Effects of Low-Dose Tadalafil in a Patient with Biventricular Heart Failure: A Case Report.

Phosphodiesterase type 5 (PDE5) inhibitors such as tadalafil, can improve cardiac output by increasing left ventricular preload; however, there are concerns that this can increase the risk of heart failure due to pulmonary congestion in patients with elevated left ventricular end-diastolic pressure. We encountered a case in which low dose tadalafil improved the hemodynamics of a 66-year-old male patient with dilated cardiomyopathy (DCM) with congestion and low cardiac output due to biventricular dysfunction. The patient received a cardiac resynchronization therapy defibrillator (CRT-D) and appropriate medical therapy for heart failure. During a hemodynamic evaluation after heart failure symptoms were alleviated, we attempted to increase the dose of renin-angiotensin-aldosterone system (RAAS) inhibitors, which contribute to low cardiac output, hypotension, and worsening of renal function. However, the administration of a low dose of tadalafil for the patient's benign prostatic hyperplasia allowed for the increase in the dose of RAAS inhibitors and markedly improved his subjective symptoms and hemodynamics. Because of the biventricular dysfunction in severe cases, we often experience further promotion of low cardiac output by standard treatments such as RAAS inhibitors, in which low doses of PDE5 inhibitors may be effective in maintaining biventricular linkage. PDE5 inhibitors may be effective in patients, who are not able to increase the dose of RAAS inhibitors due to low cardiac output.

Involvement of Rac1 in macrophage activation by brain-derived neurotrophic factor.

Brain-derived neurotrophic factor (BDNF) enhances periodontal tissue regeneration. Tissue regeneration is characterized by inflammation, which directs the quality of tissue repair. This study aimed to investigate the effect of BDNF on the phagocytic activity of RAW264.7 cells. In addition, we studied the effect of BDNF on guanosine triphosphatase (GTP)-RAS-related C3 botulinus toxin substrate (Rac)1 and phospho-Rac1 levels in RAW264.7 cells. Rac1 inhibitor inhibited BDNF-induced phagocytosis of latex-beads. In addition, BDNF enhanced Porphyromonas gingivalis (Pg) phagocytosis by RAW264.7 cells as well as latex-beads. We demonstrated for the first time that BDNF enhances phagocytic activity of RAW264.7 cells through Rac1 activation. The present study proposes that BDNF may reduce inflammatory stimuli during BDNF-induced periodontal tissue regeneration through enhanced phagocytic activity of macrophages.

Trends in nutritional intake and coronary risk factors over 60 years among Japanese men in Tanushimaru.

We investigated the relationship between time trends in nutrient intake and coronary risk factors/mortality rates in Tanushimaru, a Japanese cohort of the Seven Countries Study. All men between the ages of 40 and 64 were enrolled. Subjects numbered 628 in 1958, 539 in 1977, 602 in 1982, 752 in 1989, 402 in 1999, 329 in 2009, and 160 in 2018. Eating patterns were evaluated by 24-h dietary recall from 1958 through 1989, and by a food frequency questionnaire administered from 1999 through 2018. The total daily energy intake decreased from 2,837 kcal in 1958 to 2,096 kcal in 2018. Carbohydrate intake as a percentage of the total decreased remarkably from 84% (1958) to 53% (2018), whereas there was a large increase in fat intake (from 5 to 24%) during the same period. Age-adjusted mean cholesterol levels rose sharply (from 167.9 to 209.4 mg/dl) and body mass index levels also increased (from 21.7 to 24.4 kg/m2), but smoking rate decreased from 69% (1958) to 30% (2018). The mortality rates from stroke and cancer declined, but mortality from myocardial infarction and sudden death remained stable at low levels. The remarkable changes in dietary patterns over the last 60 years can be related to coronary risk factors, but not currently to the mortality of coronary artery disease; more follow-up is needed.

Association between physical activity, occupational sitting time and mortality in a general population: An 18-year prospective survey in Tanushimaru, Japan.

AIMS: It is well known that a decline in physical activity is associated with an increase of all-cause death including cardiovascular events and cancer. Few studies have examined the association between occupational sitting time and mortality. Therefore, we investigated this issue in a general population. METHODS: Physical activity and occupational sitting time were measured using the Baecke physical activity questionnaire in 1999. The questionnaire generated indices in three physical activity categories: work, sport and leisure-time. A total physical activity index was calculated by adding these three indices. The Baecke physical activity questionnaire was able to evaluate occupational sitting time. Hazard ratios and 95% confidence intervals (CIs) were calculated using Cox's proportional hazard regression models. RESULTS: We enrolled a total of 1680 participants, who were followed up for 15.9 ± 3.8 years. The final follow-up rate was 93%. During the follow-up period, 397 subjects died. A significant inverse association (p < 0.0001) was found between physical activity and mortality after adjustment for age and sex. Compared with lower levels of physical activity, the adjusted hazard ratio for mortality at higher levels of physical activity was 0.85 (95% CI: 0.78-0.92). Longer occupational sitting time was also significantly associated with higher mortality (p < 0.01). The adjusted hazard ratio for mortality at longer occupational sitting time was 1.16 (95% CI: 1.05-1.27). These findings were observed in males, but not in females. CONCLUSIONS: Our data demonstrated that higher levels of physical activity are associated with a reduced risk of cancer and cardiovascular death. Further, longer occupational sitting time is associated with increased mortality.

Habitual coffee intake reduces all-cause mortality by decreasing heart rate.

It is well known that subjects with metabolic syndrome show an elevated resting heart rate. We previously reported that elevated heart rate was significantly related to all-cause mortality, and that coffee consumption was inversely associated with metabolic syndrome. We hypothesized that higher coffee consumption may decrease all-cause mortality by reducing resting heart rate. We performed a longitudinal epidemiological study in Tanushimaru (a cohort of the Seven Countries Study). A total of 1920 residents aged over 40 years received health checkups in 1999. We measured components of metabolic syndrome, and eating and drinking patterns were evaluated by a food frequency questionnaire. We followed up the participants annually for 15 years. During the follow-up period, 343 of the participants died. Of these, 102 subjects died of cancer, 48 of cerebro-cardiovascular diseases, and 44 of infectious diseases. Multivariate analyses revealed that higher coffee consumption was inversely associated with resting heart rate. Kaplan-Meier curves found lower mortality rates in the higher coffee consumption groups. In the lower coffee consumption groups, elevated hazard ratios of all-cause death were observed in the increased heart rate quintiles, whereas heart rate was not associated with all-cause death in the higher coffee consumption groups. These significant associations remained after further adjustment for confounders. This prospective study suggests that higher coffee consumption may have a protective effect against all-cause death due to reducing resting heart rate.

Thrombospondin-2 as a Potential Risk Factor in a General Population.

Serum thrombospondin-2 (TSP-2) is a glycoprotein expressed in the extracellular matrix (ECM), which increases during tissue remodeling. It has been shown in recent studies that TSP-2 is a useful predictor of cardiovascular death in patients with heart failure (HF). However, the clinical importance of serum TSP-2 levels in a general population is still unknown. Therefore, we aimed to clarify the association between TSP-2 and clinical risk factors. A periodic epidemiological survey was performed in a community dwelling in the town of Uku, Nagasaki, Japan. A total of 445 residents received a health checkup examination including blood tests such as fasting serum levels of TSP-2. Uni- and multivariate analyses were performed to examine the relationship between TSP-2 and clinical risk factors. All statistical analyses were performed using SAS v9.4 program. The mean ± standard deviation of age was 67.0 ± 9.4 years old. Although serum TSP-2 levels (mean: 20.9 ± 8.5 ng/mL) showed no significant sex difference, they were significantly correlated with the levels of plasma glucose (P < 0.001), insulin (P < 0.01), homeostasis model assessment of insulin resistance (HOMA-IR) (P < 0.001), estimated glomerular filtration rate (eGFR) (P < 0.01, inversely), high-sensitivity C-reactive protein (hs-CRP) (P < 0.001), history of atrial fibrillation (P < 0.001), history of cardiovascular diseases (P < 0.001), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (P < 0.001). Moreover, in the multiple stepwise linear regression analysis, the levels of TSP-2 were independently and significantly associated with the history of atrial fibrillation (P < 0.0001), HOMA-IR (P < 0.001), high-sensitivity CRP (P = 0.011), and NT-proBNP (P = 0.043). These results indicated the significant relationship between TSP-2 and clinical risk factors in a general population, suggesting its role as a predictor of heart disease morbidity and mortality.

Twenty-four-Hour Urinary Potassium Excretion, But Not Sodium Excretion, Is Associated With All-Cause Mortality in a General Population.

BACKGROUND: Few studies have examined the relationship between accurate monitoring of sodium or potassium consumption and mortality. We aimed to investigate the association between 24-hour urinary sodium or potassium excretion and ≈30-year mortality in a Japanese population using 24-hour urine collection. METHODS AND RESULTS: We enrolled a total of 1291 participants, aged 21 to 85 years, who underwent health checkups, including a blood test and 24-hour urine collection. They were followed up for 27.5±9.9 years by December 31, 2015, and the final follow-up rate was 95.8%. Cox proportional hazards regression analysis was used to assess the association between 24-hour urinary sodium or potassium excretion and all-cause mortality. At baseline, the mean 24-hour urinary sodium and potassium excretions were 5.80±2.28 g/d and 1.85±0.82 g/d, respectively. There were 631 deaths during the follow-up. The cumulative survival rate was significantly decreased in the lowest quartile compared with the other higher groups. In the Cox proportional hazard model after adjustment for age and sex, 24-hour urinary potassium excretion, but not sodium excretion, was inversely associated with all-cause mortality. We divided the 24-hour urinary potassium excretion levels into quartiles. After adjustment for confounding factors, the hazard ratio of all-cause mortality in the highest quartile of 24-hour urinary potassium excretion versus the lowest was 0.62 (95% confidence interval, 0.48-0.79; P<0.001). CONCLUSIONS: The 24-hour urinary potassium excretion, but not sodium excretion, was significantly associated with all-cause mortality in the general population.

Impact of cystatin C and microalbuminuria on cognitive impairment in the population of community-dwelling Japanese.

BACKGROUND AND AIMS: Cognitive impairment is an important element affecting our well-being, and as such, early diagnosis is critical today. We investigated whether serum cystatin C and microalbuminuria are associated with cognitive impairment. METHODS: A total of 1943 subjects (774 males, 1169 females, mean age 65.8 years) took part in the investigation, and underwent a health examination in Tanushimaru, Japan, in 2009. The participants' cognitive function was evaluated using of mini-mental state examination (MMSE). We measured the levels of serum cystatin C using latex nephelometric immunoassay. Spot urine samples were used to measure microalbuminuria levels. Multivariate linear regression analyses were used to assess the relationship between MMSE scores and the level of cystatin C or microalbuminuria. All statistical analyses were performed using the SAS system. RESULTS: The mean values of log-transformed serum cystatin C levels and log-transformed microalbuminuria were 0.95 (range 0.41-7.11) mg/L and 10.7 (range 1.1-2600) mg/g·Cr, respectively. The means of MMSE score were 27.7 ± 2.5. In the multivariate linear regression analyses adjusted for age and sex, MMSE was significantly associated with systolic blood pressure (p = 0.024, inversely), cystatin C (p = 0.046, inversely) and microalbuminuria (p = 0.019, inversely), whereas estimated glomerular filtration rate (eGFR) had an insignificant association (p = 0.197). In the multiple stepwise linear regression analysis, age, history of stroke, systolic blood pressure, serum cystatin C were independently associated with MMSE levels. CONCLUSIONS: We demonstrated for the first time that cognitive function was significantly and inversely associated with cystatin C and microalbuminuria, in the relatively younger general population.

Elevated Plasma Transforming Growth Factor ß1 Levels Predict the Development of Hypertension in Normotensives: The 14-Year Follow-Up Study.

BACKGROUND: Transforming growth factor ß1 (TGF-ß1) is a multifunctional cytokine. There is growing evidence that TGF-ß1 is involved in the pathogenesis of hypertension and the development of target organ damage in hypertensives. Although several studies have shown that TGF-ß1 induced vascular hypertrophy and remodelling in various vascular diseases, there are no longitudinal data on hypertension in the epidemiological studies. The present study tested the hypothesis whether elevated TGF-ß1 levels can predict the development of hypertension. METHODS: In 2002-2004, 528 subjects received health examinations in Uku town, southwestern Japan. We examined blood pressure (BP), body mass index, and blood test. Data on fasting plasma TGF-ß1 were obtained from 528 individuals. Of these, 149 normotensives (BP <140/90 mm Hg without antihypertensive medications) at baseline were followed-up for 14 years. RESULTS: The receiver-operating characteristic curve was used and the calculated cutoff value was 8.9 ng/ml. Of 149 normotensives at baseline, 59 subjects developed hypertension. Plasma TGF-ß1 levels were significantly associated with the development of hypertension after adjustment for confounding factors. To further examine the association between them, we performed logistic regression analysis. We divided the baseline plasma TGF-ß1 levels into 2 groups using a cutoff value. The significant high odds ratio [3.582 (95% confidence interval, 1.025-12.525)] for the development of hypertension was found in the highest group of TGF-ß1 level vs. the lowest group after adjustment for confounders. CONCLUSIONS: This is the first report demonstrating the causal relationship between them. Elevated plasma TGF-ß1 levels predicted the development of hypertension in normotensives in a population of community-dwelling Japanese.

A Useful Tool As a Medical Checkup in a General Population-Bioelectrical Impedance Analysis.

Accumulation of visceral fat leads to metabolic syndrome and increases risks of cerebro-cardiovascular diseases, which should be recognized and improved at the early stage in general population. Accurate measurement of visceral fat area (VFA) is commonly performed by the abdominal cross-sectional image measured by computed tomography scan, which is, however, limited due to the radiation exposure. The bioelectrical impedance analysis (OMRON, HDS-2000 DUALSCANR) has been recently developed to measure VFA, which is more easily accessible modality. In the present study, we investigated the clinical usefulness of DUALSCANR in 226 subjects who received health examination, including blood chemistries, electrocardiography, cardio, and carotid ultrasonography. VFA was measured within only just 5 min. Average of VFA was 83.5 ± 36.3 cm2 in men, and 64.8 ± 28.0 cm2 in women, which was correlated to weight (r = 0.7404, p < 0.0001), body mass index (BMI) (r = 0.7320, p < 0.0001), and waist circumstance (r = 0.7393, p < 0.0001). In multivariate analyses, VFA was significantly associated with weight (p < 0.0001), BMI (p < 0.0001), and waist circumstance (p < 0.0001). Compared to the group of smaller waist and normal BMI, VFA was significantly increased (p < 0.0001) in the group of larger waist and obese subjects. In conclusion, these results indicated that DUALSCANR is useful to measure VFA easily in general population, even in a large number of subjects.

Trends in coronary risk factors and electrocardiogram findings from 1977 to 2009 with 10-year mortality in Japanese elderly males - The Tanushimaru Study.

BACKGROUND: An understanding of the trends in regard to coronary risk factors and electrocardiogram (ECG) findings has an important role in public health. We investigated the trends in coronary risk factors and main ECG findings in 1977, 1989, 1999, and 2009 in the Japanese cohort of the Seven Countries Study, in Tanushimaru, a typical farming town on Kyushu Island. METHODS AND RESULTS: A total of 1397 subjects (231 in 1977, 332 in 1989, 389 in 1999, and 445 in 2009) were enrolled in this study, and all of them were males aged over 65 years. In coronary risk factors, total cholesterol levels, diastolic blood pressure, body mass index, and uric acid significantly increased during these 3 decades. The prevalence of smokers markedly decreased from 56.7% in 1977 to 16.8% in 2009. ECG changes during 3 decades were wider QRS interval, increased prevalence of major abnormality, reduced heart rate, shortened PR interval and corrected QT, and decreased prevalence of left ventricular hypertrophy. Age, smoking habits, major and minor abnormalities in ECG were associated with mortality in 1977-1987. Age, total cholesterol levels (inversely) and corrected QT were associated with mortality in 1989-1999. Age, smoking habits, heart rate, and systolic blood pressure were associated with mortality in 1999-2009. CONCLUSIONS: Predictors of mortality have changed with the times. Coronary risk factors such as smoking, increased heart rate, and elevated blood pressure have been recently associated with mortalities in elderly male Japanese general population.

Augmentation index (AI) in a dose-response relationship with smoking habits in males: The Tanushimaru study.

We investigated the relationship between augmentation index (AI) and smoking habits in community-dwelling Japanese.This cross-sectional study enrolled 1926 subjects (769 males and 1157 females) aged 40 to 95 years who underwent a health check-up in a Japanese cohort of the Seven Countries Study, in Tanushimaru, a typical farming town in Kyushu Island in 2009. The subjects' medical history, alcohol intake, smoking habit, and current medications for hypertension, dyslipidemia, and diabetes were ascertained by questionnaire. Radial arterial pressure wave analysis was used to obtain AI. We analyzed the data stratified by gender.Age-adjusted means of AI in males showed a clear dose-response relationship in 4 categories of smoking habits (P = 0.010). There was no significant relationship between AI and smoking habits in females (P = 0.127). The significant dose-response relationship (P = 0.036) in males between AI and 4 categories of smoking habits still remained even after adjustment for age, body mass index, systolic blood pressure, estimated glomerular filtration rate, glucose, hypertensive medication, and alcohol intake.The present study demonstrated that AI values were significantly associated with smoking habits in a dose-dependent manner in Japanese males.

The ecological perspective of microbial communities in two pairs of competitive Hawaiian native and invasive macroalgae.

Marine macroalgae are known to harbor large populations of microbial symbionts, and yet, microbe symbiosis in invasive macroalgae remains largely unknown. In this study, we applied molecular methods to study microbial communities associated with two invasive algae Acanthophora spicifera and Gracilaria salicornia and the two native algae Gracilaria coronopifolia and Laurencia nidifica at spatial and temporal scales in Hawaiian coral reef ecosystems. Bacterial communities of both the invasive and native macroalgae displayed little spatial and temporal variations, suggesting consistent and stable bacterial associations with these macroalgae. Results of this study identified three types of bacterial populations: nonspecific (present in both algal and water samples); algae-specific (found in all algal species); and species-specific (only found in individual species). The bacterial diversity of invasive algae was lower than that of their native counterparts at phylum and species levels. Notably, the vast majority (71 %) of bacterial communities associated with the invasive algae G. salicornia were representatives of Cyanobacteria, suggesting a potential ecological significance of symbiotic Cyanobacteria.