Age- and sex-stratified normal values for circulatory and ventilatory power during ramp exercise derived from a healthy Japanese population.

Circulatory power (CP) and ventilatory power (VP), obtained by cardiopulmonary exercise testing (CPX), have been suggested to be excellent prognostic markers for heart failure. However, the normal values of these parameters in healthy Japanese populations remain unknown; thus, we aimed to investigate these values in such a population. A total of 391 healthy Japanese participants, 20-78 years of age, underwent CPX with a cycle ergometer with ramp protocols. Systolic blood pressure (SBP), heart rate, oxygen uptake ([Formula: see text]O2) at peak exercise, and the slope of minute ventilation ([Formula: see text]E) versus carbon dioxide ([Formula: see text]CO2) ([Formula: see text]E vs. [Formula: see text]CO2 slope) were measured. CP was calculated by multiplying the peak [Formula: see text]O2 and SBP values, and VP was calculated by dividing the peak SBP value by the [Formula: see text]E versus [Formula: see text]CO2 slope. For males and females, the average CP values were 6119 ± 1280 (mean ± standard deviation) and 4775 ± 914 mmHg·mL/min/kg, respectively (p < 0.001). The average VP values for males and females were 8.0 ± 1.3 and 6.9 ± 1.3 mmHg (p < 0.001). CP decreased with age in both sexes. VP increased with age in females, with no significant change in males. We calculated the normal values for CP and VP in a healthy Japanese population. The results can contribute to the evaluation of patients' CPX results as a reference.

Usefulness of the predicted percentage ventilatory efficiency for carbon dioxide output during exercise in patients with chronic heart failure.

The ventilatory efficiency for carbon dioxide output ([Formula: see text]CO2) during exercise, as measured by the minute ventilation vs. [Formula: see text]CO2 slope ([Formula: see text]E vs. [Formula: see text]CO2 slope), is a powerful prognostic index in patients with chronic heart failure (CHF). This measurement is higher in women than in men, and it increases with age. This study aimed to investigate the usefulness of the predicted value of the percentage [Formula: see text]E vs. [Formula: see text]CO2 slope (%[Formula: see text]E vs. [Formula: see text]CO2 slope) as a prognostic index in patients with CHF. A total of 320 patients with CHF and a left ventricular ejection fraction (LVEF) < 45% (male, 85.6%; mean age, 64.6 years) who underwent symptom-limited cardiopulmonary exercise tests using a cycle ergometer were included in the study. The %[Formula: see text]E vs. [Formula: see text]CO2 was calculated using predictive formulae based on age and sex. Cardiovascular-related death was defined as the primary endpoint. The mean follow-up duration was 7.5 ± 3.3 years. Of 101 patients who died during the study period, 75 experienced cardiovascular-related deaths. The average [Formula: see text]E vs. [Formula: see text]CO2 slope was 32.8 ± 8.0, and the average %[Formula: see text]E vs. [Formula: see text]CO2 slope was 119.6 ± 28.2%. The cumulative incidence of cardiovascular-related death after 10 years of follow-up were 44.7% (95% CI 34.4-54.6%) in patients with %[Formula: see text]E vs. [Formula: see text]CO2 slope > 120 and 15.0% (95% CI 9.4-21.8%) in patients with %[Formula: see text]E vs. [Formula: see text]CO2 slope ≤ 120. The multivariate Cox regression analysis indicated that a %[Formula: see text]E vs. [Formula: see text]CO2 slope > 120 was an independent predictor of cardiovascular-related death (adjusted hazard ratio, 3.24; 95% confidence interval 1.65-6.67; p < 0.01). The %[Formula: see text]E vs. [Formula: see text]CO2 slope can be used for risk stratification in patients with CHF and an LVEF < 45%.

Study Design of the Japanese Association of Cardiac Rehabilitation Registry (J-CARRY)　- Protocol for a Prospective, Multicenter, Open Registry.

Background: Guidelines for the prevention and management of cardiovascular disease (CVD) highly recommend cardiac rehabilitation (CR) on the basis of abundant evidence of its effectiveness. However, the current understanding and dissemination of CR in Japan are far from sufficient. Methods and Results: The Japanese Association of Cardiac Rehabilitation Registry (J-CARRY) is an academic society-led prospective multicenter observational registry conducted by the Registration and Facility Accreditation System Committee of the Japanese Association of Cardiac Rehabilitation. Data are collected prospectively using an electronic data capture system. Items related to patients' clinical background and CR, as well as mortality and major adverse cardiac and cerebrovascular events, will be collected in all cases. This Registry started in May 2014, and the number of participating medical institutions is expected to increase to >30; the targeted number of cases exceeded 3,000 per year as of April 30, 2022. Focusing on late Phase II data collection is a novel and significantly different approach compared with previous studies. The results of this study are currently under investigation. Conclusions: J-CARRY will provide real-world data regarding the current status and prognosis of CVD in patients who undergo Phase II CR in Japan.

Cardiac Telerehabilitation　- A Solution for Cardiovascular Care in Japan.

Cardiac rehabilitation (CR) is a well-known intervention for the secondary prevention of cardiovascular diseases. However, in Japan, the outpatient CR participation rate is estimated to be very low. Cardiac telerehabilitation (CTR) can be defined as a remote CR program using digital health technology to support it. Evidence regarding the use of CTR has been accumulated, and the COVID-19 pandemic has accelerated the need for CTR. Japan has sufficient potential to benefit from CTR because, nationally, digital literacy is high and the infrastructure for telemedicine is developed. To overcome several barriers, evidence of CTR in Japan, well-educated multidisciplinary CTR teams, a good combination of center-based CR and CTR, and sophisticated systems including social insurance and adequate legislation need to be developed immediately. CTR has the potential to increase the low CR participation rate in Japan. CTR also has many different effects that not only cardiologists, but also paramedics who engage in CTR, have to be aware of.

Ventilatory efficiency during ramp exercise in relation to age and sex in a healthy Japanese population.

BACKGROUND: The current understanding of ventilator efficiency variables during ramp exercise testing in the normal Japanese population is insufficient, and the responses of tidal volume (VT) and minute ventilation (V̇E) to the ramp exercise test in the normal Japanese population are not known. METHODS: A total of 529 healthy Japanese subjects aged 20-78 years underwent cardiopulmonary exercise testing using a cycle ergometer with ramp protocols. VT and V̇E at rest, at anaerobic threshold, and at peak exercise were determined. The slope of V̇E versus carbon dioxide (V̇CO2) (V̇E vs. V̇CO2 slope), minimum V̇E/V̇CO2, and oxygen uptake efficiency slope (OUES) were determined. RESULTS: For males and females in their 20 s, peak VT (VTpeak) was 2192 ± 376 and 1509 ± 260 mL (p < 0.001), peak V̇E (V̇Epeak) was 80.6 ± 18.7 and 57.7 ± 13.9 L/min (sex differences p < 0.001), the V̇E vs. V̇CO2 slope was 24.4 ± 3.2 and 25.7 ± 3.2 (p = 0.035), the minimum V̇E/V̇CO2 was 24.2 ± 2.3 and 27.0 ± 2.8 (p < 0.001), and the OUES was 2452 ± 519 and 1991 ± 315 (p < 0.001), respectively. VTpeak and V̇Epeak decreased with age and increased with weight and height. The V̇E vs. V̇CO2 slope and minimum V̇E/V̇CO2 increased with age, while conversely, the OUES decreased with age. CONCLUSIONS: We have established the normal range of VT and V̇E responses, the V̇E vs. V̇CO2 slope, the minimum V̇E/V̇CO2, and the OUES for a healthy Japanese population. Some of these parameters were influenced by weight, height, sex, and age. These results provide useful reference values for interpreting the results of cardiopulmonary exercise testing in cardiac patients.

Bioelectrical impedance analysis-derived phase angle as a determinant of protein-energy wasting and frailty in maintenance hemodialysis patients: retrospective cohort study.

BACKGROUND: Phase angle (PA), measured by bioelectrical impedance analysis (BIA) has been studied as indicator of nutritional status or muscle function in hemodialysis (HD) patients. It remains unclear if the phase angle is associated protein-energy wasting (PEW) or frailty, which are common complication in hemodialysis patients. The aim of this study is to determine whether BIA-derived PA is a marker of PEW or frailty in HD patients. METHODS: This retrospective observational study included 116 adult HD patients (35% female, 64 ± 12 years of age) in a single dialysis center. Patients were classified according to the PA quartiles into four groups; 1) first quartile: PA < 3.7°, 2) second quartile: PA 3.7-4.1°, 3) third quartile: PA 4.2-4.9°and 4) forth quartile: PA ≥ 5.0°. International Society of Renal Nutrition and Metabolism (ISRNM) criteria and Japanese version of Cardiovascular Health Study (J-CHS) criteria were used to identify PEW and frailty. RESULTS: The lower PA group was associated with a greater risk of PEW (35% vs. 24% vs. 21% vs. 3%; p = 0.032), frailty (59% vs. 40% vs. 21% vs. 3%; p < 0.001). In multivariate logistic regression analysis, the first quartile group was at a significantly greater risk of both PEW and frailty compared with the fourth quartile group after adjusting for other confounding factors. CONCLUSIONS: Lower PA was associated with a greater risk of PEW and frailty in HD patients.

Predictive factors and radiological findings of adrenohepatic adhesion during laparoscopic adrenalectomy.

Purpose: This retrospective study aimed to identify predictive factors and imaging features of adrenohepatic adhesion found during laparoscopic right adrenalectomy. Materials and Methods: Altogether, 77 patients underwent laparoscopic right adrenalectomy between January 2005 and December 2018. Adrenohepatic adhesion was defined as strict adhesion that required either partial adrenalectomy with coagulation of residual tissue or partial hepatectomy to accomplish complete resection. We assessed their surgical video records to determine if adrenohepatic adhesion was present. Age, sex, body mass index, tumor size, tumor diagnosis and radiological findings (attachment between the liver and the adrenal gland, diameters of the right and left adrenal veins and its ratio) were evaluated as preoperative variables. Results: Adrenohepatic adhesion was present in 11 of the 77 patients (14.3%). Age, sex, and body mass index were not statistically significant factors. Tumor size was significantly small in adhesion group (14.2 mm vs. 25.9 mm, p=0.02). Attachment to the liver and adrenal gland was frequently seen regardless of the adhesion. The mean right/left adrenal veins diameters ratio was significantly lower in the adhesion group (0.8 vs. 1.1, p=0.01). Multivariate logistic regression analysis demonstrated the right/left adrenal veins diameters ratio was the only significant predictor of adhesion. The sensitivity, specificity, negative predictive value and positive predictive value were 0.82, 0.76, 0.43, and 0.95 respectively when the optimal cutoff value for the ratio was 0.9 (area under the curve, 0.75; 95% confidence interval, 0.60-0.90). Conclusions: The right/left adrenal veins diameters ratio was possible predictor of adrenohepatic adhesion.

Changes in oxygen uptake kinetics after exercise caused by differences in loading pattern and exercise intensity.

AIMS: The kinetics of recovery-period oxygen uptake (VO2 ) are affected by the O2 deficit generated during exercise. However, studies using ramp tests (RTs) and constant work rate tests (CT) have differently characterized VO2 responses to increased exercise intensity differently. We used these two types of loading patterns to investigate the effects of low-intensity, medium-intensity, and high-intensity exercises on the half time (T1/2 ) of recovery-period VO2 and the mechanism. METHODS AND RESULTS: Ten healthy men aged 21.2 ± 0.9 years underwent symptom-limited cardiopulmonary exercise tests with the ramp protocol to determine their anaerobic threshold. All subjects subsequently underwent three submaximal RT and CT at low, moderate, and high intensities. In all RTs, subjects began exercise by warming up (20 W). In CT, T1/2 was significantly lengthened as exercise intensity increased (CT-low: 34.0 ± 3.9 s, CT-moderate: 39.5 ± 3.5 s, CT-high:44.6 ± 4.2 s; P < 0.01, ANOVA), whereas no significant change was observed in RT, which began with the same work rate (RT-low: 46.0 ± 5.7 s, RT-moderate: 45.7 ± 4.8 s, RT-high: 44.6 ± 3.5 s, RT-max: 44.8 ± 3.2 s; P = 0.868, ANOVA). Only high-intensity exercise resulted in two components (the fast and slow components) of VO2 decay, reflecting the increased O2 deficit by anaerobic metabolism. CONCLUSIONS: The exercise intensity at the beginning of an exercise affects early recovery-period VO2 , which is a fast component. The T1/2 of recovery-period VO2 occurs during the fast component, and an increase in O2 deficit affects both the fast and slow components, lengthening the T1/2 . The T1/2 of recovery-period VO2 in CT at moderate or high intensities, even if not symptom limited, can be used to evaluate exercise intolerance and early occurrence of anaerobic metabolism. Submaximal exercise tests may be considered as convenient methods for evaluating exercise tolerance in patients with cardiac failure.

Active Participation in Outpatient Cardiac Rehabilitation Is Associated With Better Prognosis After Coronary Artery Bypass Graft Surgery　- J-REHAB CABG Study.

BACKGROUND: There is little evidence regarding the effect of outpatient cardiac rehabilitation (CR) on exercise capacity or the long-term prognosis in patients after coronary artery bypass graft surgery (CABG). This study aimed to determine whether participation in outpatient CR improves exercise capacity and long-term prognosis in post-CABG Japanese patients in a multicenter cohort.Methods and Results:We enrolled 346 post-CABG patients who underwent cardiopulmonary exercise testing during early (2-3 weeks) and late (3-6 months) time points after surgery. They formed the Active (n=240) and Non-Active (n=106) CR participation groups and were followed for 3.5 years. Primary endpoint was a major adverse cardiac event (MACE): all-cause death or rehospitalization for acute myocardial infarction/unstable angina/worsening heart failure. Peak oxygen uptake at 3-5 months from baseline was significantly more increased in Active than in Non-Active patients (+26±24% vs. +19±20%, respectively; P<0.05), and the MACE rate was significantly lower in Active than Non-Active patients (3.4% vs. 10.5%, respectively; P=0.02). Multivariate Cox proportional hazard analysis showed that participation in outpatient CR was a significant prognostic determinant of MACE (P=0.03). CONCLUSIONS: This unique study showed that a multicenter cohort of patients who underwent CABG and actively participated in outpatient CR exhibited greater improvement in exercise capacity and better survival without cardiovascular events than their counterparts who did not participate.

Cost-Effectiveness of Cardiac Rehabilitation in Patients with Coronary Artery Disease: A Meta-Analysis.

BACKGROUND: Medical costs associated with cardiovascular disease are increasing considerably worldwide; therefore, an efficacious, cost-effective therapy which allows the effective use of medical resources is vital. There have been few economic evaluations of cardiac rehabilitation (CR), especially meta-analyses of medical cost versus patient outcome. METHODS: The target population in this meta-analysis included convalescent and comprehensive CR patients with coronary artery disease (CAD), the status most commonly observed postmyocardial infarction (MI). Here, we evaluated medical costs, quality-adjusted life year (QALY), cost-effectiveness, mortality, and life year (LY). Regarding cost-effectiveness analysis, we analyzed medical costs per QALY, medical costs per LY, and the incremental cost-utility ratio (ICUR). We then examined the differences in effects for the 2 treatment arms (CR vs. usual care (UC)) using the risk ratio (RR) and standardized mean difference (SMD). RESULTS: We reviewed 59 studies and identified 5 studies that matched our selection criteria. In total, 122,485 patients were included in the analysis. Meta-analysis results revealed that the CR arm significantly improved QALY (SMD: -1.78; 95% confidence interval (CI): -2.69, -0.87) compared with UC. Although medical costs tended to be higher in the CR arm compared to the UC arm (SMD: 0.02; 95% CI: -0.08, 0.13), cost/QALY was significantly improved in the CR arm compared with the UC arm (SMD: -0.31; 95% CI: -0.53, -0.09). The ICURs for the studies (4 RCTs and 1 model analysis) were as follows: -48,327.6 USD/QALY; -5,193.8 USD/QALY (dominant, CR is cheaper and more effective than UC); and 4,048.0 USD/QALY, 17,209.4 USD/QALY, and 26,888.7 USD/QALY (<50,000 USD/QALY, CR is costlier but more effective than UC), respectively. Therefore, there were 2 dominant and 3 effective results. CONCLUSIONS: While there are some limitations, primarily regarding data sources, our results suggest that CR is potentially cost-effective.

d-amino acid oxidase promotes cellular senescence via the production of reactive oxygen species.

d-amino acid oxidase (DAO) is a flavin adenine dinucleotide (FAD)-dependent oxidase metabolizing neutral and polar d-amino acids. Unlike l-amino acids, the amounts of d-amino acids in mammalian tissues are extremely low, and therefore, little has been investigated regarding the physiological role of DAO. We have recently identified DAO to be up-regulated in cellular senescence, a permanent cell cycle arrest induced by various stresses, such as persistent DNA damage and oxidative stress. Because DAO produces reactive oxygen species (ROS) as byproducts of substrate oxidation and the accumulation of ROS mediates the senescence induction, we explored the relationship between DAO and senescence. We found that inhibition of DAO impaired senescence induced by DNA damage, and ectopic expression of wild-type DAO, but not enzymatically inactive mutant, enhanced it in an ROS-dependent manner. Furthermore, addition of d-amino acids and riboflavin, a metabolic precursor of FAD, to the medium potentiated the senescence-promoting effect of DAO. These results indicate that DAO promotes senescence through the enzymatic ROS generation, and its activity is regulated by the availability of its substrate and coenzyme.

Health Economics　- Effect of Electronic Medical Record Systems on Cardiovascular Disease Outpatient Consultation Time.

Because electronic medical record systems may affect productivity of clinical practice, we examined the effects of different types of medical record systems on consultation time and total fee claims for outpatient consultation for cardiovascular cases. We investigated consultation time (i.e., the sum of practice time and work-up time) and total fee claims by 13 cardiovascular physicians for 862 outpatients. The means of consultation time and total fee claims were calculated for 3 types of medical records: electronic, paper-based, and hybrid. No difference in mean consultation time was seen between the electronic and paper-based medical record groups (paper based, 11.4±0.3 min/case; electronic, 12.7±0.8 min/case; hybrid, 13.5±0.5 min/case). In contrast, the electronic group had the highest mean practice time (10.9±0.6 min/case) and the lowest mean work-up time (1.7±0.4 min/case). There was no difference in total fee claims between the 3 medical record groups. The total fee claims per practice time was lower for the electronic group than the paper-based (67.5±52.8 vs. 108.8±108.1 points/min, P<0.001). The findings suggest that physicians using the electronic medical record system can be more directly involved with patients due to higher productivity, as reflected in the lower work-up time.

[A Case of Nivolumab-Induced Isolated Adrenocorticotropic Hormone Deficiency Presenting Dyspnea].

A 66-year-old man had undergone multiple treatments for metastatic renal cell carcinoma, including 11 cycles of nivolumab, which was discontinued because of disease progression. About three weeks after discontinuing nivolumab, he reported suffering from worsening of dyspnea. Pulse oximetry showed no desaturation. His cardiovascular and pulmonary functions were normal. His dyspnea slowly worsened with no underlying diagnosis. Two months after symptoms developed, he was diagnosed with isolated adrenocorticotropic hormone deficiency. His dyspnea disappeared soon after receiving hydrocortisone. Nivolumab-induced isolated adrenocorticotropic hormone deficiency may not present with typical symptoms, and can occur even after discontinuing nivolumab. Cortisol levels should be routinely monitored in patients who receive nivolumab.

Effects of Intradialytic Resistance Exercise on Protein Energy Wasting, Physical Performance and Physical Activity in Ambulatory Patients on Dialysis: A Single-Center Preliminary Study in a Japanese Dialysis Facility.

Patients under hemodialysis present protein-energy wasting (PEW), which is related with higher mortality rates. The study aimed to determine whether intradialytic resistance exercise training could improve physical performance, physical activity, and PEW in hemodialysis patients. In single center study, 75 hemodialysis patients were enrolled in an intradialytic resistance exercise training consisting of 20 min of adapted leg press, with a gymnastic ball, 3 days/week, during 9 months on the same day of hemodialysis therapy. Physical performance by short physical performance battery (SPPB), physical activity by life space assessment (LSA), and PEW score based on the nomenclature proposed by the International Society of Renal Nutrition and Metabolism in 2008 were assessed at baseline and after 9 months. Intradialytic resistance exercise training significantly improved SPPB score, LSA score, and PEW score (all, P < 0.05). In addition, intradialytic resistance exercise training improved SPPB score in patients with moderate and severe PEW subgroups (P < 0.05), associated with reduced prevalence of the patients with moderate to severe PEW (53% vs. 36%, P < 0.05). Intradialytic resistance exercise training was safe and effective to improve physical performance, physical activity, and PEW in hemodialysis patients.

Impact of chronic kidney disease and anemia on physical function in patients with chronic heart failure.

OBJECTIVE: The aim of this study was to confirm the effects of chronic kidney disease (CKD) and anemia on physical function and to clarify whether the interaction between CKD and anemia has an additive effect. DESIGN: Eligible subjects were chronic heart failure (HF) patients who were discharged between March 2007 and August 2009. A total of 102 chronic HF patients (33% females; mean age: 68 ± 14 years) were enrolled in the present study. CKD was defined as an estimated glomerular filtration rate of <60 ml/min/1.73 m(2), and anemia was defined as a hemoglobin level of <12 g/dl in males and of <11 g/dl in females. The Short Physical Performance Battery (SPPB) was used to assess physical function. RESULTS: The adjusted mean SPPB score was lower in patients with both CKD and anemia than in those with neither of the diseases or with either disease alone (p < 0.05). CONCLUSION: This study found that CKD and anemia are independently associated with reduced physical function.

Heart rate and blood pressure response to ramp exercise and exercise capacity in relation to age, gender, and mode of exercise in a healthy population.

BACKGROUND: The responses of heart rate (HR) and blood pressure to the ramp exercise test are not known and the current understanding of peak oxygen uptake and anaerobic threshold (AT) values in the normal Japanese population is insufficient. METHODS AND RESULTS: A total of 749 healthy Japanese subjects aged 20-78 years underwent a cardiopulmonary exercise test using a cycle ergometer or treadmill ergometer with ramp protocols. HR, systolic blood pressure (SBP), and oxygen uptake VO2 at rest, at AT, and at peak exercise were determined. HR and SBP at peak exercise in a cycle ergometer and treadmill ergometer test decreased with age. Work rate at peak exercise in a cycle ergometer increased with body weight and decreased with age. VO2 at AT and at peak exercise were higher in treadmill ergometer testing than in cycle ergometer testing, and were not affected by exercise protocol. Both of these decreased with age. CONCLUSIONS: The normal responses of HR and SBP to ramp exercise testing are reported for the first time. AT, peak VO2, and VO2 at each stage are shown for a healthy population. Some of these parameters were influenced by weight, gender, and age, as well as mode of exercise and the protocol used. These results provide useful reference values for interpreting the results of cardiopulmonary exercise testing.

[A case report of Cowper's syringocele in an adult treated with transurethral unroofing].

We present an adult case of Cowper's syringocele. A 19-year-old male presented with the chief complaint of persistent post-voiding dribbling 5 months after onset. Urethroscopy demonstrated a thin membrane with a small orifice on the ventral aspect distal to the external sphincter. Magnetic resonance imaging showed a restiform shadow on the left side of the corpus spongiosum. Retrograde urethrogram showed filling of diverticulum-like structure in the region of urethral bulb terminating in the urogenital diaphragm. Considering the results mentioned above, we diagnosed the patient with Cowper's syringocele. Transurethral unroofing of the Cowper's syringocele was performed with a cold knife, and the excessive tissue on the edge of syringocele was electroresected to avoid recurrence. His post-voiding dribbling resolved completely after the procedure and has not recurred in 13 months postoperatively. Cowper's syringocele is typically diagnosed presenting with hematuria, urinary tract infection, and disuria in male infants and children. Adult cases of Cowper's syringocele are rare, and only 32 cases including the present case have been reported. Proper awareness of this entity and careful evaluation are important if patients present with persistent adult-onset voiding dysfunction.