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Abstract Background Currently, two types of cryoballoon (CB) systems are available for catheter ablation of atrial fibrillation (AF). Since the POLARx (Boston Scientific) is softer during freezing than the Arctic Front Advance Pro (AFA‐Pro; Medtronic), it tends to go more deeply into the pulmonary vein (PV), risking PV stenosis. Methods Ninety‐one patients underwent initial CB ablation for paroxysmal AF (AFA‐Pro 56; POLARx 35). Twenty‐six from each group were extracted using propensity score matching. The PV cross‐sectional area (PVA) was measured by tracing the area within the PV plane at 5‐mm intervals from the PV ostium in a distal direction for 20 mm or to the bifurcation in each PV. The PVA was compared before and 3 months after ablation. Results Time to balloon temperatures of −30 and − 40°C was significantly shorter and the nadir temperature was significantly lower with POLARx than with AFA‐Pro. In the left inferior (LI) PV and right superior (RS) PV, the freezing balloon position was significantly deeper in POLARx than in AFA‐pro. The freezing position in RSPV with mild to moderate narrowing was deeper than those without (10.2 ± 3.3 mm vs. 8.2 ± 1.8 mm, p = .01). In RSPV, the reduction of PVA tended to be greater with the POLARx than with the AFA‐Pro (26.1% ± 14.1% vs. 19.9% ± 10.3%, p = .07). Conclusion There was no significant difference in the incidence of PV stenosis between POLARx and AFA‐Pro. However, if POLARx goes deep into the PVs, we will still have to be careful.

Abstract Recently, a mild elevation of the blood ketone levels was found to exert multifaceted cardioprotective effects. To investigate the effect of angiotensin receptor neprilysin inhibitors (ARNIs) on the blood ketone body levels, 46 stable pre-heart failure (HF)/HF patients were studied, including 23 who switched from angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to ARNIs (ARNI group) and 23 who continued treatment with ACE inhibitors or ARBs (control group). At baseline, there were no significant differences in the total ketone body (TKB) levels between the two groups. Three months later, the TKB levels in the ARNI group were higher than the baseline values (baseline to 3 months: 71 [51, 122] to 92 [61, 270] μmol/L, P

Abstract Background Hyperuricemia (HU) has been reported to be associated with a high incidence of atrial fibrillation (AF). However, the relationship between HUA and recurrent AF after catheter ablation (CA) is unclear. Methods Four hundred consecutive AF patients (paroxysmal/persistent AF [PAF/PsAF]: 200/200) who underwent the initial CA were retrospectively enrolled. HU was defined as serum uric acid (SUA) level >7.0 mg/dL. We measured SUA levels 1 day before (pre‐CA) and 1 month after CA (post‐CA). A second‐generation 28 mm cryoballoon was used for pulmonary vein isolation (PVI) for PAF, while PVI plus linear ablation (roof and mitral isthmus lines) by radiofrequency catheter was conducted for PsAF. Results During 57 ± 24 months of follow‐up, AF recurred in 16% and 42% in PAF and PsAF patients (p

Background: Unexpectedly low natriuretic peptide (NP) levels in proportion to heart failure severity are often observed in obese individuals. However, the magnitude of NP elevation in response to acute cardiac stress in obesity has not yet been extensively studied. This study aimed to determine the impact of obesity on the increase in plasma NP in response to cardiac hemodynamic stress during acute coronary syndrome (ACS) attacks. Methods and Results: The study population included 557 consecutive patients with ACS for whom data were collected during emergency cardiac catheterization. To determine the possible impact of body mass index (BMI) on the relationship between left ventricular ejection fraction (LVEF) and plasma B-type NP (BNP) levels, the study population was divided into two groups (Group 1: BMI

Heart failure with preserved ejection fraction (HFpEF) is a major health concern. There is a growing recognition of the causal interplay between arterial stiffness and HFpEF. We recently reported that phosphate retention is a trigger for arterial stiffness. This study focuses on whether arterial stiffness due to phosphate retention could be a predictor for HFpEF. Methods: The subjects of this study were 158 patients (68 males and 90 females, mean age 74.8 ± 11.2). HFpEF was defined according to the guidelines of the ESC 2019. Pulse wave velocity (PWV) and central systolic blood pressure (CSBP) were used as markers for arterial stiffness and afterload, respectively. We measured serum levels of fibroblast growth factor 23 (FGF23) as a marker of phosphate retention. Results: The serum levels of FGF23 had a significant relationship with PWV. PWV had significant relationships with LV mass index, plasma BNP levels, and relative wall thickness, e′, and E/e′ (p < 0.001, respectively). Multivariate logistic regression analysis revealed that higher PWV values and hypertension were significant predictors for the dependent factor (HFpEF). Arterial stiffness amplified afterload, leading to LV concentric hypertrophy and diastolic dysfunction. This study presents that arterial stiffness is a key predictor of HFpEF, and that phosphate retention is involved in the pathology of HFpEF.

Abstract Aims Although the haemodynamic effects of angiotensin receptor‐neprilysin inhibitor (ARNI) on patients with heart failure have been demonstrated, the effect on glucose metabolism has not been fully elucidated. We retrospectively investigated the effect of ARNI on abnormal glucose metabolism in patients with stable chronic heart failure using an additional structural equation model (SEM) analysis. Methods We analysed 34 patients who regularly visited to the outpatient department of our institute with heart failure from October 2021 and July 2022 and who were taking angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Seventeen patients switched from ACE inhibitors or ARBs to an ARNI (ARNI group), and the other 17 patients continued treatment with ACE inhibitors or ARBs (control group). Results At baseline, although the ARNI group included fewer patients with heart failure with preserved ejection fraction in comparison with the control group (P = 0.004), patients with heart failure with mildly reduced ejection fraction, and heart failure with reduced ejection fraction were mostly biased towards the ARNI group (although not statistically significant). The baseline insulin resistance in the ARNI group was already significantly higher in comparison with the control group [fasting blood insulin, 9.7 (7.4, 11.6) vs. 7.8 (5.2, 9.2) μU/mL, P = 0.033; homoeostasis model assessment of insulin resistance (HOMA‐IR), 3.10 (1.95, 4.19) vs. 2.02 (1.56, 2.42), P = 0.014]. Three months later, the fasting blood insulin and the HOMA‐IR levels were both found to have decreased in comparison with the baseline values [baseline to 3 months: insulin, 9.7 (7.4, 11.6) to 7.3 (4.6, 9.4) μU/mL, P

Abstract Although balloon pulmonary angioplasty (BPA) improves pulmonary hypertension and the prognosis of patients with chronic thromboembolic pulmonary hypertension (CTEPH), subsequent changes in body mass index (BMI), nutritional status, and appetite have not been fully investigated. This retrospective study aimed to clarify changes in BMI, nutritional status, and appetite after BPA. Fifty‐two consecutive patients with CTEPH who underwent complete revascularization with BPA between July 2014 and July 2023 and were available for follow‐up were evaluated. We compared the presence or absence of increased appetite, BMI change, and nutritional status before and after BPA treatment. BPA significantly improved the mean pulmonary artery pressure from 37.4 ± 8.7 mmHg to 18.7 ± 2.8 mmHg and the partial pressure of oxygen from 61.6 ± 9.3 mmHg to 82.8 ± 9.9 mmHg (both p

Abstract Aims Pulmonary congestion, reduced cardiac output, neurohumoral factor activation, and decreased renal function associated with decreased cardiac function may have various effects on haemograms. The relationship between these factors and haemograms in patients with heart failure has not been sufficiently investigated. Recently, it was suggested that the lungs are an important site for platelet (Plt) biosynthesis and that it is necessary to study the relationship between pulmonary congestion and Plt count in heart failure in detail. In this study, we examined the relationship between various haemodynamic indicators and haemograms in detail using statistical analyses. Methods and results A total of 345 patients who underwent cardiac catheterization for the evaluation of cardiac function between 1 January 2015 and 31 December 2020 were included in the study. Haemodynamic indices, including left ventricular end‐diastolic pressure (LVEDP) and cardiac index (CI), were measured. Plasma noradrenaline (Nor) concentration, estimated glomerular filtration rate (eGFR), white blood cell (WBC) count, haemoglobin (Hb) level, and Plt count were measured using blood samples collected at the same time. Structural equation modelling (SEM) was used to examine the relationship between LVEDP, CI, plasma Nor concentration, eGFR, WBC count, Hb level, and Plt count. Bayesian inference using SEM was performed for Plt count. A total of 345 patients (mean age: 66.0 ± 13.2 years) were included in this study, and 251 (73%) patients were men. After simple and multiple regression analyses, path diagrams were drawn and analysed using SEM. LVEDP showed a significant negative relationship with Plt count (standardized estimate: −0.129, P = 0.015), and CI showed a significant negative relationship with Hb level (standardized estimate: −0.263, P

Summary: We recently reported that the selective inhibition of urate transporter-1 (URAT1), which is primarily expressed in the kidneys, ameliorates insulin resistance by attenuating hepatic steatosis and improving brown adipose tissue function in diet-induced obesity. In this study, we evaluated the effects of dotinurad, a URAT1-selective inhibitor, on the hearts of high-fat diet (HFD)-fed obese mice for 16–20 weeks and on neonatal rat cardiomyocytes (NRCMs) exposed to palmitic acid. Outside the kidneys, URAT1 was also expressed in cardiomyocytes and indeed worked as a uric acid transporter. Dotinurad substantially attenuated HFD-induced cardiac fibrosis, inflammatory responses, and cardiac dysfunction. Intriguingly, among various factors related to the pathophysiology of diet-induced obesity, palmitic acid significantly increased URAT1 expression in NRCMs and subsequently induced apoptosis, oxidative stress, and inflammatory responses via MAPK pathway, all of which were reduced by dotinurad. These results indicate that URAT1 is a potential therapeutic target for metabolic heart disease.

Abstract There is growing interest in 3-iodothyronamine (T1AM), an active thyroid hormone metabolite, that induces negative inotropic and chronotropic actions in the heart and exerts systemic hypothermic action. We explored the direct impact of T1AM on cardiomyocytes with a focus on the regulation of the intracellular temperature and natriuretic peptide (NP) expression. A thermoprobe was successfully introduced into neonatal rat cardiomyocytes, and the temperature-dependent changes in the fluorescence intensity ratio were measured using a fluorescence microscope. After one-hour incubation with T1AM, the degree of change in the fluorescence intensity ratio was significantly lower in T1AM-treated cardiomyocytes than in equivalent solvent-treated controls (P

Abstract The optimal ablation strategy for persistent atrial fibrillation (PsAF) remains to be defined. We sought to compare very long-term outcomes between linear ablation and electrogram (EGM)-guided ablation for PsAF. In a retrospective analysis, long-term arrhythmia-free survival compared between two propensity-score matched cohorts, one with pulmonary vein isolation (PVI) and linear ablation including roof/mitral isthmus line (LINE-group, n = 52) and one with PVI and EGM-guided ablation (EGM-group; n = 52). Overall, 99% of patients underwent successful PVI. Complete block following linear ablation was achieved for 94% of roof lines and 81% of mitral lines (both lines blocked in 75%). AF termination by EGM-guided ablation was accomplished in 40% of patients. Non-PV foci were targeted in 7 (13%) in the LINE-group and 5 (10%) patients in the EGM-group (p = 0.76). During 100 ± 28 months of follow-up, linear ablation was associated with superior arrhythmia-free survival after the initial and last procedure (1.8 ± 0.9 procedures) compared with EGM-group (Logrank test: p = 0.0001 and p = 0.045, respectively). In multivariable analysis, longer AF duration and EGM-guided ablation remained as independent predictors of atrial arrhythmia recurrence. Linear ablation might be a more effective complementary technique to PVI than EGM-guided ablation for PsAF ablation.

Abstract Thyroid hormone metabolism can be closely associated with cardiovascular disorders. We examined the relationship between low triiodothyronine (T3) levels and heart failure status, including B-type natriuretic peptide (BNP) levels, in 625 patients with cardiovascular disorders who underwent cardiac catheterization. A multiple regression analysis revealed that the left ventricular ejection fraction (LVEF), hemoglobin (Hb) levels, sex (male), free T3 (FT3) levels, and estimated glomerular filtration rate (eGFR) were significantly negatively associated with the log BNP value, while age was significantly positively associated with the log BNP value (P

Abstract Increasing evidence suggests natriuretic peptides (NPs) coordinate inter-organ metabolic crosstalk with adipose tissues and play a critical role in energy metabolism. We recently reported A-type NP (ANP) raises intracellular temperature in cultured adipocytes in a low-temperature-sensitive manner. We herein investigated whether exogenous ANP-treatment exerts a significant impact on adipose tissues in vivo. Mice fed a high-fat-diet (HFD) or normal-fat-diet (NFD) for 13 weeks were treated with or without ANP infusion subcutaneously for another 3 weeks. ANP-treatment significantly ameliorated HFD-induced insulin resistance. HFD increased brown adipose tissue (BAT) cell size with the accumulation of lipid droplets (whitening), which was suppressed by ANP-treatment (re-browning). Furthermore, HFD induced enlarged lipid droplets in inguinal white adipose tissue (iWAT), crown-like structures in epididymal WAT, and hepatic steatosis, all of which were substantially attenuated by ANP-treatment. Likewise, ANP-treatment markedly increased UCP1 expression, a specific marker of BAT, in iWAT (browning). ANP also further increased UCP1 expression in BAT with NFD. Accordingly, cold tolerance test demonstrated ANP-treated mice were tolerant to cold exposure. In summary, exogenous ANP administration ameliorates HFD-induced insulin resistance by attenuating hepatic steatosis and by inducing adipose tissue browning (activation of the adipose tissue thermogenic program), leading to in vivo thermogenesis during cold exposure.

Aims: T1 mapping in cardiac magnetic resonance imaging enables us to distinguish various myocardial diseases showing left ventricular hypertrophy. Fabry disease is a lysosomal storage disorder causing the accumulation of glycosphingolipids into various organs, including the heart, which can be detected by native T1 values in T1 mapping. However, there is no report for the systematic evaluation of native T1 values in Fabry disease in Japan. Methods and results: We analyzed native T1 values of 30 Fabry disease patients (14 males and 16 females) obtained by 3-T cardiac magnetic resonance imaging. Averaged T1 values were significantly lower in male patients (septal T1: 1149.5 ± 63.3 ms; total T1: 1145.1 ± 59.5 ms) than in female patients (septal T1: 1210.5 ± 45.5 ms; total T1: 1198.8 ± 51.8 ms) (p

Background: It was previously reported, based on a retrospective study, that preliminary removal of air bubbles in heparinized saline water with extracorporeal balloon inflation reduced the incidence of asymptomatic cerebral embolism (ACE). The present study aims to compare the incidence of ACE between a conventional and pre-inflation method during cryoballoon ablation in a prospective randomized controlled study. Methods: A total of 98 atrial fibrillation patients were enrolled and randomized into conventional and pre-inflation groups. Patients in the pre-inflation group received balloon massaging with preliminary extracorporeal balloon inflation in saline water before the cryoballoon was inserted into the body. Results: The baseline characteristics were similar between the two groups. Post-procedural 3-Tesla MRI revealed CE in 27.6% of patients. Symptomatic CE only occurred in two patients in the pre-inflation group. One patient had transient dysarthria and mild muscle weakness in one hand; the other patient complained of transient left upper limb weakness, left lower limb paresthesia and dysarthria. The incidence of ACE detected by cerebral MRI did not differ between the two groups to a statistically significant extent (conventional vs. pre-inflation; 22.9% vs. 29.2%; P = 0.49). In the multivariable analysis, eGFR was independently associated with the presence of ACE (odds ratio 0.95; 95% confidence interval 0.907–0.995; P = 0.03). Conclusion: In this prospective randomized study, the preliminary removal of air bubbles in heparinized saline water with extracorporeal balloon inflation had no impact on the incidence of ACE.

Abstract In patients with cardiovascular disorders, blood total ketone body (TKB) levels increase with worsening heart failure and are consumed as an alternative fuel to fatty acid and glucose. We investigated factors contributing to the increase in the blood TKB levels in patients with cardiovascular disorders. The study population consisted of 1030 consecutive patients who underwent cardiac catheterization. Covariance structure analyses were performed to clarify the direct contribution of hemodynamic parameters, including the left ventricular end-diastolic pressure (LVEDP), left ventricular end-systolic volume index (LVESVI), left ventricular end-diastolic volume index (LVEDVI), and B-type natriuretic peptide (BNP) levels, to TKB by excluding other confounding factors. These analyses showed that the TKB levels were significantly associated with the BNP level (P = 0.003) but not the LVEDP, LVESVI, or LVEDVI levels. This was clearly demonstrated on a two-dimensional contour line by Bayesian structure equation modeling. The TKB level was positively correlated with the BNP level, but not LVEDP, LVESVI or LVEDVI. These findings suggested that elevated blood TKB levels were more strongly stimulated by the increase in BNP than by hemodynamic deterioration. BNP might induce the elevation of TKB levels for use as an important alternative fuel in the failing heart.

Abstract While phrenic nerve palsy (PNP) due to cryoballoon pulmonary vein isolation (PVI) of atrial fibrillation (AF) was transient in most cases, no studies have reported the results of the long-term follow-up of PNP. This study aimed to summarize details and the results of long-term follow-up of PNP after cryoballoon ablation. A total of 511 consecutive AF patients who underwent cryoballoon ablation was included. During right-side PVI, the diaphragmatic compound motor action potential (CMAP) was reduced in 46 (9.0%) patients and PNP occurred in 29 (5.7%) patients (during right-superior PVI in 20 patients and right-inferior PVI in 9 patients). PNP occurred despite the absence of CMAP reduction in 0.6%. The PV anatomy, freezing parameters and the operator’s proficiency were not predictors of PNP. While PNP during RSPVI persisted more than 4 years in 3 (0.6%) patients, all PNP occurred during RIPVI recovered until one year after the ablation. However, there was no significant difference in the recovery duration from PNP between PNP during RSPVI and RIPVI. PNP occurred during cryoballoon ablation in 5.7%. While most patients recovered from PNP within one year after the ablation, PNP during RSPVI persisted more than 4 years in 0.6% of patients.

Abstract It is generally believed that risk factors damage the coronary arteries, cause myocardial ischemia, and consequently change the shape of the heart. On the other hand, each of the risk factors may also have a negative effect on the heart. However, it is very difficult to examine the effects of each of these risk factors independently. Therefore, it is necessary to select an appropriate statistical method and apply it efficiently. In this study, the effects of coronary risk factors on left ventricular size and cardiac function were investigated using structure equation modeling (SEM), and were shown as Bayesian SEM-based frequency polygons using selected two-dimensional contours. This study showed that each risk factor directly affected the shape of the heart. Because vascular risk and heart failure risk are likely to evolve at the same time, managing risk factors is very important in reducing the heart failure pandemic.

A 42-year-old man with a 6-month-long fever was found to have chronic active Epstein-Barr virus infection complicated by aneurysmal coronary arteries with other arteries. In adult patients with this infection, coronary aneurysms are rare but are a poor prognostic factor. (Level of Difficulty: Intermediate.)

Abstract Background Previous studies have reported that being overweight, obese, or underweight is a risk factor for ischemic cardiovascular disease (CVD); however, CVD also occurs in subjects with ideal body mass index (BMI). Recently, the balance of n-3/n-6 polyunsaturated fatty acids (PUFAs) has received attention as a risk marker for CVD but, so far, no study has been conducted that investigates the association between BMI and the balance of n-3/n-6 PUFAs for CVD risk. Methods We evaluated the association between n-3/n-6 PUFA ratio and acute coronary syndrome (ACS) in three BMI-based groups (

Objective: Accumulating evidence indicates that high uric acid (UA) is strongly associated with obesity and metabolic syndrome and drives the development of nonalcoholic fatty liver disease (NAFLD) and insulin resistance. Although urate transporter-1 (URAT1), which is primarily expressed in the kidneys, plays a critical role in the development of hyperuricemia, its pathophysiological implication in NAFLD and insulin resistance remains unclear. We herein investigated the role and functional significance of URAT1 in diet-induced obese mice. Methods: Mice fed a high-fat diet (HFD) for 16–18 weeks or a normal-fat diet (NFD) were treated with or without a novel oral URAT1-selective inhibitor (dotinurad [50 mg/kg/day]) for another 4 weeks. Results: We found that URAT1 was also expressed in the liver and brown adipose tissue (BAT) other than the kidneys. Dotinurad administration significantly ameliorated HFD-induced obesity and insulin resistance. HFD markedly induced NAFLD, which was characterized by severe hepatic steatosis as well as the elevation of serum ALT activity and tissue inflammatory cytokine genes (chemokine ligand 2 (Ccl2) and tissue necrosis factor α (TNFα)), all of which were attenuated by dotinurad. Similarly, HFD significantly increased URAT1 expression in BAT, resulting in lipid accumulation (whitening of BAT), and increased the production of tissue reactive oxygen species (ROS), which were reduced by dotinurad via UCP1 activation. Conclusions: In conclusion, a novel URAT1-selective inhibitor, dotinurad, ameliorates insulin resistance by attenuating hepatic steatosis and promoting rebrowning of lipid-rich BAT in HFD-induced obese mice. URAT1 serves as a key regulator of the pathophysiology of metabolic syndrome and may be a new therapeutic target for insulin-resistant individuals, particularly those with concomitant NAFLD.

A 46-year-old man who had undergone hematopoietic stem cell transplant twice because of acute lymphoblastic leukemia with recurrence presented with dyspnea, leading to a diagnosis of pulmonary arterial hypertension which was quickly and effectively treated with the phosphodiesterase type 5 inhibitor tadalafil. To our knowledge, pulmonary arterial hypertension related to hematologic malignancies requiring hematopoietic stem cell transplant is rarely reported. Importantly, the present case suggests that early diagnosis and treatment with a pulmonary vasodilator, such as tadalafil, can greatly decrease pulmonary vascular resistance in patients with severe pulmonary arterial hypertension after hematopoietic stem cell transplant and can then improve other symptoms. Accordingly, pulmonary vascular disease should be considered if respiratory symptoms develop following hematopoietic stem cell transplant, because treatment with pulmonary vasodilator may lead to significant improvement in pulmonary arterial hypertension.

Abstract Background Recent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac sodium–glucose cotransporter (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is an important preferential substrate for myocardial energy metabolism under conditions of ischemia–reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during the acute phase of IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes. Methods and results The hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either the non-selective SGLT-inhibitor phlorizin or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia–reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with the findings in NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and a dramatically increased infarct size were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia–reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in myocardial glucose uptake. In contrast, SGLT1 expression at the plasma membrane remained constant during IRI, regardless of the diet condition, whereas SGLT2 was not detected in the hearts of any mice. Of note, phlorizin considerably reduced myocardial glucose uptake after IRI, particularly in HFD. Conclusions Cardiac SGLT1 but not SGLT2 plays a compensatory protective role during the acute phase of IRI via enhanced glucose uptake, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised.

Increasing evidence suggests natriuretic peptides (NPs) coordinate interorgan metabolic crosstalk. We recently reported exogenous ANP treatment ameliorated systemic insulin resistance by inducing adipose tissue browning and attenuating hepatic steatosis in diet-induced obesity (DIO). We herein investigated whether ANP treatment also ameliorates myocardial insulin resistance, leading to cardioprotection during ischemia–reperfusion injury (IRI) in DIO. Mice fed a high-fat diet (HFD) or normal-fat diet for 13 weeks were treated with or without ANP infusion subcutaneously for another 3 weeks. Left ventricular BNP expression was substantially reduced in HFD hearts. Intraperitoneal-insulin-administration-induced Akt phosphorylation was impaired in HFD hearts, which was restored by ANP treatment, suggesting that ANP treatment ameliorated myocardial insulin resistance. After ischemia–reperfusion using the Langendorff model, HFD impaired cardiac functional recovery with a corresponding increased infarct size. However, ANP treatment improved functional recovery and reduced injury while restoring impaired IRI-induced Akt phosphorylation in HFD hearts. Myocardial ultrastructural analyses showed increased peri-mitochondrial lipid droplets with concomitantly decreased ATGL and HSL phosphorylation levels in ANP-treated HFD, suggesting that ANP protects mitochondria from lipid overload by trapping lipids. Accordingly, ANP treatment attenuated mitochondria cristae disruption after IRI in HFD hearts. In summary, exogenous ANP treatment ameliorates myocardial insulin resistance and protects against IRI associated with mitochondrial ultrastructure modifications in DIO. Replenishing biologically active NPs substantially affects HFD hearts in which endogenous NP production is impaired.

Objective: An electrocardiogram (ECG) is an important tool for demonstrating cardiac manifestations in various heart diseases. The present study clarified the characteristics of ECG parameters in Japanese Fabry patients under long-term enzyme replacement therapy (ERT).Methods: We analyzed the ECGs of 40 Fabry patients (male, n = 17; female, n = 23) before and after treatment with ERT. To evaluate the atrio-ventricular conduction, the PQ interval, corrected PQ and PQ minus P-wave in lead II (Pend-Q) were calculated. The QRS duration, QTc, Sokolow-Lyon index, and strain pattern were also examined.Results: At the baseline, the shortening of the PQ interval, corrected PQ and Pend-Q was identified in 7.5, 25.0, and 47.5% of cases, respectively. The prolongation of QRS duration and QTc was found in 7.5 and 40.0% of cases, respectively. The strain pattern was mainly identified in female patients, irrespective of left ventricular hypertrophy (LVH). During long-term ERT, the PQ interval, corrected PQ and Pend-Q did not change significantly. The QRS duration was significantly prolonged in both genders, whereas the QTc was significantly prolonged only in male patients. A subgroup analysis revealed that the prolongation of the QRS duration and QTc only occurred in male patients with LVH and only occurred in female patients with the classical type mutation. The prevalence of the strain was significantly increased only in male patients with LVH.Conclusions: These results suggest that the shortening of the Pend-Q is a specific finding in Japanese Fabry patients, and the strain pattern without LVH in female patients can be considered Fabry disease. During long-term ERT, prolongation of the QRS duration and QTc can indicate the progression of myocardial damage in male patients with LVH and in female patients with the classical type mutation.

Balloon pulmonary angioplasty improves prognosis by alleviating pulmonary hypertension in patients with chronic thromboembolic pulmonary hypertension, even with incomplete revascularization. However, hypoxia or the requirement for pulmonary vasodilators often remain even after pulmonary hypertension relief. With this cohort study, we aimed to examine whether complete revascularization by additional balloon pulmonary angioplasty on residual lesions, even after pulmonary hypertension relief, could resolve hypoxia or the requirement for pulmonary vasodilators. During complete revascularization with balloon pulmonary angioplasty in 42 patients with chronic thromboembolic pulmonary hypertension, we investigated therapeutic effects at baseline (T1), pulmonary hypertension relief phase (T2), and at 6 months post-final balloon pulmonary angioplasty (T3). The pulmonary hypertension relief phase was defined as the first time that a mean pulmonary artery pressure ≤ 25 mmHg or pulmonary vascular resistance ≤ 240 dyn-s/cm5 was reached in right heart catheterization before balloon pulmonary angioplasty. The partial pressure of oxygen increased progressively over T1, T2, and T3 (59.2±8.5, 69.0±9.7, and 80.0±9.5 mmHg, respectively; P

Abstract Because of the lack of studies focused on the biological implications of extremely low B-type natriuretic peptide (BNP) levels, we investigated whether extremely low BNP levels could be harmful to the cardiovascular system due to compromised cardio-protection. By using cardiac troponin I (cTnI) as an indicator of cardiovascular disorder, we assessed whether cTnI was inversely associated with BNP in populations with low BNP levels. A total of 2,001 apparently healthy subjects older than 38 years were included in this study. We defined subgroups from this population by limiting the maximum BNP level with cut-off values ranging from 1 through 20 pg/mL and performed covariance structure analyses by comparing log(BNP) with log(cTnI) in each subgroup. The beta values between log(BNP) and log(cTnI) sharply decreased as the BNP cut-off was reduced from 20 pg/mL (beta = 0.04) to 1 pg/mL (beta = −0.29) and became significant when the BNP cut-off levels were lower than 4 pg/mL (p

Introduction The association among smoking history, eicosapentaenoic acid (EPA) to arachidonic acid (AA) ratio and acute coronary syndrome (ACS) is yet to be investigated. The present study aimed to clarify the association between the EPA/AA ratio and ACS prevalence in patients admitted to the cardiology department based on their smoking history. Material and Methods We enrolled 1733 patients from five cardiology divisions located in Tokyo, Japan, and measured their levels of polyunsaturated fatty acids, including EPA and AA, from January 2004 to May 2011. We assessed the association between the EPA/AA ratio and ACS in the subgroups stratified according to smoking history (never, former, current smokers) using multivariate logistic models. Results A high EPA/AA ratio was significantly associated with decreased odds of ACS among patients without a smoking history (adjusted odds ratio AOR=0.20, 95% CI: 0.04–0.86) but not in patients with a smoking history (former smoker, AOR=1.50, 95% CI: 0.44–5.03; current smoker, AOR=3.73, 95% CI: 0.34–40.6). Conclusions The EPA/AA ratio and ACS occurrence were found to be significantly associated in patients without a smoking history; however, no such association existed in patients with a smoking history.

Abstract Background A unicuspid aortic valve is a rare congenital cardiac abnormality. Despite its uncommon finding on an initial presentation, aortic insufficiency is accompanied with unicuspid aortic valve and this might reflect the natural history of progression in the morphology of unicuspid aortic valve. Case presentation We describe a 65-year-old Japanese man who was evaluated for endocarditis and found to have a unicuspid aortic valve concomitant with moderate aortic insufficiency, which was, owing to the lack of evidence of valve membrane destruction, independent of underlying infectious endocarditis. In addition, aortic insufficiency was progressed because of nonbacterial thrombotic endocarditis on the ventricular side, in areas of high turbulence around the heart valve. Conclusions Our case is unusual given the unicuspid aortic valve concomitant with aortic insufficiency, which was presumably independent of underlying infectious endocarditis because of the location of the vegetation and the lack of evidence of valve destruction. Therefore, attention should be paid to a variety of complications in the setting of unicuspid aortic valve.

Abstract The effects of left ventricular (LV) cavity size on cardiac function and overload have not yet been fully elucidated. We performed a covariance structure analysis and drew theoretical path models to clarify the effects of hemodynamic parameters on the stroke volume index (SVI) as a marker of cardiac function and on the plasma B-type natriuretic peptide (BNP) level as a marker of cardiac overload. We simultaneously measured various hemodynamic parameters and the BNP levels during cardiac catheterization in 1,715 inpatients of our institution. The current path models tested the validity of the Frank-Starling law in patients with heart failure using the SVI, the LV end-systolic volume index (LVESVI) and the LV end-diastolic volume index (LVEDVI). Using the BNP levels, the path models clearly demonstrated that LVESVI substantially augmented cardiac overload, whereas LVEDVI palliated this parameter. These volume indices exerted opposite effects on cardiac function and overload. These results advance the understanding of the relationships between LV cavity size and both cardiac function and overload and indicate the increasing importance of LV diastolic volume in heart failure and the utility of LVESVI as an important marker of cardiac remodeling for further relevant studies.

Abstract High serum uric acid (UA) level has been assumed to be a risk factor for left ventricular (LV) dysfunction; however, the precise relationship between these conditions has not been fully examined because many confounding factors are associated with UA level. We herein examined the precise relationship by proposing structural equation models. The study population consisted of 1432 cases with ischemic heart disease who underwent cardiac catheterization. Multiple regression analyses and covariance structure analyses were performed to elucidate the cause-and-effect relationship between UA level and LV ejection fraction (LVEF). A path model exploring the factors contributing to LVEF showed that high UA was a significant cause of reduced LVEF (P = 0.004), independent of other significant factors. The degree of atherosclerosis, as estimated by the number of diseased coronary vessels, was significantly affected by high UA (P = 0.005); and the number of diseased coronary vessels subsequently led to reduced LVEF (P

OBJECTIVES:One of the mechanisms of early recurrence of atrial fibrillation (ERAF) after AF ablation is considered to be the inflammatory reaction of the atrial tissue. The aim of this study is to compare the clinical significance of ERAF at each stage for true AF recurrence between cryoballoon (CB) and radiofrequency (RF) ablation. METHODS:Among 798 paroxysmal AF patients who underwent an initial ablation, 460 patients (CB, n = 230; RF, n = 230) were selected by propensity score matching. Very ERAF (VERAF), ERAF-1M, ERAF-3M and true AF recurrence were defined as AF recurrence at 0-2, 3-30, 31-90 days and more than 90 days after the procedure, respectively. RESULTS:The patient characteristics of the two groups were similar. ERAF was observed 21% and 27% in the CB and RF groups, respectively. In both the CB and RF group, VERAF, ERAF-1M and ERAF-3M were more frequently observed in patients with true AF recurrence than in those without. In a multivariable analysis, ERAF-1M and ERAF-3M were found to be independent predictors of true AF recurrence in both the CB (P = 0.04 and P

It is widely accepted that progression of organic stenosis in the coronary arteries and onset of acute coronary syndrome (ACS) are similar in the development of atherosclerosis. However, the extent of the association of each risk factor with the respective pathological conditions has not been fully elucidated.We investigated the differences in risk factors between these conditions using a statistical procedure.The study population consisted of 1,029 patients with ischemic heart disease (IHD). We divided the study population into two groups (ACS and non-ACS) and by diseased vessels (organic stenosis). Covariance structure analysis was simultaneously performed in one equation model for determination and comparison of the risk factors for organic stenosis and ACS.The analysis revealed that age (standardized regression coefficient, β: 0.206, P < 0.001), male gender (β: 0.126, P < 0.001), HbA1c level (β: 0.109, P < 0.001), HDL level (β: -0.109, P < 0.001) and LDL level (β: 0.127, P = 0.002) were significant for the advancement of organic stenosis. HDL level (β: 0100, P = 0.002) and MDA-LDL level (β: 0.335, P < 0.001) were significant for the onset of ACS, but age, HbA1c and LDL (P = NS or β < 0.1, respectively) were not. Among the risk factors, age, HbA1c and LDL were significantly more strongly associated with organic stenosis than ACS, while MDA-LDL was significantly more strongly associated with ACS than organic stenosis.The current statistical analysis revealed clear differences among the risk factors between the progression of organic stenosis and the onset of ACS. Among them, the MDA-LDL level should be considered to indicate a substantial risk of ACS.

It is conceivable that contemporary valvular heart disease (VHD) is affected largely by an age-dependent atherosclerotic process, which is similar to that observed in coronary artery disease (CAD). However, a comorbid condition of VHD and CAD has not been precisely examined. The first objective of this study was to examine a possible comorbid condition. Provided that there is no comorbidity, the second objective was to search for the possible reasons by using conventional risk factors and plasma B-type natriuretic peptide (BNP) because BNP has a potentiality to suppress atherosclerotic development.The study population consisted of 3,457 patients consecutively admitted to our institution. The possible comorbid condition of VHD and CAD and the factors that influence the comorbidity were examined by covariance structure analysis and multivariate analysis.The distribution of the patients with VHD and those with CAD in the histograms showed that the incidence of VHD and the severity of CAD rose with seniority in appearance. The real statistical analysis was planned by covariance structure analysis. The current path model revealed that aging was associated with VHD and CAD severity (P < 0.001 for each); however, as a notable result, there was an inverse association regarding the comorbid condition between VHD and CAD (Correlation coefficient [β]: -0.121, P < 0.001). As the second objective, to clarify the factors leading to this inverse association, the contribution of conventional risk factors, such as age, gender, hypertension, smoking, diabetes, obesity and dyslipidemia, to VHD and CAD were examined by multivariate analysis. However, these factors did not exert an opposing effect on VHD and CAD, and the inverse association defied explanation. Since different pathological mechanisms may contribute to the formation of VHD and CAD, a differentially proposed path model using plasma BNP revealed that an increase in plasma BNP being drawn by VHD suppressed the progression of CAD (β: -0.465, P < 0.001).The incidence of VHD and CAD showed a significant conflicting relationship. This result supported the likely presence of unknown diverse mechanisms on top of the common cascade of atherosclerosis. Among them, the continuous elevation of plasma BNP due to VHD might be one of the explicable factors suppressing the progression of CAD.

OBJECTIVE:Although glucose-insulin-potassium (GIK) therapy ought to be beneficial for ischemic heart disease in general, variable outcomes in many clinical trials of GIK in acute coronary syndrome (ACS) had a controversial impact. This study was designed to examine whether "insulin resistance" is involved in ACS and to clarify other potential intrinsic compensatory mechanisms for GIK tolerance through highly statistical procedure. METHODS AND RESULTS:We compared the degree of insulin resistance during ACS attack and remission phase after treatment in individual patients (n = 104). During ACS, homeostasis model assessment of insulin resistance (HOMA-IR) values were significantly increased (P

Obesity is believed to be one of the major risk factors for cardiovascular disease in Western countries. However, the effects of obesity should be continuously examined in the Japanese population because the average bodily habitus differs among countries. In this study, we collectively examined the significance of obesity and obesity-triggered risk factors including the low reactivity of B-type natriuretic peptide (BNP), for ischemic heart disease (IHD) in Japanese patients.The study patients consisted of 1252 subjects (IHD: n = 970; non-IHD: n = 282). Multiple logistic regression analysis revealed that dyslipidemia, hypertension, diabetes, and the low reactivity of BNP were significant risk factors for IHD, but body mass index (BMI) was not. A theoretical path model was proposed by positioning BMI at the top of the hierarchical model. Exploratory factor analysis revealed that BMI did not play a causative role in IHD (P = NS). BMI was causatively linked to other risk factors (P

We present the case of a patient who developed regular, narrow QRS tachycardia after ablation for long-standing persistent atrial fibrillation. During the electrophysiological study, this tachycardia was diagnosed as macroreentrant atrial tachycardia circulating around the mitral annulus. Catheter ablation was performed to treat the tachycardia by targeting the linear region between the annulus and the left inferior pulmonary vein. Although linear radiofrequency application along the mitral isthmus (MI) line resulted in the termination of this tachycardia, a unidirectional conduction block was observed through the MI. Bidirectional conduction block was subsequently achieved by delivering supplemental radiofrequency energies at the gap on the MI.

BackgroundMitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a key role in removing toxic aldehydes. Deficient variant ALDH2*2 genotype is prevalent in up to 40% of the East Asians and reported to be associated with acute myocardial infarction (AMI). To elucidate the mechanisms underlying the association of ALDH2*2 with AMI, we compared the clinical features of AMI patients with ALDH2*2 to those with wild‐type ALDH2*1/*1. Methods and ResultsThe study subjects consisted of 202 Japanese patients with acute ST‐segment elevation myocardial infarction (STEMI) (156 men and 46 women; mean age, 67.3±12.0) who underwent primary percutaneous coronary intervention (PCI). In 85 patients, provocation test for coronary spasm was also done 6 month post‐PCI. ALDH2 genotyping was performed by direct application of the TaqMan polymerase chain system. Of the 202 patients, 103 (51.0%) were carriers of ALDH2*2 and 99 (49.0%) those of ALDH2*1/*1. There were no differences in clinical features between ALDH2*2 and ALDH2*1/*1 carrier groups except higher frequencies of coronary spasm and alcohol flush syndrome (AFS) (88.6% vs 56.1%; P=0.001 and 94.3% vs 17.6%; P

Increased short-term blood pressure (BP) variability on 24-hour ambulatory BP monitoring (ABPM) is known to be a risk factor for cardiovascular events. However, very few studies have evaluated the effect of salt restriction on BP variability particularly in hypertensive patients with type 2 diabetes. This study aimed to investigate the effect of salt restriction on systolic BP (SBP) variability.10 hypertensive patients with type 2 diabetes and not receiving antihypertensive agents were enrolled in the study. After admission, all patients received a salt-restricted diet and appropriate anti-diabetic treatments and were followed up for 7 consecutive days using ABPM. After the 7-day treatment, the median [interquartile range (IQR)] coefficient of variation (CV) for diurnal SBP variability changed from day 1 to day 7-13.0 [10.8 to 16.8] % to 13.3 [9.1 to 18.9] % (P = 0.959)--and the median [IQR] change between days 1 and 7 was -0.3 [-3.2 to 2.9] %. In addition, CV for BP variability and circadian rhythm of BP varied greatly on a day-by-day basis for 7 days, compared to mean BP values. Interestingly, increased SBP variability was associated with greater day-by-day changes in circadian rhythm of BP.Salt restriction during 7-day hospitalization led to a -0.3 [-3.2 to 2.9] (median [IQR]) % change from baseline in CV for diurnal SBP variability in 10 hypertensive patients with type 2 diabetes not receiving antihypertensive agents.UMIN Clinical Trials Registry UMIN000016243.

The case of a patient with narrow QRS tachycardia is herein presented. During an electrophysiological study, this tachycardia was diagnosed as a focal atrial tachycardia with a high sensitivity to adenosine-5′-triphosphate (2 mg), and originating from near the His-bundle region. We could not ablate the earliest activation site in the right atrium because of the simultaneous recording of the His potential. The radiofrequency applications in the right atrium around the earliest activation site failed to terminate the tachycardia. Subsequent attempt of radiofrequency application in the non-coronary aortic cusp, where the earliest atrial activation without His potential was obtained, successfully eliminated the tachycardia without any atrioventricular nodal injury.

Sodium-glucose cotransporter 1 (SGLT1) is thought to be expressed in the heart as the dominant isoform of cardiac SGLT, although more information is required to delineate the subtypes of SGLTs in human hearts. Moreover, the functional role of SGLTs in the heart remains to be fully elucidated. We herein investigated whether SGLT1 is expressed in human hearts and whether SGLTs significantly contribute to cardiac energy metabolism during ischemia-reperfusion injury (IRI) via enhanced glucose utilization in mice.We determined that SGLT1 was highly expressed in both human autopsied hearts and murine perfused hearts, as assessed by immunostaining and immunoblotting with membrane fractionation. To test the functional significance of the substantial expression of SGLTs in the heart, we studied the effects of a non-selective SGLT inhibitor, phlorizin, on the baseline cardiac function and its response to ischemia-reperfusion using the murine Langendorff model. Although phlorizin perfusion did not affect baseline cardiac function, its administration during IRI significantly impaired the recovery in left ventricular contractions and rate pressure product, associated with an increased infarct size, as demonstrated by triphenyltetrazolium chloride staining and creatine phosphokinase activity released into the perfusate. The onset of ischemic contracture, which indicates the initiation of ATP depletion in myocardium, was earlier with phlorizin. Consistent with this finding, there was a significant decrease in the tissue ATP content associated with reductions in glucose uptake, as well as lactate output (indicating glycolytic flux), during ischemia-reperfusion in the phlorizin-perfused hearts.Cardiac SGLTs, possibly SGLT1 in particular, appear to provide an important protective mechanism against IRI by replenishing ATP stores in ischemic cardiac tissues via enhancing availability of glucose. The present findings provide new insight into the significant role of SGLTs in optimizing cardiac energy metabolism, at least during the acute phase of IRI.

OBJECTIVE: Although the plasma B-type natriuretic peptide (BNP) level is a marker of heart failure, it is unclear whether BNP per se plays a pivotal role for pathogenic mechanisms underlying the development of ischemic heart disease (IHD). In this study, we retrospectively examined the plasma BNP levels in stable patients with IHD and compared to stable patients with cardiovascular diseases other than IHD. METHODS: The study population was 2088 patients (1698 males and 390 females) who were admitted to our hospital due to IHD (n = 1,661) and non-IHD (n = 427) and underwent cardiac catheterization. Measurements of the hemodynamic parameters and blood sampling were performed. RESULTS: The plasma BNP levels were significantly lower in the IHD group than in the non-IHD group (p

OBJECTIVE: Thrombin, the final coagulation product of the coagulation cascade, has been demonstrated to have many physiological effects, including pro-fibrotic actions via protease-activated receptor (PAR)-1. Recent investigations have demonstrated that activation of the cardiac local coagulation system was associated with atrial fibrillation. However, the distribution of thrombin in the heart, especially difference between the atria and the ventricle, remains to be clarified. We herein investigated the expression of thrombin and other related proteins, as well as tissue fibrosis, in the human left atria and left ventricle. METHODS: We examined the expression of thrombin and other related molecules in the autopsied hearts of patients with and without atrial fibrillation. An immunohistochemical analysis was performed in the left atria and the left ventricle. RESULTS: The thrombin was immunohistologically detected in both the left atria and the left ventricles. Other than in the myocardium, the expression of thrombin was observed in the endocardium and the subendocardium of the left atrium. Thrombin was more highly expressed in the left atrium compared to the left ventricle, which was concomitant with more tissue fibrosis and inflammation, as detected by CD68 expression, in the left atrium. We also confirmed the expression of prothrombin in the left atrium. The expression of PAR-1 was observed in the endocardium, subendocardium and myocardium in the left atrium. In patients with atrial fibrillation, strong thrombin expression was observed in the left atrium. CONCLUSIONS: The strong expression levels of thrombin, prothrombin and PAR-1 were demonstrated in the atrial tissues of human autopsied hearts.