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Background Heart failure (HF)‐related congestive hepatopathy is a well‐recognized problem in management of HF. The fibrosis‐4 (FIB4) index calculated by [age × aspartate aminotransferase (IU/L)/platelet count (109/L) × square root of alanine aminotransferase (IU/L)] is useful for evaluating liver stiffness. We aimed to investigate the impact of the FIB4 index on prognosis in patients with HF. Methods and results Consecutive HF patients referred for hospitalization at Kumamoto University Hospital, Japan, were registered between 2006 and 2015. We observed cardiovascular outcomes in each type of HF [HF with reduced left ventricular ejection fraction (LVEF) (HFrEF), HF with mid‐range LVEF (HFmrEF) and with preserved LVEF (HFpEF)] according to their FIB4 index; Group 1 (FIB4 index 2.67). This study enrolled 83 HFrEF patients, 117 HFmrEF patients, and 504 HFpEF patients. In HFpEF patients, the Kaplan–Meier curve revealed that Group 3 had a significantly higher rate of total cardiovascular events compared with the other two groups. By contrast, the occurrences of total cardiovascular events were not different among three groups in HFrEF and HFmrEF patients. Multivariate Cox proportional hazard analysis with significant factors in univariate analysis identified that the FIB4 index as an independent and significant predictor for future total cardiovascular events in HFpEF patients (hazard ratio: 1.09, 95% confidence interval: 1.03–1.15, P = 0.001). Conclusions The FIB4 index was a significant predictor for total cardiovascular events in HFpEF.

BACKGROUND Collagen disease is an important cause of aortic regurgitation (AR). Although aortic valve surgery is recommended for patients with AR and depressed left ventricular (LV) function, there have been few reports about risk factors for LV dysfunction in patients with AR concomitant with collagen disease. METHODS AND RESULTS We conducted this study at Kumamoto University Hospital in Japan. A total of 41 patients who had moderate to severe AR and concomitant collagen disease between January 2014 and December 2019 were enrolled. With regard to baseline characteristics, there were no significant differences in the type of collagen disease or El Khoury class between patients with preserved LV function and those with reduced LV function. B-type natriuretic peptide (375.2 [257.9-3852.6]pg/ml vs. 64.0 [33.3-133.6]pg/ml, p

Background: Using transthoracic echocardiography, including 2D speckle tracking imaging (STI), this study examined cardiac function after domino liver transplantation (DLT) with liver grafts explanted from patients with hereditary amyloidogenic transthyretin amyloidosis. Methods and Results: In all, 14 patients who underwent DLT at Kumamoto University Hospital and for whom 2D STI information was available were enrolled in the study; time-dependent echocardiographic changes were evaluated in 7. Although left ventricular (LV) systolic and diastolic function did not differ between the pre- and post-DLT periods (mean [±SD] 5.4±1.0 years after DLT), there were significant (P−14%) than preserved basal LS (57.2±3.5 vs. 39.6±16.0 years; P−14%; odds ratio 28.39, 95% confidence interval 1.89–427.45, P

BACKGROUND We previously reported that a high score (2 or 3 points) according to the Kumamoto criteria, a combination of high-sensitivity cardiac troponin T (hs-cTnT) ≥0.308 ng/mL, the length of QRS ≥ 120 ms in electrocardiogram, and left ventricular (LV) posterior wall thickness ≥ 13.6 mm, increases the pretest probability of 99m Tc-labeled pyrophosphate (99m Tc-PYP) scintigraphy in patients with suspected transthyretin amyloid cardiomyopathy (ATTR-CM). However, some patients with a low score (0 or 1 point) show positive findings on 99m Tc-PYP scintigraphy. Therefore, we evaluated the usefulness of additional examinations, including echocardiographic assessment of myocardial strain, to raise the pretest probability of 99m Tc-PYP scintigraphy for these patients. METHODS AND RESULTS We examined 109 consecutive patients aged ≥70 years with low scores according to the Kumamoto criteria who underwent 99m Tc-PYP scintigraphy. Nineteen patients (17%) had positive 99m Tc-PYP scintigraphy findings. The relative apical longitudinal strain (LS) index (apical LS/ basal LS + mid LS) (RapLSI) was significantly higher in patients with positive than negative 99m Tc-PYP scintigraphy findings (1.04 ± 0.37 vs 0.70 ± 0.28, P

Background: There are few reports on current awareness and status of transthoracic echocardiography (TTE), including the actual performance rate according to echocardiographic guidelines, in a specific area or region. Methods and Results: This cross-sectional survey study was conducted in Kumamoto Prefecture from October 2018 to March 2019. There are 366 medical institutions advocating cardiology in Kumamoto Prefecture. Of these, 259 (101 hospitals and 158 clinics) returned questionnaires regarding TTE. In all, 150,570 TTEs were performed in 2017. Of these, 132,771 (88%) were performed in hospitals and 17,799 (12%) were performed in clinics. Physicians performed only 5% of TTEs, whereas sonographers performed 86%. Although the modified Simpson method was performed in 90% of hospitals, 3-dimensional echocardiography was performed in only 2% of hospitals. In addition, the left atrial volume index was not examined in approximately 60% of hospitals, and the mean E/E′ ratio was not examined in 80% of hospitals. Multivariable logistic regression analysis revealed that having a Fellow of the Japan Society of Ultrasonic in Medicine was significantly and independently associated with guideline-oriented TTE (odds ratio 9.43; 95% confidence interval 1.22–72.71, P

Background: Anthracycline therapies cause myocardial damage and the onset of heart failure, depending on their doses. We investigated prognostic factors for cancer therapeutics-related cardiac dysfunction (CTRCD) in patients receiving modern anthracycline therapies. Methods: We retrospective investigated 625 consecutive patients who were diagnosed with breast cancer and received anthracycline therapy at Kumamoto University Hospital between January 2007 and December 2018. We excluded 153 patients because of missing data, and the remaining 472 patients were enrolled in this study. The primary endpoint was the onset of CTRCD. The exact observation end date was December 31, 2020. Results: Of 472 breast cancer patients with complete data treated with anthracycline, 8 were diagnosed with CTRCD. Multivariate regression analyses revealed that the anthracycline cumulative dose, concomitant use of molecular targeted drugs and a prechemotherapy left ventricular ejection fraction < 50% were independent and significant predictors of the onset of CTRCD. Conclusions: Even in the modern era, the anthracycline cumulative dose is an independent risk factor for the onset of CTRCD.

Introduction: This study was performed to investigate whether right ventricular global longitudinal strain (RV-GLS) provides prognostic information in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). Methods and Results: Among 129 patients who were diagnosed with ATTRwt-CM at Kumamoto University Hospital from December 2002 to December 2019, 111 patients who had enough information for two-dimensional speckle tracking imaging were retrospectively analyzed in this study. During a median follow-up of 615 days (25 th -75 th percentile; 318-1082 days), 26 cardiovascular deaths occurred. Compared with patients in the non-event group, those in the cardiovascular death group had significantly lower RV-GLS (10.9±2.7% vs. 12.8±3.5%, p Conclusions: RV-GLS has significant prognostic value in patients with ATTRwt-CM and provides greater prognostic power than conventional echocardiographic parameters.

Introduction: We previously reported that a high monocyte count was an independent and incremental of cardiovascular events in patients with coronary artery disease. To elucidate the prognostic value of monocyte in heart failure (HF), we investigated the association of monocyte counts in patients with HF with their future cardiovascular events. Methods: Consecutive HF patients referred for hospitalization at Kumamoto University Hospital between 2006 and 2013 were registered. We further divided HF patients into two types according to left ventricular ejection fraction (LVEF) (HF with reduced LVEF (HFrEF) and HF with preserved LVEF (HFpEF)). We defined high monocyte group as monocyte counts≥420/mm 3 in HFrEF patients and as monocyte counts≥308/mm 3 in HFpEF patients. Results: In this study, HFrEF was 200 patients and HFpEF was 478 patients. Kaplan-Meier analysis revealed that HFrEF patients with high monocyte group (≥420/mm 3 ) had a significant higher risk of HF-related events (P=0.001) compared with those with low monocyte groups (3 ). By contrast, high and low monocyte groups in HFpEF patients had no significant difference in HF-related events. Multivariate Cox hazard analysis identified a high monocyte count as an independent and significant predictor of future HF-related events in HFrEF patients (hazard ratio:2.24, 95% confidence interval: 1.01-4.99, P=0.04). Conclusions: A high monocyte count was an independent and incremental predictor of HF-related events in HFrEF, but not in HFpEF patients.

Background: Aortic stenosis (AS) and transthyretin amyloid cardiomyopathy (ATTR-CM) are common in the elderly. We evaluated the usefulness of two-dimensional (2D) speckle strain imaging to diagnose concomitant ATTR-CM in patients with AS. Methods and Results: We analyzed 72 consecutive patients with moderate to severe AS who underwent 99m Tc-pyrophosphate (PYP) scintigraphy, a useful modality for diagnosis of ATTR-CM, at Kumamoto University Hospital from January 2012 to September 2020. There were no significant differences in the baseline clinical characteristics or conventional echocardiographic findings between the 99m Tc-PYP scintigraphy-positive and -negative groups. In 2D speckle strain imaging of the left ventricle, the relative apical longitudinal strain (LS) index [apical LS/ (basal LS + mid LS)] was significantly higher in the 99m Tc-PYP scintigraphy-positive than -negative group (p99m Tc-PYP scintigraphy-positive than -negative group (peak LSR:0.36±0.14 vs. 0.55±0.20, p99m Tc-PYP scintigraphy positivity (area-under-the-curve, 0.79). Multivariable logistic analysis using two forced inclusion models identified the peak LSR in the LA was more significant factor of 99m Tc-PYP scintigraphy positivity in patients with AS. Conclusion: The peak LSR in the LA may be a useful predictor of the presence of ATTR-CM in patients with AS.

This study was performed to investigate whether right ventricular global longitudinal strain (RV-GLS) provides prognostic information in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM).Among 129 patients who were diagnosed with ATTRwt-CM at Kumamoto University Hospital from December 2002 to December 2019, 111 patients who had enough information for two-dimensional speckle tracking imaging were retrospectively analyzed. During a median follow-up of 615 days, 26 cardiovascular deaths occurred. Compared with patients in the non-event group, those in the cardiovascular death group were significantly older (81.1 ± 7.4 years vs. 78.2 ± 6.2 years, p = 0.009) and had significantly higher interventricular septal thickness in diastole (16.6 ± 3.1 mm vs. 15.3 ± 2.4 mm, p = 0.048), lower RV-GLS (10.9 ± 2.7% vs. 12.8 ± 3.5%, p = 0.010), and lower right ventricular free wall longitudinal strain (RVFWLS) (13.1 ± 3.3% vs. 15.5 ± 3.8%, p = 0.004). In the univariate Cox proportional hazard analysis, age, left atrial volume index (LAVI), RV-GLS, and RVFWLS were significantly associated with cardiovascular death [age, hazard ratio (HR), 1.10; 95% confidence interval (CI), 1.02-1.19, p = 0.010; LAVI, HR, 1.02; 95% CI, 1.00-1.03, p = 0.009; RV-GLS, HR, 0.86; 95% CI, 0.75-0.97, p = 0.017; RVFWLS, HR 0.89; 95% CI, 0.79-1.00; p = 0.041]. Multivariable Cox proportional hazard analysis showed RV-GLS was significantly and independently associated with cardiovascular death in patients with ATTRwt-CM (HR, 0.86; 95% CI, 0.74-0.99; p = 0.038). Receiver operating characteristic analysis showed that the area under the curve of RV-GLS for cardiovascular death was 0.668 and that the best cut-off value of RV-GLS was 11.59% (sensitivity, 69.2%; specificity, 63.5%). In the Kaplan-Meier analysis, patients with ATTRwt-CM who had low RV-GLS (11.59%) had a significantly higher probability of total cardiovascular death (p = 0.004) and heart failure-related hospitalization (p = 0.013).RV-GLS has significant prognostic value in patients with ATTRwt-CM and provides greater prognostic power than conventional echocardiographic findings.

Aims This study was performed to investigate whether left atrial (LA) strain by echocardiography provides prognostic information in patients with wild‐type transthyretin amyloid cardiomyopathy (ATTRwt‐CM). Methods and results Among 129 patients who were diagnosed with ATTRwt‐CM at Kumamoto University Hospital from December 2002 to December 2019, 113 patients who had enough information for two‐dimensional speckle tracking echocardiography were enrolled in this study. During a median follow‐up of 668 days, 28 cardiovascular deaths occurred. Compared with patients in the non‐event group, those in the cardiovascular death group were significantly older (81.5 ± 7.4 vs. 78.1 ± 6.1 years, P

We here present a 59-year-old man who had undergone peritoneal dialysis (PD) for 7 years and hemodialysis for the following 6 years in the Japanese Red Cross Kumamoto Hospital. Six years after commencing PD, transthoracic echocardiography showed a highly echoic mass with a transverse diameter of almost 15 mm in the posterior mitral leaflet. Because the mass increased from 2 years after initiation of hemodialysis, reaching over 25 mm by 6 years after commencing hemodialysis, tumor resection and mitral valve replacement were performed. When the surface of the mass was incised, white opalescent liquid drained out of the mass and histological examination showed multiple calcified nodules and granulation tissue, resulting in diagnosis of a caseous calcification of mitral annulus.

BACKGROUND Although pulse wave velocity (PWV) is recognized to be a risk predictor for various cardiovascular diseases, the association of brachial–ankle PWV (baPWV) with cardiovascular outcomes in heart failure (HF) with reduced ejection fraction (HFrEF) patients remains uncertain. METHODS We measured ankle-brachial pressure index (ABI) and baPWV values at stable condition after optimal therapy for HF in 201 consecutive HFrEF patients admitted to Kumamoto University Hospital from 2007 to 2015 who were enrolled and followed until the occurrence of cardiovascular events. We defined peripheral artery disease (PAD) as ABI value ≤ 0.9. RESULTS Kaplan–Meier analysis revealed that HFrEF patients with peripheral artery disease PAD had a significant higher risk of total cardiovascular and HF-related events than those without PAD (P = 0.03 and P = 0.01, respectively). Next, we divided HFrEF patients without PAD into 3 groups according to baPWV values. In the Kaplan–Meier analysis, total cardiovascular and HF-related events in the highest baPWV group (1,800 cm/second ≤ baPWV) had a significantly higher frequency than those in the mid-level baPWV group (1,400 cm/second ≤ baPWV < 1,800 cm/second) (P = 0.007 and P = 0.004, respectively). The hazard ratio between HFrEF patients in the mid-level baPWV group and those with other baPWV groups was compared after adjustment for other cofounders. The probabilities of HF-related events were significantly higher in the lowest and highest baPWV group. CONCLUSION Identifying complications of PAD and measuring baPWV values in HFrEF patients were useful for predicting their prognosis. Trial Registration: UMIN000034358.

Cardiotoxicity in the late phase after anthracycline drugs administration remains to be defined. Of the 44 patients who received anthracycline treatment, 7 were found to have cancer therapeutics-related cardiac dysfunction (CTRCD). The global longitudinal strain determined by echocardiography and myocardial extracellular volume fraction (ECV) determined by cardiac computed tomography (CCT) of the CTRCD(+) group were significantly higher than those of the control group and CTRCD(-) group, whereas there were no significant differences between the control and CTRCD(-) groups. Our findings indicated that CCT may be a tool comparable to echocardiography, indicating the effective evaluation of CTRCD by CCT.

Background We investigated the clinical significance of derivatives of reactive oxygen metabolites (DROMs), a new marker of reactive oxygen species, in patients with nonischemic heart failure (HF) and compared them among new categories of HF. Methods and Results We recruited 201 consecutively hospitalized patients with HF and measured DROM under stable conditions. Then, we divided them according to new categories of HF (HF with reduced ejection fraction [EF], HF with midrangeEF, and HF with preserved EF) without coronary artery disease. In subgroup analysis, we followed EF changes in patients with HF with reduced EF and classified them into HF with recovered EF or nonrecovered EF according to whether EF had improved to >40%. DROMs are significantly and independently associated with HF‐related events in patients with NIHF. There were no significant differences in DROM and the probability of HF‐related events among HF categories in Kaplan–Meier analysis. However, patients with HF with reduced EF and HF with preserved EF but not HF with midrange EF with HF‐related events had higher DROM than those without HF‐related events. In subgroup analysis, Kaplan–Meier analysis demonstrated that the probabilities of HF‐related events in HF with recovered EF were dramatically decreased. DROM were significantly higher in patients with HF with nonrecovered EF than in HF with recovered EF. In receiver operating characteristic analysis, the cutoff level of DROM for predicting improvements in HF with recovered EF was 347 Carratelli units. Furthermore, the C‐statistic value for predicting EF improvement for the DROM levels was 0.703. In multivariable logistic regression analysis, DROM was independently and significantly associated with the prediction of HF with recovered EF. Conclusions DROM measurements can provide important prognostic information for risk stratification in any category of NIHF. Registration URL: https://www.umin.ac.jp/ctr/ ; Unique identifier: UMIN000035827.

Backgrounds: The relationship between cardiovascular outcomes and the Controlling Nutritional Status (CONUT) score in heart failure (HF) with preserved ejection fraction (HFpEF) patients is unknown. This study aimed to evaluate the relationship between the score and cardiovascular outcomes in HFpEF patients. Methods and results: A total of 506 consecutive HFpEF patients were prospectively observed for up to 1500 days or until the occurrence of cardiovascular events. The mean age was 71.6 ± 9.4 years. Cardiovascular outcomes were compared between the CONUT score 0–1 group with a normal nutritional state (normal group), the CONUT score 2–4 group with a light degree of undernutrition (light group), and the CONUT score 5–8 group with a moderate degree of undernutrition (moderate group). In this study, there were no patients who scored 9–12, which was defined as a severe state of undernutrition. Overall, 238 cardiovascular events were observed during the follow-up period (median: 1159 days). Kaplan–Meier analysis showed that the moderate group was at higher risk of composite cardiovascular events than the normal group (P

Background/Aims: The Heart Failure Association (HFA)-PEFF score is recognized as a simple method to diagnose heart failure (HF) with preserved ejection fraction (HFpEF). This study aimed to evaluate the relationship between HFA-PEFF scores and cardiovascular outcomes in HFpEF patients.Methods: A total of 502 consecutive HFpEF patients were prospectively observed for up to 1,500 days. Cardiovascular outcomes were compared between two groups of patients, defined by their HFA-PEFF scores: those who scored 2–4 (the intermediate-score group) and those who scored 5–6 group (the high-score group). Overall, 236 cardiovascular events were observed during the follow-up period (median, 1,159 days).Results: Kaplan-Meier analysis showed that there were significant differences in composite cardiovascular events and HF-related events between the intermediate-score group and the high-score group (p = 0.003 and p < 0.001, respectively). Multivariate Cox proportional hazards analysis showed that the HFA-PEFF scores significantly predicted future HF-related events (hazard ratio, 1.66; 95% confidence interval [CI], 1.11 to 2.50; p = 0.014); receiver operating characteristic analysis confirmed this relationship (area under the curve, 0.633; 95% CI, 0.574 to 0.692; p < 0.001). The cutoff HFA-PEFF score for the identification of HF-related events was 4.5. Decision curve analysis revealed that combining the HFA-PEFF score with conventional prognostic factors improved the prediction of HF-related events.Conclusions: HFA-PEFF scores may be useful for predicting HF-related events in HFpEF patients.

Background Immune checkpoint by programmed cell death (PD)-1 and its ligand (PD-L1) play crucial role in T cell tolerance toward vascular wall antigens. PD-L1 is widely expressed on a number of cells including immune cells and vascular endothelium. It was reported that increased expression of PD-L1 in dendritic cells implicates upregulated inflammation in atherosclerotic lesions that is associated with plaque instability. Although plaque rupture in coronary atherosclerosis is an important pathogenesis of acute coronary syndrome (ACS), the association between PD-L1 and ACS is still unknown. Purpose We hypothesize that circulating PD-L1 might be associated with ACS, reflecting endothelial damage and coronary plaque rupture. To elucidate this hypothesis, we compared serum levels of soluble PD-L1 (sPD-L1) in stable coronary artery disease (CAD) patients with those in ACS patients. Methods Serum levels of sPD-L1 were measured by using commercially available ELISA kit (Human PD-L1/B7-H1 DuoSet, R&D Systems) in consecutive patients with CAD admitted to our University Hospital from February 2016 to March 2017. Patients with any malignant disease or severe inflammatory disease were excluded from this study. Serum levels of sPD-L1 and clinical backgrounds were compared between stable-CAD and ACS patients. Results In total, 269 patients with CAD were enrolled (28 cases [10.4 %] with ACS and 241 cases [89.6 %] with stable-CAD). PD-L1 had no correlation to C-reactive protein, cardiac troponin, and classical atherosclerotic risks such as age, body mass index, estimated glomerular filtration rate, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol, and hemoglobin A1c. Although age, sex, history of smoking, and the prevalences of hypertension, diabetes mellitus and dyslipidemia were comparable between both groups, the level of LDL-C was significantly higher in patients with ACS compared with those with stable-CAD (94.0 [77.0–112.0] mg/dL vs. 78.5 [65.0–97.0] mg/dL, P = 0.008). Also serum level of sPD-L1 was significantly increased in patients with ACS compared with those with stable-CAD (106.1 [60.9–157.7] pg/mL vs. 64.8 [30.9–102.5] pg/mL, P = 0.003). Univariate logistic regression analysis identified that serum levels of both sPD-L1 and LDL-C were independently associated with ACS. Moreover, multivariable logistic regression analysis with factors from univariate analysis identified that serum level of sPD-L1 was significantly and independently associated with ACS (odds ratio: 1.006, 95 % confidence interval: 1.001–1.012, P = 0.03). Conclusions This is the first study to elucidate that the increased serum levels of sPD-L1 was associated with ACS. This study suggests that sPD-L1 could be a risk marker and therapeutic target for ACS.

BACKGROUND Although pulse-wave velocity (PWV) is a recognized risk predictor for cardiovascular diseases, its association with cardiovascular outcomes in heart failure with preserved left ventricular ejection fraction (HFpEF) is unclear. METHODS AND RESULTS The 502 patients with HFpEF finally enrolled in this study (mean follow-up duration: 1017 days) were divided into those with or without peripheral artery disease (PAD). The latter were further grouped according to brachial-ankle PWV (baPWV) quintiles using an ankle-brachial pressure index device. Kaplan-Meier analysis revealed a significantly higher risk of all-cause mortality and total cardiovascular events (both P = 0.01) in HFpEF patients with than without PAD. Multivariate Cox hazard analysis, including predictors identified as significant by simple Cox hazard analysis, identified PAD as a significant and independent predictor of cardiovascular events (hazard ratio: 1.85; 95% confidence interval: 1.01-3.39; P = 0.04). In an analysis of HFpEF patients without PAD grouped according to baPWV quintiles, estimated glomerular filtration rate (r = 0.21, P

Background Heart failure (HF) is characterized as a complex syndrome of structural and functional cardiac disorder that impair ventricular filling and/or blood ejection. Peripheral arterial disease (PAD) is accompanied by systemic inflammation and is frequently associated with other cardiovascular diseases. Although PAD and HF share cardiovascular risk and pathophysiological features, and each has been associated with increased morbidity and mortality. Pulse wave velocity (PWV) is known to be an indicator of arterial stiffness. We previously reported the prognostic significance of brachial–ankle PWV (baPWV) in patients with HF with preserved left ventricular ejection fraction. However, its association with cardiovascular outcomes in HF with reduced EF (HFrEF) and HF with mid-range EF (HFmrEF) patients remains uncertain. Purpose The first aim of this study was to investigate the impact of PAD on prognosis in HFrEF and HFmrEF. The second aim was to investigate the relationship between baPWV and the occurrence of cardiovascular events in patients with HFrEF and HFmrEF. Methods We measured ankle-brachial pressure index (ABI) and baPWV values at stable condition after optimal therapy for HF in 201 consecutive HFrEF and HFmrEF patients admitted to Kumamoto University Hospital from 2007 to 2015 who were enrolled and followed until the occurrence of cardiovascular events. Results The mean age of the two groups of patients was 67.5±11.8 years. The prevalence of PAD, defined as an ABI 0.9 or less, was 14% in patients. Kaplan–Meier analysis revealed that HFrEF and HFmrEF patients with PAD had a significant higher risk of total cardiovascular and HF-related events than those without PAD (P=0.03 and P=0.01, respectively). The hazard ratio (HR) between HFrEF and HFmrEF patients without PAD and those with PAD was compared after adjustment for other confounders. The probabilities of total cardiovascular and HF-related events in HFrEF and HFmrEF patients with PAD were significantly higher than those in HFrEF and HFmrEF patients without PAD (HR: 2.19; 95% CI: 1.02–4.73; P=0.04, and HR: 3.5; 95% CI: 1.27–9.66; P=0.01, respectively). Next, we divided HFrEF and HFmrEF patients without PAD into three groups according to baPWV values. In the Kaplan–Meier analysis, total cardiovascular and HF-related events in the highest baPWV group (1800 cm/s ≤ baPWV) had a significantly higher frequency than those in the mid-level baPWV group (1400 cm/s ≤ baPWV < 1800 cm/s) (P=0.007 and P=0.004, respectively) (Figure A, B). The hazard ratio (HR) between HFrEF and HFmrEF patients in the mid-level baPWV group and those with other baPWV groups was compared after adjustment for other cofounders. The probabilities of total cardiovascular and HF-related events were significantly higher in the highest baPWV group. Conclusion Identifying complications of PAD and measuring baPWV values in HFrEF and HFmrEF patients were useful for predicting their prognosis.

Supplemental Digital Content is available in the text, Although serum magnesium (Mg) levels are closely associated with the prognosis of heart failure (HF) patients, the clinical significance of sMg levels on the cardiovascular outcomes of HF with preserved ejection fraction (HFpEF) patients is not fully understood. This study was a retrospective, single-center, observational study. We enrolled 452 consecutive HFpEF patients admitted to Kumamoto University Hospital. We defined lower sMg as

Background In heart failure (HF) patients, various factors, such as hyperactivity of the renin-angiotensin system, influence of drug therapy such as loop and thiazide diuretics, undernutrition and others, can causes hypokalemia and hypomagnesemia. Although serum magnesium (Mg) levels are closely associated with the prognosis of HF patients, the clinical significance of serum Mg levels in cardiovascular outcomes of HF with preserved ejection fraction (HFpEF) patients is not fully understood. Purpose We examined the relationship between serum Mg and future HF-related events in patients with HFpEF. Methods This study was a retrospective, single-center, observational study. We enrolled 452 consecutive HFpEF patients admitted to our university hospital between January 2007 and September 2013 and followed them for 4 years or until occurrence of HF-related events. We defined lower serum Mg as Results The mean serum Mg level was 2.12 mg/dL (median, 2.1 mg/dL; interquartile range, 2.0–2.28 mg/dL). The follow-up period was 0–50 months (median, 47.3 months) and 48 HF-related events (10.6%) were recorded. The frequency of HF-related events was significantly higher in the lower serum Mg group compared with the higher serum Mg group (n=16, 17.4% vs. n=32, 8.9%; P=0.018). There were no significant differences between groups in the use of all drugs (loop diuretics, mineralcorticoid receptor antagonists, renin-angiotensin-aldosterone system inhibitors, calcium channel blockers, β-blockers, statins and Mg preparations). The lower serum Mg group (n=92) showed significantly higher prevalence of diabetes mellitus (DM), uric acid levels and B-type natriuretic peptide (BNP)levels compared with the higher serum Mg group (n=360). Kaplan-Meier curve revealed a significantly higher probability of HF-related events in the lower serum Mg group compared with the higher serum Mg group (log-rank test, P=0.012, Figure). Multivariate Cox proportional hazard analysis revealed that the lower serum Mg group had significantly and independently higher probabilities of HF-related events compared with those in the higher serum Mg group (hazard ratio: 2.37, 95% confidence intervals: 1.27–4.41, P=0.007). We reclassified the risk of a HF-related events after adding the lower serum Mg to the prognostic factors (age, previous hospitalization for HF, DM, ln-BNP); the continuous net reclassification improvement was 29.0% (p=0.041). Conclusion We first demonstrated that serum Mg was significantly correlated with the occurrence of future HF-related events in HFpEF patients. Lower serum Mg is able to successfully predict future HF-related events, and management of serum Mg in HFpEF patients is thus important. Acknowledgement/Funding None

We investigated the clinical significance of the derivative of reactive oxygen metabolites (DROM), a new marker of reactive oxygen species (ROS), in patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF) (HFrEF).Serum DROM concentrations were measured in 201 consecutive patients with HFrEF (EF50%) in stable condition. DROM values were significantly higher in patients with HFrEF than in risk-matched patients without HF (P0.01). They also correlated significantly with high-sensitivity C-reactive protein and B-type natriuretic peptide. Kaplan-Meier analysis demonstrated significantly higher probabilities of HF-related events in the high-DROM group than in the low-DROM group (log-rank test, P0.01). Multivariable Cox hazard analysis revealed that DROM were independent and significant predictors of cardiovascular events. In a subgroup analysis, DROM levels were also measured at the aortic root and coronary sinus in 49 patients. The transcardiac gradient of DROM values was significantly higher in patients with HFrEF than in patients without HF (P = 0.04), indicating an association between DROM production in the coronary circulation and HFrEF development. Changes in DROM following optimal therapy were significantly associated with LVEF improvement (r = 0.34, P = 0.04).The higher levels of DROM and their association with cardiovascular events suggest the clinical benefit of DROM measurements in the risk stratification of patients with HFrEF.

Because diastolic late mitral annular velocity (a') obtained by transthoracic-echocardiography (TTE) represents left atrial (LA) function, we investigated the clinical significance of a' in heart failure (HF) with a preserved left ventricular (LV) ejection fraction (HFpEF).We enrolled 448 consecutive HFpEF patients (sinus rhythm: 66.3%, atrial fibrillation [AF] rhythm: 33.7%) and performed TTE under stable conditions after optimal therapy. In patients with sinus rhythm, a' values were measured at septal mitral annuli.A' had weak but significant negative correlations with the natural-logarithm-B-type natriuretic peptide (Ln-BNP), LA diameter, LV mass index and tricuspid regurgitation pressure gradient. Receiver operating characteristic (ROC) curve analysis showed that the best cut-off value of a' and systolic mitral annular velocity (s') for the prediction of HF-related events were 7.45 cm/s and 6.5 cm/s with areas under the curve (AUC) of 0.841 and 0.682, respectively. The AUC of ROC analysis for the logistic regression model of a' plus s' was improved to 0.97. In Kaplan-Meier analysis, HFpEF patients with low-a' (7.45 cm/s) had a significantly higher risk of total cardiovascular and HF-related events (both p .01 by log-rank test) than those with high-a' (≥ 7.45 cm/s) and were prognostically equivalent to those with AF. Multivariate Cox proportional hazard analysis identified low-a' as an independent predictor of both total cardiovascular (hazard ratio [HR]: 0.823, 95% confidence interval [CI]: 0.714-0.949, p = .007) and HF-related events (HR: 0.551, 95% CI: 0.422-0.720, p .001).A' value measurement is a non-invasive and useful method for risk stratification in HFpEF.

Background The H2FPEF score is recognized as a simple method to diagnose heart failure (HF) with preserved left ventricular ejection fraction (HFpEF). We investigated the value of the H2FPEF score in predicting subsequent cardiovascular events in HFpEF patients. Methods This study was a retrospective, single-center, observational study. We calculated the H2FPEF scores for 404 consecutive HFpEF patients. Subjects were subdivided into low- (0–3), intermediate- (4–6), and high-score (7–9) groups and followed for 50 months. The primary and secondary endpoints were composite cardiovascular/cerebrovascular events (cardiovascular death, nonfatal myocardial infarction, unstable angina pectoris, hospitalization for HF decompensation, and nonfatal stroke) occurrence and HF-related events (hospitalization for HF decompensation) occurrence at 50 months, respectively. Results Kaplan–Meier analyses demonstrated a significantly higher incidence of cardiovascular/cerebrovascular events among those with a higher H2FPEF score (log-rank test, P = 0.005). The HF-related event rate was higher in proportion to the H2FPEF score (log-rank test, P < 0.001). Multivariate Cox hazard analyses identified the H2FPEF score (per 1 point) as an independent predictor of cardiovascular and HF-related events (hazard ratio [HR], 1.179; 95% confidence interval [CI], 1.066–1.305; P = 0.001 and HR, 1.288; 95% CI, 1.134–1.463; P = 0.001, respectively). Receiver operating characteristic analysis showed that the H2FPEF significantly predicted cardiovascular events (area under the curve [AUC], 0.626; 95% CI, 0.557–0.693; P < 0.001) and HF-related events (AUC, 0.680; 95% CI, 0.600–0.759; P < 0.001). The cutoff H2FPEF score was 5.5 for the identification of cardiovascular and HF-related events. Conclusion The H2FPEF score might be a potentially useful marker for the prediction of cardiovascular and HF-related events in HFpEF patients. Clinical Trails Registration Trail Number UMIN000029600.

BACKGROUND Although serum potassium (sK) levels are closely associated with the prognosis of chronic heart failure patients, the clinical significance of sK levels in cardiovascular outcomes of heart failure with preserved ejection fraction (HFpEF) patients is not fully understood. METHODS This study was a retrospective, single-center, observational study. We enrolled 506 consecutive HFpEF patients admitted to Kumamoto University Hospital and divided them into four groups according to the quartiles of the sK levels at discharge (Q1: sK < 4.1 mEq/l, Q2: 4.1 ≤ sK < 4.4 mEq/l, Q3: 4.4 ≤ sK < 4.7 mEq/l, and Q4: sK ≥ 4.7 mEq/l). RESULTS No significant differences were observed in the use of all drugs (loop diuretics, mineralocorticoid receptor antagonists, renin-angiotensin-aldosterone system inhibitors, calcium channel blockers, β-blockers, and statins) among the four groups. Hemoglobin, the estimated glomerular filtration rate, and pulse wave velocity levels were lower, and the serum sodium levels were higher in the Q4 group compared with those in the Q2 group. Kaplan–Meier analysis revealed significantly higher probabilities of both cardiovascular and HF-related events in the Q1, Q3, and Q4 groups than those in the Q2 group. Multivariate Cox proportional hazard analysis revealed that the Q1, Q3, and Q4 groups had significantly and independently higher probabilities of cardiovascular events compared with those in the Q2 group, indicating a J-shaped association between sK levels and cardiovascular events. CONCLUSIONS sK levels at discharge could provide important prognostic information in regard to HFpEF. Further evaluation in a larger number of patients might be needed. Clinical Trials Registration UMIN-CTR (http://www.umin.ac.jp/ctr/). Identifier UMIN000029600. Public Access Information Opt-out materials are available at the website: http://www.kumadai-junnai.com/home/wp-content/uploads/houkatsu.pdf.

Thrombus formation is one of the main pathogeneses of acute coronary syndrome with atherosclerotic rupture. Previous studies have reported that atherosclerosis increases platelet aggregability and that vascular endothelial dysfunction reflects early change of atherosclerosis. However, the relationship between coronary endothelial dysfunction and platelet reactivity remains unclear. Therefore, in this study, we investigated the relationship between them in non-obstructive ischemic heart disease (IHD) patients.Three hundred sixty-eight consecutive stable patients with suspected angina presenting non-obstructive coronary arteries (50% diameter) in coronary angiography were investigated with the intracoronary acetylcholine provocation test and measured adenosine triphosphate-induced coronary flow reserve. Finally, 25 non-obstructive IHD patients who had no anti-platelet agents were assessed for the relationship between coronary blood flow volume (CBFV) change and platelet aggregability as P2Y12 reaction unit (PRU) by VerifyNow P2Y12 assay system.CBFV change by intracoronary 20 μg/kg per minute acetylcholine provocation showed a significant negative correlation with platelet aggregability as PRU (r = 0.44, P = 0.03). Conversely, there was no significant correlation between PRU and endothelial function as coronary flow reserve. Furthermore, multivariable linear regression analysis indicated that an incremental CBFV change was independently associated with PRU (β = 0.63, P 0.001) in non-obstructive IHD patients.In patients with non-obstructive IHD, CBFV change was significantly associated with platelet aggregability, indicating that coronary endothelial dysfunction might mediate higher platelet aggregability.

The prognostic significance of systemic atherothrombosis in heart failure (HF) with preserved ejection fraction (HFpEF) remains unclear. This study aimed to investigate the relation between the presence of polyvascular disease (PVD) and cardiovascular outcomes in HFpEF patients. A total of 510 consecutive HFpEF patients were prospectively observed for up to 1500 days or until occurrence of cardiovascular events. PVD was defined as ≥2 coexistence of coronary artery disease, peripheral arterial disease, and cerebrovascular disease. Overall, 124 cardiovascular events were observed during follow-up (median: 1430 days). Kaplan–Meier curve showed HFpEF with PVD (n = 84) experienced more cardiovascular events than did those without PVD patients (44.0% vs 20.4%, log-rank: P