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Despite the advances in the treatment of cardiovascular diseases, effective treatment remains to be established to improve the quality of life of patients with chronic coronary syndrome. The aim of this study was to evaluate the effectiveness and safety of the low-intensity pulsed ultrasound (LIPUS) therapy, which we have developed as a novel non-invasive angiogenic therapy. We conducted a randomized, double-blind, placebo-controlled (RCT) pilot trial of the LIPUS therapy for patients with refractory angina pectoris without indication for PCI or CABG despite optimal medical therapy. The primary endpoint, the changes in weekly use of nitroglycerin were comparable; -3.06 (95% CI: -4.481 to -1.648) in the LIPUS group and − 3.10 (95% CI: -4.848 to -1.356) in the placebo group (both P

Background This study evaluated the mechanism of decline in coronary pressure from the proximal to the distal part of the coronary arteries in the left anterior descending (LAD) versus the right coronary artery (RCA) from the insight of coronary hemodynamics using wave intensity analysis (WIA). Methods Twelve patients with angiographically normal LAD and RCA were prospectively enrolled. Distal coronary pressure, mean aortic pressure, and average peak velocity were measured at 4 different positions: 9, 6, 3, and 0 cm distal from each coronary ostium. Results The distal-to-proximal coronary pressure ratio during maximum hyperemia gradually decreased in proportion to the distance from the ostium (0.92±0.03 and 0.98±0.03 at 9 cm distal to the LAD and RCA ostium). WIA showed the dominant forward-traveling compression wave gradually decreased and the backward-traveling suction wave gradually decreased in proportion to the decrease in coronary pressure through the length of the non-diseased LAD but not the RCA. Conclusions The pushing wave and suction wave intensities on WIA were diminished in proportion to the distance from the ostium of the LAD despite the wave intensity not changing across the length of the RCA, which may lead to gradual intracoronary pressure drop in the angiographically normal LAD.

Iron deficiency is linked to worse clinical status and outcomes in heart failure. Although metabolic syndrome contributes to the development of heart failure, the impact of iron deficiency in heart failure complicated with metabolic syndrome remains obscure. KKAy mice were used as a model of metabolic syndrome. Four-week-old male C57BL/6J and KKAy mice were fed either a normal diet or iron-restricted (IR) diet for 12 weeks. During the experiment, 40% of mice died due to pulmonary congestion in KKAy mice with IR diet (KKAy-IR), while no mice died in other groups. Necropsy showed the presence of multiple white lesions on the cardiac surface in those KKAy-IR mice. Echocardiography and histological analyses revealed that KKAy-IR mice exhibited cardiac hypertrophy and cardiac dysfunction with cardiac calcification. Cardiac mRNA of ectonucleotide pyrophosphatase/phosphodiesterase-1 (Enpp1), a key enzyme for bone mineralization, was highly abundant in KKAy-IR mice. Of note, iron restriction-induced cardiac calcification and dysfunction were attenuated by etidronate, an inhibitor of bone mineralization, with decreased cardiac Enpp1 mRNA abundance in KKAy-IR mice. In conclusion, iron deficiency leads to ectopic cardiac calcification and dysfunction with the increase of Enpp1 in metabolic syndrome model mice.

Iron is a necessary element for life; however, excess iron leads to oxidative stress by the Fenton reaction. Iron deficiency is prevalent in patients with heart failure, while iron overload is associated in the pathogenesis of atherosclerosis. These findings suggest the "iron paradox" in cardiovascular diseases. Iron metabolism in cardiovascular diseases is complex, and the mechanisms regulating systemic and cellular iron metabolism in cardiovascular diseases remain completely unknown. In this review, we focus on the role of iron in cardiovascular diseases.

Background: Recently, the left ventricular early inflow-outflow index (LVEIO), calculated by dividing mitral E-wave velocity by the left ventricular outflow velocity time integral, has been proposed as a simple method for evaluating mitral regurgitation (MR). This study determined the optimal LVEIO threshold to assess severe MR with different etiologies and assessed its prognostic value. Methods and Results: The records of 18,692 consecutive patients who underwent echocardiography were reviewed. MR was classified into 4 groups: Grade 0/1, no, trivial, or mild MR; Grade 2, moderate MR; Grade 3, moderate to severe MR; and Grade 4, severe MR. The mean (±SD) LVEIO of Grades 0/1, 2, 3, and 4 was 3.6±1.4, 6.0±2.5, 7.4±3.1, and 9.5±2.8, respectively. An optimal LVEIO threshold of 5.4 was determined to distinguish moderate to severe or severe MR from non-severe MR (sensitivity 84%, specificity 91%). Kaplan-Meier survival analysis revealed high mortality in the group with LVEIO ≥5.4 (P=0.009, hazard ratio 1.833). This was found only in primary MR when separate analyses were performed according to etiology. Multivariate analysis revealed that LVEIO was an independent predictor for all-cause death only in primary MR. Conclusions: Using appropriate thresholds, LVEIO is a simple and useful method to diagnose severe MR regardless of etiology. LVEIO can also be useful for predicting prognosis in primary MR.

The emergency room is a principal entrance for the initial management of patients with acute heart failure. Echocardiography may be performed by cardiologists and noncardiologists in the emergency room. Echocardiographic studies require effective technical skills and precise diagnostic knowledge. This article contributes to physicians in the emergency room, general practitioners in training, and medical staff who engage in emergency medicine. This article emphasized the role of echocardiography in light of pathophysiology of acute heart failure in the emergency room and refining the clinical workflow by integrating conventional and innovative knowledge for the initial management of acute heart failure.

Purpose: To identify intravascular ultrasound (IVUS) findings that predict midterm stent patency in femoropopliteal (FP) lesions. Materials and Methods: A retrospective analysis was undertaken of 335 de novo FP lesions in 274 consecutive patients (mean age 72.4±8.2 years; 210 men) who had IVUS assessment before and after successful stent implantation. The mean lesion length was 13.2±9.8 cm. The primary outcome was primary patency at 24 months, defined as freedom from major adverse limb event (MALE) and in-stent restenosis (ISR). MALE was defined as major amputation or any target lesion revascularization (TLR). ISR was defined by a peak systolic velocity ratio >2.4 by duplex ultrasonography. Logistic regression analyses were performed to identify independent predictors of stent patency at 24 months; the results are presented as the odds ratio (OR) and 95% confidence interval (CI). Receiver operator characteristic (ROC) curve analysis was performed to determine the optimal threshold for prediction of stent patency at 24 months. Results: Over the 24-month follow-up, 18 (7%) patients died and 43 (15%) of 286 lesions were responsible for MALE (42 TLRs and 1 major amputation). Primary patency was estimated at 82.5% (95% CI 78.1% to 86.9%) at 12 months and 73.2% (95% CI 67.9% to 78.5%) at 24 months. Multivariable analysis revealed that longer lesion length (OR 0.89, 95% CI 0.82 to 0.97, p2 as the optimal cut-point for prediction of 24-month stent patency (area under the ROC curve 0.764). Kaplan-Meier estimates of 24-month primary patency were 83.7% (95% CI 78.3% to 89.2%) in lesions with a distal EEM area >29.0 mm2 vs 53.1% (95% CI 42.9% to 63.3%) in those with a distal EEM area ≤29.0 mm2 (p

Left ventricular ejection fraction (LVEF) is critical for determining the prognosis and treatment of patients with heart failure (HF). However, the influence of serial LVEF changes in patients with stable chronic HF (CHF) has not yet been completely investigated. We analyzed data of 263 outpatients with CHF from the J-MELODIC study cohort and evaluated the frequency of cardiac events. We stratified patients into tertiles based on the relative difference in LVEF in 1 year and that at baseline. We found a significant difference in the cardiac event rate among the three groups (log-rank test, p = 0.042). We identified a relative 11% LVEF reduction as the optimal cutoff value based on the receiver operating characteristics analysis. LVEF (OR, 1.04; 95% CI, 1.01–1.07; p = 0.015) and E/e′ (OR, 1.06; 95% CI, 1.01–1.12; p = 0.023) at baseline were predictors of >11% LVEF reduction. After adjusting the variables including age and sex, >11% LVEF reduction was an independent predictor of subsequent cardiac events (HR, 5.79; 95% CI, 2.49–13.2; p 11% LVEF reduction may have subsequent worsening outcomes. Such patients should be carefully followed-up as high risk population for development of cardiac events.

Objectives This study sought to compare the procedural outcomes of percutaneous coronary intervention for chronic total occlusion between the periods before and after introduction of 3-dimensional (3D) wiring. Background Previously, we reported a 3D wiring method by which the operator can construct real-time mental 3D images from 2 perpendicular angles of X-ray system monitor during percutaneous coronary intervention for chronic total occlusion. Methods A total of 137 chronic total occlusion lesions that could not be passed by tapered soft wires in our hospital between 2012 and 2017 were retrospectively enrolled in the study. Results Overall success rate was significantly higher in the 3D wiring group (n = 69) than the non-3D wiring group (n = 68) (98% vs. 90%, respectively; p = 0.027). In the primary antegrade cases, the first antegrade approach time was significantly shorter in the 3D wiring group than the non-3D wiring group (42 ± 29 vs. 30 ± 16 min, respectively; p = 0.01). In cases where the antegrade approach was continued throughout the procedure, the success rate was significantly higher in the 3D wiring group than the non-3D wiring group (100% vs. 89.2%, respectively; p = 0.033). Vessel perforation by the antegrade wire tended to be lower in the 3D wiring group than the non-3D wiring group (1% vs. 11%, respectively; p = 0.055). Conclusions 3D wiring enables accurate guidewire control, which improves the success rate of antegrade wiring and reduces the antegrade procedure time, resulting in improvement of the overall success rate.

Acute exercise has been reported to increase thyroid hormone levels and decrease arterial stiffness in healthy young subjects. However, the effect of acute aerobic exercise on circulating thyroid hormone levels and arterial stiffness in patients with subclinical hypothyroidism remains unclear. The aim of this study was to investigate the effects of acute aerobic exercise on arterial stiffness and thyroid hormone levels, and any relationship between these endpoints, in patients with subclinical hypothyroidism. We studied patients with untreated subclinical hypothyroidism (n = 53, 65 ± 12 years old) compared with euthyroid subjects (n = 55, 64 ± 10 years old). Exercise analysis was performed with a ramp cycle ergometer test. Arterial stiffness (cardio-ankle vascular index, CAVI) was measured at baseline and 5 min after exercise. We collected participant blood samples for serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) measurements before and 5 min after exercise. The CAVI and serum TSH levels significantly decreased after exercise in the subclinical hypothyroidism group (CAVI; 8.1 ± 1.6 vs. 8.5 ± 1.5, p

BACKGROUND We used dual Doppler echocardiography to measure the time interval between the mitral and tricuspid valve opening (MO-TO time), which we expected would reflect the balance between left and right ventricular hemodynamics. Methods and Results: We prospectively enrolled 60 patients with heart failure (HF) and sinus rhythm. The MO-TO time was measured in addition to routine echocardiography parameters, invasive hemodynamic parameters and plasma B-type natriuretic peptide (BNP) level in all patients. Patients were divided into 2 groups based on the MO-TO time: MOP (mitral opening preceding tricuspid opening), and TOP (tricuspid opening preceding mitral opening) groups. We followed up the predefined adverse outcomes (cardiovascular [CV] death and hospitalization due to worsening HF) for 1 year. Pulmonary artery wedge pressure (PAWP) and mean pulmonary artery pressure (mPAP) were higher in the MOP than in the TOP group (P

Background Weight loss is a strong prognostic factor in chronic heart failure (CHF); however, little is known about its effects in patients with mild CHF. Therefore, we investigated the effects of weight loss in patients with mild CHF. Methods and Results We analyzed a total of 242 outpatients with mild CHF from the J-MELODIC study cohort. Weight loss was defined as ≥5% weight loss in 1 year. Twenty-seven patients (11.2%) lost ≥5% weight in 1 year. Weight loss was associated with higher rates of underweight and worsening renal function in 1 year compared with the absence of ≥5% weight loss. The predictors of weight loss included edema, B-type natriuretic peptide, and diabetes mellitus at baseline. Although weight loss was significantly associated with subsequent cardiovascular death or hospitalization for HF (log-rank P = .002) and subsequent death from any cause (log-rank P = .002), underweight was not associated with these outcomes (log-rank P = .356 and P = .168, respectively). Even after adjusting for covariates, weight loss was a significant and independent risk factor for subsequent cardiovascular death or hospitalization for HF (hazard ratio 3.22, 95% confidence interval 1.10–8.41; P = .034). Conclusions In patients with mild CHF, ≥5% weight loss was a significant predictor for subsequent cardiovascular death or hospitalization for HF.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2-I) have beneficial cardiovascular effects, including reduction in hospitalization for heart failure (HF). The aim of this study is to explore the efficacy and safety of canagliflozin compared with standard diabetes treatment in elderly patients with type 2 diabetes (T2DM) and HF with preserved ejection fraction (HFpEF). Methods and Results: This is a multicenter, randomized, open-label, parallel-group comparison study designed to evaluate the effects of canagliflozin on fluid retention and cardiac function in T2DM patients with HFpEF. Eligible participants are patients aged ≥65 years with insufficient glycemic control. Qualified patients will be randomly assigned to treatment with 100 mg of canagliflozin or standard diabetic treatment other than SGLT2-I; both groups will be treated for 24 weeks. The primary endpoints are changes in body weight as an indicator of fluid retention and plasma brain natriuretic peptide as an indicator of cardiac function. The secondary endpoints include cardiovascular event rates, changes in the dose of loop diuretics, echocardiographic left ventricular function, and nutritional status. Conclusions: This study is expected to provide valuable findings regarding the mechanisms of canagliflozin on cardiac function and a potential new therapeutic approach for HFpEF. (UMIN000028668 and jRCTs051180030).

We studied the mechanisms of anemia and the influence of anemia on renal pathology in Dahl/Salt Sensitive (Dahl/SS) rat, a model of cardio-renal-anemia syndrome. Erythrocyte lifespan was shortened and associated with decreased hemoglobin level in the Dahl/SS rats given high-salt diet. Serum haptoglobin decreased, reticulocytes increased, and erythropoiesis in the bone marrow and extramedullary hematopoiesis in the spleen was markedly stimulated by increased serum erythropoietin in them. As a mechanism of hemolysis, we investigated the incidence of eryptosis, suicidal death of erythrocytes. Eryptosis was increased, and red blood cell-derived microparticles, small particle which are generated in hemolytic disease, were also increased in Dahl/SS rats fed with high-salt diet. Deposition of hemosiderin and mitochondrial morphologic abnormality, a sign of ferroptosis, in proximal renal tubules was associated with intravascular hemolysis. Treatment with deferasirox, an oral iron chelator, reduced the renal proximal tubular injury and the glomerular sclerosis in Dahl/SS rats fed with high-salt diet. In conclusion, reduced half-life of erythrocytes induced by hemolysis is the major cause of anemia in Dahl/SS rat. Iron accumulation induced by hemolysis causes renal proximal tubule injury and accelerates renal damage in this model.

Background Qing-Dai (QD) treatment of patients with ulcerative colitis (UC) sometimes causes pulmonary arterial hypertension (PAH). However, the relationship of QD treatment to pulmonary arterial systolic pressure (PASP) in patients with UC has not been clarified.Methods and Results:The 27 patients with UC who were screened for PAH by transthoracic echocardiography (TTE) and underwent repeat TTE at 1 year were analyzed in this prospective observational study. Mean age was 44.0 years old, and median follow-up duration was 392. During the follow-up, 21 patients continued QD treatment (continuous group) and 6 patients discontinued the treatment (discontinuous group). In all patients, no significant difference in PASP levels between baseline and at follow-up was observed (21.4 vs. 21.3 mmHg, P=0.802). Furthermore, the mean PASP of patients in the continuous group did not differ from baseline to follow-up (21.4 mmHg to 22.6 mmHg, P=0.212); however, in the discontinuous group mean PASP was significantly decreased (21.5 mmHg to 16.8 mmHg, P=0.005). Moreover, changes in PASP from baseline to follow-up differed between the continuous and discontinuous groups (+1.1 mmHg vs. -4.7 mmHg, P=0.004). In addition, multivariable analyses revealed that only the duration of oral QD at baseline affected the increase of PASP. Conclusions In patients with UC, QD treatment may have an undesirable association with an increase in PASP.

Transverse aortic constriction (TAC) has been widely used to create pressure overload induced heart failure in mice. However, this conventional model has some limitations such as low reproducibility and long creation period of cardiac failure. In order to establish a highly reproducible cardiac failure model that mimics adverse cardiac remodeling (ACR) we combined pressure overload and beta-adrenergic receptor stimuli using isoproterenol (ISO) and explored the optimal TAC model by changing the durations of TAC and the doses of ISO. Thus we constructed a suitable model for ACR with an effective combination of 3-week TAC and subsequent one-week ISO (3 mg/kg/day) infusion. Using RNA-Seq analyses, we identified that the up-regulated genes were mainly related to fibrosis including Fbn1, C1qtnf6 and Loxl2; and that the down-regulated genes were associated with mitochondrial function including Uqcrc1, Ndufs3, and Idh2 in failing hearts of our ACR model. Next, we followed the changes in cardiac function after ceasing ISO infusion. Left ventricular function gradually recovered after cessation of ISO, suggesting cardiac reverse remodeling (CRR). Gene expression signatures of hearts, which exhibited CRR, were almost identical to that of TAC hearts without ISO. In conclusion, our new model exhibits a transition to ACR and subsequent CRR with high reproducibility. This murine model might add new insights into the experiments of heart failure technically as well as scientifically.

We investigated the medical or mechanical therapy, and the present knowledge of Japanese cardiologists about aborted sudden cardiac death (ASCD) due to coronary spasm. A questionnaire was developed regarding the number of cases of ASCD, implantable cardioverter–defibrillator (ICD), and medical therapy in ASCD patients due to coronary spasm. The questionnaire was sent to the Japanese general institutions at random in 204 cardiology hospitals. The completed surveys were returned from 34 hospitals, giving a response rate of 16.7%. All SCD during the 5 years was observed in 5726 patients. SCD possibly due to coronary spasm was found in 808 patients (14.0%) and ASCD due to coronary spasm was observed in 169 patients (20.9%). In 169 patients with ASCD due to coronary spasm, one or two coronary vasodilators was administered in two-thirds of patients [113 patients (66.9%)], while more than 3 coronary vasodilators were found in 56 patients (33.1%). ICD was implanted in 117 patients with ASCD due to coronary spasm among these periods including 35 cases with subcutaneous ICD. Majority of cause of ASCD was ventricular fibrillation, whereas pulseless electrical activity was observed in 18 patients and complete atrioventricular block was recognized in 7 patients. Mean coronary vasodilator number in ASCD patients with ICD was significantly lower than that in those without ICD (2.1 ± 0.9 vs. 2.6 ± 1.0, p

BACKGROUND Coronary angioscopy (CAS) is used to comprehensively evaluate vascular responses after drug-eluting stent (DES) implantation. This study sought to evaluate the capability of CAS for evaluating DES strut coverage grade and color grade of the intima compared with histological images in coronary autopsy specimens. Methods and Results: A total of 23 DES extracted from 11 autopsy hearts were imaged by CAS. All stent segments were graded as white or yellow according to the luminal surface color, and thrombus was evaluated according to a previous report. Neointimal coverage over the DES was graded as 0 (stent struts fully visible) to grade 3 (stent struts fully embedded and invisible). Of 76 segments, neointimal coverage was graded as 0 in 35 (46%), 1 in 22 (29%), 2 in 8 (11%), and 3 in 11 (14%). The neointimal thickness increased significantly with increasing neointimal coverage grade on angioscopy. Neointimal color was graded as white in 40 (53%) and yellow in 36 segments (47%). Histological analysis revealed that yellow neointima contained fibroatheroma, foam cells accumulation or superficial calcium deposition. A thrombus was identified in 13 segments. Thrombi adherent around the stent strut were partly intimal erythrocyte accumulation around the strut. CONCLUSIONS In-stent yellow segment had atherosclerotic components. CAS could evaluate vascular status comprehensively after DES implantation.

This study evaluated the impact of optical coherence tomography (OCT)-derived low-backscattered tissue on mid-term coronary endothelial function after drug-eluting stent (DES) implantation. Although OCT enables detailed in vivo evaluation of neointimal tissue characterization after DES implantation, its association with physiological vascular healing response is unclear. Thirty-three stable angina pectoris patients underwent OCT examination and endothelial function testing with intracoronary infusion of incremental doses of acetylcholine 8-month after DES implantation in a single lesion of the left anterior descending artery. Neointimal tissue was classified into two patterns based on the predominant OCT light backscatter: high backscatter and low backscatter. Although the presence of uncovered or malapposed stent strut was not associated with the degree of vasoconstriction, the degree of vasoconstriction was significantly greater in the DES with low-backscattered neointima than in the DES without low-backscattered neointima (- 32.1 ± 25.7 vs. - 4.1 ± 20.1%, p = 0.003). Moreover, there was an inverse linear relationship between low backscatter tissue index and degree of vasoconstriction after acetylcholine infusion (r = 0.50 and p = 0.003). The endothelium-dependent vasomotor response after 8-month of DES was impaired in patients with low neointimal tissue backscatter on OCT imaging. OCT assessment of low-backscattered tissue may be used as surrogate markers for impairment of endothelial function after DES.

Hypertension is a major public health problem leading to death. To reduce the morbidity and mortality in patients with hypertension, it is crucial to develop a novel strategy for prevention of hypertension. We have currently reported an attempt at dietary iron intake restriction as non-pharmacological treatment of hypertension in patients with hypertension. However, it remains fully unknown whether dietary iron restriction prevents the development of hypertension. We investigated the influence of dietary iron restriction on the development of hypertension in weanling pre-hypertensive model rats. 3-week-old male stroke-prone spontaneously hypertensive rats (SHR-SP) were randomly divided into two groups and were given an ad libitum normal diet or an iron-restricted diet for 12 weeks. Blood pressure was progressively increased in SHR-SP according to growth, while dietary iron restriction attenuated the development of hypertension. Proteinuria was also increased in SHR-SP according to growth, whereas dietary iron restriction suppressed the increment of proteinuria. SHR-SP exhibited glomerulosclerosis and exacerbated renal interstitial fibrosis at 15 weeks old, indicating that SHR-SP developed hypertensive nephropathy in the adult stage; however, these changes were attenuated by dietary iron restriction. Gelatin zymography showed dietary iron restriction decreased both renal MMP-2 and MMP-9 activities in SHR-SP at 15 weeks old. Of interest, dietary iron restriction suppressed renal TGFβ-RI expression and Smad2 phosphorylation in SHR-SP. Furthermore, dietary iron restriction decreased renal fibrosis, renal MMP-2 and MMP-9 activities, renal TGFβ-RI expression, and Smad2 phosphorylation in rats with unilateral ureteral obstruction. Dietary iron restriction prevented the development of hypertension in weanling pre-hypertensive rats.

In-stent restenosis (ISR) remains a tough problem after percutaneous coronary intervention (PCI) despite advances in technology of drug-eluting stents (DES). A 63-year-old man undergoing hemodialysis was diagnosed with non-ST elevation acute coronary syndrome (NSTE-ACS). An emergency coronary angiography (CAG) revealed severe stenosis in the middle left circumflex artery (LCx). After pre-dilatation with non-compliant balloon, primary PCI was successfully performed with DES implantation. Four months after, CAG was performed again and verified ISR of LCx under diagnosis of recurrent NSTE-ACS. Subsequently multimodality intravascular imaging assessment was performed for the ISR lesion. Optical frequency domain imaging showed the eccentric protruding mass with irregular surface with high-backscatter, whereas angioscopy revealed the in-stent bump with yellow color. The ISR lesion was successfully treated by drug-coated balloon angioplasty. However, he suffered recurrent NSTE-ACS five months later. CAG revealed de novo stenotic lesions not only in re-restenosis of LCx but also in proximal left anterior descending artery and ostium of right coronary artery. He was scheduled to undergo coronary artery bypass grafting for three-vessel disease. Multimodality assessment is useful to diagnose the recurrent restenosis lesion with calcified nodule. .

Aims Cardiac function varies in the population of patients with heart failure (HF) with preserved left ventricular ejection fraction (LVEF; HFpEF). This study investigated the heterogeneity of clinical features associated with HF and the prognostic value of BNP levels in patients with HFpEF. Methods and results The study enrolled 288 patients with stable HF and serum creatinine 40%, n = 205). Patients with HFpEF were further categorized as having relatively low LVEF (HFrlEF; EF 40–60%, n = 107) or as having relatively high LVEF (HFrhEF; EF ≥ 60%, n = 98). We defined cardiovascular death and hospitalization for HF as adverse events and evaluated the prognostic value of the BNP levels in each group. There was no significant difference in event-free survival between HFpEF and HFrEF patients or between HFrhEF and HFrlEF patients. A multivariate Cox proportional hazards model revealed that the BNP level was an independent predictor of adverse events in HFrEF patients (hazard ratio: 4.088, 95% confidence interval: 1.178–14.179, P = 0.027) and in HFrlEF patients (hazard ratio: 14.888, 95% confidence interval: 4.969–44.608, P

Background Interleukin-18 (IL-18) neutralization protects against lipopolysaccharide (LPS)-induced injuries, including myocardial dysfunction. However, the mechanism is yet to be fully elucidated. The aim of the present study was to determine whether IL-18 gene deletion prevents sepsis-induced cardiac dysfunction and to elucidate the potential mechanisms underlying IL-18-mediated cardiotoxicity by LPS. Methods and results Ten-week-old male wild-type (WT) and IL-18 knockout (IL-18 KO) mice were intraperitoneally administered LPS. Serial echocardiography showed better systolic pump function and less left ventricular (LV) dilatation in LPS-treated IL-18 KO mice compared with those in LPS-treated WT mice. LPS treatment significantly decreased the levels of phospholamban (PLN) and Akt phosphorylation in WT mice compared with those in saline-treated WT mice, while the LPS-induced decrease in the phosphorylation levels was attenuated in IL-18 KO mice compared with that in WT mice. IL-18 gene deletion also attenuated an LPS-induced increase of type 2 protein phosphatase 2A (PP2A) activity, a molecule that dephosphorylates PLN and Akt. There was no difference in type 1 protein phosphatase (PP1) activity. To address whether IL-18 affects PLN and Akt phosphorylation via PP2A activation in cardiomyocytes, rat neonatal cardiac myocytes were cultured and stimulated using 100ng/ml of recombinant rat IL-18. Exogenous IL-18 decreased the level of PLN and Akt phosphorylation in cardiomyocytes. PP2A activity but not PP1 activity was increased by IL-18 stimulation in cardiomyocytes. Conclusions IL-18 plays a pivotal role in advancing sepsis-induced cardiac dysfunction, and the mechanisms underlying IL-18-mediated cardiotoxicity potentially involve the regulation of PLN and Akt phosphorylation through PP2A activity.

The interaction among heart failure (HF), chronic kidney disease (CKD), and anemia is called cardio-renal anemia syndrome. The mechanism of anemia in cardio-renal anemia syndrome is complex and remains completely unknown. We have previously reported that impaired intestinal iron transporters may contribute to the mechanism of anemia in HF using in vivo HF model rats. In this study, we assessed intestinal iron transporters in CKD model rats to investigate the association of intestinal iron transporters in the mechanism of cardio-renal anemia syndrome. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. Sham-operated rats served as a control. After 24-week surgery, CKD rats exhibited normocytic normochromic anemia and normal serum erythropoietin levels despite of anemia. Serum iron levels were decreased in CKD rats compared with the controls. Of interest, intestinal expression of critical iron importers, such as duodenal cytochrome b (Dcyt-b) and divalent metal transporter 1 (DMT-1), was decreased in CKD rats compared with the controls. On the other hand, intestinal expression of ferroportin, an intestinal iron exporter, was not different in the control and CKD groups. Moreover, hepatic expression of hepcidin, a regulator of iron homeostasis, did not differ between the control and CKD groups. These results suggest that impaired intestinal expression of Dcyt-b and DMT-1 might be associated with the reduction of an iron uptake in CKD. Taken together, impaired these intestinal iron transporters may become a novel therapeutic target for cardio-renal anemia syndrome.

In addition to plaque rupture (PR), calcified nodule (CN) may also have the potential to develop into arterial thrombus in the peripheral arteries. This study evaluated the distribution of plaque ruptures and calcified nodules in the peripheral arteries and their impact on the outcome of endovascular therapy (EVT). Consecutive 159 patients who underwent EVT with intravascular ultrasound guidance were enrolled. The position of CNs and PRs were assigned to any of common iliac artery, external iliac artery, common femoral artery, and superficial femoral artery. Forty-six (29%) patients had calcified nodule and twenty-eight (18%) patients had plaque rupture somewhere in the lower limb arteries. Although calcified nodules were evenly distributed throughout the length of the arteries plaque ruptures were predominantly located in the proximal segment of the iliofemoral arteries. Stent expansion ratio was significantly smaller in the target arteries with calcified nodules than in those with plaque rupture. Multivariate logistic regression analysis identified hemodialysis as an independent clinical predictor of calcified nodule (odds ratio 8.15, 95% confidence interval 1.73-38.3; P = 0.008). CN definitely affects incomplete stent deployment in the peripheral artery contributing to adverse events, on the other hand, PR has more acceptable outcomes after stent implantation. In the clinical setting, it is important that we realize the features of peripheral artery disease and its patient characteristics which having CNs and PRs to make a strategy for revascularization.

INTRODUCTION Transforming growth factor-β1 (TGF-β1 ) is an important factor that induces atrial fibrosis and atrial fibrillation (AF). The purpose of this study was to evaluate the association between TGF-β1 level and clinical factors before catheter ablation (CA), and to investigate the impact of TGF-β1 level on the outcome after CA for AF. METHODS AND RESULTS This prospective study included 151 patients (persistent AF group: n = 59, paroxysmal AF [PAF] group: n = 54, and control group: n = 38). All patients who underwent CA for AF were followed up for 12 months. The PAF group had the highest TGF-β1 levels in all patients. An early recurrence of AF (ERAF: defined as episodes of atrial tachyarrhythmia within a 3-month blanking period) was detected in 60 patients (53%). Recurrent AF after the blanking period was detected in 36 patients (32%). On multivariate analysis, low TGF-β1 level was the only independent factor associated with recurrent AF. Moreover, the AF recurrence ratio was higher in the low TGF-β1 group (< 12.56 ng/mL) than in the high TGF-β1 group (16 of 29 patients, 55% vs. 20 of 84 patients, 24%, P = 0.002 by log-rank test). CONCLUSIONS PAF was associated with a higher TGF-β1 level. Moreover, lower TGF-β1 level in AF patients could be a cause of recurrent AF after CA.

Patients with peripheral artery disease (PAD) are at high risk of cardiovascular events, including myocardial infarction (MI), stroke, and cardiovascular death. However, the impact of PAD on prognosis in Japanese patients with acute MI remains unclear.The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective multicenter registry that registered 3283 patients with acute MI. Among them, 2970 patients with available data of PAD were divided into the following 4 groups: 2513 patients without prior MI or PAD (None group), 320 patients with only prior MI (Prior MI group), 100 patients with only PAD (PAD group), and 37 patients with both previous MI and PAD (Both group). The primary endpoint was a composite of all-cause death, non-fatal MI, non-fatal stroke, cardiac failure, and urgent revascularization for unstable angina.The 3-year cumulative incidence of the primary endpoint was 26.9% in None group, 41.4% in Prior MI group, 48.0% in PAD group, and 60.3% in Both group (p 0.001). In multivariate analysis, hazard ratio using None group as reference was 1.55 (95% confidence intervals 1.25-1.91; p 0.001) for MI group, 2.26 (1.61-3.07; p 0.001) for PAD group, and 2.52 (1.52-3.90; p 0.001) for Both group.Concomitant PAD was associated with poor prognosis in Japanese patients with acute MI.

Renal fibrosis is the final pathological process common for several types of end-stage renal diseases, including obstructive nephropathy and diabetic kidney disease. Substantial renal iron loads and oxidative stress have been reported to contribute to the development of renal diseases. TfR1 (transferrin receptor 1) plays a crucial role in cellular iron transport. However, there are no studies investigating TfR1 in the pathophysiology of renal fibrosis. Here, we investigate the role of TfR1 in the development of renal fibrosis. Primarily, to ascertain an association of TfR1 in the pathophysiology of renal fibrosis, we induced unilateral ureteral obstruction in wild-type (WT) and heterozygous TfR1 deleted ( TfR1 +/− ) mice. TfR1 +/− mice exhibited attenuated renal fibrosis, along with reduced renal expression of ferritin and 4-hydroxynonenal as compared with WT mice after unilateral ureteral obstruction. In addition, renal expression of TGFβ-RI (transforming growth factor-β receptor I) and Smad2, downstream signaling of TGFβ-RI was attenuated in TfR1 +/− mice compared with WT mice after unilateral ureteral obstruction. Next, we investigated the role of TfR1 in the development of diabetic kidney disease. No difference was observed in blood glucose levels and urinary albumin:creatinine ratios between WT and TfR1 +/− diabetic mice after streptozotocin administration. In contrast, TfR1 +/− mice showed suppressed renal fibrosis, along with reduced renal expression of ferritin, 4-hydroxynonenal, TGFβ-RI, and Smad2 compared with WT mice after streptozotocin administration. These results suggest that TfR1 plays an important role in the development of renal fibrosis.

BACKGROUND Because premature ventricular contractions (PVCs) are one of the most common arrhythmias, but with unclear causative mechanisms, we studied the hemodynamic features that can cause symptomatic PVCs.Methods and Results:We studied 109 patients (48 males, age 60±19 years) with frequent monomorphic PVCs and no structural heart disease. The left ventricular inflow diastolic filling velocity was recorded by transthoracic echocardiography (TTE) at the time of PVCs in all patients. We assessed the PVC E wave flow (E wave velocity×duration at PVC). A total of 38 patients (35%) had PVC-related symptoms (19 palpitations, 12 pulse deficit, 6 shortness of breath, 6 malaise, 1 syncope). These patients showed reduced PVC E wave flow (9.3±6.0 vs. 14.6±6.5 cm, P

Background In the current clinical guidelines, cardiac resynchronization therapy (CRT) is recommended in heart failure (HF) patients with left bundle branch block (LBBB) with QRS width ≥150ms as Class I indication. In terms of HF patients with intermediate ECG criteria, prediction for benefit of CRT is still controversial in routine echocardiography. Purpose The aim was to assess whether three-dimensional (3D) echocardiographic indexes of global LV function at baseline has a prognostic value following CRT implantation in patients who fulfilled with intermediate ECG criteria. Methods We studied 62 HF patients who fulfilled with the indication criteria of CRT implantation according to current the clinical guidelines. In addition to routine two-dimensional echo, 3D echo dataset was acquired for determination of 3D global tangential strain (GTS) and 3D global longitudinal strain (GLS). We tracked predefined unfavorable outcomes for 3 years after CRT implantation: death, hospitalization due to worsening HF. Results LBBB with QRS width ≥150ms was evident in 26 of 62 patients (aged 68±11 years with 160±26 ms of QRS duration and 29±7% of LV ejection fraction), and the other 36 patients only fulfilled intermediate ECG criteria (QRS width 120–149ms or non-LBBB). Unfavorable events occurred in 21 patients (34%). The median GTS was −15.4%. Although GLS was not predictive, GTS greater than −15.4% had high probability of unfavorable outcomes over 3 years (Log-rank, p−15.4% (Log-rank: p Conclusions Baseline GTS by 3D echocardiography is useful for predicting outcome over 3 years after CRT implantation regardless of the ECG criteria for CRT indication.