Background:We evaluated the association between rectus femoris muscle thickness adjusted by body mass index (RFT/BMI) and oxygen uptake at anaerobic threshold (AT-V̇O2) in patients with heart failure (HF) to assess whether RFT/BMI was associated with AT-V̇O2, a key indicator of exercise tolerance and a known prognostic factor in HF. Methods and Results:In this retrospective cross-sectional study, 103 patients with HF who underwent ultrasound-derived RFT measurement and cardiopulmonary exercise testing (CPX) were included. RFT/BMI was examined using multivariable linear regression and restricted cubic spline analysis. Receiver operating characteristic curve analysis identified optimal RFT/BMI cutoffs, and propensity score-adjusted modified Poisson regression assessed associations with subthreshold AT-V̇O2. RFT/BMI was independently associated with AT-V̇O2 (β=0.62, 95% confidence interval (CI): 0.45 to 0.79, P<0.001), with a significant nonlinear relationship. Cutoffs of 0.55 and 0.69 discriminated AT-V̇O2 ≥10.5 and ≥14.0 mL/min/kg, with AUCs of 0.89 and 0.75, respectively. In the modified Poisson regression, RFT/BMI ≥0.55 and ≥0.69 was associated with lower risk of AT-V̇O2 <10.5 mL/min/kg (aRR=0.22, 95% CI: 0.09 to 0.53, P=0.001) and <14.0 mL/min/kg (aRR=0.45, 95% CI: 0.28 to 0.73, P=0.001). Conclusions:Ultrasound-derived RFT/BMI was associated with AT-V̇O2 in patients with HF, and thus may provide supportive information on exercise tolerance when CPX is not feasible.

INTRODUCTION:Uric acid (UA), a major endogenous antioxidant involved in oxidative stress regulation and energy metabolism, has been linked to skeletal muscle health. However, evidence regarding its association with muscle function and muscle mass in underweight young women is limited. This study investigated the associations between serum UA levels, handgrip strength, and skeletal muscle mass in underweight young women. METHODS:This cross-sectional study included 73 underweight female university students (body mass index <18.5 kg/m²) who underwent detailed assessments following annual health checkups at Shimane University, Japan, between 2022 and 2024. Participants were categorized by muscle mass and handgrip strength status based on the Asian Working Group for Sarcopenia (AWGS) 2019 cut-off values. Serum UA levels were compared among groups. Associations between UA and muscle-related parameters were examined using correlation analyses. Multivariable linear regression analyses were performed with handgrip strength as the dependent variable and serum UA as the independent variable, adjusting for age, skeletal muscle index (SMI), estimated glomerular filtration rate (eGFR), daily energy intake, and physical activity. RESULTS:Serum UA was positively correlated with handgrip strength (r = 0.273, p = 0.013) but not with SMI (r = 0.080, p = 0.503). Participants with low muscle mass and reduced handgrip strength had significantly lower UA levels than those with low muscle mass only (3.4 ± 0.7 vs. 4.1 ± 0.6 mg/dL, p = 0.020). In multivariable linear regression analyses, serum UA was independently associated with handgrip strength after adjustment for age, SMI, eGFR, daily energy intake, and physical activity. CONCLUSIONS:Serum UA was associated with handgrip strength but not with skeletal muscle mass in underweight young women. These findings suggest that serum UA may be more closely related to muscle function than muscle mass in this population. Further studies are needed to clarify the mechanisms underlying this association.

Extremely low uric acid (UA) levels or increased urinary UA (Uua) excretion might be risk factors for kidney disease in renal hypouricemia (RHU) patients, but their relationship with kidney dysfunction is unclear. This study investigated time-dependent changes in eGFR in RHU patients. This multicenter retrospective study assessed UA metabolism and changes in eGFR (median 5.5 years) in 13 RHU patients. We then compared eGFR change in 7 of 13 RHU patients whose eGFR could be measured for 4 years with those in normouricemic group (n = 31). In addition, 7 RHU patients were divided into two groups based on URAT1 gene mutations: homozygote and compound heterozygote mutations (Homo/Com group, n = 3), and wild-type and heterogeneous mutations (WT/Hetero group, n = 4). In 13 RHU patients, the median and mean serum UA (SUA) were 0.8 (0.4–2.5) and 1.1 ± 0.7 mg/dL. The median and mean Uua were 44.3 (12.7–141.1) and 49.7 ± 36.2 mg/dL. The median and mean urinary urate clearance (Cua/Ccr) were 46.8 (11.3–73.6) and 43.3 ± 19.7

Background Transcatheter aortic valve implantation (TAVI) has recently become more common as a treatment for severe, symptomatic aortic stenosis (AS). Cognitive impairment (CI) is strongly associated with the prognosis of TAVI patients. However, some cognitive assessments currently in use are difficult to perform routinely in the clinical setting. To easier CI evaluation, we investigated whether CI using the clock-drawing test (CDT), one part of the Mini-Cog, affects the postoperative prognosis of TAVI patients with AS. Methods The present study enrolled 52 patients (median age, 85 years; 28.8% male) who underwent TAVI and were discharged between 2019 and 2021. The outcome was readmission for all causes within one year of discharge and patients were grouped according to whether they were readmitted or not. Cognitive function was assessed using the Mini-Cog which combines verbal playback and CDT. Results Of the 52, 11 patients (21.2%) comprised readmission group, including 4 (36.4%) each for fracture and infection, and 1 (9.1%) each for heart failure, subdural hematoma, and pneumothorax. Median Mini-Cog score was lower in the readmission group than in the non-readmission group (4 vs. 5; P < 0.05). The frequency of Mini-Cog score < 3 (indicative of CI) and CDT failure were significantly higher in the readmission group than in the non-readmission group, respectively (46% vs. 7%, P < 0.01) (46% vs. 12%, P < 0.05). Both of Mini-Cog score < 3 and CDT failure were independently associated with readmission. The areas under the curve showed CDT was an indicator of readmission with similar accuracy to the Mini-Cog score < 3. Kaplan-Meier curves showed significant differences in readmission after 1 year between the 2 Mini-Cog groups with scores of < 3 or ≥ 3 points and CDT failure and success. Conclusion The CDT may be a very easy and simple screening assessment of preoperative CI with readmission within one year after TAVI.

Uric acid (UA) forms monosodium urate (MSU) crystals to exert proinflammatory actions, thus causing gout arthritis, urolithiasis, kidney disease, and cardiovascular disease. UA is also one of the most potent antioxidants that suppresses oxidative stress. Hyper andhypouricemia are caused by genetic mutations or polymorphism. Hyperuricemia increases urinary UA concentration and is frequently associated with urolithiasis, which is augmented by low urinary pH. Renal hypouricemia (RHU) is associated with renal stones by increased level of urinary UA, which correlates with the impaired tubular reabsorption of UA. Hyperuricemia causes gout nephropathy, characterized by renal interstitium and tubular damage because MSU precipitates in the tubules. RHU is also frequently associated with tubular damage with elevated urinary beta2-microglobulin due to increased urinary UA concentration, which is related to impaired tubular UA reabsorption through URAT1. Hyperuricemia could induce renal arteriopathy and reduce renal blood flow, while increasing urinary albumin excretion, which is correlated with plasma xanthine oxidoreductase (XOR) activity. RHU is associated with exercise-induced kidney injury, since low levels of SUA could induce the vasoconstriction of the kidney and the enhanced urinary UA excretion could form intratubular precipitation. A U-shaped association of SUA with organ damage is observed in patients with kidney diseases related to impaired endothelial function. Under hyperuricemia, intracellular UA, MSU crystals, and XOR could reduce NO and activate several proinflammatory signals, impairing endothelial functions. Under hypouricemia, the genetic and pharmacological depletion of UA could impair the NO-dependent and independent endothelial functions, suggesting that RHU and secondary hypouricemia might be a risk factor for the loss of kidney functions. In order to protect kidney functions in hyperuricemic patients, the use of urate lowering agents could be recommended to target SUA below 6 mg/dL. In order to protect the kidney functions in RHU patients, hydration and urinary alkalization may be recommended, and in some cases an XOR inhibitor might be recommended in order to reduce oxidative stress.

Objective Both renal hypouricemia (RHU) and gout are associated with renal dysfunction and urolithiasis. The difference in renal complications associated with RHU and gout, however, has not been studied. We characterized the urate metabolism and complications of patients with RHU and compared them with patients with gout. Methods Eighteen patients with RHU who had a serum uric acid (SUA) level <2 mg/dL (10 men and 8 women), 44 patients with gout (44 men) and 16 normouricemic patients (4 men and 12 women) were included. The blood and urinary biochemical data were evaluated. A genetic analysis of uric acid transporter 1 (URAT1) was also conducted in 15 cases with RHU. Results The SUA level of RHU was 0.9±0.5/mg/dL, and the Uur/Ucr and Cur/Ccr were 0.56±0.14% and 45.7±18.0%, respectively. A genetic analysis of URAT1 in 15 RHU patients showed that 13 harbored a URAT1 gene mutation, whereas 2 harbored the wild-type gene. The SUA level was significantly lower in RHU patients (n=11) than in either gout patients (n=44) or normouricemic patients (n=16). This reduction was accompanied by the elevation of Cua/Ccr. Urinary beta 2-microglobulin levels were higher in RHU patients than in gout or normouricemia patients. Cua/Ccr correlated with normalized urinary beta 2-microglobulin levels. The prevalence of urolithiasis was 18.2% in RHU cases and 6.8% in gout cases. A homozygous URAT1 mutation was associated with urolithiasis. Conclusion Besides urolithiasis, RHU can be associated with tubular dysfunction, such as elevated urinary beta 2-microglobulin levels.

Whether or not extremely low levels of serum uric acid (SUA) in xanthinuria are associated with impairment of the endothelial function and exercise-induced acute kidney injury (EIAKI) is unclear. A 59-year-old woman without EIAKI or urolithiasis had undetectable levels of UA in serum and urine and elevated levels of hypoxanthine and xanthine in urine. A genetic analysis revealed homozygous mutations in the XDH gene [c.1585 C>T (p. Gln529*)]. Flow-mediated dilation was within the normal range. This is the first report of a case with extremely low levels of SUA, xanthinuria with novel mutations of xanthine dehydrogenase (XDH) and a normal endothelial function.

Background：The biological actions of fucoidan depend on its molecular weight. 20-30 kDa fucoidan has been reported to stimulate angiogenesis in ischemic limbs. We purified very high molecular weight fucoidan (HMWF) from mozuku (brown algae of the Okinawan coontail family) to assess its effect on angiogenesis. Methods and Results：We examined the angiogenic effects of mozuku HMWF (300 kDa) and akamoku (Sargassum seaweed) HMWF (80 kDa) in a mouse ischemic limb model by measuring laser Doppler blood flow (LDBF) and capillary density. We also studied the angiogenic actions of mozuku HMWF administered pre- and post-ischemia as compared to post-ischemia treatment. Mozuku HMWF increased both LDBF and capillary density in the ischemic leg, whereas akamoku HMWF did not. Treatment with mozuku HMWF pre- and post-ischemia increased both LDBF and capillary density, which was not seen in post-ischemia treatment alone. Conclusions：This study demonstrated the therapeutic effect of pre- and post-ischemia treatment with mozuku HMWF in ischemic limbs, and the timing of administration is important for its angiogenic activity.

Background：When macrophages are primed by lipopolysaccharides, mono sodium urate (MSU) crystals activate NLRP3 inflammasomes and promote IL-1β and IL-18 production after phagocytosis of MSU. It was previously reported that anti-IL-1β antibodies suppress symptoms of gout and the occurrence of cardiovascular disease. Thus, inhibition of NLRP3 inflammasomes, which produce IL-1β and IL-18, may be a novel therapeutic strategy against these diseases. Purpose：To reveal the effects of dotinurad, a selective urate reabsorption inhibitor, and other uric acid lowering agents on MSU crystal-induced activation of NLRP3 inflammasomes in macrophages. Methods：Activity of NLRP3 inflammasomes in J774 mouse macrophages was evaluated by quantifying secreted caspase-1 and IL-1β using a western blot and ELISA in both the absence and presence of dotinurad or other uric acid lowering agents. Results：MSU increased protein levels of caspase-1 and IL-1β. This effect was inhibited by a clinical concentration of dotinurad. Neither febuxostat nor allopurinol influenced the levels of caspase-1 and IL-1β, whereas benzbromarone decreased their levels. The inhibitory effects of dotinurad and other uric acid lowering agents on secretions of IL-1β from the macrophages were confirmed by ELISA. Conclusion：Dotinurad, a selective urate reabsorption inhibitor, suppresses MSU-induced activation of NLRP3 inflammasomes in macrophages.

Polypharmacy is a common problem in heart failure (HF). Drug-induced taste disorder is the most frequent cause of dysgeusia in patients evaluated at a taste and smell clinic. Several drugs commonly prescribed in HF are reported to cause taste disorders. Drug-induced taste disorders can reduce compliance with medications, decrease quality of life and impact food intake and nutritional status, particularly in the elderly. However, the association between polypharmacy and taste disorder, and its effects on energy intake (EI) in HF patients, is unknown. We enrolled a total of 43 HF outpatients who did not take steroids, anticancer agents and antidepressants, because these drugs induce appetite loss and taste disorders. Polypharmacy was defined as greater than or equal to the mean number of prescribed medications in the cohort (eight medications). The recognition thresholds (RTs) for four basic tastes (sweet, salty, sour, bitter) were assessed by filter paper disc test. The averages of the RT scores on the right and left lateral parts of the tongue were calculated for each taste, and we defined an RT score of 3 or greater as impaired RT for taste in accordance with a previous study. Estimated dietary EI (kcal/day) was evaluated using brief self-administered diet history questionnaires. To adjust for age and gender, %EI was defined as the percentage of EI divided by estimated energy requirement that was determined from dietary reference intakes for the Japanese population (2015 revised version). Differences between the two groups were tested using the t-test, and categorical variables were tested using Fisher’s exact test. Stepwise multivariate models (forward selection) were performed to assess the independent factors associated with high RTs for all four tastes and %EI. The median age of the cohort was 75 (69–83) years, and 58.1% of the patients were men. The incidences of high RTs for sweet, salty, sour, and bitter were 83.7%, 67.4%, 81.4%, and 69.8%, respectively. Nearly half (41.9%) had high RTs for all four tastes. Patients with polypharmacy had a significantly higher prevalence of bitter taste disorder than those without polypharmacy (84.6% vs. 47.1%, P1⁄4 0.016), and polypharmacy was associated with RT elevations for all four tastes, as well as the decreased %EI (Figure 1). Zinc levels were not significantly different between patients with or without polypharmacy. On multivariate analysis, polypharmacy was independently associated with high RT for all four tastes, and the increased total numbers of impaired RTs for tastes were independently associated with decreased %EI (P< 0.05). The present study demonstrated that RTs for all four basic tastes – sweet, salty, sour and bitter – were concurrently impaired in about 40% of patients with HF, and polypharmacy was related to multiple taste disturbances that were closely related to decreased EI. Numerous medications affect the sense of taste through various mechanisms, including drug–receptor interaction and neurological dysfunction. Polypharmacy can alter the bioavailability or pharmacological effects of co-administered drugs. Drug–drug interactions from polypharmacy contribute to a significant number of chemosensory disturbances and elevate the RTs for all four tastes. Malnutrition is related to muscle loss and weakness, leading to physical frailty and poor prognosis in HF. Minimising polypharmacy is likely to be a key action to recover EI and to maintain nutritional status in patients with HF.

RATIONALE:Acute kidney injury (AKI) has a high prevalence and mortality in critically ill patients. It is also a powerful risk factor for heart failure incidence driven by hemodynamic changes and neurohormonal activation. However, no drugs have been approved by the Food and Drug Administration. Endogenous pGC-A (particulate guanylyl cyclase A receptor) activators were reported to preserve renal function and improve mortality in AKI patients, although hypotension accompanied by pGC-A activators have limited their therapeutic potential.OBJECTIVE:We investigated the therapeutic potential of a nonhypotensive pGC-A activator/designer natriuretic peptide, CRRL269, in a short-term, large animal model of ischemia-induced AKI and also investigated the potential of uCNP (urinary C-type natriuretic peptide) as a biomarker for AKI.METHODS AND RESULTS:We first showed that CRRL269 stimulated cGMP generation, suppressed plasma angiotensin II, and reduced cardiac filling pressures without lowering blood pressure in the AKI canine model. We also demonstrated that CRRL269 preserved glomerular filtration rate, increased renal blood flow, and promoted diuresis and natriuresis. Further, CRRL269 reduced kidney injury and apoptosis as evidenced by ex vivo histology and tissue apoptosis analysis. We also showed, compared with native pGC-A activators, that CRRL269 is a more potent inhibitor of apoptosis in renal cells and induced less decreases in intracellular Ca2+ concentration in vascular smooth muscle cells. The renal antiapoptotic effects were at least mediated by cGMP/PKG pathway. Further, CRRL269 inhibited proapoptotic genes expression using a polymerase chain reaction gene array. Additionally, we demonstrated that AKI increased uCNP levels.CONCLUSIONS:Our study supports developing CRRL269 as a novel renocardiac protective agent for AKI treatment.

The number of patients with heart failure has been dramatically increasing in Japan in association with aging of the society. This phenomenon is referred to as a heart failure pandemic. The fundamental origin of heart failure is cardiac dysfunction. Echocardiography is widely used to assess cardiac function, as well as to diagnose heart diseases that cause cardiac dysfunction. However, the severity of heart failure is not necessarily correlated with that of cardiac dysfunction. This is partly explained by the fact that heart failure induces dysfunction of organs other than the heart through hemodynamic deterioration and neurohumoral changes. In addition, one of the characteristics of patients with heart failure, particularly elderly patients, is the presence of numerous comorbidities. Symptoms of heart failure are not specific, and assessment of cardiac function, particularly left ventricular diastolic function, has not been established. Thus, ultrasonographic assessment of organs other than the heart helps the diagnosis of heart failure, assessment of the severity of heart failure, and development of our understanding of the pathophysiology in each patient. This review summarizes current knowledge about the usefulness of ultrasonographic assessment of organs other than the heart in heart failure.

AIMS:Patients with end-stage heart failure (HF) often require surrogate decision making for end-of-life care owing to a lack of decision-making capacity. However, the clinical characteristics of surrogate decision making for life-sustaining treatments in Japan remain to be investigated.METHODS AND RESULTS:Among 934 patients admitted to our hospital for HF from January 2004 to December 2015, we retrospectively reviewed the medical records of consecutive 106 patients who died in hospital (mean age 73 ± 13 years; male, 52.6%). During hospitalization, attending physicians conducted an average of 2.1 ± 1.4 end-of-life conversations with patients and/or their families. Only 4.7% of patients participated in the conversations and declared their preferences; surrogates made medical care decisions in 95.3% of cases. Most decisions by surrogates (98.1%) were made without the patient's advance directive. During initial end-of-life conversations, 49.4% of surrogates requested cardiopulmonary resuscitation (CPR). However, 72.0% of CPR preferences were changed to do not attempt resuscitation (DNAR) orders in the final conversation. Female surrogates were more likely to change the preference from CPR to DNAR than were male surrogates (47.1% vs. 25.0%, P = 0.023).CONCLUSIONS:Compared with male surrogates, female surrogates wavered more often in their decisions regarding life-sustaining treatments of Japanese patients with end-stage HF.

Background: Irbesartan has been reported to inhibit renal uric acid reabsorption and thereby decrease serum uric acid (Sur) levels. However, its effect on uric acid metabolism in hypertensive patients has not been reported. Methods and Results: We conducted a retrospective observational study that included 40 hypertensive patients to clarify the effects of irbesartan (mean dose 87.5 mg) on blood pressure (BP) and uric acid metabolism [Sur, urinary uric acid (Uur), serum creatinine (Scr), urinary creatinine (Ucr), uric acid clearance (Cur), creatinine clearance (Ccr), urinary uric acid to urinary creatinine ratio (Uur/Ucr), and uric acid clearance to creatinine clearance ratio (Cur/Ccr) ] at baseline and after 3 months of treatment. We allocated patients into two groups, patients with Uur/Ucr <0.5 (low Uur/Ucr group) or those with Uur/Ucr ≥0.5 (normal/high Uur/Ucr group), into other two groups, patients with Cur/Ccr <5.5% (low Cur/Ccr group) or those with Cur/Ccr ≥5.5% (normal/ high Cur/Ccr group). The hypoexcretion group contained low Uur/Ucr group and low Cur/Ccr group, and the normal/ hyperexcretion group contained normal/high Uur/Ucr group and normal/ high Cur/Ccr group. Further, we allocated patients into another two groups, patients with Sur ≥7 mg/dl (hyperuricemic group) or those with Sur <7 mg/dl (normouricemic group). Irbesartan significantly decreased systolic BP without affecting heart rate, and decreased Sur without altering Uur/Ucr or Cur/Ccr. In the hypoexcretion group, irbesartan decreased Sur while increasing Uur/Ucr and Cur/Ccr. In contrast, in the normal/hyperexcretion and hyperuricemic groups, irbesartan decreased Sur without changing Uur/Ucr or Cur/Ccr. In a normouricemic group, patients showed no changes in Sur after treatment with irbesartan. Conclusions: Irbesartan improved the secretion of uric acid, and reduced Sur in the hypoexcretion group, but did not influence uric acid excretion in the normal/hyperexcretion group. In hyperuricemic patients, irbesartan did not affect uric acid excretion but may have influenced uric acid production.

Background：Activation of angiotensin receptor type1 (AT1R) and xanthine oxidase (XO) generates reactive oxygen species (ROS), that causes cardiac dysfunction after myocardial infarction (MI). However, it remains unknown whether its inhibition could restore the cardiac function after MI. In the present study, we examined effects of irbesartan and topiroxostat on cardiac function after MI. Methods and results：We studied blood pressure and cardiac function in a rat myocardial infraction model using tail cuff system and echocardiography. Irbesartan and topiroxostat as well as vehicle were orally administered for 35 days to rats 7 days before MI induction. Neither irbesartan nor topiroxostat altered mean blood pressure and heart rate after MI. Treatment with either drugs significantly improved cardiac function after MI. The potency of topiroxostat to restore the cardiac function was approximately half of that of irbesartan. Conclusions：A non-purine XO inhibitor, topiroxostat improved cardiac function after MI, suggesting that like irbesartan, topiroxostat may be a promising drug to treat congestive heart failure after MI.