Development of Machine Learning-Based Web System for Estimating Pleural Effusion Using Multi-Frequency Bioelectrical Impedance Analyses.

BACKGROUND: Transthoracic impedance values have not been widely used to measure extravascular pulmonary water content due to accuracy and complexity concerns. Our aim was to develop a foundational model for a novel system aiming to non-invasively estimate the intrathoracic condition of heart failure patients. METHODS: We employed multi-frequency bioelectrical impedance analysis to simultaneously measure multiple frequencies, collecting electrical, physical, and hematological data from 63 hospitalized heart failure patients and 82 healthy volunteers. Measurements were taken upon admission and after treatment, and longitudinal analysis was conducted. RESULTS: Using a light gradient boosting machine, and a decision tree-based machine learning method, we developed an intrathoracic estimation model based on electrical measurements and clinical findings. Out of the 286 features collected, the model utilized 16 features. Notably, the developed model demonstrated high accuracy in discriminating patients with pleural effusion, achieving an area under the receiver characteristic curves (AUC) of 0.905 (95% CI: 0.870-0.940, p < 0.0001) in the cross-validation test. The accuracy significantly outperformed the conventional frequency-based method with an AUC of 0.740 (95% CI: 0.688-0.792, and p < 0.0001). CONCLUSIONS: Our findings indicate the potential of machine learning and transthoracic impedance measurements for estimating pleural effusion. By incorporating noninvasive and easily obtainable clinical and laboratory findings, this approach offers an effective means of assessing intrathoracic conditions.

Association between mitral annulus calcification and subtypes of heart failure rehospitalization.

BACKGROUND: Mitral annulus calcification (MAC) has been associated with cardiovascular diseases, including heart failure (HF); however, the associations between MAC and both the category and etiology of HF have not been fully elucidated. The aim of this study was to investigate the relationship between MAC and three types of HF rehospitalization: HF with preserved ejection fraction (HFpEF), HF with mid-range EF (HFmrEF), and HF with reduced EF (HFrEF). METHODS: We enrolled consecutive patients undergoing echocardiography, who were admitted to our hospital for clinically indicated congestive HF between April 2014 and March 2018. Cox proportionalhazards models were used after adjusting for age, gender, and hypertension. RESULTS: Of 353 patients, 40 (11.3%) had MAC. With a median follow-up of 2.8 years, 100 (28%) patients were rehospitalized for congestive HF (HFpEF 40%, HFmrEF 16%, HFrEF 44%, respectively). According to the Kaplan-Meier method, the estimated incidence of HFpEF rehospitalization in the MAC group was significantly greater than that in the non-MAC group (p < 0.001) whereas the incidences of HFmrEF and HFrEF rehospitalization were comparable between the groups (p = 0.101 and p = 0.291, respectively). In a multivariate analysis, MAC remained significantly associated with HFpEF rehospitalization (hazard ratio: 3.379; 95% confidence interval: 1.651-6.597). At initial HF hospitalization, E/e' was significantly higher in the MAC group (both septum and lateral, p < 0.05), suggesting a possible relationship between MAC and left ventricular diastolic function. CONCLUSIONS: Mitral annulus calcification was associated with increased HFpEF rehospitalization and might be a cause of left ventricular diastolic dysfunction.

Acute Myocarditis with Severe Fever and Thrombocytopenia Syndrome.

A 67-year-old man, hospitalized with fever and pancytopenia, experienced cardiogenic shock on the 3rd day of hospitalization. He complained of chest pain and exhibited cardiac dysfunction, upregulated serum troponin levels, and an ST elevation on electrocardiogram. Severe fever with thrombocytopenia syndrome (SFTS) was suspected based on the symptom course after a tick bite and was definitively diagnosed using the serum polymerase chain reaction (PCR) test. An endomyocardial biopsy performed in the convalescent phase revealed a sign of myocardial inflammation with increases in CD3- and CD68-positive cells. We herein report the first case of acute myocarditis complicated with SFTS.

Impact of Controlling a Nutritional Status Score on Wound Healing in Patients with Chronic Limb-Threatening Ischemia after Endovascular Treatment.

BACKGROUND: Chronic limb-threatening ischemia (CLTI) is the most advanced stage of peripheral artery disease. Therefore, a multidisciplinary approach is necessary to avoid major amputation in CLTI patients. Malnutrition worsens the condition of CLTI patients, and therefore, it may be important to evaluate the nutritional status in patients with CLTI. This study was designed to evaluate the baseline patient characteristics and the influence of the controlling nutritional status (CONUT) score on the clinical results. METHOD AND RESULTS: A retrospective, single-center, non-randomized study was conducted to evaluate the associations of death, major amputation, and wound healing rate at 12 months with the CONUT score on admission. Consecutive CLTI patients (mean age 73.2 ± 10.4 years; 84 males) who underwent endovascular therapy (EVT) for infra-popliteal lesions at Fukuoka University Hospital from January 2014 to May 2019 were enrolled and divided into two groups (higher and lower CONUT score groups). The higher CONUT group showed a higher percentage of dialysis (66.7% vs. 33.9%, p < 0.001) and a higher clinical frailty scale (5.9 ± 1.4 vs. 4.9 ± 1.9, p = 0.005) than the lower CONUT group. Rates of amputation-free survival were 89.5% and 69.8% in the lower and higher CONUT groups, respectively. In addition, rates of wound healing at 12 months were 98.0% and 78.3% in the lower and higher CONUT groups, respectively. Multivariate regression analysis demonstrated that a higher CONUT score was an independent predictor for delayed wound healing (OR: 11.2; 95% CI: 1.29-97.5; p = 0.028). CONCLUSION: An assessment of the nutritional status using the CONUT score could be useful for predicting wound healing, and earlier nutritional intervention may improve the outcome of CLTI patients. Early examination and treatment, along with raising awareness of the issue, may be important for improving the prognosis.

Aberrant accumulation of TMEM43 accompanied by perturbed transmural gene expression in arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) caused by TMEM43 p.S358L is a fully penetrant heart disease that results in impaired cardiac function or fatal arrhythmia. However, the molecular mechanism of ACM caused by the TMEM43 variant has not yet been fully elucidated. In this study, we generated knock-in (KI) rats harboring a Tmem43 p.S358L mutation and established induced pluripotent stem cells (iPSCs) from patients based on the identification of TMEM43 p.S358L variant from a family with ACM. The Tmem43-S358L KI rats exhibited ventricular arrhythmia and fibrotic myocardial replacement in the subepicardium, which recapitulated the human ACM phenotype. The four-transmembrane protein TMEM43 with the p.S358L variant (TMEM43S358L ) was found to be modified by N-linked glycosylation in both KI rat cardiomyocytes and patient-specific iPSC-derived cardiomyocytes. TMEM43S358L glycosylation increased under the conditions of enhanced endoplasmic reticulum (ER) stress caused by pharmacological stimulation or age-dependent decline of the ER function. Intriguingly, the specific glycosylation of TMEM43S358L resulted from the altered membrane topology of TMEM43. Moreover, unlike TMEM43WT , which is mainly localized to the ER, TMEM43S358L accumulated at the nuclear envelope of cardiomyocytes with the increase in glycosylation. Finally, our comprehensive transcriptomic analysis demonstrated that the regional differences in gene expression patterns between the inner and outer layers observed in the wild type myocardium were partially diminished in the KI myocardium prior to exhibiting histological changes indicative of ACM. Altogether, these findings suggest that the aberrant accumulation of TMEM43S358L underlies the pathogenesis of ACM caused by TMEM43 p.S358L variant by affecting the transmural gene expression within the myocardium.

Coronavirus disease (COVID-19) associated delayed-onset fulminant myocarditis in patient with a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

A healthy 35-year-old man was admitted to a rural hospital with coronavirus disease (COVID-19). During 14 days of hospitalization, he had no symptoms and was not given supplemental oxygen. About 3 weeks after discharge, he was re-admitted to the same hospital with new-onset continuous fever and general weakness. At the time of his second admission, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RT-PCR was performed on a retro-nasal swab and the result was negative. Four days after admission, the patient was transferred to our intensive care unit (ICU) following deterioration of his respiratory and haemodynamic conditions, where he received mechanical ventilation, intra-aortic balloon pumping, and veno-arterial extracorporeal membrane oxygenation. A nasopharyngeal swab was obtained again at ICU admission, but RT-PCR was negative for SARS-CoV-2. All antibody titres measured against other viruses were low. Blood cultures were negative, and no bacteria were observed in sputum samples. However, SARS-CoV-2 RNA was detected by RT-PCR from sections obtained by myocardial biopsy. The patient's final diagnosis was delayed-onset SARS-CoV-2-induced fulminant myocarditis (FM). We strongly suggested that one of the proposed mechanisms of COVID-19-related myocardial injury will be the direct invasion of SARS-CoV-2 into cardiomyocytes even if delayed-onset. And this is the first case of delayed-onset FM in which diagnosis of active myocarditis was proven by pathological examination following endomyocardial biopsy and SARS-CoV-2 was detected in the myocardium by RT-PCR.

A Rare Case of Submassive Pulmonary Embolism with a Right Aberrant Subclavian Artery and Thrombosed Kommerell Diverticulum.

An 81-year-old man presented with shortness of breath and was referred to our hospital with suspected acute pulmonary embolism. Enhanced computed tomography revealed a right aberrant subclavian artery with a thrombosed Kommerell diverticulum (KD), as well as deep vein thrombosis in the left leg and bilateral pulmonary artery thrombosis. Thrombosis in the KD disappeared after one month of anticoagulation treatment with rivaroxaban. Thrombosis of a KD is a rare condition that may cause distal emboli and subclavian steal syndrome, although this syndrome was not present in this case. Rivaroxaban is an effective anticoagulant for treating thrombosis of a KD.

Efficacy of Super Slow Inflation as Lesion Preparation for Drug-Coated Balloons in Femoropopliteal Lesions.

Background: Drug-coated balloon strategies in endovascular therapy often result in severe dissection, so lesion preparation must be improved. We evaluated the efficacy of a gradual inflation method, termed "super slow inflation" (SSI), in preparing lesions to avoid severe dissections. Methods and Results: The association between balloon pressure and the dilatation of a model constricted vessel, as well as the load applied to the balloon surface, were determined using a burst leak detector for a quick inflation (QI; 1 atm/s) protocol and SSI (1 atm/20 s). A retrospective, single-center, non-randomized study evaluated differences in vessel dissection patterns after balloon angioplasty depending on inflation method in 81 consecutive patients (mean [±SD] age 74.6±9.2 years; 54 males) who underwent balloon angioplasty for de novo femoropopliteal lesions between January 2017 and March 2019. In the constricted vessel model, vessel dilatation increased gradually using SSI, with the maximum dilatation load being approximately 100 g lower for the SSI than QI protocol. In patients, the rate of severe vessel dissection was significantly lower in the SSI than non-SSI group (17.6% vs. 55.2%, respectively; P<0.001). Multivariate regression analysis revealed that SSI was an independent factor preventing severe dissection (odds ratio 0.18; 95% confidence interval 0.06-0.53; P=0.002). Conclusions: SSI is a gentle and effective method for the preparation of femoropopliteal lesions to reduce the incidence of severe angiographic dissection when using drug-coated balloons.

Differential prognostic impact between completion and non-completion of a 5-month cardiac rehabilitation program in outpatients with cardiovascular diseases.

BACKGROUND: Cardiac rehabilitation (CR) is an essential component of care for patients with cardiovascular diseases (CVD). We aimed to evaluate clinical outcomes in outpatients with CVD who did and did not complete a 5-month CR program. METHODS: Three hundred thirty-two outpatients with CVD who participated in a 5-month CR program and were followed-up for maximum 5 years were registered. We divided the patients into two groups: those who completed the CR program (success group, n = 175) and those who could not (non-success group, n = 157). Both long-term (5 years) and short-term (5 months) clinical outcomes were compared between the two groups. RESULTS: There were no significant differences in patient characteristics at baseline between the success and non-success groups. With regard to both long-term and short-term clinical outcomes, the rates of all-cause death and hospital admission in the success group were significantly lower than those in the non-success group by a Kaplan-Meier analysis. There was a significant difference in short-term CVD death and hospital admission between the groups, but not for long-term CVD death and hospital. In long-term period, all-cause death and hospital admission was independently associated with completion of the CR program in addition to the presence of peripheral artery disease and VE vs. VCO2 slope after adjusting for age, gender, body mass index, types of CVD and medications. CONCLUSIONS: Completion of a 5-month CR program was associated with the prevention of all-cause death and hospital admission, but not CVD death and hospital admission in the long-term, which suggests that we need to reconsider this issue.

Possibility of Cardio-renal Protection by Long-term Cardiac Rehabilitation in Elderly Patients with Cardiovascular Diseases.

Objective Cardiac rehabilitation (CR) improves the mortality in patients with cardiovascular disease (CVD). Even in elderly patients with CVD, CR may improve the activities of daily living (ADL). Methods Eighty-eight outpatients over 65 years of age at the beginning of a CR program (baseline) at Fukuoka University Hospital who had CVD and could be followed-up for up to 5 years were enrolled. CVD included ischemic heart disease, postoperative valvular heart disease, dissecting aneurysm of the aorta and peripheral artery disease. The patients were divided into 2 groups according to the average estimated glomerular filtration rate (eGFR) at baseline (55.4±14.8 mL/min/1.73 m2): high (≥55.4, n=44) and low (<55.4, n=44)-eGFR groups. The anaerobic threshold (AT) during exercise and left ventricular ejection fraction (LVEF) were measured by cardiopulmonary exercise (CPX) and ultrasound cardiography, respectively. The serum brain natriuretic protein (BNP) was also measured every year. Results The average age at baseline in all patients was 73±6 years. In all patients, the level of eGFR did not significantly change for 5 years (55±15 mL/min/1.73 m2 at baseline vs. 48±14 at the end of the study). The AT (3.7±1.0 METs at baseline vs. 3.3±0.5), LVEF (57±13% vs. 64±10%) and BNP (260±452 pg/mL vs. 308±345) were also maintained for 5 years. In both the low- and high-eGFR groups, the eGFR, AT during exercise, LVEF and BNP at the end of the study were not significantly changed compared to the baseline values, although some changes were observed during the follow-up period. Conclusion Long-term CR in CVD outpatients over 65 years of age helped maintain the AT, LVEF, BNP and eGFR for 5 years. CR afforded cardio-renal protection in elderly patients with CVD.

Recommendations of Lifestyle Modification According to a Survey of First-Year University Students.

BACKGROUND: We analyzed what kind of lifestyle modification first-year university students need based on the results of a health-consciousness survey conducted in first-year students immediately after they entered a university. METHODS: This population-based cross-sectional study used a "questionnaire survey on lifestyle and health for promoting health" conducted in Japan in 2015. From among an initial pool of 3,912 students, we excluded 314 due to insufficient data. The remaining 3,598 students (2,206 males and 1,392 females) were divided into four groups according to body mass index (BMI) based on Japan Society for the Study of Obesity "Guidelines for the management of obesity disease 2016": low (18.5 > BMI), less than standard (22.0 > BMI ≥ 18.5), standard or higher (25.0 > BMI ≥ 22.0) and obesity (BMI ≥ 25.0). RESULTS: Females had an ideal body image that was at a lower body weight regardless of their BMI. Males in the low BMI and obesity groups tended to be less aware of health issues. For each level of BMI, and in both males and females, the most frequent report of stress was "sometimes feel". The most frequent method for relieving stress was spending time with friends. Among males, those in the obesity group spent more time with "personal computers, televisions and games, etc." in a sitting position. When students were asked to rank which of their lifestyle habits needed the most improvement, "lack of exercise" was the highest, followed by "irregular schedule" and "dietary habits". In daily living behavior, a significant difference was observed for "exercise" among males, but not females. CONCLUSION: The attitudes of both males and females regarding the importance of physical activity and the necessity of efforts to improve health are presented. Health education for university students based on the attitudes may be useful for the prevention of lifestyle-related diseases for themselves in the future and before they become parents.

Cardiac rehabilitation in patients with cardiovascular disease leads various hemodynamic parameters obtained using simple non-invasive tests to their appropriate levels.

We evaluated whether comprehensive cardiac rehabilitation (CR) in patients with cardiovascular disease (CVD) could improve various hemodynamic parameters obtained using simple non-invasive tests. We analyzed 48 CVD patients with (n = 38, CR group) or without (n = 10, non-CR group) a CR program, and prospectively followed them for 12 months. Various parameters were measured at baseline and after 12 months using 3 simple non-invasive tests: blood pressure (BP) and severity of atherosclerosis [arterial velocity pulse index (AVI) and atrial pressure volume index] were determined using PASESA®, an index of total autonomic nerve activity and a coefficient of variation of the R-R interval (CVRR) were determined using eHEART®, and the total peripheral resistance, stroke volume and cardiac index (CI) were determined using nico®. The main hemodynamic parameters did not change between baseline and 12 months in both groups. Patients in the CR group were divided into higher (H-) and lower (L-) systolic BP (SBP) or AVI according to the average value of SBP or AVI at baseline in the CR group. Patients with H-SBP or H-AVI in the CR group showed a significant reduction of SBP or AVI at 12 months. In addition, patients in the CR group were divided into H- and L- CI or CVRR according to the average value of CI or CVRR at baseline in the CR group. Patients with L-CI or L-CVRR in the CR group significantly improved after 12 months. In conclusion, CR may lead various hemodynamic parameters obtained using simple non-invasive tests to their appropriate levels.

Effects of Tolvaptan With or Without the Pre-Administration of Renin-Angiotensin System Blockers in Hospitalized Patients With Acute Decompensated Heart Failure.

We examined whether tolvaptan combined with an angiotensin II receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACE-I) is more effective than tolvaptan alone in the treatment of patients with heart failure (HF). Sixty-five hospitalized patients with acute decompensated HF were included in this study. They were divided into 2 groups; an ARB/ACE-I group (n = 44, who received ARB or ACE-I before the use of tolvaptan) and a non-ARB/ACE-I group (n = 21). There were no significant differences in patient characteristics including medications at baseline between the non-ARB/ACE-I and ARB/ACE-I groups with the exception of the percentages of hypertension and ischemic heart disease. Urinary volume (UV) at baseline in the ARB/ACE-I group was slightly higher than that in the non-ARB/ACE-I group. The increase in UV after the use of tolvaptan in the non-ARB/ACE-I group was significantly higher than that in the ARB/ACE-I group. The cardiothoracic ratio and the reduction in body weight were similar between the groups after tolvaptan use. Finally, in a logistic regression analysis, a response to the use of tolvaptan was independently associated with the non-use of ARB/ACE-I, but not with age, gender, body mass index, loop diuretic, or human arterial natriuretic peptide. In conclusion, tolvaptan alone might induce an increase in UV in decompensated HF patients without ARB/ ACE-I, although the treatment of HF with ARB/ACE-I is the first choice strategy.

Significance of Cardiac Rehabilitation on Visit-to-Visit Variability of Blood Pressure in Patients With Cardiovascular Disease in a 12-Month Follow-Up.

BACKGROUND: Visit-to-visit variability (VVV) in blood pressure (BP) has been shown to be a strong predictor of cardiovascular disease (CVD). However, the long-term effect of comprehensive cardiac rehabilitation (CR) with exercise training on VVV in BP has not yet been established. Therefore, we evaluated the long-term effects of CR on VVV in BP in patients with CVD. METHODS: Twenty-two CVD patients in a 12-month CR program who had at least six clinic visits per month to measure BP were enrolled. We determined VVV in BP expressed as the standard deviation of average BP every month for 12 months. RESULTS: The mean age was 70 ± 8 years and the body mass index was 24.4 ± 4.9 kg/m2. In addition, the percentage (%) of males, % heart failure and % ischemic heart disease were 77%, 55% and 27%, respectively. Patients who had uncontrolled BP at baseline showed a significant reduction of both systolic BP (SBP) and diastolic BP (DBP). VVV in SBP in the first month was significantly less than that in the last month, although there was no difference in VVV in DBP. Patients were divided into larger (L-) and smaller (S-) VVV in SBP groups according to the average value of VVV in SBP as a cut-off. The L-VVV in SBP group, but not the S-VVV in SBP group, showed a significant reduction of VVV in SBP. CONCLUSION: Comprehensive CR may improve VVV in SBP in CVD patients who have larger VVV in SBP.

The Change in Body Weight During Hospitalization Predicts Mortality in Patients With Acute Decompensated Heart Failure.

BACKGROUND: In our experience, the change in body weight (BW) during hospitalization varies greatly in patients with acute decompensated heart failure (HF). Since the clinical significance of a change in BW is not clear, we investigated whether a change in BW could predict mortality. METHODS: We retrospectively enrolled 130 patients (72 males; aged 68 ± 10 years) who were hospitalized due to acute decompensated HF and followed for 2 years after discharge. The change in the BW index during hospitalization (ΔBWI) was calculated as (BW at hospital admission minus BW at hospital discharge)/body surface area at hospital discharge. RESULTS: The patients were divided into quartiles according to ΔBWI, and the 2-year mortality rates in the quartiles with the lowest, second, third and highest ΔBWI were 18.8%, 12.1%, 3.1% and 9.1%, respectively. In a multivariate Cox proportional hazards analysis after adjusting for variables with a P value less than 0.05, ΔBWI was independently associated with 2-year mortality (P = 0.0002), and the quartile with the lowest ΔBWI had a higher relative risk (RR) for 2-year mortality than the quartile with the highest ΔBWI (RR: 7.46, 95% confidence interval: 1.03 - 53.99, P = 0.04). CONCLUSION: In conclusion, ΔBWI was significantly associated with 2-year mortality after discharge, which indicates that ΔBWI might be a simple predictor of prognosis in acute decompensated HF.

Efficacy and Safety of Combination Therapy Consisting of Angiotensin II Type 1 Receptor Blocker, Calcium Channel Blocker and Hydrochlorothiazide in Patients With Hypertension.

BACKGROUND: Many patients continue to have high blood pressure (BP) even after treatment with high-dose (H)-angiotensin II type 1 receptor blocker (ARB)/calcium channel blocker (CCB) or middle-dose (M)-ARB/CCB/hydrochlorothiazide (HCTZ). METHODS: Thirty-two hypertensive patients who had the use of H-ARB/CCB or M-ARB/CCB/HCTZ were enrolled in this study. We applied a changeover with a switch to H-ARB (telmisartan 80 mg/day)/CCB (amlodipine 5 mg/day or nifedipine CR 40 mg/day)/HCTZ (12.5 mg/day). RESULTS: Systolic BP (SBP) and diastolic BP (DBP) were significantly decreased in all patients and in the H-ARB/CCB and M-ARB/CCB/HCTZ groups after 3 months. Percentage (%) of patients who reached the target BP after 3 months (72%) in all patients was significantly higher than that at 0 months (19%). There were no serious adverse effects in any of the patients. CONCLUSIONS: Combination therapy with H-ARB/CCB/HCTZ was associated with a significant reduction of BP.

Advanced glycation of high-density lipoprotein and the functionality of aldosterone release in type 2 diabetes.

Patients with type 2 diabetes mellitus (DM) exhibit modification of high-density lipoprotein (HDL), which is likely to have an important role in the development of atherosclerotic cardiovascular disease (ASCVD). Excess production of aldosterone (Ald) results in hypertension as well as ASCVD. However, the biological activity of modified HDL in steroidogenesis is not clear. We measured the accumulation of thiobarbituric acid-reactive substances (TBARSs) and Nɛ-(carboxymethyl)lysine (CML) levels (markers of oxidation and glycoxidation, respectively) in isolated HDL from 41 patients with type 2 diabetes mellitus (DM group) and 41 age- and gender-matched patients in a non-DM group. We quantified angiotensin II-sensitized and -nonsensitized Ald release using a validated living adrenocortical cell assay. TBARS levels in isolated HDL were similar between patients in the DM and non-DM groups, whereas the CML content of HDL in the DM group was lower than that in the non-DM group, irrespective of higher blood glucose and hemoglobin A1c levels. There was no difference in the HDL-induced ex vivo Ald release between the groups. Although sustained hyperglycemia was not a determinant of HDL-induced Ald release, the degree of HDL glycoxidation was inversely associated with HDL-induced Ald release (r=-0.40, P<0.001). In conclusion, in vivo advanced glycoxidation of HDL had an inverse effect on HDL-induced Ald release, independent of the prevalence of type 2 DM.

Depressor and Anti-Inflammatory Effects of Angiotensin II Receptor Blockers in Metabolic and/or Hypertensive Patients With Coronary Artery Disease: A Randomized, Prospective Study (DIAMOND Study).

BACKGROUND: We compared the efficacy and safety of azilsartan to those of olmesartan in a prospective, randomized clinical trial. METHODS: Forty-four hypertensive patients who had coronary artery disease (CAD) were enrolled. We randomly assigned patients to changeover from their prior angiotensin II receptor blockers (ARBs) to either azilsartan or olmesartan, and followed the patients for 12 weeks. RESULTS: Office systolic blood pressure (SBP) in the azilsartan group was significantly decreased after 12 weeks. SBP and diastolic blood pressure (DBP) after 12 weeks in the azilsartan group were significantly lower than those in the olmesartan group. The percentage of patients who reached the target BP at 12 weeks (78%) in the azilsartan group was significantly higher than that at 12 weeks (45%) in the olmesartan group. There were no significant changes in pentraxin-3, high-sensitively C-reactive protein or adiponectin in blood after 12 weeks in either group. Although serum levels of creatinine (Cr) in the azilsartan group significantly increased, these changes were within the respective normal range. CONCLUSION: In conclusion, the ability of azilsartan to reduce BP may be superior to that of prior ARBs with equivalent safety in hypertensive patients with CAD.

Visit-to-Visit Variability and Reduction in Blood Pressure After a 3-Month Cardiac Rehabilitation Program in Patients With Cardiovascular Disease.

Visit-to-visit variability (VVV) in blood pressure (BP) has been shown to be a predictor of cardiovascular events. It is unknown whether CR can improve VVV in BP as well as reducing BP. We enrolled 84 patients who had cardiovascular disease (CVD) and participated in a 3-month CR program. We measured systolic and diastolic BP (SBP and DBP), pulse pressure (PP), and heart rate (HR) before exercise training at each visit and determined VVV in BP or HR expressed as the standard deviation of the average BP or HR. Patients who had uncontrolled BP at baseline and who did not change their antihypertensive drugs throughout the study period showed a significant reduction of both SBP and DBP with a decrease in PP after 3 months. Patients who did not change their antihypertensive drugs were divided into larger (L-) and smaller (S-) VVV in the SBP groups and L- and S-VVV in the DBP groups according to the average value of VVV in SBP or DBP. In the L-VVV in the SBP and DBP groups, VVV in SBP and DBP in the 1st month was significantly decreased after the 3rd month in both groups. HR at baseline was significantly decreased after 3 months. In addition, CR induced a significant increase in the level of high-density lipoprotein cholesterol (HDL-C) in blood. In conclusion, CR improved VVV in BP in patients with L-VVV in BP and evoked a significant reduction in HR and an increase in HDL-C. These effects due to the CR program may be cardioprotective.

The angiotensin II type 1 receptor-neprilysin inhibitor LCZ696 blocked aldosterone synthesis in a human adrenocortical cell line.

A recent clinical study indicated that an angiotensin II (Ang II) type 1 (AT1) receptor-neprilysin inhibitor (ARNi) designated LCZ696 (sacubitril/valsartan, as combined sodium complex) was superior to enalapril at reducing the risks of death and hospitalization due to heart failure. Therefore, we investigated the possible mechanisms of the beneficial effect of LCZ696, in which the inhibition of neprilysin enhances atrial natriuretic peptide (NP) or brain NP (ANP or BNP)-evoked signals that can block Ang II/AT1 receptor-induced aldosterone (Ald) synthesis in human adrenocortical cells. The binding affinity of valsartan+LBQ657 (active moiety of sacubitril) to the AT1 receptor was greater than that of valsartan alone in an AT1 receptor-expressing human embryonic kidney cell-based assay. There was no difference in the dissociation from the AT1 receptor between valsartan+LBQ657 and valsartan alone. In Ang II-sensitized human adrenocortical cells, ANP or BNP alone, but not LBQ657 or valsartan alone, significantly decreased Ald synthesis. The level of suppression of Ald synthesis by ANP or BNP with LBQ657 was greater than that by ANP or BNP without LBQ657. The suppression of ANP was blocked by inhibitors of regulator of G-protein signaling proteins and cyclic GMP-dependent protein kinase. The inhibition of neprilysin did not change the mRNA levels of the AT1 receptor, ANP receptor A, regulator of G-protein signaling protein, renin or 3ß-hydroxysteroid dehydrogenases. In conclusion, the inhibition of neprilysin by LBQ657 enhances the NP-evoked signals that can block Ang II/AT1 receptor-induced Ald synthesis in human adrenocortical cells.