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Aims To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. Methods and results In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0–10.0% (42–86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), −0.0155–0.0182] mm and 0.0015 (95% CI, −0.0155–0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of −0.0001 mm (95% CI, −0.0191–0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [−0.1% (95% CI, −0.2–0.1); P = 0.359]. Conclusion Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes.

Sepsis-related myocardial calcification (SRMC) is a life-threatening complication. However, it is a rare entity and its clinical course is not well-understood. A 54-year-old man after bone graft surgery presented with septic shock due to surgical site infection. The initial computed tomography (CT) showed no deposit of calcium in the left ventricle (LV), and echocardiography demonstrated preserved left ventricular ejection fraction (LVEF) of 61%. On the 10th day of admission, CT detected new-onset LV myocardial calcification with preserved LVEF of 60% in echocardiography. On the 63rd day, follow-up CT revealed an increased density of the calcified lesion in the LV, and echocardiography showed a significantly reduced LVEF of 30%. This case report clarified a clinical course of SRMC that the calcium deposit began early after the onset of sepsis and LV systolic function declined subsequently along with the progression of the LV calcification. A serial assessment of CT and echocardiography from the initial stage in sepsis could be helpful for early detection and appropriate management of SRMC patients. Learning objective:Sepsis-related myocardial calcification (SRMC) is under-diagnosed in daily clinical practice because most cases progress silently. By serially assessing computed tomography and echocardiography in patients with sepsis from the initial stage, we can detect SRMC early and follow a change in the calcium in the left ventricle (LV) and LV function.>

Patients with heart failure with preserved ejection fraction (HFpEF) are often elderly and likely to have cardiac comorbidities such as coronary artery disease (CAD) and atrial fibrillation (AF). The primary chronic symptom of HFpEF patients is severe exercise intolerance. The inability to adequately increase heart rate during exercise is commonly present in HFpEF patients and contributes to their exercise intolerance. Although beta-blockers are frequently used for the treatment of myocardial ischemia and tachycardia in HFpEF patients, there is a concern that slowing heart rate by beta-blockers may worsen chronotropic incompetence and further exacerbate their symptoms. Although the effect of beta-blockers on heart failure severity in HFpEF patients has been examined in randomized controlled trials (RCTs), results are inconsistent due partly to limited power. We aimed to conduct a meta-analysis of RCTs on the effect of beta-blockers on heart failure severity in HFpEF patients. The search of electronic databases identified 5 RCTs including 538 patients. In pooled analyses, beta-blockers did not significantly change the New York Heart Association (NYHA) class, exercise capacity expressed as metabolic equivalents, or plasma B-type natriuretic peptide (BNP) levels compared with control but with substantial heterogeneity across trials. In meta-regression analyses, the higher proportion of CAD or AF in the included trials was associated with a decrease in NYHA class and BNP levels and with an increase in exercise capacity. Thus, we found no clear beneficial effect of beta-blockers on heart failure severity in HFpEF patients. However, beta-blockers may be beneficial in HFpEF patients with CAD or AF.

Heart failure (HF) with mid-range left ventricular ejection fraction (LVEF) (HFmrEF) is considered a new category of HF and LVEF p = 0.002). According to the ROC curve analysis, an LVEF ≥ 58% indicated that the LV could maintain the IFLSAF. We concluded that the loss of IFLSAF, which could reflect even slight impairment in LV contractile performance, was a reliable indicator for new-onset HF in patients with LVEF ≥ 40%. LVEF ≥ 58% could be taken as a surrogate for the IFLSAF maintenance; this threshold could be useful for risk stratification of new-onset HF in patients with preserved LVEF.

Despite the major progress in the treatment of heart failure, the burden of heart failure is steadily increasing in the Western world. Heart failure is characterized by increased sympathetic activity, and chronic sympathetic activation is involved in the maintenance of the pathological state. Recent studies have shown that catheter-based renal denervation (RDN) presents a safe and minimally invasive treatment option for uncontrolled hypertension, a condition that is driven by increased sympathetic activity. Although randomized controlled trials (RCTs) have examined the effect of RDN in heart failure patients, results are inconsistent due partly to limited power with small sample sizes. We aimed to conduct a meta-analysis of RCTs on the effect of RDN in heart failure patients with reduced left ventricular (LV) ejection fraction (EF). Electronic search identified 5 RCTs including 177 patients. In the pooled analysis, RDN increased LVEF (weighted mean difference (WMD) [95% CI] = 6.289 [1.883, 10.695]%) and 6-min walk distance (61.063 [24.313, 97.813] m) and decreased B-type natriuretic peptide levels (standardized mean difference [95% CI] = − 1.139 [− 1.824, − 0.454]) compared with control. In contrast, RDN did not significantly change estimated glomerular filtration rate (WMD [95% CI] = 5.969 [− 2.595, 14.533] ml/min/1.73 m2) and systolic (− 1.991 [− 15.639, 11.655] mmHg) or diastolic (− 0.003 [− 10.325, 10.320] mmHg) blood pressure compared with control. Our meta-analysis suggests that RDN may improve LV function and exercise capacity in heart failure patients with reduced EF, providing the rationale to conduct large-scale multicenter trials to confirm the observed potential benefits of RDN.

The impact of quantitative pathological findings derived from endomyocardial biopsies (EMB) on clinical prognosis in patients with hypertrophic cardiomyopathy (HCM) remains unclear.We retrospectively studied 55 consecutive HCM patients who underwent EMB. We quantified the collagen area fraction (CAF), the cardiomyocyte diameter, the nuclear area and circularity, and the number of myocardial infiltrating CD3During the median follow-up of 37.2 months, the primary endpoint was found in 12 patients. No significant difference in the risk score of 5-year sudden cardiac death was observed between the event-occurrence group and the event-free group. In the multivariable Cox proportional-hazard analysis, CAF [hazard ratio (HR) per 10% increase: 1.555, 95% CI: 1.014-2.367, p = 0.044] and the number of infiltrating CD3The higher CAF and the higher number of infiltrating CD3

AIM With increasing lifespans, patients requiring a pacemaker are older than they were in the past. Data regarding all-cause mortality in older patients implanted with a pacemaker are scarce. As physical activity is associated with a decrease in all-cause mortality, we investigated whether daily physical activity time, expressed as the activity rate determined by pacemakers, can predict all-cause mortality in older patients (aged ≥75 years) with a pacemaker. METHODS We retrospectively investigated the baseline characteristics, echocardiographic indices, laboratory data and pacemaker parameters of 107 consecutive older patients with a newly implanted pacemaker at our hospital (age 83.8 ± 5.0 years; 54.2% men). The study end-point was all-cause mortality. RESULTS During the follow-up period (mean 3.0 years), 21 cases of all-cause death were reported. The area under the receiver operating characteristic curve for activity rate to predict all-cause mortality was 0.82 (95% confidence interval 0.72-0.92, P

Background: Non-invasive evaluation of left ventricular (LV) diastolic dysfunction (DD) and elevated LV filling pressure are crucial for diagnosing heart failure. The 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) recommendations for evaluating elevated LV filling pressure (algorithm B) have acceptable diagnostic accuracy, including in patients with reduced LV ejection fraction (EF). No prior study, however, has assessed the diagnostic accuracy of algorithm A of the ASE/EACVI recommendations for evaluating LVDD in patients with normal LVEF. Methods and Results: We evaluated the clinical relevance of algorithm A in 94 patients who underwent invasive LV pressure measurement. Algorithm A identified invasively defined LVDD (time constant τ≥48 ms and/or LV end-diastolic pressure ≥16 mmHg) with low sensitivity (22.4%) but high specificity (90.7%). Algorithm A also identified elevated LV filling pressure with low sensitivity (41.7%) but high specificity (87.5%), and with a high negative predictive value (90.9%). Conclusions: Algorithm A may not be useful for screening LVDD in patients with normal LVEF. Negative findings using algorithm A, however, may identify a patient with normal LVDD with high specificity, and most of such patients will have LV pre-A pressure in the normal range.

Background Identifying risk factors for cancer therapeutics-related cardiac dysfunction (CTRCD) is essential for early detection and prompt initiation of medial therapy for CTRCD. There has been no study investigating whether the sigmoid septum is a risk factor for anthracycline-induced CTRCD. Methods We enrolled 167 patients with malignant lymphoma who received a CHOP-like regimen from January 2008 to December 2017 and underwent both baseline and follow-up echocardiography. Patients with LVEF ≤ 50% were excluded. CTRCD was defined as ≥ 10% decline in LVEF and LVEF < 50% after chemotherapy. The angle between the anterior-wall of the aorta and the ventricular septal surface (ASA) was measured to quantify the sigmoid septum. Results CTRCD was observed in 36 patients (22%). The average LVEF and GLS were lower (61.6 vs. 65.0%, 18.7 vs. 20.3), LV mass index was higher (101.1 vs. 92.8 g/m2), and ASA was smaller (112.1 vs. 119.4 degree) in patients with CTRCD. In a multivariable Cox proportional hazard analysis, GLS (HR per 1% decrease 1.20, 95% CI 1.07-1.35, P = 0.002), ASA (HR per 1 degree increase 0.97, 95% CI 0.95-0.99, P = 0.003) and the history of ischemic heart disease (HR 5.13, 95% CI 1.94-13.56, P = 0.001) were identified as the independent determinants of CTRCD. C-statistics analysis and integrated discrimination improvement proved the significant incremental value of ASA for developing CTRCD. Conclusion Smaller ASA was the independent risk factor and had significant incremental value for CTRCD in patients with malignant lymphoma who received the CHOP-like regimen.

Background The prevalence of multimorbidity and polypharmacy and its association with all‐cause mortality in older patients with pacemakers are largely unknown. We aimed to clarify the prevalence of multimorbidity and polypharmacy, and its association with all‐cause mortality in patients ≥75 years of age with pacemakers. Methods We retrospectively investigated 256 patients aged ≥75 years (mean age 84.0 ± 5.3 years; 45.7% male) with newly implanted pacemakers. The study endpoint was all‐cause mortality (“with events”). Multimorbidity was defined as a Charlson Comorbidity Index ≥3. Polypharmacy was defined as the use of ≥5 medications. Results During the follow‐up period (median, 3.1 years), 60 all‐cause deaths were reported. The Charlson Comorbidity Index (2.9 ± 1.9 vs. 1.7 ± 1.7, p

Background: Chronic elevation of left ventricular (LV) diastolic pressure (DP) or chronic elevation of left atrial (LA) pressure, which is required to maintain LV filling, may determine LA wall deformation. We investigated this issue using transthoracic 3-dimensional speckle tracking echocardiography (3D-STE). Methods and Results: We retrospectively enrolled 75 consecutive patients with sinus rhythm and suspected stable coronary artery disease who underwent diagnostic cardiac catheterization and 3D-STE on the same day. We computed the global LA wall area change ratio, termed the global LA area strain (GLAS), during both the reservoir phase (GLAS-r) and contraction phase (GLAS-ct). The LVDP at end-diastole (LVEDP) and mean LVDP (mLVDP) were measured with a catheter-tipped micromanometer in each patient. GLAS-r and GLAS-ct were significantly correlated with both mLVDP (r=−0.70 [P

A left ventricular ejection fraction (LVEF) of 50% as the cutoff for heart failure (HF) with preserved LVEF is controversial. We previously reported that patients with an LVEF of ≥58% have good prognoses. In this study, 123I-metaiodobenzylguanidine scintigraphy was performed to evaluate cardiac sympathetic nervous system (SNS) activity in 63 HF patients (78.4±9.6 years; males, 49.2%). During the follow-up period (median, 3.0 years), 18 all-cause deaths occurred. The delayed heart/mediastinum (H/M) ratio was significantly higher in the LVEF ≥58% group (n=15) than the LVEF

BACKGROUND It is well acknowledged that left ventricular (LV) contractile performance affects LV relaxation via LV elastic recoil. Accordingly, we aimed to investigate whether global longitudinal strain (GLS), particularly longitudinal strain at LV apical segments at end-systole (ALS), obtained by 2-dimensional speckle-tracking echocardiography could be used to assess LV relaxation.Methods and Results:We enrolled 121 patients with suspected or definite coronary artery disease in whom echocardiography and diagnostic cardiac catheterization were performed on the same day. We obtained conventional echo-Doppler parameters and GLS, as well as ALS prior to catheterization. LV functional parameters were obtained from the LV pressure recorded using a catheter-tipped micromanometer. In all patients, GLS and ALS were significantly correlated with the time constant τ of LV pressure decay during isovolumetric relaxation (r=0.63 [P

Background: Remote monitoring of cardiac implantable electronic devices improves clinical outcomes, but data on the association between the transmission rate (TR) of the remote monitoring, calculated in percentage as the ratio between days of transmission and days of follow-up after remote monitoring introduction, and death in patients with a pacemaker are limited. Methods and Results: In this single-center retrospective observational study, we investigated 180 patients with a newly implanted pacemaker capable of using a specific remote monitoring system with daily transmission (79.5±8.8 years, men 50.6%). The study endpoint was all-cause death. During the follow-up period (median 2.7 years), 33 all-cause deaths were reported, and the TR was significantly lower in the deceased patients than in the survivors (89.6±9.6% vs. 95.4±7.0%, P

Background Anthracycline-induced cardiotoxicity is a serious complication in patients with malignant lymphoma (ML) who received chemotherapy, which threatens life prognosis and quality of life of patients. However, incidence and risk factors of cardiotoxicity in patients with ML who undergo intensive chemotherapy which aims complete remission is not clarified. Furthermore, prognosis after cardiotoxicity and that after recovery from cardiotoxicity have not been elucidated. Method We screened 443 ML patients who received either rituximab (R)-CHOP or CHOP regimen between January 2008 and December 2017 at Nagoya City University Hospital. Two handled forty-four patients who underwent echocardiography before and after chemotherapy were enrolled and data were analyzed retrospectively. Cardiotoxicity was defined as a decline in left ventricular ejection fraction (LVEF) of 10% or greater and an LVEF was below 50%. Partial recovery was defined as a 5% or more of increase in LVEF and an LVEF was ≥50% after cardiotoxicity. Complete recovery was defined as an increase in LVEF became more than 95% of the baseline value. Patient's basic characteristics, chemotherapeutic regimen, laboratory data, echocardiographic data, and prognosis were collected from the medical records by two cardiologists and two hematologists. Result At baseline, the median age was 71 years, the median cumulative dose of doxorubicin was 302 mg/m2 and the median LVEF was 69%. During the follow-up period, cardiotoxicity was observed in 52 out of 244 patients (21%), 30 patients (12%) had a symptomatic heart failure, and 5 patients died from cardiovascular cause. Thirty-five patients developed cardiotoxicity during the first year of chemotherapy. Multivariate analysis identified that only the baseline LVEF (HR 0.949, 95% CI 0.919–0.981, p=0.002) was an independent risk factor for cardiotoxicity. In our study, patients who received more than 200 mg/m2 of doxorubicin developed cardiotoxicity frequently. Among 52 patients who experienced cardiotoxicity, partial recovery and full recovery were observed in 18 (35%) and 4 (8%) patients, respectively. Four patients without recovery died due to heart failure and 1 patient with partial recovery died suddenly. Six out of 18 patients with partial recovery developed re-cardiotoxicity. Conclusion ML patients who undergo more than 200 mg/m2 of doxorubicin need a watchful follow-up. Only a baseline LVEF was an independent risk factor for cardiotoxicity. one third of patients with partial recovery developed re-cardiotoxicity. Funding Acknowledgement Type of funding source: None

Targeting the renin-angiotensin system (RAS) pathways has been considered a logical intervention for patients with heart failure with preserved ejection fraction (HFpEF), due to its hypothesized link to left ventricular (LV) remodeling. Although the effects of RAS inhibitors including angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and direct renin inhibitors (DRIs) on LV structure and function and exercise capacity in HFpEF patients have been examined in multiple randomized controlled trials (RCTs), results are inconsistent due partly to limited power. We conducted a meta-analysis of RCTs on the effects of RAS inhibitors on LV structure and function as well as exercise capacity in HFpEF patients. The search of electronic databases identified 7 trials including 569 patients; 4 trials were on ACE-Is; 2 on ARBs; and 1 on DRIs. Follow-up duration ranged across trials from 12 to 52 weeks. The pooled analysis showed that RAS inhibitors significantly increased EF compared with control (weighted mean difference [95% CI] = 2.182 [0.462, 3.901] %). In contrast, RAS inhibitors did not significantly change the ratio of peak early to late diastolic mitral inflow velocities (weighted mean difference [95% CI] = 0.046 [− 0.012, 0.105]), early diastolic mitral annular velocity (0.327 [− 0.07, 0.725] cm/s), the ratio of early diastolic mitral inflow to annular velocities (0.291 [− 0.937, 1.518]), LV mass (− 6.254 [− 15.165, 2.656] g), or 6-min walk distance (1.972 [− 14.22, 18.163] m) compared with control. The present meta-analysis suggests that RAS inhibitors may increase LVEF in HFpEF patients.

Left ventricular (LV) diastolic dysfunction is associated with the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and contributes importantly to exercise intolerance that results in a reduced quality of life (QOL) in HFpEF patients. Experimental studies have shown that aldosterone plays a role in the genesis of myocardial hypertrophy and fibrosis, thereby enhancing LV diastolic dysfunction, and that aldosterone antagonists (mineralocorticoid receptor antagonists [MRAs]) prevents myocardial hypertrophy and fibrosis. Although the effects of MRAs on LV diastolic function, exercise capacity, and QOL in HFpEF patients have been examined in randomized clinical trials (RCTs), results are inconsistent due partly to limited power with small sample sizes. We aimed to conduct a meta-analysis of RCTs on the effects of MRAs on LV diastolic function, exercise capacity, and QOL in HFpEF patients. The search of electronic databases identified 6 studies including 755 HFpEF patients. In the pooled analysis, MRAs increased early diastolic mitral annular velocity (weighted mean difference [95% CI] = 0.455 [0.232–0.679] cm/s; Pfix

Despite the high mortality rate, there is no therapy to improve survival in heart failure with preserved ejection fraction (HFpEF). Large randomized controlled trials (RCTs) did not show clear mortality benefit of renin-angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) in HFpEF. However, because of the strict enrollment criteria, the patients who participated in these trials might represent a selected group of patients that is poorly representative of patients treated in routine clinical practice. In contrast, clinical characteristics of real-world patients are similar to those of patients enrolled in observational cohort studies (OCSs). Although many OCSs have examined the prognostic effect of RAS inhibitors in HFpEF, the results are inconsistent due to limited power with small sample sizes and/or inadequate adjustment for known prognostic factors. We aimed to conduct a meta-analysis of OCSs with and those without propensity score (PS) analysis and RCTs on the effect of RAS inhibitors on mortality in HFpEF patients. The search of electronic databases identified 4 OCSs with PS analysis (10,164 patients), 8 OCSs without PS analysis (16,393 patients), and 3 RCTs (8001 patients). Use of RAS inhibitors was associated with reduced mortality in the pooled analysis of OCSs with PS analysis (RR [95% CI] = 0.90 [0.81-1.00]) and in that of OCSs without PS analysis (0.81 [0.68-0.96]) but not in that of RCTs (0.99 [0.87-1.12]). In conclusion, the present meta-analysis suggests the potential mortality benefit of RAS inhibitors in HFpEF, emphasizing the importance of conducting new well-designed RCTs.

Background and Purpose It is important to evaluate exercise capacity to detect the development of heart failure (HF) in patients with heart disease. The pathology of exercise capacity is multi-factorial, and cardiac function is recognized as one of the most important determinants. However, the correlation between right ventricular (RV) function and exercise capacity is not fully understood in the subjects without HF. Therefore, we assessed the relationship between RV function and exercise capacity, both in patients with HF (HF+) and in patients with heart disease but not developed HF (HF-). Methods Two hundred and fifty-two patients with heart disease who underwent both Doppler echocardiography at rest and cardio-pulmonary exercise testing (CPET) for the assessment of heart function were enrolled (HF+: n = 142, HF-: n = 110). We measured left ventricular ejection fraction (LVEF), peak early diastolic transmitral flow velocity (E), peak late diastolic transmitral flow velocity (A), early diastolic mitral annular velocity (e’), left atrial volume (LAV), and tricuspid annular plane systolic excursion (TAPSE) by echocardiography. After echocardiographic examination, symptom-limited exercise testing was performed with simultaneous respiratory gas analysis, and peak oxygen consumption (pVO2) was determined. Blood examination including hemoglobin (Hb) and brain natriuretic peptide (BNP) was done on the same day. Results There were significant relationships between pVO2 and LVEF (r = 0.16, p = 0.005), e" (r = 0.51, p Conclusion RV function is the prime determinant of exercise capacity in patients at risk of HF, as well as in patients with HF. Abstract P743 Figure.

Left ventricular (LV) diastolic dysfunction is associated with the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and contributes importantly to exercise intolerance that results in a reduced quality of life (QOL) in HFpEF patients. Although the effects of exercise training on LV diastolic function, exercise capacity, or QOL in HFpEF patients have been examined in randomized clinical trials (RCTs), results are inconsistent due partly to limited power with small sample sizes. We aimed to conduct a meta-analysis of RCTs examining the effects of exercise training on LV diastolic function and exercise capacity as well as QOL in HFpEF patients. The search of electronic databases identified 8 RCTs with 436 patients. The duration of exercise training ranged from 12 to 24 weeks. In the pooled analysis, exercise training improved peak exercise oxygen uptake (weighted mean difference [95% CI], 1.660 [0.973, 2.348] ml/min/kg), 6-min walk distance (33.883 [12.384 55.381] m), and Minnesota Living With Heart Failure Questionnaire total score (9.059 [3.083, 15.035] point) compared with control. In contrast, exercise training did not significantly change early diastolic mitral annular velocity (weighted mean difference [95% CI], 0.317 [− 0.952, 1.587] cm/s), the ratio of early diastolic mitral inflow to annular velocities (− 1.203 [− 4.065, 1.658]), or LV ejection fraction (0.850 [− 0.128, 1.828] %) compared with control. In conclusion, the present meta-analysis suggests that exercise training improves exercise capacity and QOL without significant change in LV systolic or diastolic function in HFpEF patients.

Background Nearly half of patients with heart failure (HF) have preserved ejection fraction (EF) and the mortality of patients with HF with preserved EF (HFpEF) is high. However, there is no therapy to improve survival in HFpEF. Although observational cohort studies (OCSs) have examined the survival benefit of beta-blockers in HFpEF, the results are inconsistent due to limited power with small sample sizes and/or lack of adjustment for known confounders. Furthermore, recent randomized controlled trial (RCT)s failed to show the mortality benefit of beta-blockers in HFpEF. However, these RCTs were not adequately powered and thus the definite conclusion cannot be drawn. Methods and results We aimed to conduct a meta-analysis of the effect of beta-blockers on mortality in HFpEF. The search of electronic databases identified 5 OCSs with propensity score (PS) analysis (12,315 patients), 6 OCSs without PS analysis (15,275 patients), and 3 RCTs (1046 patients). Beta-blocker use was associated with improved survival in the pooled analysis of OCSs with PS analysis (RR [95% CI]=0.79 [0.66–0.95]) and in that of OCSs without PS analysis (0.70 [0.52–0.94]). In the pooled analysis of RCTs, beta-blocker use was associated with non-significant reduced risk for mortality (RR [95% CI]=0.80 [0.61–1.05]). Overall, use of beta-blockers reduced the risk of mortality by 21% (RR [95% CI]=0.79 [0.71–0.88]). Conclusion Our meta-analysis suggests the potential mortality benefit of beta-blockers in HFpEF. Well-designed and powered RCTs should be planned to confirm our observed potential survival benefit of beta-blockers in HFpEF.

Atrial fibrillation (AF) is an exacerbating factor for exercise tolerance due to the loss of atrial kick. However, many patients with permanent AF, which lasts for at least a year without interruption, and preserved left ventricular ejection fraction (LVEF ≥ 50%) are asymptomatic and have good exercise tolerance. In such cases, the possible mechanism that compensates for the decrease in cardiac output accompanying the loss of atrial kick is a sufficient increase in heart rate (HR) during exercise. We investigated the relationship between exercise tolerance and peak HR during exercise using cardiopulmonary exercise testing in 242 male patients with preserved LVEF, 214 with sinus rhythm (SR) and 28 with permanent AF. Peak HR was significantly higher in the AF group than the SR group (148.9 ± 41.9 vs. 132.0 ± 22.0 beats/min, p = 0.001). However, oxygen uptake at peak exercise did not differ between the AF and SR groups (19.4 ± 5.7 vs. 21.6 ± 6.0 mL/kg/min, p = 0.17). In multiple regression analysis, peak HR (β, 0.091; p < 0.001) and the interaction term constructed by peak HR and presence of permanent AF (β, 0.05; p = 0.04) were selected as determinants for peak VO2; however, presence of permanent AF was not selected (β, -0.38; p = 0.31). Therefore, the impact of peak HR on exercise tolerance differed between the AF and SR groups, suggesting that a sufficient increase in HR during exercise is an important factor to preserve exercise tolerance among patients with AF.

Influenza infection is associated with increased risk for mortality and hospitalization in heart failure patients. Although there are no published randomized controlled trials examining the effect of influenza vaccination on clinical outcomes in heart failure patients, the effect has been examined in observational cohort studies. Nevertheless, results are inconsistent due partly to limited power with small sample sizes and use of different definitions of outcomes. We therefore aimed to conduct a systematic review and meta-analysis of the effect of influenza vaccination on mortality and hospitalization in heart failure patients. The search of electronic databases identified 6 observational cohort studies with 22,486 patients examining the effect of influenza vaccination on mortality and hospitalization in heart failure patients. Pooled analysis of confounder-adjusted hazard ratio showed that influenza vaccination was associated with reduced risk of mortality during 1-year follow-up (risk ratio [95% CI] = 0.76 [0.63–0.92], Pfix

We herein report an unusual case of an infected descending aortic pseudoaneurysm with luminal pathognomonic oscillating vegetation with serological findings and clinical features mimicking anti-proteinase 3-antineutrophil cytoplasmic antibody-associated vasculitis. The positive blood cultures and imaging findings, including a pseudoaneurysm and vegetations in the aorta, suggested the presence of an infected aortic aneurysm. The patient was successfully treated with antibiotics and endovascular aortic repair. A precise diagnosis is crucial in order to avoid inappropriate therapy such as immunosuppressive treatment, which could result in life-threatening consequences in a patient with an infected aortic aneurysm.

Increased aortic stiffness may be an important cause of acute heart failure (AHF). Clinical scenario (CS), which classifies the pathophysiology of AHF based on the initial systolic blood pressure (sBP), was proposed to provide the most appropriate therapy for AHF patients. In CS, elevated aortic stiffness, vascular failure, has been considered as a feature of patients categorized as CS1 (sBP > 140 mmHg at initial presentation). However, whether elevated aortic stiffness, vascular failure, is present in such patients has not been fully elucidated. Therefore, we assessed aortic stiffness in AHF patients using the cardio-ankle vascular index (CAVI), which is considered to be independent of instantaneous blood pressure. Sixty-four consecutive AHF patients (mean age, 70.6 ± 12.8 years; 39 men) were classified with CS, based on their initial sBP: CS1: sBP > 140 mmHg (n = 29); CS2: sBP 100-140 mmHg (n = 22); and CS3: sBP < 100 mmHg (n = 13). There were significant group differences in CAVI (CS1 vs. CS2 vs. CS3: 9.7 ± 1.4 vs. 8.4 ± 1.7 vs. 8.3 ± 1.7, p = 0.006, analysis of variance). CAVI was significantly higher in CS1 than in CS2 (p = 0.02) and CS3 (p = 0.04). CAVI did not significantly correlate with sBP at the time of measurement of CAVI (r = 0.24 and p = 0.06). Aortic stiffness assessed using blood pressure-independent methodology apparently increased in CS1 AHF patients. We conclude that vascular failure is a feature of CS1 AHF initiation.

BACKGROUND Early-diastolic mitral annular velocity (e') and the ratio of early-diastolic left ventricular (LV) inflow velocity (E) to e' (E/e') have been widely used as indexes of LV relaxation and filling pressure, respectively. However, many recent studies have demonstrated that they are not reliable in various clinical settings. We thus investigated the factors influencing these echocardiographic parameters in a multicenter study.Methods and Results:The study group comprised 69 patients, referred for cardiac catheterization, and enrolled in 5 university hospitals. Time constant (τ) and LV mean diastolic pressure (LVMDP) were measured using a micromanometer-tipped catheter. Although e' only weakly correlated with τ (r=-0.35, P

Based on our previous observation, inertia stress (IS) of late systolic aortic flow was often observed in left ventricles with relatively higher left ventricular (LV) ejection fraction (EF). Most left ventricles with relatively lower LVEF did not have IS. Accordingly, lack of IS may correlate with LV diastolic dysfunction through the loss of LV elastic recoil and may contribute to the pathogenesis of heart failure (HF) and reduced survival. We enrolled 144 consecutive patients that underwent cardiac catheterization for the diagnosis of coronary artery disease. Left ventricular ejection fraction (LVEF) was obtained from left ventriculography. The IS was calculated from the LV pressure (P)−dP/dt relation. The study endpoint of this retrospective outcome-observational study was combined subsequent acute decompensated heart failure (ADHF) and all-cause mortality. During the follow-up period (median 6.1 years), seven unscheduled hospitalizations for ADHF and nine all-cause deaths were observed. The event-free survival rate was significantly higher among patients with IS than among patients without IS (log-rank, p = 0.001). On a multivariate Cox regression analysis, lack of IS was a prime predictor of the endpoint during follow-up (hazard ratio: 6.98; 95 % confidence interval: 1.48–33.03; p = 0.01). An LVEF ≥ 58 % was a surrogate indicator for the presence of IS, and patients with LVEF ≥ 58 % had fewer incidences of the endpoint than patients with LVEF

Despite the recent advances in the management of heart failure, the mortality of heart failure patients remains high. It is of urgent need to develop new therapy for heart failure. Heart failure is characterized by increased sympathetic activity, and chronic sympathetic activation is involved in the maintenance of the pathological state. Catheter-based renal denervation (RDN) has emerged as an invasive but safe approach that can reduce sympathetic activation. Studies have reported inconsistent results regarding the effect of RDN in heart failure patients due to limited power with small sample sizes. We aimed to conduct a meta-analysis of the effect of RDN on heart failure patients with reduced left ventricular (LV) ejection fraction (EF). An electronic search for studies examining the effect of RDN on LV function in heart failure patients with reduced EF was conducted. Two controlled (80 patients) and 2 uncontrolled studies (21 patients) were included in this meta-analysis. In the pooled analysis, 6 months after RDN, there was a greater increase in EF (weighted mean difference [95% CI] = 8.63 [6.02, 11.24] %) and a greater decrease in LV end-diastolic diameter (−0.58 [−0.83, −0.34] cm) in RDN group than in control group. No serious adverse events such as acute renal artery stenosis and dissection occurred. Our meta-analysis of feasibility studies suggests that RDN may improve LV function in heart failure patients with reduced EF, providing the rationale to conduct next phase trials to confirm the observed potential benefits of RDN.

Patients with heart failure with preserved ejection fraction (HFpEF) are often elderly and their primary chronic symptom is severe exercise intolerance that results in a reduced quality of life (QOL).Thus, improvement of exercise capacity and QOL presents an important clinical outcome in HFpEF patients. Although the effects of interventions such as cardiovascular drugs and exercise training on exercise capacity and QOL in HFpEF patients have been examined in a number of clinical trials, the results are inconsistent due in part to limited power with small sample sizes. We aimed to conduct a meta-analysis of the randomized controlled trial (RCT)s on the effect of drug or exercise intervention on exercise capacity and QOL in HFpEF patients.The search of electronic databases identified five RCTs on exercise (245 patients) and eight RCTs on cardiovascular drugs (1080 patients). The pooled analysis showed that exercise training improved peak exercise oxygen uptake (VO2) (weighted mean difference (WMD) 2.283, 95% confidence interval (CI)) (1.318-3.248) ml/min/kg), six-minute walk distance (6MWD) (30.275 m (4.315-56.234)), and Minnesota Living with Heart Failure Questionnaire (MLHFQ) total score (8.974 points (3.321-14.627)) compared with usual care. In contrast, drug intervention did not improve peak VO2 (WMD (95% CI), -0.393 (-1.005-0.220) ml/min/kg), 6MWD (-9.463 (-21.455-2.530) m), or MLHFQ total score (1.042 (-0.982-3.066) point) compared with placebo or no treatment.Our meta-analysis indicates that exercise training may be a therapeutic option to improve functional capacity and QOL in HFpEF patients.

A 53-year-old woman with systemic lupus erythematosus and antiphospholipid syndrome presented with central nervous system (CNS) lupus and vegetation of the mitral and aortic valves. Her CNS lupus was relieved with methylprednisolone pulse therapy; however, her mitral regurgitation worsened, and she developed acute decompensated heart failure. The mitral and aortic valves were replaced with mechanical heart valves. Microscopic examination of the excised valves showed no bacterial invasion, and Libman-Sacks (LS) endocarditis of both valves was confirmed. This was a case of LS endocarditis with clear vegetation that spread over the mitral and aortic valves.

A man in his late seventies was suffering from right-sided pleural effusion and worsening leg edema. He was diagnosed with a rare case of secondary protein-losing enteropathy caused by constrictive pericarditis (CP) using technetium 99m-labeled human serum albumin abdominal scintigraphy and comprehensive Doppler echocardiography. We herein report the importance of evaluating a low cardiac output in addition to established Doppler echocardiographic findings for making a diagnosis of CP coexistent with protein-losing enteropathy.

BACKGROUND Diagnosis of left ventricular (LV) diastolic dysfunction by blood testing is expedient in the clinical setting. METHODS AND RESULTS In 98 patients with LV ejection fraction ≥50% who underwent cardiac catheterization for evaluation of coronary artery disease, LV pressure (LVP) was measured using a catheter-tipped micromanometer. A time constant, τ, of LV relaxation was computed from LVP decay; the inertia force (IF) of late systolic aortic flow, a surrogate index of LV elastic recoil, was also computed from the LVP-dP/dt relation (phase loop). Patients were classified into 2 groups: those with impaired LV relaxation (τ ≥48 ms) and those with preserved LV relaxation (τ

Although obesity has been reported to be associated with decreased plasma B-type natriuretic peptide (BNP) levels, it is unknown whether the reduced BNP levels in obesity results from decreased left ventricular (LV) hemodynamic load.We examined the relationships between body mass index (BMI), plasma BNP levels, and LV systolic and diastolic function (ejection fraction [EF] and end-diastolic pressure [EDP]) in 271 consecutive patients undergoing cardiac catheterization for coronary artery disease. When patients were grouped by tertile of BMI, with increasing tertiles of BMI, there was a progressive increase in EDP (lower, middle, and upper tertiles of BMI, 13.5 ± 5.8, 14.9 ± 5.3, and 16.3 ± 5.4 mmHg, respectively; p for trend0.01) and a progressive decrease in log BNP levels (lower, middle, and upper tertiles of BMI, 3.52 ± 1.29, 2.96 ± 1.08, and 2.87 ± 1.21 ln[pg/ml], respectively, p for trend0.001). There was no clear difference in EF across BMI tertiles (p for trend0.1). Plasma BNP levels correlated positively with EDP (r = 0.38, p0.001). In multivariate linear regression including EDP and known correlates of plasma BNP levels, BMI correlated negatively with BNP levels (standardized β = -0.31, p0.001).We found that increased BMI was associated with LV diastolic abnormalities without change in systolic function and that patients with increased BMI had reduced plasma BNP levels despite having elevated EDP. These results suggest that the reduced BNP levels in obesity are not explained by altered LV hemodynamics.

It is acknowledged that expansion of the remote normal region of the left ventricle causes remodeling after myocardial infarction (MI). However, the characteristics of that region have not been fully elucidated. We studied 13 patients with atypical chest pain (controls) and 15 patients with a prior anterior MI who underwent cardiac catheterization. With Doppler strain imaging, we measured the peak radial myocardial systolic strain and peak radial early diastolic strain rate at the posterior wall of the left ventricle. None of the patients with atypical chest pain exhibited significant stenosis of the three major coronary arteries or left ventricular (LV) wall motion abnormality in cardiac catheterization. The patients with a prior anterior MI had single anterior descending artery disease without wall motion abnormality in the LV inferoposterior wall. LV ejection fraction and the LV relaxation time constant were also measured. The LV ejection fraction was significantly smaller in patients with a prior MI compared to controls. The peak radial systolic strain in the LV posterior wall was not significantly different between the patients with a prior MI and controls (125 ± 49 vs. 122 ± 29%). In contrast, the peak radial early diastolic strain rate in the same area was significantly lower in the patients with a prior MI than in controls (−7.4 ± 2.7 vs. −13.2 ± 4.0 s−1, p

When one bends the elbow by shortening of the biceps, a knot of muscle is observed in his or her upper arm, indicating that muscle shortening is converted to muscle standing in the perpendicular direction due to the incompressibility of skeletal muscle. A similar mechanism may work in the thickening process of the left ventricular (LV) wall. Although myocardial fibers of the left ventricle shorten by about 20% along the fiber direction when they contract, thickening of the LV wall during contraction often exceeds 50%. Thus, the aim of the present study was to clarify the mechanism by which myocardial fiber shortening produces such remarkable thickening of the LV wall. We hypothesized that myocardial fiber shortening in the circumferential direction causes myocardial transformation perpendicular to the fiber direction, thereby producing LV wall thickening. We evaluated this hypothesis using an incompressible model of the LV wall. In 15 healthy male volunteers (38±13 years), we calculated theoretical peak thickening values of the inner and outer LV wall layers and compared them with directly measured peak thickening values using Doppler strain imaging at the corresponding areas. The theoretical peak thickening and directly measured peak thickening were >60% in the LV inner layer. The theoretical peak thickening was correlated with the directly measured peak thickening in the inner (r=0.75, p

Background: Although left ventricular (LV) diastolic dysfunction is associated with increased risk for incident heart failure in patients with coronary artery disease (CAD), no specific treatment for diastolic abnormalities has been established. Animal and small human studies have shown that an acute increase in LV afterload adversely impacts on LV early diastolic relaxation, but little is known about its chronic effect on diastolic function. Methods and Results: The relationships of various components of arterial load (arterial compliance, total vascular resistance index, and augmentation index [AI] in the ascending aorta) with LV diastolic function indices determined on cardiac catheterization (relaxation time constant [Tau] and end-diastolic pressure [EDP]) and those on tissue Doppler echocardiography (early diastolic mitral annular velocity [E'] and the ratio of early diastolic mitral inflow to annular velocities [E/E']) were investigated in 303 consecutive patients undergoing cardiac catheterization for CAD. All components of arterial load correlated with diastolic function indices, with AI, an index reflecting late-systolic load, having the strongest correlations with diastolic function indices. After adjustment for potential confounders, AI correlated with Tau (standardized β=0.25, P

Left ventricular (LV) remodeling occurs in the remote normal region in the LVs after myocardial infarction (MI) and is closely involved in heart failure. We assessed myocardial oxygen consumption using a clearance rate constant K mono for the time activity curves of 11C-acetate in 15 patients with a prior anterior wall MI, 8 with a prior inferior wall MI, and 10 age-matched normal control subjects. LV end-systolic volume index (ESVI) was determined by echocardiography. The LVESVI was significantly greater in patients with an anterior and inferior MI than in control subjects. The heart rate systolic pressure product did not differ among the groups. K mono in the remote normal region in patients with an anterior MI was significantly less than that in the corresponding area in control subjects (0.055 ± 0.005 vs 0.065 ± 0.008 min−1, P

Although higher red cell distribution width (RDW) has recently been reported to be associated with increased mortality independent of anemia in patients with heart failure and those with coronary artery disease (CAD), the mechanism underlying this association is unknown. We hypothesized that higher RDW may reflect neurohumoral activation and a chronic inflammatory state that each contribute to adverse clinical outcomes in these populations. We measured RDW and plasma levels of B-type natriuretic peptide (BNP) and high-sensitive C-reactive protein (hs-CRP) in 226 consecutive patients undergoing cardiac catheterization for CAD (age, 67 +/- 8 years; males, 77%; RDW, 45.8 +/- 3.3 fL; hemoglobin, 13.2 +/- 1.4 g/dL; BNP, median [interquartile range], 26.0 [9.0-58.4] pg/mL; hs-CRP, 679 [345-1920] ng/mL). Plasma BNP (r = 0.21, P0.01) but not hs-CRP (r = 0.04, P0.1) levels correlated with RDW. After adjustment for potential confounders including age, gender, body mass index, glomerular filtration rate, hemoglobin, and known hemodynamic determinants of BNP, including elevated left ventricular end-diastolic pressure and volume and slow left ventricular relaxation, RDW was independently predicted by BNP (r(2) = 0.058, P0.001). In conclusion, elevated BNP levels are independently associated with higher RDW in patients with CAD. Neurohumoral activation may be a mechanistic link between increased RDW and adverse clinical outcomes in this population.

BACKGROUND Speckle-tracking echocardiography (STE)-derived parameters may have better correlation with left ventricular (LV) relaxation and filling pressure than tissue Doppler-derived parameters. However, it has not been elucidated which parameter - strain or strain rate - and which direction of myocardial deformation - longitudinal or circumferential - is the most useful marker of LV relaxation and filling pressure. METHODS AND RESULTS We conducted a prospective multicenter study and compared the correlation of tissue Doppler- and STE-derived parameters with the time constant of LV pressure decay (τ) and LV mean diastolic pressure (MDP) in 77 patients. The correlation of early-diastolic mitral annular velocity (e´) with τ was weak (r=-0.32, P

Background Nearly half of patients with heart failure (HF) have preserved ejection fraction (EF) and the mortality and morbidity of patients with HF with preserved EF (HFpEF) are high. However, no pharmacological therapy has been shown to improve survival in HFpEF patients. Previous retrospective and prospective observational studies have examined the prognostic impact of hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) in patients with HFpEF. However, the results are inconsistent due to limited power with small sample sizes and/or lack of adjustment for known prognostic factors and differences in baseline characteristics between patients treated with and without statins. Methods We aimed to conduct a meta-analysis of prospective observational studies examining the effect of statin therapy on mortality in HFpEF patients with the use of propensity score analysis. Results A total of 4 studies with 5,536 patients (2,768 patients [50%] on statins; mean age, 65-77 years; male, 43-66%; coronary artery disease, 42-64%; hypertension, 61-82%; diabetes, 20-29%; follow-up duration, 12-36 months) were included in this meta-analysis. The pooled analysis showed that statin therapy was associated with reduced mortality (odds ratio [95% CI] = 0.690 [0.493-0.965], P=0.030). Conclusion Our meta-analysis suggests the potential mortality benefit of statins in HFpEF. Further prospective observational studies and randomized controlled trials should be planned to confirm our observed potential survival benefit of statins in HFpEF.

Introduction: Chronotropic incompetence (CI), defined as the inability of the heart to increase its rate commensurate with increased activity, produces exercise intolerance, and is an independent predictor of overall mortality. Cardiac sympathetic nerve (SNS) activity has been suggested to have a relation to CI. However, the mechanisms for CI have not been fully elucidated. Thus, we investigated the cardiac SNS activity in patients with CI using cardiac I-123 metaiodobenzylguanidine (MIBG) scintigraphy. Methods: Sixteen patients with CI and 17 subjects who served as controls were enrolled in this study (age 77.5±9.2years; male 57.6%). Patients with CI were defined as who were implanted with pacemaker due to sick sinus syndrome. Results: There were no significant differences in age, sex, or left ventricular ejection fraction (66.3±14.3 vs 58.3±22.2%, ns) between patients with CI and controls. Plasma BNP level was also similar between two groups (79.0[IQR, 41.0-175.3] vs 90.9[IQR, 35.5-185.3]pg/mL, ns). The delayed heart/mediastinum (H/M) ratio was significantly higher in patients with CI than in controls (2.3±0.3 vs 2.0±0.4%, p=0.04). The early H/M ratio did not differ between two groups. The washout rate (WR) was significantly lower in patients with CI compared with that in controls (20.2±11.2 vs 33.3±14.1%, p=0.006). Conclusions: Decreased cardiac sympathetic nerve activity was associated with CI, and I-123 MIBG scintigraphy may be a useful modality for understanding the mechanism for CI.

ObjectivesWe investigated whether a lack of inertia force of late systolic aortic flow and/or apical asynergy provoke early diastolic dysfunction in patients with coronary artery disease (CAD).BackgroundLeft ventricular (LV) isolated diastolic dysfunction is a well-recognized cause of heart failure.MethodsWe evaluated LV apical wall motion and obtained left ventricular ejection fraction (LVEF) by left ventriculography in 101 patients who underwent cardiac catheterization to assess CAD. We also computed the LV relaxation time constant (Tp) and the inertia force of late systolic aortic flow from the LV pressure (P)–first derivative of left ventricular pressure (dP/dt) relation. Using color Doppler echocardiography, we measured the propagation velocity of LV early diastolic filling flow (Vp). Patients with LVEF ≥50% (preserved systolic function [PSF], n = 83) were divided into 2 subgroups: patients with inertia force (n = 53) and without inertia force (n = 30). No patient with systolic dysfunction (SDF) (LVEF