Overlapping states of AWGS muscle dysfunction and inverse feasibility of ADL recovery by rehabilitation in older inpatients.

Rehabilitation based on guided walking is effective to recover activity of daily living (ADL) in frail older adults, even octogenarians. However, muscle dysfunction obviously reflects disability, and few studies have focused on ADL recovery by rehabilitation. We employed the state of muscle dysfunctions proposed by the Asian Working Group for Sarcopenia (AWGS) in 2019 and attempted to clarify the relation between the overlapping dysfunctions and the feasibility of ADL recovery after rehabilitation. In total, 297 frail older patients (the mean age: 82.8 years, 46.1% of patients were male) participated in a walking-guided rehabilitation program to achieve the goal of ambulatory discharge. Muscle dysfunction was categorized by four standardized methods at the start of rehabilitation (grip strength, gait speed, time of five sit-to-stand, and short physical performance battery: SPPB), according to the AWGS proposal. ADLs were monitored by Barthel index before admission, at the start of rehabilitation, and at discharge. At least one dysfunction was present in 95.3% of patients. If a single patient had three or more muscle dysfunction, the ADLs recovery was significantly limited (interaction: p < 0.05). The overlapped counts of AWGS muscle dysfunction helps to predict inverse feasibility of ADL recovery in frail older patients through rehabilitation.

Association of adipokines with frailty in heart failure.

Background Frailty is a multifactorial physiological syndrome most often associated with age but which has received increasing recognition as a component of chronic illnesses such as heart failure. Patients with heart failure are likely to be frail, irrespective of their age. Adipokine dysregulation, which is associated with frailty, occurs in patients with heart failure. In this study, we tested the hypothesis that adipokines are associated with frailty in patients with heart failure. Methods Thirty-five patients with heart failure (age, 67 ± 14 years; 25 males; left ventricular ejection fraction, 45 ± 19%) were included. Serum adipokine levels, physical performance, and body composition were measured. Results Adiponectin and leptin were inversely correlated with grip strength. Adiponectin was inversely correlated with bone mineral density. Leptin was positively correlated with fat mass. Adipokines were not correlated with skeletal muscle mass. Conclusions Adipokines were associated with frailty in patients with heart failure. Adipokine dysregulation may play a role in the development of frailty in heart failure.

Characteristics of Elderly Patients with Heart Failure and Impact on Activities of Daily Living: A Registry Report from Super-Aged Society.

BACKGROUND: To assess the health care burden of elderly patients with heart failure (HF) in an aging Japanese community-based hospital, we investigated the outcomes of cardiac rehabilitation. METHODS AND RESULTS: We enrolled all patients with HF aged ≥65 years admitted to 3 hospitals in the Niigata Prefecture. We prospectively collected data on their hospital stays and for 2 years postdischarge. The cohort comprised 617 patients (46.5% men; mean age 84.7 years), 76.2% of whom were aged ≥80 years. Among these patients, 15.6% were nursing home residents, 57.7% required long-term care insurance, only 37.6% could walk unaided at the time of admission, and 70.5% required cardiac rehabilitation; age had no significant rehabilitative effect on the degree of improvement in activities of daily living (ADLs). Two years postdischarge, all-cause mortality, and HF rehospitalization were 41.1% and 38.6%, respectively. The ADL score at discharge was an independent prognostic factor for mortality. The incidence of mortality and rehospitalization was lower in elderly patients with preserved ADLs at discharge. CONCLUSIONS: Elderly patients with HF in our super-aged society were mainly octogenarians who required disease management and personalized care support. Although their ADL scores increased with comprehensive cardiac rehabilitation, improved scores at discharge were closely associated with prognosis.

Clinical impact of bifurcation angle change between diastole and systole in complex stenting for left main distal bifurcation: The Milan and New-Tokyo (MITO) Registry.

OBJECTIVES: We assessed the impact of pre-percutaneous coronary intervention (PCI) bifurcation angle change (BAC) on clinical outcomes. BACKGROUND: There are little available data about the impact of BAC in unprotected left main distal bifurcation lesions (ULMD) PCI. METHODS: We identified consecutive 300 patients with ULMD underwent complex stenting using drug-eluting stent in three high-volume centers (Tokyo and Milan). We measured the widest BA of ULMD at both end-diastole and end-systole before stenting with two-dimensional quantitative coronary angiographic assessment and calculated the BAC value as a difference of two BA value in each lesion. We divided them into small and large BAC group according to the median BAC value (7.2°). The primary endpoint was target lesion failure (TLF), which was defined as a composite of cardiac death, target lesion revascularization (TLR) and myocardial infarction. RESULTS: TLF rate at 3-year was significantly higher in the large BAC group than in the small BAC group (adjusted hazard ratio [HR] 5.85; 95% confidence interval [CI], 3.40-10.1; p < .001). TLR rate for left main (LM) to left anterior descending artery (LAD) and ostial left circumflex artery (LCXos) at 3-year were significantly higher in large BAC group than in small BAC group (adjusted HR 5.91; 95% CI, 2.03-17.2; p = .001 and adjusted HR 10.6; 95% CI, 5.20-21.6; p < .001, respectively). CONCLUSIONS: A large BAC before stenting is strongly associated with adverse events after complex stenting for ULMD, mainly driven by repeat PCI for restenosis of the LCXos and of the LM-LAD.

The baseline speed of 10-m gait predicts ambulatory discharge for hospitalized frail elderly after DOPPO rehabilitation.

The discharge of elderly patients from hospital on the basis of their independent gait program (DOPPO) is a new rehabilitation strategy for physically frail hospitalized elderly that aims to recover independent gait and to achieve ambulatory discharge. We retrospectively investigated baseline determinants of physical measures associated closely with the 6-min walking distance (6MWD) after DOPPO. Participants were 137 consecutive elderly inpatients, irrespective of the causative disease (mean age: 82±7 years; 76 women), who had a Short Physical Performance Battery (SPPB) score of less than 12 and low independent walking capacity. The rehabilitation comprised muscle stretching, muscle strengthening, balance training, and endurance exercise, including walking. The exercises were gradually increased until the goal of ambulatory discharge was attained. The SPPB, isometric knee-extension muscle strength (IKEMS), functional reach test (FRT), one-leg stance time (OLST), and the 10-m gait speed (TMGS) were measured, before and after the DOPPO intervention, and their association with the 6MWD was evaluated. All participants achieved ambulatory discharge, requiring on average 35±19 hospital days and 32±18 h of rehabilitation. The SPPB, IKEMS, FRT, OLST, and TMGS improved. The SPPB scores increased from 7.1 at baseline to 9.2 at discharge. Eighty-eight patients completed the 6MWD. The SPPB, IKEMS, FRT, OLST, and TMGS were strongly associated with the 6MWD. Only the baseline TMGS and SPPB predicted the 6MWD, with a cut-off TMGS value of 0.84 m/s providing the best prediction of achieving a distance of more than 300 m on the 6MWD. Thus, the baseline TMGS is the best prediction of the ambulatory outcome after the present DOPPO rehabilitation.

Immune activation with peptide assemblies carrying Lewis y tumor-associated carbohydrate antigen.

Molecular assemblies varying morphologies in a wide range from spherical micelle, nanosheet, curved sheet, nanotube and vesicle were prepared and loaded with Lewis y (Ley ) tumor-associated carbohydrate antigen on the assembly surface. The molecular assemblies were composed of poly(sarcosine)m -block-poly(L-lactic acid)30 (m = 15 or 50, Lactosome), poly(sarcosine)m -block-(D/L-Leu-Aib)n (m = 22 or 30, n = 6 or 8) and their combinations. The molecular assemblies carrying Ley on the surface were administered in BALB/c nu/nu mice. The major epitopes of the molecular assemblies are commonly Ley and poly(sarcosine). IgM productions upon administrations of the molecular assemblies were assayed by ELISA, showing that anti-poly(sarcosine) IgM was highly produced by Lactosome of spherical micelle but with a negligible amount of anti-Ley IgM. On the other hand, the nanosheet of the interdigitated monolayer triggered the production of anti-Ley IgM but with less anti-poly(sarcosine) IgM production. Taken together, IgM specificity differs according to the molecular environment of the epitopes in the molecular assemblies. The antigenicity of poly(sarcosine) was augmented in polymeric micelle providing loose environment for B cells to penetrate in, whereas a high density of Ley on the molecular assembly was required for anti-Ley IgM production. The antigenicity of Ley is therefore dependent on the molecular assemblies on which Ley is displayed on the surface. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

Failing Left Ventricles Have an Enhanced Post-Stimulation Potentiation Despite Their Impaired Force Frequency Relationship.

The left ventricular contractile force (LV dP/dtmax) of patients with left ventricular systolic dysfunction does not increase effectively with an increase in heart rate. In other words, their force-frequency relationship (FFR) is impaired. However, it is unknown whether a longer coupling interval subsequent to tachycardia causes a stronger contraction (poststimulation potentiation, PSP) in a rate-dependent manner.In 16 patients with idiopathic dilated cardiomyopathy (DCM) (48 ± 2 years old, LVEF 30 ± 10%) and 6 control patients (58 ± 4 years old, LVEF 70 ± 7%), FFR was assessed by right atrial pacing using a micro-manometer-tipped catheter. At each pacing rate, the increase of LV dP/dtmax over basal LV dP/dt (ΔFFR) and the increase of LV dP/dtmax of the first beat after pacing cessation over LV dP/dtmax during pacing (ΔPSP) were evaluated.Patients with DCM had smaller LV dP/dtmax at baseline (872 ± 251 versus 1370 ± 123 mmHg/second, P = 0.0002) and developed smaller ΔFFR (eg, at 120/minute, 77 ± 143 versus 331 ± 131 mmHg/second, P = 0.0011). In contrast, they showed a rate-dependent increase of LV dP/dtmax of PSP and had greater ΔPSP (eg, at 120/minute, 294 ± 173 versus -152 ± 131 mmHg/second, P < 0.0001).Failing left ventricles develop little contractile force during tachycardia despite their rate-dependent enhancement in post-stimulation potentiation, suggesting that refractoriness of contractile force underlies impaired FFR.

Synthesis of type 2 Lewis antigens via novel regioselective glycosylation of an orthogonally protected lactosamine diol derivative.

The novel and efficient synthesis of type 2 Lewis antigens is reported in this study. The rationally designed lactosamine-3,2'-diol derivative with an orthogonal set of protecting groups is efficiently glycosylated with a benzyl protected 1-thio-l-fucoside donor in a unique regioselective manner to produce Lewis x (Le(x)) and Lewis y (Le(y)) derivatives in good yields. These derivatives can be prepared not only exclusively but also synchronously by choosing the appropriate reaction temperature and donor-acceptor molar ratio. The Le(x) derivatives are easily converted into sulfated or non-sulfated Le(x) bearing a terminal azido functionalized oligo-(ethyleneoxide) linker; the Le(y) derivative having the same linker can also be prepared, all of which can be further used for the chemical modification of other compounds and materials.

Elevated Endomyocardial Biopsy Macrophage-Related Markers in Intractable Myocardial Diseases.

Tissue macrophages can be activated by endogenous danger signals released from cells that are stressed or injured, leading to infiltration of inflammatory macrophages and neutrophils. We postulated that macrophage-related markers might be closely associated with the existence of endogenous danger signals, reflecting ongoing tissue injury in the absence of foreign substances. This study was designed to assess the ability of macrophage-related markers in endomyocardial biopsies to predict ongoing cardiac injury in non-inflammatory myocardial diseases. We examined levels of macrophage-related markers (CD68, CD163, CD45) in endomyocardial biopsies from patients (n = 86) with various myocardial diseases by quantitative reverse transcription-polymerase chain reaction (n = 78) and immunohistochemistry (n = 56). Thirty-three patients without inflammatory cardiac disease such as myocarditis and sarcoidosis were classified as "improved" or "non-improved" defined as a 10% increase in left ventricular ejection fraction by echocardiograph and a value greater than 30% at the time of follow-up. All macrophage-related (MacR) markers levels were not higher in non-improved dilated cardiomyopathy (DCM) patients than improved patients. However, patients with cardiac amyloidosis, cardiac Fabry disease, mitochondrial cardiomyopathy, and biventricular arrhythmogenic right ventricular cardiomyopathy (ARVC), which were categorized as "non-improvement diseases," had elevated macrophage-related markers compared to improved patients. Macrophage-related markers levels were increased in endomyocardial biopsy samples of patients with intractable myocardial diseases such as amyloidosis, mitochondrial disease, Fabry disease, and biventricular ARVC.

Liver congestion in heart failure contributes to inappropriately increased serum hepcidin despite anemia.

Hepcidin is a key regulator of mammalian iron metabolism and mainly produced by the liver. Hepcidin excess causes iron deficiency and anemia by inhibiting iron absorption from the intestine and iron release from macrophage stores. Anemia is frequently complicated with heart failure. In heart failure patients, the most frequent histologic appearance of liver is congestion. However, it remains unclear whether liver congestion associated with heart failure influences hepcidin production, thereby contributing to anemia and functional iron deficiency. In this study, we investigated this relationship in clinical and basic studies. In clinical studies of consecutive heart failure patients (n = 320), anemia was a common comorbidity (41%). In heart failure patients without active infection and ongoing cancer (n = 30), log-serum hepcidin concentration of patients with liver congestion was higher than those without liver congestion (p = 0.0316). Moreover, in heart failure patients with liver congestion (n = 19), the anemia was associated with the higher serum hepcidin concentrations, which is a type of anemia characterized by induction of hepcidin. Subsequently, we produced a rat model of heart failure with liver congestion by injecting monocrotaline that causes pulmonary hypertension. The monocrotaline-treated rats displayed liver congestion with increase of hepcidin expression at 4 weeks after monocrotaline injection, followed by anemia and functional iron deficiency observed at 5 weeks. We conclude that liver congestion induces hepcidin production, which may result in anemia and functional iron deficiency in some patients with heart failure.

Inappropriate expression of hepcidin by liver congestion contributes to anemia and relative iron deficiency.

BACKGROUND: Anemia and relative iron deficiency (RID) are prevalent in patients with heart failure (HF). The etiology of anemia and RID in HF patients is unclear. Hepcidin expression may be closely related to anemia and RID in HF patients. Although hepcidin is produced mainly by the liver, and the most frequent histologic appearance of liver in HF patients is congestion, the influence of liver congestion (LC) on hepcidin production has not yet been investigated. We investigated whether hepcidin contributed to anemia and RID in rats with LC. METHODS AND RESULTS: LC was induced in rats by ligating the inferior vena cava and compared with bleeding anemia (BA) model induced by phlebotomy and hemolytic anemia (HA) model induced by injection of phenylhydrazine. BA and HA strongly suppressed expression of hepcidin in liver and so did not cause decrease in serum iron and transferrin saturation. However, hepcidin expression did not decrease in LC rats, which resulted in anemia and lower transferrin saturation. In addition, many cells with hemosiderin deposits were observed in the liver and spleen and not in the bone marrow, and this appeared to be related to suppression of hepcidin expression. Iron accumulated in hepatocytes, and bone morphogenetic protein 6, which induces hepcidin, increased. Inflammation was observed in the congestive liver, and there was an increase in interleukin-6, which also induced hepcidin and was induced by free heme and hemoglobin via Toll-like receptor 4. CONCLUSIONS: We conclude that LC contributes to RID and anemia, and it does so via inappropriate expression of hepcidin.

Relative refractoriness of left ventricular contraction underlies human tachycardia-induced mechanical and electrical alternans.

BACKGROUND: Mechanical alternans (MA) and electrical alternans (EA) are predictors of cardiac events. Experimental studies have suggested that refractoriness of calcium cycling underlies these cardiac alternans. However, refractoriness of left ventricular contraction has not been examined in patients with cardiac alternans. METHODS: In 51 patients with miscellaneous heart diseases, incremental right atrial pacing was performed to induce MA and EA. MA was quantified by alternans amplitude (AA: the difference between left ventricular dP/dt of a strong beat and that of a weak beat), and AA at 100/min (AA100) and maximal AA (AAmax) were measured. EA was defined as alternation of T wave morphology in 12-lead electrocardiogram. Relative refractoriness of left ventricular contraction was examined by drawing the mechanical restitution curve under a basal coupling interval (BCL) of 600 ms (100/min) and was assessed by the slope at BCL (Δmechanical restitution). Postextrasystolic potentiation (PESP) was also examined and the slope of PESP curve (ΔPESP) was assessed as a property to alternate strong and weak beats. RESULTS: MA and EA were induced in 19 patients and in none at 100/min or less, and at any heart rate in 32 and in 10, respectively. AA100 and AAmax correlated positively with Δmechanical restitution and negatively with ΔPESP. Patients with EA had a significantly larger Δmechanical restitution and a significantly larger absolute value of ΔPESP than those without. CONCLUSIONS: In patients with MA and EA, the left ventricular contractile force during tachycardia is under relative refractoriness and prone to cause large fluctuation of contractile force.

Oral administration of a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity for pulmonary arterial hypertension.

BACKGROUND: Continuous administration of prostacyclin has improved the survival of patients with pulmonary arterial hypertension (PAH). However, this treatment has some problems, including its short duration of activity and difficult delivery. Therefore, we developed ONO-1301, an orally active, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. METHODS AND RESULTS: We investigated whether oral administration of ONO-1301 can both prevent and reverse monocrotaline (MCT)-induced PAH in rats. Rats were randomly assigned to receive repeated oral administration of ONO-1301 twice daily beginning either 1 or 8 days after subcutaneous injection of MCT. A control group received oral saline, and a sham group received a subcutaneous injection of saline instead of MCT. MCT-treated controls developed significant pulmonary hypertension. Treatment with ONO-1301 from day 1 or 8 significantly attenuated the increases in right ventricular systolic pressure and the increase in medial wall thickness of pulmonary arterioles. Kaplan-Meier survival curves demonstrated that the effect of ONO-1301 was equivalent to that of an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. A single oral dose of ONO-1301 increased plasma cAMP levels for up to 6h. Treatment with ONO-1301 significantly decreased urinary 11-dehydro-thromboxane B2 and increased the plasma hepatocyte growth factor concentration. CONCLUSIONS: Oral administration of ONO-1301 ameliorated PAH in rats, an effect that may occur through cAMP and hepatocyte growth factor.

A mutant mRNA expression in an endomyocardial biopsy sample obtained from a patient with a cardiac variant of Fabry disease caused by a novel acceptor splice site mutation in the invariant AG of intron 5 of the α-galactosidase A gene.

We herein describe the case of a 58-year-old man who presented with dilated-phase hypertrophic cardiomyopathy (HCM) and required an implantable cardioverter defibrillator implant. Subsequently, the patient was diagnosed with Fabry disease (FD), which was suspected based on the results of an endomyocardial biopsy and diagnosed following demonstration of deficient α-galactosidase A (GLA) activity. Molecular studies showed a novel point mutation in the 3' splice site consensus sequence of intron 5 in the gene encoding GLA that created a new splicing site, resulting in the expression of mutant mRNA. FD should be considered a cause of HCM in patients with severe tachyarrhythmia without other remarkable manifestations of FD.

Estimation of paracrine signaling using quantitative RT-PCR from multiple patchy lesion samples.

We investigated whether correlations between mRNA levels of cytokines versus other proteins from patchy lesion could estimate cytokine paracrine signaling in vivo. Experiments with rat experimental autoimmune myocarditis (EAM), a patchy myocarditis model, indicated IL-1 and other protein levels were correlated, indicating paracrine signaling pathways in vivo.

Mechanical alternans in human idiopathic dilated cardiomyopathy is caused with impaired force-frequency relationship and enhanced poststimulation potentiation.

Mechanical alternans (MA) is frequently observed in patients with heart failure, and is a predictor of cardiac events. However, there have been controversies regarding the conditions and mechanisms of MA. To clarify heart rate-dependent contractile properties related to MA, we performed incremental right atrial pacing in 17 idiopathic dilated cardiomyopathy (DCM) patients and in six control patients. The maximal increase in left ventricular dP/dt during pacing-induced tachycardia was assessed as the force gain in the force-frequency relationship (FG-FFR), and the maximal increase in left ventricular dP/dt of the first post-pacing beats was examined as the force gain in poststimulation potentiation (FG-PSP). As a result, MA was induced in 9 DCM patients (DCM MA(+)) but not in the other 8 DCM patients (DCM MA(-)), and not in any of the control patients. DCM MA(+) had significantly lower FG-FFR (34.7 ± 40.9 vs 159.4 ± 103.9 mmHg/s, P = 0.0091) and higher FG-PSP (500.0 ± 96.8 vs 321.9 ± 94.9 mmHg/s, P = 0.0017), and accordingly a wider gap between FG-PSP and FG-FFR (465.3 ± 119.4 vs 162.5 ± 123.6 mmHg/s, P = 0.0001) than DCM MA(-) patients. These characteristics of DCM MA(+) showed clear contrasts to those of the control patients. In conclusion, MA is caused with an impaired force-frequency relationship despite significant poststimulation potentiation, suggesting that MA reflects ineffective utilization of the potentiated intrinsic force during tachycardia.