intracellular accumulation of soluble UA generates ROS in atrial myocytes via nicotinamide adenine dinucleotide phosphate oxidase, which phosphorylates ERK/Akt and heat shock factor 1 (HSF1), thereby increasing transcription and translation of Hsp70, which stabilizes Kv1.5. In macrophages, MSU activates the NLRP3 inflammasome and proteolytic processing mediated by caspase-1 with enhanced interleukin (IL)-1β and IL-18 secretion. Use of an XOR inhibitor, antioxidants, a UAT inhibitor such as a uricosuric agent, and an NLRP3 inflammasome inhibitor, might become a potential strategy to reduce the risk of hyperuricemia-induced AF, and control serum UA level.
Abdominal aortic aneurysms (AAA) are referred to as “time bombs”. The only way to prevent AAA rupture is elective repair beforehand using surgical replacement or an endovascular procedure. Non-surgical strategies to prevent AAA expansion are under intense investigation. At each AAA stage, that is, occurrence, expansion, and rupture, the mechanisms and risk factors are different, as discussed in this review. Based on the mechanism and risk factors for AAA expansion, the most effective strategy against AAA expansion need to be identified, but so far none has. Exercise is known to be essential for preventing atherosclerosis related to the coexistence of AAA and CAD, but some doctors are hesitant to prescribe exercise programs to AAA patients given that BP elevation during exercise can cause AAA expansion or rupture. In our retrospective study and prospective study on the safety and effectiveness of exercise for AAA patients, the protective role of mild-moderate exercise against expansion of small AAA was clearly shown. The stability of AAA on exercise might be related to reduced inflammatory activity in the aortic wall, stabilized elevation in BP during exercise, increased aortic blood flow, upregulation of transforming growth factor-β1, moderated BMI and/or fat, or improved endothelial function. Until a revolutionary drug emerges that can regress AAA, cardiac rehabilitation remains the best strategy for preventing AAA expansion and rupture.
The 12-lead electrocardiogram (ECG) is a fast, non-invasive, powerful tool to diagnose or to evaluate the risk of various cardiac diseases. The vast majority of arrhythmias are diagnosed solely on 12-lead ECG. Initial detection of myocardial ischemia such as myocardial infarction (MI), acute coronary syndrome (ACS) and effort angina is also dependent upon 12-lead ECG. ECG reflects the electrophysiological state of the heart through body mass, and thus contains important information on the electricity-dependent function of the human heart. Indeed, 12-lead ECG data are complex. Therefore, the clinical interpretation of 12-lead ECG requires intense training, but still is prone to interobserver variability. Even with rich clinically relevant data, non-trained physicians cannot efficiently use this powerful tool. Furthermore, recent studies have shown that 12-lead ECG may contain information that is not recognized even by well-trained experts but which can be extracted by computer. Artificial intelligence (AI) based on neural networks (NN) has emerged as a strong tool to extract valuable information from ECG for clinical decision making. This article reviews the current status of the application of NN-based AI to the interpretation of 12-lead ECG and also discusses the current problems and future directions.
Variant types and sites in a single gene could influence the age of onset, severity, and pattern of affected organs of the genetic disease, such as in Marfan syndrome (MFS)-causingFBN1, and understanding the genotype-phenotype relationship could aid in determining the treatment strategy. In contrast, completely distinct system and/or organ diseases induced by 1 gene mutation have been rarely reported. Transforming growth factor-β (TGF-β) type I receptor-encodingTGFBR1is such a gene, causing Loeys-Dietz syndrome (LDS) closely related to MFS, and also multiple self-healing squamous epithelioma (MSSE) without clinical overlap. The detailed mechanisms underlying this effect, however, remain elusive. We recently reported the significance of 2 distinct intronic variants (c.973+1G>A and c.806-2A>C) ofTGFBR1, which were both predicted to mediate in-frame exon 5 skipping but caused LDS and MSSE, respectively. On ex vivo minigene splicing assay analysis we demonstrated that 2 different cryptic splice sites were activated, and in-frame and out-of-frame transcripts were produced in LDS and MSSE, respectively, supporting the previously proposed but not yet approved mechanism that loss-of-function and haploinsufficiency-causing variants in serine/threonine kinase domains induce LDS and MSSE, respectively. In this review, we briefly summarize the recent findings and unresolved problems for the pathogenesis of LDS, including the TGF-β signaling paradox: most variants have been verified or predicted to be loss of function in vitro, but these variants enhanced TGF-β signaling in vivo.
Background:The relationship between outcome and trigger in takotsubo syndrome (TTS) has been recently discussed, but the data are still limited.
Methods and Results:We enrolled 745 consecutive patients with TTS from the Tokyo Cardiovascular Care Unit Network registry. The patients were divided into 4 groups based on trigger: (1) medical illness, 202 (27%); (2) physical activity, trauma and injury, 54 (7%); (3) emotional trigger, 199 (27%); and (4) unidentifiable trigger, 290 (39%). Compared with other groups, the medical illness group had the lowest percentage of female patients (68%, 85%, 89%, and 79%, respectively; P<0.001) and the highest mean patient age (75±11 years, 72±11, 73±12, and 75±11 years, respectively; P=0.02). In-hospital all-cause mortality was higher (11%) in this group (0%, 2%, and 2%, respectively; P<0.001). On multivariate logistic regression analysis, the medical illness group independently predicted all-cause death (OR, 4.73; 95% CI: 1.33–16.87); although there was no significant difference in cardiac deaths between the 4 groups.
Conclusions:TTS has a wide spectrum of outcome depending on the trigger. The medical illness trigger was a powerful predictor of outcome but the main cause of death is not cardiac complication.
Background:Increase of collagen in the extracellular matrix occurs with ageing. We investigated whether a collagen marker, tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), was associated with risk of stroke.
Methods and Results:In a nested case-control study of 953 subjects from the general population, we evaluated determinants of TIMP-1 level and stroke risk. Mean subject age was 65.7±8.6 years (53.0% men); TIMP-1 was 72.4±28.2 pg/mL in the control group and 75.3±30.9 pg/mL in the stroke group. The relationship between TIMP-1 quartile and stroke was J-curved. Subjects in the highest TIMP-1 quartile (≥89 ng/mL) had a significantly higher OR of stroke (59–72 ng/mL; OR, 1.90; 95% CI: 1.09–3.31, P=0.023) than those in the second TIMP-1 quartile, and this tended toward significance even after adjusting for confounding factors (P=0.059). Elevation of serum TIMP-1 became more marked after age 65 years. On multiple linear regression analysis, significant determinants of TIMP-1 were older age (B=0.21 per 1 year; 95% CI: 0.52–1.07, P<0.001) and higher systolic blood pressure (SBP; B=0.19 per 1 mmHg, 95% CI: 0.08–0.42, P=0.004).
Conclusions:TIMP-1 increased with ageing and with SBP, and can be associated with stroke.
Background:Levocarnitine has been reported to improve the left ventricular (LV) systolic function and decrease LV hypertrophy in hemodialysis (HD) patients. Its effect on LV diastolic dysfunction, however, has not yet been clarified.
Methods and Results:HD patients (n=88) were given levocarnitine i.v. 1,000 mg for 12 months at the end of every dialysis session through the dialysis circuit of the venous site. LV ejection fraction (EF), E/A, E/e’, left atrial volume index (LAVI) and LV mass index (LVMI) were measured before and 3, 6, 9, and 12 months after the start of levocarnitine on echocardiography. We regarded E/A≤0.8, E/e’>14 and LAVI>34 mL/m2as LV diastolic dysfunction, and LVEF<55% as LV systolic dysfunction. We also investigated the effect of levocarnitine on HFpEF. Plasma brain natriuretic peptide, total carnitine, free carnitine, and acyl-carnitine and biochemistry parameters were measured. Levocarnitine significantly improved LV diastolic function in HD patients with LV diastolic dysfunction, but did not affect LV diastolic function in those with normal LV diastolic function. Levocarnitine significantly improved HFpEF. Levocarnitine significantly improved the LV systolic function in HD patients with LV systolic dysfunction but did not affect the LV systolic function in those with normal LV systolic function. Levocarnitine significantly decreased LVMI and increased plasma total, free, and acyl-carnitine.
Conclusions:Levocarnitine ameliorates LV diastolic as well as LV systolic dysfunction in HD patients.
Background:We sought to explore the effects of previous heart failure (HF) hospitalization on mortality in patients hospitalized for acute decompensated HF (ADHF) in a large Japanese contemporary observational database.
Methods and Results:We prospectively enrolled consecutive patients with ADHF in 19 participating hospitals between October 2014 and March 2016. Of 4,056 patients, 1,442 patients (35.4%) had at least 1 previous HF hospitalization (previous hospitalization group), while 2,614 patients (64.5%) did not have a history of HF hospitalization (de novo hospitalization group). Patients with previous hospitalization were older and more often had comorbidities such as anemia, and renal failure than those without. The cumulative 1-year incidence of all-cause death was significantly higher in the previous hospitalization group than in the de novo hospitalization group (28% vs. 19%, P<0.001). After adjusting confounders, the excess risk of the previous hospitalization group relative to the de novo hospitalization group for all-cause death remained significant (HR, 1.28; 95% CI: 1.10–1.50, P=0.001). The excess risk was significant in patients without advanced age, anemia, or renal failure, but not significant in patients with these comorbidities, with significant interaction. Increase in the number of hospitalizations was associated with an increased risk for mortality.
Conclusions:In a contemporary ADHF cohort in Japan, repeated hospitalization was associated with an increasing, higher risk for 1-year mortality.
Background:Non-invasive evaluation of left ventricular (LV) diastolic dysfunction (DD) and elevated LV filling pressure are crucial for diagnosing heart failure. The 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) recommendations for evaluating elevated LV filling pressure (algorithm B) have acceptable diagnostic accuracy, including in patients with reduced LV ejection fraction (EF). No prior study, however, has assessed the diagnostic accuracy of algorithm A of the ASE/EACVI recommendations for evaluating LVDD in patients with normal LVEF.
Methods and Results:We evaluated the clinical relevance of algorithm A in 94 patients who underwent invasive LV pressure measurement. Algorithm A identified invasively defined LVDD (time constant τ≥48 ms and/or LV end-diastolic pressure ≥16 mmHg) with low sensitivity (22.4%) but high specificity (90.7%). Algorithm A also identified elevated LV filling pressure with low sensitivity (41.7%) but high specificity (87.5%), and with a high negative predictive value (90.9%).
Conclusions:Algorithm A may not be useful for screening LVDD in patients with normal LVEF. Negative findings using algorithm A, however, may identify a patient with normal LVDD with high specificity, and most of such patients will have LV pre-A pressure in the normal range.
Background:Although “disaster-related death” as a category awarded disaster-related compensation includes death not caused by the tragedy itself, the actual definition remains unclear.
Methods and Results:In the Kumamoto earthquake 2016, compared with the Great East Japan Earthquake 2011, excessive mental and physical stress and suicide were observed significantly more as causes of disaster-related death.
Conclusions:It is essential to give maximum consideration to refugees to support them while in shelters.
Background:The incidence of thromboembolism in patients with cancer is approximately 11%, and the risk of thrombosis in patients with malignant tumors is 6-fold higher than that in healthy persons. Thrombosis not only disrupts the treatment of cancer but also induces deterioration of quality of life (QOL). Knowledge about thrombus treatment is limited, and evidence is scarce. Clarification of the status and safety of venous thromboembolism (VTE) treatment in patients with cancer will contribute to active intervention and improvement of prognosis and QOL. In this study, the therapeutic effects of a non-vitamin K antagonist oral anticoagulant for VTE and the prognosis of cancer after treatment will be examined to establish a therapeutic method for VTE in patients with cancer.
Methods and Results:A multicenter, non-interventional, observational study will be conducted in patients with cancer who developed VTE and underwent anticoagulant therapy with rivaroxaban (group A) or warfarin (group B) for 24 weeks. The primary endpoint will be the recurrence/aggravation of symptomatic VTE or occurrence/aggravation of deep vein thrombosis. Registration of 500 patients is needed in order to calculate the 95% confidence interval of the event rate at ±1% precision.
Conclusions:The investigation period will run from January 2019 to December 2023 with ongoing selection of patients. Trial registration: no. 5-18-32 (approved 1 August 2018).