Right Ventricular Dimension for Heart Failure With Preserved Ejection Fraction Involving Right Ventricular-Vascular Uncoupling.

Background: Right ventricular (RV) to pulmonary artery (PA) uncoupling is known to be important for the prognosis of not only heart failure (HF) with reduced ejection fraction but also HF with preserved ejection fraction (HFpEF). We further investigated key factors in the poor prognosis for HFpEF patients with RV-PA uncoupling. Methods: We studied 817 patients with HFpEF who were discharged alive in a multicentred cohort using post hoc analyses, with a primary endpoint of cardiac mortality or HF readmission. A total of 288 RV-PA uncoupled patients were observed, namely those with a tricuspid annular plane systolic excursion (TAPSE)/PA systolic pressure (PASP) ratio < 0.46 mm/mm Hg. Results: Among the RV-PA uncoupled patients, 101 adverse outcomes occurred over a median of 340 days. Echocardiographic RV dimension (RVD) was significantly important for prognosis in both univariable and multivariable Cox regression testing (hazard ratio 1.044, 95% confidence interval 1.014-1.074, P = 0.0042, and hazard ratio 1.036, 95% confidence interval 1.001-1.072, P = 0.0438, respectively) considered with the covariates of age, atrial fibrillation, renal function, N-terminal pro-brain natriuretic peptide, and other echocardiographic parameters. We further divided the patients into 4 groups, first into 2 groups with a TAPSE/PASP either ≥ or < 0.46 mm/mm Hg, and then into 4 groups by RVD medians of 31.9 mm and 33.3 mm, respectively. Kaplan-Meier curve analysis showed that outcomes were worst in patients with a low TAPSE/PASP ratio and larger RVD (log-rank P < 0.0001). Conclusions: This multicentre observational study highlighted the further prognostic importance of larger RVD among HFpEF patients with RV-PA uncoupling.

Contexte: On sait que le découplage entre le ventricule droit (VD) et l'artère pulmonaire (AP) est important pour établir le pronostic de l'insuffisance cardiaque à fraction d'éjection réduite, mais également celui de l'insuffisance cardiaque à fraction d'éjection préservée (ICFEP). Nous avons étudié en détail les facteurs clés liés au pronostic défavorable de l'ICFEP chez les patients présentant un découplage VD-AP. Méthodologie: À partir des données d'une cohorte multicentrique, nous avons réalisé des analyses a posteriori sur 817 patients présentant une ICFEP qui sont sortis de l'hôpital en vie, avec comme critère d'évaluation principal la mortalité d'origine cardiaque ou la réadmission en raison de l'insuffisance cardiaque. Au total, 288 patients affichant un découplage VD-AP ont été observés, principalement ceux dont le rapport excursion systolique dans le plan annulaire tricuspide (TAPSE; tricuspid annular plane systolic excursion)-pression artérielle pulmonaire systolique (PAPs) était < 0,46 mm/mm Hg. Résultats: Au total, 101 événements indésirables ont été recensés sur une période médiane de 340 jours chez les patients qui présentaient un découplage VD-AP. La dimension ventriculaire droite mesurée par échocardiographie était un facteur pronostique significativement important dans les analyses de régression de Cox à une et à plusieurs variables (rapport des risques instantanés [RRI] : 1,044; intervalle de confiance à 95 % : 1,014 à 1,074; p : 0,0042; et RRI : 1,036; intervalle de confiance à 95 % : 1,001 à 1,072; p : 0,0438; respectivement) avec prise en compte des covariables de l'âge, de la fibrillation auriculaire, de la fonction rénale, du fragment N-terminal du propeptide natriurétique de type B, et d'autres paramètres échocardiographiques. Nous avons ensuite réparti les patients en quatre groupes, d'abord en deux groupes, selon que leur rapport TAPSE-PAPs était ≥ ou < 0,46 mm/mm Hg, puis en quatre groupes selon des dimensions ventriculaires droites médianes de 31,9 et de 33,3 mm, respectivement. L'analyse de la courbe de Kaplan-Meier a révélé des résultats moins favorables chez les patients qui présentaient un faible rapport TAPSE-PAPs et une grande dimension ventriculaire droite (valeur de p < 0,0001 selon le test du log-rank). Conclusions: Cette étude observationnelle multicentrique a mis en évidence l'importance d'une grande dimension ventriculaire droite dans l'établissement du pronostic chez les patients atteints d'ICFEP qui présentent un découplage VD-AP.

Predictors and Outcomes of Heart Failure With Preserved Ejection Fraction in Patients With a Left Ventricular Ejection Fraction Above or Below 60.

Background Although potential therapeutic candidates for heart failure with preserved ejection fraction (HFpEF) are emerging, it is still unclear whether they will be effective in patients with left ventricular ejection fraction (LVEF) of 60% or higher. Our aim was to identify the clinical characteristics of these patients with HFpEF by comparing them to patients with LVEF below 60%. Methods and Results From a multicenter, prospective, observational cohort (PURSUIT-HFpEF [Prospective Multicenter Obsevational Study of Patients with Heart Failure with Preserved Ejection Fraction]), we investigated 812 consecutive patients (median age, 83 years; 57% women), including 316 with 50% ≤ LVEF <60% and 496 with 60% ≤ LVEF, and compared the clinical backgrounds of the 2 groups and their prognoses for cardiac mortality or HF readmission. Two hundred four adverse outcomes occurred at a median of 366 days. Multivariable Cox regression tests adjusted for age, sex, heart rate, atrial fibrillation, estimated glomerular filtration rate, N-terminal pro-B-type natriuretic peptide, and prior heart failure hospitalization revealed that systolic blood pressure (hazard ratio [HR], 0.925 [95% CI, 0.862-0.992]; P=0.028), high-density lipoprotein to C-reactive protein ratio (HR, 0.975 [95% CI, 0.944-0.995]; P=0.007), and left ventricular end-diastolic volume index (HR, 0.870 [95% CI, 0.759-0.997]; P=0.037) were uniquely associated with outcomes among patients with 50% ≤ LVEF <60%, whereas only the ratio of peak early mitral inflow velocity to velocity of mitral annulus early diastolic motion e'(HR, 1.034 [95% CI, 1.003-1.062]; P=0.034) was associated with outcomes among patients with 60% ≤ LVEF. Conclusions Prognostic factors show distinct differences between patients with HFpEF with 50% ≤ LVEF <60% and with 60% ≤ LVEF. These findings suggest that the 2 groups have different inherent pathophysiology. Registration URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024414; Unique identifier: UMIN000021831 PURSUIT-HFpEF.

Prognostic Importance of Pulmonary Arterial Capacitance in Acute Decompensated Heart Failure With Preserved Ejection Fraction.

Background Although the prognostic importance of pulmonary arterial capacitance (PAC; stroke volume/pulmonary arterial pulse pressure) has been elucidated in heart failure with reduced ejection fraction, whether its significance in patients suffering from heart failure with preserved ejection fraction is not known. We aimed to examine the association of PAC with outcomes in inpatients with heart failure with preserved ejection fraction. Methods and Results We prospectively studied 705 patients (median age, 83 years; 55% women) registered in PURSUIT-HFpEF (Prospective Multicenter Observational Study of Patients With Heart Failure With Preserved Ejection Fraction). We investigated the association of echocardiographic PAC at discharge with the primary end point of all-cause death or heart failure rehospitalization with a mean follow-up of 384 days. We further tested the acceptability of the prognostic significance of PAC in a subgroup of patients (167/705 patients; median age, 81 years; 53% women) in whom PAC was assessed by right heart catheterization. The median echocardiographic PAC was 2.52 mL/mm Hg, with a quartile range of 1.78 to 3.32 mL/mm Hg. Univariable and multivariable Cox regression testing revealed that echocardiographic PAC was associated with the primary end point (unadjusted hazard ratio, 0.82; 95% CI, 0.72-0.92; P=0.001; adjusted hazard ratio, 0.86; 95% CI, 0.74-0.99; P=0.035, respectively). Univariable Cox regression testing revealed that PAC assessed by right heart catheterization (median calculated PAC, 2.82 mL/mm Hg) was also associated with the primary end point (unadjusted HR, 0.70; 95% CI, 0.52-0.91; P=0.005). Conclusions A prospective cohort study revealed that impaired PAC diagnosed with both echocardiography and right heart catheterization was associated with adverse outcomes in inpatients with heart failure with preserved ejection fraction. Registration URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024414. Unique identifier: UMIN000021831.

Prognostic relevance of elevated plasma osmolality on admission in acute decompensated heart failure with preserved ejection fraction: insights from PURSUIT-HFpEF registry.

BACKGROUND: Complicated pathophysiology makes it difficult to identify the prognosis of heart failure with preserved ejection fraction (HFpEF). While plasma osmolality has been reported to have prognostic importance, mainly in heart failure with reduced ejection fraction (HFrEF), its prognostic meaning for HFpEF has not been elucidated. METHODS: We prospectively studied 960 patients in PURSUIT-HFpEF, a multicenter observational study of acute decompensated HFpEF inpatients. We divided patients into three groups according to the quantile values of plasma osmolality on admission. During a follow-up averaging 366 days, we examined the primary composite endpoint of cardiac mortality or heart failure re-admission using Kaplan-Meier curve analysis and Cox proportional hazard testing. RESULTS: 216 (22.5%) patients reached the primary endpoint. Kaplan-Meier curve analysis revealed that the highest quantile of plasma osmolality on admission (higher than 300.3 mOsm/kg) was significantly associated with adverse outcomes (Log-rank P = 0.0095). Univariable analysis in the Cox proportional hazard model also revealed significantly higher rates of adverse outcomes in the higher plasma osmolality on admission (hazard ratio [HR] 7.29; 95% confidence interval [CI] 2.25-23.92, P = 0.0009). Multivariable analysis in the Cox proportional hazard model also showed that higher plasma osmolality on admission was significantly associated with adverse outcomes (HR 5.47; 95% CI 1.46-21.56, P = 0.0113) independently from other confounding factors such as age, gender, comorbid of atrial fibrillation, hypertension history, diabetes, anemia, malnutrition, E/e', and N-terminal pro-B-type natriuretic peptide elevation. CONCLUSIONS: Higher plasma osmolality on admission was prognostically important for acute decompensated HFpEF inpatients.

Distinctive prognostic factor of heart failure with preserved ejection fraction stratified with admission blood pressure.

AIMS: The prognostic importance of admission systolic blood pressure (SBP) in heart failure with preserved ejection fraction (HFpEF) is elusive. We aimed to clarify the pathophysiological differences between patients categorized with admission SBP among HFpEF patients. METHODS AND RESULTS: We studied 1008 inpatients from PURSUIT-HFpEF, a multicentre prospective observational registry. We classified patients as having elevated (>140 mmHg), preserved (90-140 mmHg), or low (<90 mmHg) admission SBP. Most cases had elevated (n = 584) or preserved (n = 420) SBP; the four cases with low SBP were excluded. Univariable Cox regression testing revealed that preserved SBP patients had a higher risk of a composite of cardiac death and heart failure re-hospitalization [hazard ratio (HR) 1.48, 95% confidence interval (CI) 1.14-1.92, P = 0.0035] than elevated SBP patients. In multivariable Cox regression models, while prior heart failure hospitalization (HR 1.36, 95% CI 1.01-2.84, P = 0.0453), atrial fibrillation (HR 1.82, 95% CI 1.10-2.99, P = 0.0209), and N-terminal pro-B-type natriuretic peptide (HR 1.94, 95% CI 1.10-3.43, P = 0.0229) at discharge were significantly associated with adverse outcomes in elevated SBP patients, N-terminal pro-B-type natriuretic peptide (HR 2.06, 95% CI 1.04-4.07, P = 0.0373) and right ventricular-pulmonary artery uncoupling reflected by the tricuspid annular plane systolic excursion/pulmonary artery systolic pressure ratio (HR 0.19, 95% CI 0.05-0.65, P = 0.0075) at discharge were significant prognostic factors in preserved SBP patients. CONCLUSIONS: Patients with preserved admission SBP had significant higher risks for adverse outcomes than those with elevated SBP in HFpEF. Tricuspid annular plane systolic excursion/pulmonary artery systolic pressure was the distinctive prognostic factor between the two groups.

Prognostic Importance of Right Ventricular-Vascular Uncoupling in Acute Decompensated Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Recent accumulating evidence reveals that the right ventricular (RV)-pulmonary artery (PA) uncoupling is associated with poor outcome in patients with heart failure (HF), RV dysfunction, and pulmonary hypertension. However, the prognostic utility of RV-PA uncoupling in HF with preserved ejection fraction (HFpEF) remains elusive. In this study, we aim to investigate the associations of RV-PA uncoupling with outcomes of HFpEF inpatients. METHODS: We prospectively studied 655 patients, registered in PURSUIT-HFpEF (The Prospective Multicenter Obervational Study of Patients with Heart Failure with Preserved Ejection Fraction), a multicenter observational study of Japanese HFpEF inpatients. We assigned registered patients based on the determined value of tricuspid annular plane systolic excursion/pulmonary artery systolic pressure ratio that can predict primary outcome as an indicator of RV-PA uncoupling. RESULTS: Univariable Cox regression testing revealed that RV-PA uncoupling was associated with the primary endpoint of all-cause death, HF rehospitalization, and cerebrovascular events (hazard ratio [HR] 1.77 [95% CI, 1.34-2.32], P<0.0001) and the secondary endpoints of all-cause death and HF rehospitalization (HR 2.75 [95% CI, 1.77-4.33], P<0.0001, HR 1.63 [95% CI, 1.18-2.26], P=0.0036, respectively). Multivariable analysis also showed that RV-PA uncoupling was significantly associated with primary endpoint and all-cause death independent of age, sex, atrial fibrillation, renal dysfunction, elevated E/e', and elevated NT-proBNP (N-terminal pro-B-type natriuretic peptide) (HR 1.38 [95% CI, 1.01-1.88], P=0.0413, HR 1.85 [95% CI, 1.14-3.01], P=0.0129, respectively). CONCLUSIONS: Prospective study of a hospitalized cohort revealed that RV-PA uncoupling was independently associated with adverse outcomes in acute decompensated patients with HFpEF. Registration: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024414. Unique identifier: UMIN000021831.

Relationships between clinicopathological features and cerebrospinal fluid biomarkers in Japanese patients with genetic prion diseases.

A national system for surveillance of prion diseases (PrDs) was established in Japan in April 1999. Here, we analyzed the relationships among prion protein gene (PRNP) mutations and the clinical features, cerebrospinal fluid (CSF) markers, and pathological characteristics of the major genotypes of genetic PrDs (gPrDs). We retrospectively analyzed age at onset and disease duration; the concentrations and incidences of 14-3-3 protein, tau protein, and abnormal prion protein (PrP(Sc)) in the CSF of 309 gPrD patients with P102L, P105L, E200K, V180I, or M232R mutations; and brain pathology in 32 autopsied patients. Three clinical phenotypes were seen: rapidly progressive Creutzfeldt-Jakob disease (CJD), which included 100% of E200K cases, 70% of M232R, and 21% of P102L; slowly progressive CJD, which included 100% of V180I and 30% of M232R; and Gerstmann-Sträussler-Scheinker disease, which included 100% of P105L and 79% of P102L. PrP(Sc) was detected in the CSF of more than 80% of patients with E200K, M232R, or P102L mutations but in only 39% of patients with V180I. V180I was accompanied by weak PrP immunoreactivity in the brain. Patients negative for PrP(Sc) in the CSF were older at disease onset than positive patients. Patients with mutations associated with high 14-3-3 protein levels in the CSF typically had synaptic deposition of PrP in the brain and a rapid course of disease. The presence of small PrP protein fragments in brain homogenates was not correlated with other clinicopathological features. Positivity for PrP(Sc) in the CSF may reflect the pathological process before or at disease onset, or abnormality in the secretion or metabolism of PrP(Sc). The amount of 14-3-3 protein in the CSF likely indicates the severity of the pathological process and accompanying neuronal damage. These characteristic features of the CSF in cases of gPrD will likely facilitate accurate diagnosis and clinicopathological study of the various disease subtypes.

Prospective 10-year surveillance of human prion diseases in Japan.

We analysed the epidemiological data and clinical features of patients with prion diseases that had been registered by the Creutzfeldt-Jakob Disease Surveillance Committee, Japan, over the past 10 years, since 1999. We obtained information on 1685 Japanese patients suspected as having prion diseases and judged that 1222 patients had prion diseases, consisting of definite (n=180, 14.7%) and probable (n=1029, 84.2%) cases, except for dura mater graft-associated Creutzfeldt-Jakob disease which also included possible cases (n=13, 1.1%). They were classified into 922 (75.5%) with sporadic Creutzfeldt-Jakob disease, 216 (17.7%) with genetic prion diseases, 81 (6.6%) with acquired prion diseases, including 80 cases of dura mater graft-associated Creutzfeldt-Jakob disease and one case of variant Creutzfeldt-Jakob disease, and three cases of unclassified Creutzfeldt-Jakob disease (0.2%). The annual incidence rate of prion disease ranged from 0.65 in 1999 to 1.10 in 2006, with an average of 0.85, similar to European countries. Although methionine homozygosity at codon 129 polymorphism of the prion protein gene was reported to be very common (93%) in the general Japanese population, sporadic Creutzfeldt-Jakob disease in Japan was significantly associated with codon 129 homozygosity (97.5%), as reported in western countries. In sporadic Creutzfeldt-Jakob disease, MM1 type (Parchi's classification) is the most common, as in western countries. Among atypical sporadic Creutzfeldt-Jakob disease cases, the MM2 type appeared most common, probably related to the very high proportion of methionine allele in the Japanese population. As for iatrogenic Creutzfeldt-Jakob disease, only dura mater graft-associated Creutzfeldt-Jakob disease cases were reported in Japan and, combined with the data from previous surveillance systems, the total number of dura mater graft-associated Creutzfeldt-Jakob disease was 138, comprising the majority of worldwide dura mater graft-associated Creutzfeldt-Jakob disease patients. Regarding genetic prion diseases, the most common mutation of prion protein gene was V180I (41.2%), followed by P102L (18.1%), E200K (17.1%) and M232R (15.3%), and this distribution was quite different from that in Europe. In particular, V180I and M232R were quite rare mutations worldwide. Patients with V180I or M232R mutations rarely had a family history of prion diseases, indicating that a genetic test for sporadic cases is necessary to distinguish these from sporadic Creutzfeldt-Jakob disease. In conclusion, our prospective 10-year surveillance revealed a frequent occurrence of dura mater graft-associated Creutzfeldt-Jakob disease, and unique phenotypes of sporadic Creutzfeldt-Jakob disease and genetic prion diseases related to the characteristic distribution of prion protein gene mutations and polymorphisms in Japan, compared with those in western countries.

Horizontal saccadic palsy associated with gliosis of the brainstem midline.

We studied premotor cell groups involved in the generation of saccades in a patient with a disturbance of voluntary horizontal gaze. The only neurological symptom found was a slowing of horizontal saccades, reported since birth and unaltered over his lifetime. We attribute this disorder, for the first time, to a fibrous gliosis of the brainstem midline, which may disrupt neuronal elements of the horizontal saccade generator crossing the brainstem midline, but it caused no obvious loss of omnipause-, excitatory burst-, and inhibitory burst neurons. No neuronal loss or demyelination, was apparent elsewhere in the brainstem; but there was evidence of an ependymal infection throughout the entire ventricular system. A diagnosis of Gaucher disease was made from the bone marrow of this patient shortly before his death, but for several reasons we considered this complication unlikely to be the cause of the saccadic disorder.

Contribution of early lumen loss after balloon angioplasty for in-stent restenosis to lumen loss at follow-up.

The treatment of in-stent restenosis using balloon angioplasty alone often produces excellent early results, but is associated with high rate of recurrence. Previous studies have demonstrated significant tissue reintrusion shortly after the treatment of in-stent restenosis with balloon angioplasty. The study was designed to elucidate the contribution of early lumen loss 6 hr after balloon angioplasty to lumen loss at follow-up. We prospectively performed quantitative coronary angiography and intravascular ultrasound in 12 patients with in-stent restenosis before intervention, after the final procedure, 6 hr later (5.6 +/- 1.4 hr), and at follow-up (7.7 +/- 2.3 months). Compared with immediately after balloon angioplasty, by 6 hr postintervention, the minimum lumen diameter (MLD) and lumen cross-sectional area had decreased significantly (2.48 +/- 0.44 to 2.01 +/- 0.57 mm, P = 0.01, and 7.0 +/- 1.2 to 5.5 +/- 1.4 mm2, P = 0.004, respectively). Furthermore, the MLD decreased further between 6 hr postintervention and long-term follow-up (2.01 +/- 0.57 to 1.55 +/- 0.64 mm; P = 0.001). Patients who showed recurrence of restenosis at follow-up had greater early lumen loss than patients without recurrence of restenosis (0.71 +/- 0.31 vs. 0.23 +/- 0.13 mm; P = 0.006). Diffuse lesions had greater early lumen loss compared to focal lesions (0.75 +/- 0.35 vs. 0.28 +/- 0.13 mm; P = 0.008). Early lumen loss is common after the treatment of in-stent restenosis by balloon angioplasty. Within the first 6 hr postintervention, 32% +/- 29% of acute lumen gain is lost, and early lumen loss contributed to 42% +/- 18% of total lumen loss at follow-up.

Neuropathological features of a case with schizophrenia and prion protein gene P102L mutation before onset of Gerstmann-Sträussler-Scheinker disease.

Gerstmann-Sträussler-Scheinker disease (GSS) is a hereditary transmissible spongiform encephalopathy associated with prion protein gene mutation P102L. The age of onset is roughly restricted to around the sixth decade; however, it is unclear whether the disease-specific pathology of GSS is already evident in the pre-clinical stage. We had a chance to examine an autopsy case with PRNP P102L mutation. The patient had died at 50 years of age before the clinical symptoms of GSS had appeared; neither neuronal loss, gliosis nor spongiform change was found anywhere in the brain. Immunohistochemistry failed to detect any deposition of prion protein. It is thus considered that amyloid plaque formation in GSS probably develops in a relatively rapid fashion compared with Alzheimer's disease. Although the patient suffered from schizophrenia, no significant pathological changes were detected except for astrocytic inclusion bodies in the cerebral cortex. The nature and significance of the inclusion bodies, which are not observed in patients with GSS, remain unclear.

Hepatocyte growth factor as a potential predictor of the presence of atherosclerotic aorto-iliac artery disease.

BACKGROUND: Hepatocyte growth factor (HGF), a member of the endothelial-specific growth factors with the greatest mitogenic activity, may play a role in the protection and/or repair of vascular endothelial cells injured by atherosclerosis. As a result, plasma HGF concentration may increase in response to endothelial cell damage. To test this hypothesis, we measured plasma concentrations of HGF in patients with or without aorto-iliac artery atherosclerotic disease. METHODS: One hundred ten consecutive patients who underwent coronary angiography were enrolled in this study. Abdominal aortography was performed after coronary arteriography to determine whether aorto-iliac artery atherosclerotic disease was present. Peripheral venous blood samples were obtained to measure the plasma HGF concentration. RESULTS: Aortography revealed aorto-iliac atherosclerotic disease in 35 patients (32%). The plasma HGF concentration was significantly higher in patients with arteriosclerotic lesions (0.35 +/- 0.11 ng/mL) than in patients without atherosclerotic lesions (0.27 +/- 0.09 ng/mL, P =.0002). On the basis of multiple logistic regression analysis of the relationships between coronary risk factors, age, sex, severity of coronary artery disease, plasma HGF concentration, and the presence of arteriosclerotic lesions, plasma HGF concentration (P =.0005) and age (P =.035) were found to predict independently the presence of aorto-iliac arteriosclerosis. CONCLUSION: Plasma HGF concentration can be used to predict the presence of arteriosclerotic lesions in the region from the abdominal aorta to the femoral arteries.