Search

Clinical risk stratification is a key strategy used to identify low- and high-risk subjects to optimize the management, ranging from pharmacological treatment to palliative care, of patients with heart failure (HF). Using statistical modeling techniques, many HF risk prediction models that combine predictors to assess the risk of specific endpoints, including death or worsening HF, have been developed. However, most risk prediction models have not been well-integrated into the clinical setting because of their inadequacy and diverse predictive performance. To improve the performance of such models, several factors, including optimal sampling and biomarkers, need to be considered when deriving the models; however, given the large heterogeneity of HF, the currently advocated one-size-fits-all approach is not appropriate for every patient. Recent advances in techniques to analyze biological "omics" information could allow for the development of a personalized medicine platform, and there is growing awareness that an integrated approach based on the concept of system biology may be an excessively naïve view of the multiple contributors and complexity of an individual's HF phenotype. This review article describes the progress in risk stratification strategies and perspectives of emerging precision medicine in the field of HF management.

Background: Ventilatory inefficiency during exercise assessed using the lowest minute ventilation/carbon dioxide production (V̇E/V̇CO2) ratio was recently proven to be a strong prognostic marker of heart failure (HF) regardless of left ventricular ejection fraction (LVEF). Its physiological background, however, has not been elucidated. Methods and Results: Fifty-seven HF patients underwent cardiopulmonary exercise testing and exercise-stress echocardiography. The lowest V̇E/V̇CO2 ratio was assessed on respiratory gas analysis. Echocardiography was obtained at rest and at peak exercise. LVEF was measured using the method of disks. Cardiac output (CO) and the ratio of transmitral early filling velocity (E) to early diastolic tissue velocity (e’) were calculated using the Doppler method. HF patients were divided into preserved EF (HFpEF) and reduced EF (HFrEF) using the LVEF cut-off 40% at rest. Twenty-four patients were classified as HFpEF and 33 as HFrEF. In HFpEF, age (r=0.58), CO (r=−0.44), e’ (r=−0.48) and E/e’ (r=0.45) during exercise correlated with the lowest V̇E/V̇CO2 ratio (P

BACKGROUND An inverse relationship exists between hospital case volume and mortality in patients with heart failure (HF). However, hospital performance factors associated with mortality in HF patients have not been examined. We aimed to identify these using exploratory factor analysis and assess the relationship between these factors and 7-day, 30-day, and in-hospital mortality among HF patients in Japan.Methods and Results:We analyzed the records of 198,861 patients admitted to 683 certified hospitals of the Japanese Circulation Society between 2012 and 2014. Records were obtained from the nationwide database of the Japanese Registry Of All cardiac and vascular Diseases-Diagnostic Procedure Combination (JROAD-DPC). Using exploratory factor analysis, 90 hospital survey items were grouped into 5 factors, according to their collinearity: "Interventional cardiology", "Cardiovascular surgery", "Pediatric cardiology", "Electrophysiology" and "Cardiac rehabilitation". Multivariable logistic regression analysis was performed to determine the association between these factors and mortality. The 30-day mortality was 8.0%. Multivariable logistic regression analysis showed the "Pediatric cardiology" (odds ratio (OR) 0.677, 95% confidence interval [CI]: 0.628-0.729, P

Prediction models are combinations of predictors to assess the risks of specific endpoints such as the presence or prognosis of a disease. Many novel predictors have been developed, modelling techniques have been evolving, and prediction models are currently abundant in the medical literature, especially in cardiovascular medicine, but evidence is still lacking regarding how to use them. Recent methodological advances in systematic reviews and meta-analysis have enabled systematic evaluation of prediction model studies and quantitative analysis to identify determinants of model performance. Knowing what is critical to model performance, under what circumstances model performance remains adequate, and when a model might require further adjustment and improvement will facilitate effective utilization of prediction models and will enhance diagnostic and prognostic accuracy in clinical practice. In this review article, we provide a current methodological overview of the attempts to implement evidence-based utilization of prognostic prediction models for all potential model users, including patients and their families, health-care providers, administrators, researchers, guideline developers and policy makers.

Background: The vasopressin type-2 receptor antagonist tolvaptan is an essential tool in the management of decompensated heart failure (HF) in the inpatient setting for short-term use with careful monitoring. There is conflicting evidence, however, for its long-term use. Methods and Results: In this prospective, multi-center, open-labeled, randomized control trial, Assessment of QUAlity of life during long-term treatment of ToLVaptan in refractory HF (AQUA-TLV study), patients with congestive HF refractory to furosemide ≥60 mg/day were randomly assigned to a control group or tolvaptan add-on group and followed for 6 months, after confirmation of baseline urine osmolality ≥350 mOsm/L. Twenty-nine patients (median age, 60 years; 22 male) were enrolled and assigned to a control group (n=16) or a tolvaptan group (n=13). Minnesota Living with Heart Failure Questionnaire score improved significantly in the tolvaptan group (from 58 to 10, P=0.030). In the tolvaptan group, diuretics dose reduced (P=0.001), serum creatinine decreased (P=0.040), and hyponatremia tended to improve (P=0.12). The tolvaptan group had a lower HF readmission rate compared with the control group (0.213 vs. 1.242 events/year, P=0.13). Conclusions: Six-month tolvaptan therapy improved quality of life and renal function and reduced HF readmissions, when given to the estimated responders (UMIN Clinical Trial Registry Number: UMIN 000009604).

BACKGROUND Little is known about palliative sedation in terminally ill heart failure (HF) patients.Methods and Results:We retrospectively reviewed terminally ill HF patients who received palliative sedation from September 2013 to August 2018. Among 95 terminally ill HF patients, 25 were prescribed dexmedetomidine and 12 were prescribed midazolam at the end of life. Richmond Agitation-Sedation Scale was significantly reduced (P

Background The ideal mortality prediction model (MPM) for acute heart failure (AHF) patients would have sufficient and stable predictive ability for long-term as well as short-term mortality. However, published MPMs for AHF predominantly predict short-term mortality up to 90 days, and their prognostic performance for long-term mortality remains unclear. Methods and Results: We analyzed 609 AHF patients in a prospective registry from January 2013 to May 2016. We compared the prognostic performance for long-term mortality among 8 systematically identified MPMs for AHF that predict short-term mortality up to 90 days from admission. The PROTECT 7-day model showed the highest c-index for long-term as well as short-term mortality among the studied MPMs. Sensitivity analyses revealed serum albumin and total cholesterol to be the most important variables, as dropping these variables resulted in a significant decline in c-index, when compared with other variables specific to the PROTECT 7-day model. Furthermore, significant improvements in c-index and net reclassification were observed when serum albumin or serum albumin plus total cholesterol was added to the studied MPMs, other than the PROTECT 7-day model. Conclusions The PROTECT 7-day model demonstrated the highest predictive performance for long-term as well as short-term mortality in AHF patients among the published MPMs. Our findings indicate the importance of accounting for nutritional status such as serum albumin and total cholesterol in AHF patients when developing a MPM.

BACKGROUND Statins might be associated with improved survival in patients with heart failure with preserved ejection fraction (HFpEF). The effect of statins in HFpEF without coronary artery disease (CAD), however, remains unclear. Methods and Results: From the JASPER registry, a multicenter, observational, prospective cohort with Japanese patients aged ≥20 years requiring hospitalization with acute HF and LVEF ≥50%, 414 patients without CAD were selected for outcome analysis. Based on prescription of statins at admission, we divided patients into the statin group (n=81) or no statin group (n=333). We followed them for 25 months. The association between statin use and primary (all-cause mortality) and secondary (non-cardiac death, cardiac death, or rehospitalization for HF) endpoints was assessed in the entire cohort and in a propensity score-matched cohort. In the propensity score-matched cohort, 3-year mortality was lower in the statin group (HR, 0.21; 95% CI: 0.06-0.72; P=0.014). The statin group had a significantly lower incidence of non-cardiac death (P=0.028) and rehospitalization for HF (P

Background In patients undergoing transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS), a sigmoid septum, characterized by subaortic interventricular hypertrophy, often results in the need for new pacemaker implantation (PMI). In this study, we reviewed the feasibility and treatment efficacy of TAVR for AS in patients with a sigmoid septum. Methods and Results: Between 2011 and 2016, 48 patients (25.4%; mean age 84.9±5.4 years; 9 males) with a sigmoid septum and 141 (74.6%; mean age 82.9±5.5 years; 61 males) without underwent TAVR. Their operative outcomes, echocardiographic and electrocardiographic findings, and long-term outcomes were retrospectively compared. Second TAVR because of valve malposition was performed in 3 patients with a sigmoid septum (6.3%) and in 2 patients without a sigmoid septum (1.4%), with no significant difference between the 2 groups. Although there was no significant difference in valve hemodynamics between the 2 groups, sigmoid septum and deep implantation (implantation depth ≥10 mm) were independent predictors of new PMI following TAVR. Conclusions Although a sigmoid septum did not preclude the feasibility, safety, or efficacy of TAVR for severe AS, its presence was associated with new PMI. Our approach to TAVR in patients with a sigmoid septum may contribute to clinical outcomes comparable to those of patients without this pathology.

Background: Oxygen uptake (V̇O2) at peak workload and anaerobic threshold (AT) workload are often used for grading heart failure (HF) severity and predicting all-cause mortality. The clinical relevance of respiratory exchange ratio (RER) during exercise, however, is unknown.Methods and Results: We retrospectively studied 295 HF patients (57±15 years, NYHA class I–III) who underwent cardiopulmonary exercise testing. RER was measured at rest; at AT workload; and at peak workload. Peak V̇O2 had an inverse correlation with RER at AT workload (r=−0.256), but not at rest (r=−0.084) or at peak workload (r=0.090). Using median RER at AT workload, we divided the patients into high RER (≥0.97) and low RER (

Background Despite the specific characteristics of heart failure with preserved ejection fraction (HFpEF) having been demonstrated predominantly from registries in Western countries, important international differences exist in terms of patient characteristics, management and medical infrastructure between Western and Asian countries.Methods and Results:We performed nationwide registration of consecutive Japanese hospitalized HFpEF patients with left ventricular EF ≥50% from 15 sites between November 2012 and March 2015. Follow-up data were obtained up to 2 years post-discharge. A total of 535 patients were registered. The median age was 80 years and 50% were female. The most common comorbid conditions were hypertension (77%) and atrial fibrillation (AF: 62%), but body mass index was relatively low. In-hospital mortality rate was 1.3% and the median length of hospitalization was 16 days. By 2 years post-discharge, 40.8% of patients had all-cause death or HF hospitalization. Approximately one-half of deaths had a cardiac cause. Lower serum albumin on admission was one of the strongest independent determinants of worse clinical outcome. Conclusions Japanese HFpEF patients were less obese, but had a substantially higher prevalence of AF and lower incidence of subsequent events compared with previous reports. Our findings indicated that specific preventative and therapeutic strategies focusing on AF and nutritional status might need to be considered for Japanese hospitalized patients with HFpEF.

BACKGROUND The valve-in-valve procedure, in which a transcatheter heart valve (THV) is implanted over a prosthetic valve, has been shown to be safe and therapeutically effective, depending on the size of the replacement valve.Methods and Results:We report 3 cases of successful valve-in-valve procedure to replace a degenerated 19-mm stented prosthetic aortic valve. Balloon-expanding THVs were implanted: 20-mm in the 1st case and 23-mm in the next 2. Aortic stenosis was almost completely resolved in all patients, who recovered promptly and without cardiac adverse events. CONCLUSIONS Using the valve-in-valve procedure for a 19-mm degenerated bioprosthesis was feasible and safe.

Acute kidney injury (AKI) and acute hyperglycemia are associated with unfavorable outcomes. The impact of acute hyperglycemia on the development of AKI after acute myocardial infarction (AMI), however, remains unclear. This study was undertaken to assess the relationship between admission glucose and incidence of AKI after AMI.This study consisted of 760 patients with AMI admitted to the National Cerebral and Cardiovascular Center within 48h after symptom onset. Blood sample was obtained on admission and repeated sampling was done at least every 1 or 2 days during the first week. AKI was diagnosed as increase in serum creatinine ≥0.3mg/dl or ≥50% within any 48h. Ninety-six patients (13%) had AKI during hospitalization for AMI, and these patients had higher in-hospital mortality than those without AKI (25% vs. 3%, P0.001). Patients with AKI had higher plasma glucose (PG) on admission than those without (222±105mg/dl vs. 166±69mg/dl, P0.001). The incidence of AKI increased as admission PG rose: 7% with PG120mg/dl; 9% with PG 120-160mg/dl; 11% with PG 160-200mg/dl; and 28% with PG200mg/dl (P0.01). On multivariate analysis admission PG was an independent predictor of AKI (odds ratio, 1.10; 95% confidence interval: 1.03-1.18, P=0.02).Admission hyperglycemia might have contributed to the development of AKI in patients with AMI.

Background: Tumor necrosis factor (TNF)-α, which is released as a soluble form by ectodomain shedding of TNF-α converting enzyme (Tace), is known to play a pivotal role in obesity-induced insulin resistance. The role of Tace in obesity-induced metabolic disorders was to be clarified in this study. Methods and Results: Transgenic mice with temporal systemic Tace deletion (TaceMx1) and their non-transgenic littermates (CON) were fed a standard diet or a high-fat diet (HFD) from 6 weeks of age. The increased body, liver and epididymal adipose tissue (EAT) weights, systolic blood pressure, and fasting glucose and lipid levels and decreased serum adiponectin level 12 weeks after starting a HFD were suppressed by Tace inactivation. A HFD/TaceMx1 showed ameliorated glucose tolerance and insulin sensitivity compared with HFD/CON. Indirect calorimetry showed that energy expenditure and oxidation of both fat and carbohydrate were higher in HFD/TaceMx1 than HFD/CON. Marked hepatosteatosis, increased triglyceride content and TNF-α expression in liver, and increased adipocyte size, macrophage infiltration and TNF-α and monocyte chemoattractant protein-1 expression in EAT induced by a HFD were attenuated in HFD/TaceMx1. Conclusions: Inactivation of Tace suppressed HFD-induced obesity, insulin resistance, hepatosteatosis and adipose tissue remodeling in association with increased energy expenditure, suggesting an important role of Tace in the development of obesity-induced metabolic disorders. (Circ J 2011; 75: 2482-2490)

Background: C-reactive protein (CRP) is known to be a pathogenic agent in the cardiovascular system. However, the effect of CRP on heart failure has not been elucidated. The effect of human CRP on cardiac dysfunction induced by diabetes mellitus (DM) using human CRP-overexpressing transgenic mice (CRP-Tg) was examined. Methods and Results: DM was induced in male wild-type mice (Wt/DM) and CRP-Tg (CRP/DM) by an injection of streptozotocin. Non-diabetic wild-type mice (Wt/Con) and CRP-Tg (CRP/Con) served as controls. Echocardiography and hemodynamic measurements 6 weeks after injection showed lower fractional shortening and left ventricular (LV) dP/dt max in CRP/DM compared with Wt/DM. Myocardial mRNA levels of interleukin-6, tumor necrosis factor-α, plasminogen activator inhibitor-1, angiotensin type 1 receptor, angiotensinogen, NADPH oxidase subunits (p47phox, gp91phox), glutathione peroxidase-3. and connective tissue growth factor were increased in CRP/DM compared with Wt/DM. Nuclear staining of 8-hydroxydeoxyguanosine was also increased in CRP/DM compared with Wt/DM. CRP/DM was associated with increased terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling positive cells and a higher ratio of Bax/Bcl-2 proteins compared with Wt/DM. The extent of cardiac fibrosis assessed by Sirius red staining and immunohistochemical staining for collagen type 1 was significantly increased in CRP/DM compared with Wt/DM. Conclusions: Overexpression of human CRP exacerbates LV dysfunction and remodeling in diabetic cardiomyopathy, possibly through enhancement of the inflammation, renin-angiotensin system, and oxidative stress. (Circ J 2011; 75: 1717-1727)

Background: The angiographic view (AGV) image is a new post-processing method that is similar to conventional coronary angiography (CAG). The purpose of this study was to evaluate its accuracy for coronary stenosis detection by 64-detector row computed tomography (CT). Methods and Results: CT evaluation results of 17 patients were compared with the results of invasive CAG on a coronary segment basis concerning the presence of stenoses >50% diameter reduction. All images of the 3 viewing methods (combination of conventional methods, AGV image alone, and axial images alone) were evaluated in consensus by 3 cardiovascular radiologists. Among 196 assessable segments, invasive CAG showed significant coronary artery stenoses in 44 segments. 43 of 44 lesions were detected with the AGV image, and absence of significant stenosis was correctly identified in 135 of 152 segments (sensitivity 98%; specificity 89%; accuracy 91%; positive predictive value 72%, negative predictive value 99%). The sensitivity of the AGV image was the same as that of conventional methods (98%). There was no significant difference in accuracy between the AGV image (91%) and conventional methods (94%). The accuracy of the AGV image was significantly higher than the axial images alone (78%). Conclusions: AGV image shows promise as a post-processing method for identifying coronary artery stenosis with high accuracy. (Circ J 2009; 73: 691 - 698)

Background Monocyte chemoattractant protein-1 (MCP-1) is a key mediator of left ventricular (LV) remodeling during the early phase of myocardial infarction (MI). The hypothesis tested was that myocardial MCP-1 expression would increase during the chronic phase of MI and an angiotensin-II type 1 receptor blocker (ARB) would attenuate macrophage infiltration through decreased myocardial MCP-1 expression. Methods and Results MI was produced by ligation of the left coronary artery in Wistar rats, which were then randomized to treatment with vehicle (MI/C), candesartan (10 mg · kg-1 ·day-1) for 6 weeks (MI/ARB0-6W), or candesartan for 2 weeks, starting 4 weeks after MI (MI/ARB4-6W). LV systolic and end-diastolic pressures 6 weeks after MI were decreased in MI/ARB0-6W compared with MI/C or MI/ARB4-6W, however, there were no differences in other hemodynamic or echocardiographic parameters among infarcted rat groups. Both long- and short-term treatments with ARB similarly reduced mRNA expressions of MCP-1, transforming growth factor-β1, and procollagen type I and III, macrophage infiltration, and myocardial fibrosis in the border zone. Conclusions In post-MI heart failure, ARB attenuated MCP-1 expression and macrophage infiltration in the border zone, resulting in less myocardial fibrosis. ARB may exert its beneficial effect, at least in part, by inhibiting myocardial macrophage-related inflammation. (Circ J 2008; 72: 1685 - 1692)

Background Epoprostenol (prostaglandin I2) has become recognized as a therapeutic breakthrough that can improve hemodynamics and survival in patients with primary pulmonary hypertension (PPH). However, a significant number of patients have PPH that is refractory to epoprostenol, and lung transplantation has been the only remaining treatment option. Methods and Results The study subjects included 20 consecutive patients with PPH (mean pulmonary arterial pressure: 65±15 mmHg) who had received epoprostenol for more than 12 months. The patients were divided into 2 groups; responders and non-responders. In the non-responders, New York Heart Association (NYHA) functional class did not improve and mean right atrial pressure (mRA) increased to 8 mmHg or more, and additional sildenafil, a phosphodiesterase-5 inhibitor, was started. Six patients were included in the non-responders, whose mRA was 9±5 mmHg before and significantly increased to 13±3 mmHg after epoprostenol administration (p

Increased neurohormone and cytokine concentrations are associated with adverse outcome in patients with congestive heart failure, so minimizing these increases may improve outcome, even in the acute phase of decompensated heart failure. The present study was designed to test the hypothesis that phosphodiesterase inhibitors, but not catecholamines, could favorably affect neurohormone and cytokine profiles in patients with acutely decompensated heart failure. Twenty-nine patients underwent monitoring using a Swan-Ganz catheter and were randomly allocated to receive phosphodiesterase inhibitors (PDEI group, n=19) or catecholamines (CA group, n=10). Pulmonary capillary wedge pressure decreased significantly in both groups and cardiac output showed a slight, but not statistically significant increase, in both groups. There was a significant decrease in plasma brain natriuretic peptide concentration in the PDEI group, but not in the CA group, whereas plasma interleukin-6 concentration increased in the CA group, but not in the PDEI group. Phosphodiesterase inhibitors favorably affect neurohormone and cytokine concentrations in patients with acutely decompensated heart failure. (Jpn Circ J 2001; 65: 858 - 862)

Background There is no post-processing technique that can display an overview image of the lumen and vessel wall of a whole heart in one image. A merging coronary lumen view (Angiographic View) with a plaque image can provide a single, comprehensive image of plaque distribution. Methods and Results A color-coded plaque image is assigned to different computed tomography attenuation ranges in the coronary artery to visualize plaques. This plaque image is re-formatted into a maximum intensity projection image and loaded onto the Angiographic View image. Conclusions The integrated image of the coronary lumen and vessel wall of a whole heart is feasible. This image (Plaque-loaded Angiographic View) will give effective information in explaining the distribution of coronary lesions in patients as well as providing opportunities to discuss treatment strategies. (Circ J 2008; 72: 671 - 673)

This study focused on the role of the baroreceptor-mediated control during the compensatory process after acute left ventricular overloading induced by aortic regurgitation (AR). Baroreceptor-heart rate sensitivity was measured using a phenylephrine-induced increase in blood pressure according to the steady state method before, 1 day, 1 week and 4 weeks after production of AR in 7 rabbits, and compared with 6 other rabbits that underwent a sham operation. Blood pressure was monitored noninvasively using Finapres in the unanesthetized state. Four weeks after the procedure, the left ventricular diameters of both end-diastole and end-systole were larger in the rabbits with AR than in the sham-operated rabbits. There was no difference in the left ventricular end-diastolic pressure or cardiac output. Left ventricular weight was higher in the rabbits with AR than in the sham-operated rabbits. Myocardial β-adrenergic receptor density and norepinephrine content were comparable between the two groups. Baroreceptor-heart rate sensitivity significantly decreased 1 week after production of AR, and this alteration in sensitivity was partially restored 4 weeks after production of AR. These findings suggested that the altered baroreceptor-heart rate sensitivity was reversible, relating to the compensatory process after acute left ventricular overloading, and that these changes had some role in its pathophysiology. (Jpn Circ J 1998; 62: 773 - 778)

Background A method of displaying coronary computed tomography (CT) angiography, which enables evaluation of coronary artery disease (CAD) with fewer images and is understandable to the third person, is preferable. Methods and Results A maximum intensity projection image was created in which contrast media in the ventricles is eliminated, enabling an overview of CAD in a single 3-dimensional (D) image that can be rotated to be viewed at various angles and is easily understood by a third person. Conclusions A novel method of displaying coronary CT angiography in a single 3-D image has been developed and we believe it should become available for many workstations. (Circ J 2006; 70: 1661 - 1662)