Diagnostic performance of pressure-bounded coronary flow reserve.

Fluid dynamics studies have proposed that coronary flow reserve can be calculated from coronary artery pressure instead of coronary blood flow. We sought to investigate the diagnostic performance of pressure-bounded coronary flow reserve (pb-CFR) compared with CFR measured by conventional thermodilution method (CFRthermo) in the clinical setting. Pressure guidewire was used to measure CFRthermo and fractional flow reserve (FFR) in left anterior descending coronary artery in 62 patients with stable coronary artery disease. Pb-CFR was calculated only with resting distal coronary artery pressure (Pd), resting aortic pressure (Pa) and FFR. Pb-CFR was moderately correlated with CFRthermo (r = 0.54, P < 0.001). Pb-CFR showed a poor agreement with CFRthermo, presenting large values of mean difference and root mean square deviation (1.5 ± 1.4). Pb-CFR < 2.0 predicted CFRthermo < 2.0 with an accuracy of 79%, sensitivity of 83%, specificity of 78%, positive predictive value of 48%, negative predictive value of 95%. The discordance presenting CFRthermo < 2.0 and pb-CFR ≥ 2.0 was associated with diffuse disease (P < 0.001). The discordance presenting CFRthermo ≥ 2 and pb-CFR < 2 was associated with a high FFR (P = 0.002). Pb-CFR showed moderate correlation and poor agreement with CFRthermo. Pb-CFR might be reliable in excluding epicardial coronary artery disease and microcirculatory disorders.

A First-Class Degrader Candidate Targeting Both KRAS G12D and G12V Mediated by CANDDY Technology Independent of Ubiquitination.

"Undruggable" targets such as KRAS are particularly challenging in the development of drugs. We devised a novel chemical knockdown strategy, CANDDY (Chemical knockdown with Affinity aNd Degradation DYnamics) technology, which promotes protein degradation using small molecules (CANDDY molecules) that are conjugated to a degradation tag (CANDDY tag) modified from proteasome inhibitors. We demonstrated that CANDDY tags allowed for direct proteasomal target degradation independent of ubiquitination. We synthesized a KRAS-degrading CANDDY molecule, TUS-007, which induced degradation in KRAS mutants (G12D and G12V) and wild-type KRAS. We confirmed the tumor suppression effect of TUS-007 in subcutaneous xenograft models of human colon cells (KRAS G12V) with intraperitoneal administrations and in orthotopic xenograft models of human pancreatic cells (KRAS G12D) with oral administrations. Thus, CANDDY technology has the potential to therapeutically target previously undruggable proteins, providing a simpler and more practical drug targeting approach and avoiding the difficulties in matchmaking between the E3 enzyme and the target.

Longitudinal Associations between Alcohol Intake and Arterial Stiffness, Pressure Wave Reflection, and Inflammation.

AIMS: This prospective observational study, which utilized repeated annual measurements performed over a 9-year period, applied mixed model analyses to examine age-related differences in longitudinal associations between alcohol intake and arterial stiffness, pressure wave reflection, and inflammation. METHODS: In 4016 middle-aged (43±9 years) healthy Japanese male employees, alcohol intake, brachial-ankle pulse wave velocity (baPWV), radial augmentation index (rAI), and serum C-reactive protein (CRP) levels were measured annually during a 9-year study period. RESULTS: The estimated marginal mean baPWV (non-drinkers=1306 cm/s, mild-moderate drinkers=1311 cm/s, and heavy drinkers=1337 cm/s, P＜0.01) and that of rAI showed significant stepped increases in an alcohol dose-dependent manner in the entire cohort, but an increase in rAI was not observed in subjects aged ≥ 50 years. The estimated slope of the annual increase in baPWV, but not rAI, was higher for heavy drinkers than for non-drinkers (slope difference, 1.84; P＜0.05), especially for subjects aged ＜50 years (slope difference, 2.84; P＜0.05). CONCLUSION: In middle-aged male Japanese employees, alcohol intake may attenuate inflammatory activity. While alcohol intake may exacerbate the progression of arterial stiffening in a dose-dependent manner without mediating inflammation, especially in subjects under 50 years of age, it may promote pressure wave reflection abnormalities with aging at earlier ages without further exacerbation at older ages.

Bidirectional Longitudinal Relationships Between Arterial Stiffness and Hypertension Are Independent of Those Between Arterial Stiffness and Diabetes: A Large-Scale Prospective Observational Study in Employees of a Japanese Company.

Background Hypertension and diabetes frequently coexist; however, it has not yet been clarified if the bidirectional longitudinal relationships between arterial stiffness and hypertension are independent of those between arterial stiffness and diabetes. Methods and Results In this 16-year prospective observational study, 3960 middle-aged employees of a Japanese company without hypertension/diabetes at the study baseline underwent annual repeated measurements of blood pressure, serum glycosylated hemoglobin A1c levels, and brachial-ankle pulse wave velocity. By the end of the study period, 664, 779, 154, and 406 subjects developed hypertension, prehypertension, diabetes, and prediabetes, respectively. Increased brachial-ankle pulse wave velocity at the baseline was associated with a significant odds ratio (per 1 SD increase) for new onset of prehypertension/hypertension with (2.45/3.28; P<0.001) or without (2.49/2.76; P<0.001) coexisting prediabetes/diabetes, but not for new onset of prediabetes/diabetes without coexisting hypertension. Analyses using the latent growth curve model confirmed the bidirectional relationships between brachial-ankle pulse wave velocity and hypertension, but no such relationship was observed between brachial-ankle pulse wave velocity and abnormal glucose metabolism. Conclusions In middle-aged employees of a Japanese company, while bidirectional relationships were found to exist between increased arterial stiffness and hypertension, such a relationship was not found between increased arterial stiffness and diabetes. Therefore, it appears that increased arterial stiffness may be associated with the development of hypertension but not with that of diabetes.

The Contribution of Deleterious Rare Alleles in ENPP1 and Osteomalacia Causative Genes to Atypical Femoral Fracture.

CONTEXT: Atypical femoral fractures (AFFs) are very rare atraumatic or mild trauma fractures in the subtrochanteric region or femoral shaft. Some unique genetic variants in Asian populations might confer susceptibility to AFF, since the incidence of AFFs is higher in Asian populations. OBJECTIVE: Because rare variants have been found to be causative in some diseases and the roles of osteomalacia causative genes have not been reported, we investigated rare variants in genes causing abnormal mineralization. METHODS: Exome sequencing was performed to detect variants in gene coding and boundary regions, and the frequencies of deleterious rare alleles were compared between Japanese patients with AFF (n = 42) and controls of the 4.7KJPN panel of Tohoku Medical Megabank by whole genome sequencing (n = 4773). RESULTS: The frequency of the deleterious rare allele of ENPP1 was significantly increased in AFF (P = .0012, corrected P [Pc] = .0155, OR 4.73, 95% CI 2.15-10.40). In multigene panel analysis, the frequencies of deleterious rare alleles of candidate genes were increased in AFF (P = .0025, OR 2.72, 95% CI 1.49-4.93). Principal component analysis of bone metabolism markers identified a subgroup of patients with AFF with higher frequencies of deleterious rare alleles in ENPP1 (P = 4.69 × 10-5, Pc = .0006, OR 8.47, 95% CI 3.76-19.09) and the candidate genes (P = 1.08 × 10-5, OR 5.21, 95% CI 2.76-9.86). CONCLUSION: AFF is associated with genes including ENPP1 that cause abnormal mineralization, suggesting that osteomalacia is an underlying condition predisposing to AFF and that higher incident rates of AFFs in Asian populations might be explained by the genetic risk factors including ENPP1.

Longitudinal Association of Arterial Stiffness and Pressure Wave Reflection with Decline of the Cardiac Systolic Performance in Healthy Men.

AIMS: This prospective observational study aimed to examine the individual longitudinal associations of the increases in the arterial stiffness and pressure wave reflection with the decline in the cardiac systolic performance during the study period in healthy middle-aged Japanese men. METHODS: In 4016 middle-aged Japanese healthy men (43±9 years), the brachial-ankle pulse wave velocity (baPWV), radial augmentation index (rAI), and pre-ejection period/ejection time (pre-ejection period (PEP)/ET) were measured annually during a 9-year study period. RESULTS: The baPWV, rAI, and PEP/ET showed steady annual increases during the study period. According to the results of multivariate linear regression analyses, both the baPWV and rAI measured at the baseline showed significant independent associations with the PEP/ET measured at the baseline (baPWV: beta=0.17, p＜0.01 and rAI: beta=0.11, p＜0.01), whereas neither showed any association with the PEP/ET measured at the end of the study period. The results of the mixed-model linear regression analysis of the repeated-measures data collected over the 9-year study period revealed that the baPWV, but not the rAI, showed a significant longitudinal association with the PEP/ET (estimate=0.69 x 10-4, p＜0.01). CONCLUSION: In apparently healthy middle-aged Japanese men, the annual increase of the arterial stiffness, rather than the annual increase of the pressure wave reflection, appears to be more closely associated with the annual decline of the cardiac systolic performance as assessed by the systolic time interval.

Moderate to severe obstructive sleep apnea is independently associated with inter-arm systolic blood pressure difference: Tokyo Sleep Heart Study.

OBJECTIVE: Obstructive sleep apnea (OSA) is recognized as an independent risk factor for cardiovascular disease. On the other hand, inter-arm systolic blood pressure difference (IAD), inter-ankle systolic blood pressure difference (IAND), and ankle-brachial index (ABI) are all known predictors of cardiovascular events. The aim of the present study was to investigate the association between OSA and four-limb blood pressure differences. METHODS: We conducted this cross-sectional study in a large sleep cohort from Tokyo Sleep Heart Study. In 2643 consecutive patients who visited our sleep clinic for polysomnography between 2005 and 2017, all the patients underwent blood pressure measurement simultaneously in all the four limbs by oscillometric methods. RESULTS: The prevalence rate of IAD ≥10 mmHg was significantly higher in the moderate OSA (15 ≤ apnea-hypopnea index [AHI] < 30) group (4.2%) and severe OSA (AHI ≥ 30) group (4.6%) than that in the no/mild (AHI < 15) OSA group (1.4%). Multivariate logistic regression analysis also identified moderate to severe OSA as being significantly associated with IAD ≥10 mmHg, even after adjustments for confounding variables (moderate OSA: odds ratio [OR], 4.869; 95% confidence interval [CI], 1.080-21.956; P = 0.039; severe OSA: OR, 5.301; 95% CI, 1.226-22.924; P = 0.026). However, there were no significant associations of the OSA severity with IAND ≥15 mmHg or ABI <0.9. CONCLUSIONS: Moderate to severe OSA was independently associated with the IAD, not but with the IAND or ABI.

Mediation of Arterial Stiffness for Hyperuricemia-Related Decline of Cardiac Systolic Function in Healthy Men.

Background: This prospective observational study examined whether hyperuricemia may be associated with impaired left ventricular (LV) systolic function and increased cardiac load resulting from increased arterial stiffness. Methods and Results: In 1,880 middle-aged (mean [±SD] age 45±9 years) healthy men, serum uric acid (UA) levels, pre-ejection period/ejection time (PEP/ET) ratio, serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, and brachial-ankle pulse wave velocity (baPWV) were measured at the start and end of the 3-year study period. Linear regression analysis revealed that serum UA levels measured at baseline were significantly associated with the PEP/ET ratio, but not with serum NT-proBNP levels, measured at baseline (ß=0.73×10-1, P<0.01) and at the end of the study period (ß=0.68×10-1, P<0.01). The change in the PEP/ET ratio during the study period was significantly greater in the High-UA (UA >7 mg/dL in 2009 and 2012) than Low-UA (UA ≤7 mg/dL in 2009 and 2012) group. Mediation analysis demonstrated both direct and indirect (via increases in baPWV) associations between serum UA measured at baseline and the PEP/ET ratio measured at the end of the study period. Conclusions: In healthy middle-aged Japanese men, hyperuricemia may be associated with an accelerated decline in ventricular systolic function, both directly and indirectly, via increases in arterial stiffness.

The Predictive Value of Changes in Body Mass Index for the Incidence of Device-Specific Infections in Patients With Implantable Left Ventricular Assist Devices.

BACKGROUND: Implantable left ventricular assist devices (LVAD) have improved quality of life and survival in patients with advanced heart failure. However, LVAD-specific infections and predicting which patients will develop infections remain challenging. This study investigated whether changes in body mass index (BMI) during hospitalization following LVAD implantation are associated with LVAD-specific infections within 1 year of implantation.Methods and Results:Patients (n=135) undergoing LVAD implantation were retrospectively divided into 2 groups based on changes in BMI from LVAD implantation to discharge: those with and without decreases in BMI. Each group was further subdivided according to baseline albumin concentrations (high [>3.7 g/dL] and low [≤3.7 g/dL]). Twenty patients developed LVAD-specific infections within 1 year. Receiver operating characteristic curve analysis resulted in a ∆BMI cut-off of less than -0.128 kg/m2. In multivariate analysis, younger patients and those with decreases in BMI had significantly higher rates of LVAD-specific infection (P=0.010 and P=0.035, respectively). LVAD-specific infection rates were significantly higher for patients with low albumin and decreases in BMI than for patients with low albumin but no decrease in BMI. CONCLUSIONS: Decreases in BMI during hospitalization after LVAD implantation and younger age were independently associated with LVAD-specific infection within 1 year. Strict patient management may be needed to avoid decreases in BMI during hospitalization after LVAD implantation, particularly in patients with low baseline albumin concentrations.

Differences in longitudinal associations of cardiovascular risk factors with arterial stiffness and pressure wave reflection in middle-aged Japanese men.

The present prospective observational study was conducted to examine the differences in longitudinal associations of the conventional risk factors for cardiovascular disease (CVD) with arterial stiffness and with abnormal pressure wave reflection using repeated measurement data. In 4016 healthy middle-aged (43 ± 9 years) Japanese men without CVD at baseline, the conventional risk factors for CVD, brachial-ankle pulse wave velocity (brachial-ankle PWV) and radial augmentation index (rAI) were measured annually over a 9-year period. Mixed-model linear regression analysis demonstrated a significant independent positive longitudinal association of the mean blood pressure with both the brachial-ankle PWV (estimate = 5.51, standard error = 0.30, P < 0.01) and the rAI (estimate = 0.19, standard error = 0.02, P < 0.01). On the other hand, the serum levels of glycohemoglobin, low-density lipoprotein cholesterol and triglycerides showed longitudinal associations only with the brachial-ankle PWV and not the rAI. In addition, while the radial AI was found to show a significant longitudinal association with the brachial-ankle PWV, the inverse association was not significant. In conclusion, the conventional risk factors for CVD showed heterogeneous longitudinal associations with arterial stiffness and/or abnormal pressure wave reflection. Elevated blood pressure showed independent longitudinal associations with both arterial stiffness (macrovascular damage) and abnormal pressure wave reflection, suggesting that BP is also longitudinally associated, at least in part, with microvascular damage. On the other hand, abnormal glucose metabolism and dyslipidemia showed independent longitudinal associations with only arterial stiffness (macrovascular damage).

Correlation of the Fatty Liver Index with the Pathophysiological Abnormalities Associated with Cardiovascular Risk Markers in Japanese Men without any History of Cardiovascular Disease: Comparison with the Fibrosis-4 Score.

AIM: Fatty liver and the liver fibrosis are known risk factors for cardiovascular disease (CVD). The severity of fatty liver can be assessed by determining the fatty liver index (FLI), and the severity of liver fibrosis can be assessed by determining the fibrosis-4 (FIB-4) score. We examined the differences in the associations of these two liver scoring systems with the pathophysiological abnormalities associated with the risk of development of CVD. METHODS: The FLI and FIB-4 score were calculated in 2,437 Japanese men without any history of CVD. The serum NT-pro-BNP levels and brachial-ankle pulse wave velocity (baPWV) were also measured at the start of the study and the end of three years' follow-up. RESULTS: The FLI was significantly correlated with the baPWV (p＜0.01) and the FIB-4 score was significantly correlated with the serum NT-pro-BNP level (p＜0.01). Furthermore, the delta change of the FLI was significantly correlated with the delta change of the baPWV during the study period (p=0.01), and the delta change of the FIB-4 score was significantly correlated with the delta change of the serum NT-pro-BNP level during the study period (p＜0.01). CONCLUSIONS: While the FIB-4 score may serve as a marker of the risk of development of heart failure, the FLI may be a marker of arterial stiffness in Japanese men without any history of CVD.

Arterial stiffness and pressure wave reflection in the development of isolated diastolic hypertension.

OBJECTIVES: This prospective study was conducted to clarify the significance of augmented pressure wave reflection without accompanying increased arterial stiffness in the development of isolated diastolic hypertension (IDHT). METHODS: A total of 3022 Japanese men without hypertension at the start of this study were included in the analyses. The blood pressure, brachial--ankle pulse wave velocity (brachial-ankle PWV), and radial augmentation index (rAI) were measured annually from year 2007 through year 2015. RESULTS: At the end of the study period, 129 participants were diagnosed as having systolic/diastolic hypertension (SDHT), 112 as having isolated systolic hypertension (ISHT), and 74 as having IDHT. Both the brachial--ankle PWV and rAI showed significant individual odds ratios for new onset of SDHT and new onset of ISHT. However, only rAI, but not the brachial--ankle PWV, showed a significant odds ratio (1.44, P < 0.01) for new onset of IDHT. This association was significant in participants without elevated brachial--ankle PWV values at the start of the study, but not in those with elevated brachial--ankle PWV at the start of the study. Generalized estimating equation analyses demonstrated a significant longitudinal association of the rAI, but not brachial--ankle PWV, with the development of IDHT. CONCLUSION: Although increased arterial stiffness and augmented pressure wave reflection present concomitantly may be associated with the development of SDHT and ISHT, augmented pressure wave reflection alone, which may be related to isolated peripheral vascular damage, in the absence of accompanying increase of the arterial stiffness, may be a significant factor in the development of IDHT.

Delay in seeking treatment before emergent heart failure readmission and its association with clinical phenotype.

BACKGROUND: Many patients with emergent heart failure (HF) readmission have a delay between symptom onset and hospitalization. The present study aimed to characterize the interval between symptom onset and hospitalization in patients being readmitted for HF and to compare the clinical phenotypes of patients with delay before emergent readmission with those who presented to the hospital earlier. METHODS: Data for a total of 2073 consecutive patients was collected from the Tokyo CCU Network database; the patients were divided into delayed (those who sought medical help > 2 days after symptom onset; n = 271) and early groups (remaining patients; n = 1802), and their clinical characteristics and mode of presentation were compared. RESULTS: Age, sex, and laboratory findings including brain natriuretic peptide and serum creatinine levels were not significantly different between the two groups. Patients in the delayed group had greater chronic fluid retention and symptoms not associated with respiratory failure, whereas those in the early group were more likely to have acute respiratory distress, faster heart and respiration rates, and higher systolic blood pressure. CONCLUSIONS: More than one in ten patients with HF readmission delay seeking treatment > 2 days after symptom onset. Patients who delayed seeking treatment showed the phenotype of chronic fluid retention, whereas those who presented to the hospital earlier had the phenotype of acute respiratory failure.

Preoperative radiographic features of trochanteric fractures irreducible by closed reduction.

INTRODUCTION: The aim of this study was to clarify the relationship between the preoperative radiographic classification of trochanteric fractures and the success/failure of closed reduction. Identification of irreducible fractures would be important to proceed promptly to direct reduction. PATIENTS AND METHODS: Our retrospective analysis included 141 trochanteric fractures, in 122 women and 17 men, with a mean age of 85.7 years (range, 45-101 years). Evans' classification of trochanteric fractures, as modified by Jensen, and the lateral view classification were used, based on preoperative plain radiographs and computed tomography images. Features predictive of irreducible fractures were identified. RESULTS: Among the 141 fractures, 16 (11.3%) were irreducible by closed reduction. The position of the proximal fragment, relative to the shaft on lateral view, and the fracture pattern of the lesser and greater trochanters were predictive of the feasibility of obtaining a successful closed reduction. These criteria identified success/failure of closed reduction in 99.3% of cases. CONCLUSION: Our findings should be useful for identifying patients in whom closed reduction would be suitable and for avoiding ineffectual manipulation in unsuitable patients.

Mid-term prognostic impact of residual pulmonary congestion assessed by radiographic scoring in patients admitted for worsening heart failure.

AIMS: Pulmonary congestion is associated with poor prognosis following hospitalization for worsening heart failure (HF), although its quantification and optimal timing during HF hospitalization remains challenging. The aim of this study was to assess the prognostic value of radiographic pulmonary congestion at admission and discharge in patients with worsening HF. METHODS AND RESULTS: Clinical, echocardiographic, laboratory and chest X-ray data of 292 acute decompensated HF patients were retrospectively studied (follow-up 1 year). Lung congestion was blindly scored on chest X-ray performed at admission and discharge using a systematic 6-zone approach. Primary clinical outcome was a composite outcome of re-hospitalization for worsening HF or all cause death. Patients were stratified according to the median of congestion score index (CSI) at both admission (median CSI(A) = 1.33) and discharge (median CSI(D) = 0.33). BNP levels, LVEF and eGFR did not differ between CSI categories. In multivariable Cox regression analysis, discharge CSI (HR for 1-point increase = 1.83 [1.02 to 3.27] p = 0.04) and discharge BNP were significantly associated with the composite outcome whereas NYHA class, physical signs, admission CSI and echocardiographic data were not. Furthermore, discharge CSI significantly increased reclassification on top of clinical covariates (continuous NRI = 19.6% [4.0 to 30.0] p = 0.03 and IDI = 2.2% [0.0 to 7.6] p = 0.046) while discharge BNP did not significantly improve risk reclassification. CONCLUSIONS: Residual pulmonary congestion assessed by radiographic scoring predicts poor prognosis beyond physical assessment, echocardiographic parameters and BNP. These findings further support the capital prognostic value of radiographic pulmonary congestion in patients hospitalized for worsening HF.

Correction to: Prognostic value of estimated plasma volume in acute heart failure in three cohort studies.

Unfortunately, an error occurred in the methods section of the abstract.

Prognostic value of estimated plasma volume in acute heart failure in three cohort studies.

AIMS: Estimated plasma volume status (ePVS) predicts prognosis in patients with heart failure (HF). It remains unclear whether admission, discharge or change ePVS best predicts post-discharge outcome in patients with acute decompensated heart failure (ADHF). METHODS: We retrospectively analyzed three cohort studies: 383 patients admitted at the Tokyo Medical University hospital, 165 patients admitted at the Centro Hospitalar do Porto and 164 patients admitted at the Nancy University Hospital (ICALOR study). ePVS at admission and at discharge as well as its change thereof were, respectively, calculated using the Duarte and Strauss formulas, both derived from hemoglobin and hematocrit ratios. Clinical variables including physical assessment, biological and echocardiographic parameters were recorded. The clinical outcome was a composite of re-hospitalization for worsening HF or all-cause mortality [corrected]. RESULTS: The primary outcomes occurred in 27.2% at 1 year (in the Tokyo cohort), 45.3% at 6 months (in the Porto cohort) and 53.9% at median terms of 298.3 days (in the ICALOR study). After adjusting for potential confounders including natriuretic peptide, discharge ePVS remained significantly associated with increased rates of composite outcome in the Tokyo and Porto cohorts and ICALOR study [hazard ratio (HR) 1.21 (1.01-1.44), p = 0.04; HR 1.45 (1.16-1.81), p < 0.01; HR 1.45 (1.16-1.81), p < 0.01, respectively]. In addition, a pooled analysis yielded a significant improvement in reclassification with discharge ePVS [net reclassification index 13.6% (5.9-22.7), p = 0.004]. CONCLUSIONS: As validated in three independent ADHF cohorts, ePVS at discharge was independently associated with post-discharge clinical outcomes and improved the risk stratification of patients admitted for ADHF on top of well-established prognostic markers.

Effects of Lactotripeptide Supplementation on Tele-Monitored Home Blood Pressure and on Vascular and Renal Function in Prehypertension　- Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study.

Background: This randomized, double-blind, placebo-controlled, cross-over study was conducted to examine the effects of lactotripeptide supplementation on 7-day mean tele-monitored home blood pressure (BP), and also on the markers of vascular function and renal damage in Japanese subjects with prehypertension. Methods and Results: A total of 26 subjects with prehypertension were randomly allocated to receive the active product (lactotripeptide tablet) or a placebo tablet for 8 weeks each in a cross-over manner. Urinary liver-type fatty acid-binding protein-to-creatine ratio (UFABPCR) and vascular function were measured at the end of each intervention. Home systolic and diastolic BP at the end of the lactotripeptide supplementation period was significantly lower than that at the end of the placebo period (P<0.05). On mixed linear model analysis there was a significant difference in the change in home diastolic BP after intervention between the 2 interventions (P=0.04). UFABPCR was significantly lower at the end of the lactotripeptide intervention period than at the end of the placebo period (P<0.05). Conclusions: The beneficial effect of lactotripeptide supplementation on 7-day mean tele-monitored home BP was confirmed in Japanese subjects with prehypertension. In addition, this intervention also seemed to have a protective effect against the progression of renal function decline.

Possible Mechanisms Underlying Elevated Serum N-Terminal Pro-Brain Natriuretic Peptide in Healthy Japanese Subjects.

Background: The precise mechanisms underlying elevation of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in healthy subjects have not been fully clarified. Methods and Results: In 2,844 Japanese healthy subjects with serum NT-proBNP <125 pg/mL, (1) brachial-ankle pulse wave velocity and (2) second peak of the peripheral systolic blood pressure minus diastolic blood pressure (pulse pressure 2 [PP2]), as markers of cardiac afterload; (3) fibrosis 4 score (FIB-4 score, a marker of liver fibrosis), as a marker of cardiac preload; and (4) ratio of the pre-ejection time to ejection time (PEP/ET), as a marker of cardiac systolic function, were measured. At the first examination, after the adjustments, log-transformed serum NT-proBNP was associated with PP2 and FIB-4 score, but not with PEP/ET. These parameters were successfully measured again after a 3-year interval in 1,978 subjects. On Pearson's correlation analysis, change in PP2 and FIB-4 score during the study period was significantly correlated with change in serum NT-proBNP (r=0.05, 0.09, respectively; P<0.01). Conclusions: In apparently healthy Japanese subjects, both increased cardiac preload and increased cardiac afterload, but not impaired cardiac systolic function, may be associated with elevated serum NT-proBNP.

Liver stiffness and arterial stiffness/abnormal central hemodynamics in the early stage of heart failure.

BACKGROUND: It remains to be clarified whether liver stiffness is a direct risk factor for heart failure (HF) or whether its association with HF is mediated by vascular damage. We conducted cross-sectional and prospective longitudinal studies to examine whether fibrosis 4 score (FIB-4 score) is directly associated with the serum NT-pro-BNP levels or the association is mediated by arterial stiffness and/or abnormal central hemodynamics. METHODS AND RESULTS: In 3040 health Japanese subjects with serum NT-pro-BNP levels < 125 pg/ml, the FIB-4 score was calculated, and the serum NT-pro-BNP levels, brachial-ankle pulse wave (baPWV) velocity and radial augmentation index (rAI) were measured. These parameters were measured again after a 3-year interval in 2135 subjects. Multivariate linear regression analysis demonstrated a significant cross-sectional association of the FIB-4 scores with the log-transformed the serum NT-pro-BNP levels (beta = 0.08, p < 0.01), but not with the baPWV or rAI. The change of serum NT-pro BNP levels during the study period was significantly higher in subjects with increase of the FIB-4 score during the study period (8.2 ±â€¯22.5 pg/ml) than that in those with decrease/no change (5.4 ±â€¯22.3 pg/ml) (p < 0.05). CONCLUSION: Liver stiffness may have a significant direct association with the development of HF from the early stage, without the mediation of arterial stiffness and/or abnormal central hemodynamics. Therefore, the FIB-4 score appears to serve as a direct risk factor for HF from the early stage, and its association with HF may not be mediated by vascular damages.