A scoring evaluation for the practical introduction of guideline-directed medical therapy in heart failure patients.

AIMS: The guideline-directed medical therapy (GDMT) has been recommended for heart failure (HF) with reduced ejection fraction (HFrEF) based on the accumulating clinical evidence. However, it is difficult to implement all the trial-proven medications for every patient in the real world. METHODS AND RESULTS: A simple GDMT score was created, according to the combination of GDMT drugs (renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose transporter 2 inhibitors) administration and their dosage (0-9 points). Its impact on the prognosis of HF patients was investigated. Admitted HF patients [HFrEF and HF with mildly reduced ejection fraction (HFmrEF), n = 1054] were retrospectively analysed (excluding those with in-hospital death and dialysis). A simple GDMT score ≥5, but not the number of medications, was significantly associated with a reduction of all-cause death, HF readmission, and composite outcome (HF readmission and all-cause death) (P < 0.001). Subgroup analysis showed that almost all groups with a simple GDMT score of 5 or higher had a better prognosis. CONCLUSIONS: The developed simple GDMT score was associated with prognosis in HFrEF and HFmrEF patients. Even if all four drugs cannot be introduced for some reason, a regimen with a simple GDMT score ≥5 may lead to a prognosis in HF patients.

Early Initiation of Sodium-Glucose Cotransporter 2 Inhibitor Leads to a Shorter Hospital Stay in Patients With Acute Decompensated Heart Failure.

Background: The efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with acute chronic heart failure (HF) is increasingly being reported. However, it is not clear when SGLT2i should be initiated in patients with acute decompensated HF (ADHF) after hospitalization. We retrospectively analyzed ADHF patients with newly prescribed SGLT2i. Methods and Results: Among the 694 patients hospitalized due to HF between May 2019 and May 2022, data were extracted for 168 patients with newly prescribed SGLT2i during the index hospitalization. These patients were divided into 2 groups: and early group (92 patients who started SGLT2i within 2 days of admission) and a late group (76 patients who started SGLT2i after 3 days). Clinical characteristics were comparable between the 2 groups. The date of cardiac rehabilitation initiation was significantly earlier in the early than late group (2.5±1.2 vs. 3.8±2.2 days; P<0.001). Hospital stay was significantly shorter in the early group (16.4±6.5 vs. 24.2±16.0 days; P<0.001). Although there were significantly fewer HF readmissions within 3 months in the early group (2.1% vs. 10.5%; P=0.044), the association disappeared in a multivariate analysis including clinical confounders. Conclusions: Early initiation of SGLT2i may shorten hospital stays.

Use of a Cutting Balloon Reduces the Incidence of Distal Embolism in Acute Coronary Syndrome Requiring Predilatation Before Stenting.

Background: Acute coronary syndrome (ACS) patients with solid lesions often require predilatation before stenting. Predilatation with high pressure may increase the risk of distal embolism, whereas direct stenting increases the risk of stent underexpansion. We recently reported that, in severely calcified lesions, using a cutting balloon (CB) can provide greater acute gain compared with other scoring balloons. Therefore, we hypothesized that predilatation with CB may reduce the incidence of distal embolism in ACS patients with solid lesions. Methods and Results: This study retrospectively analyzed data for 175 ACS patients who required predilatation, either with a conventional balloon (n=136) or CB (n=39). The occurrence of distal embolism was significantly lower in the CB than conventional balloon group (10.3% vs 32.4%, respectively; P=0.007). Multivariate analysis showed that the occurrence of distal embolism was positively associated with Thrombolysis in Myocardial Infarction (TIMI) grade and the presence of attenuated plaque, but negatively associated with the use of a CB. To support this clinical observation, we compared thrombus dispersal using a CB and non-compliant balloon in an ex vivo experimental model using a pseudo-thrombus. In this model, pseudo-thrombus dispersal was significantly smaller when a CB rather than non-compliant balloon was used (1.8±1.0% vs 2.6±1.2%, respectively; n=20, for each; P=0.002). Conclusions: In ACS patients with solid lesions that require predilatation, predilatation with a CB may reduce the incidence of distal embolism.

Diagnostic performance of nutritional indicators in patients with heart failure.

AIMS: The aim of this study was to compare the diagnostic performance of the nutritional indicators, the mini nutritional assessment-short form (MNA-SF), the geriatric nutritional risk index (GNRI), and the controlling nutritional status (CONUT), in heart failure (HF) patients. METHODS AND RESULTS: Nutritional status was prospectively assessed by the aforementioned three nutritional indicators in 150 outpatients with HF who were then followed for 1 year. The prevalence of patients with the nutritional risk as assessed by the MNA-SF, GNRI, and CONUT scores was 50.0%, 13.3%, and 54.0%, respectively. There was slight agreement of nutritional risk assessment between the MNA-SF and GNRI scores (κ coefficient = 0.16), as well as the GNRI and CONUT scores (κ = 0.11), but poor agreement between the MNA-SF and CONUT scores (κ = -0.09). The CONUT score had the lowest area under the curve (AUC) for the identification of low body weight, low muscle mass, and low physical function among the three indicators (all P < 0.05). Compared with the MNA-SF score, both the GNRI and CONUT scores had lower AUCs for the identification of reduced dietary intake and weight loss (all P < 0.05). There was no significant difference in predicting all-cause mortality or HF rehospitalization among the three indicators. The prescription of statins reduced the diagnostic performance of the CONUT score, as the CONUT score includes cholesterol level assessment. CONCLUSIONS: Of the three indicators, the diagnostic ability of the MNA-SF score was the highest, and that of the CONUT score was the lowest, for the assessment of HF patient nutritional status. The CONUT score may misrepresent nutritional status, particularly in patients receiving statins.

Impact of citrus fruit intake on the mental health of patients with chronic heart failure.

BACKGROUND: The full impact of the intake of citrus fruits on the risk of depression in individuals with chronic heart failure (HF) is unknown. Here, we examined the associations between the estimated habitual intakes of citrus fruits and depressive symptoms in patients with chronic HF. METHODS: We enrolled 150 stable outpatients with chronic HF who had a history of worsening HF. To assess the patients' daily dietary patterns, we used a brief self-administered diet-history questionnaire to calculate the daily consumption of foods and nutrients. To assess the patients' mental state, we used a nine-item Patient Health Questionnaire (PHQ-9). RESULTS: Twelve patients (8%) were identified as having moderate-to-severe depression (PHQ-9 score ≥10). The patients with PHQ-9 ≥10 had lower daily intakes of citrus fruits compared to those with no or mild depressive symptoms (PHQ-9 <10). The daily intakes of various antioxidants, including vitamin C, ß-carotene, and ß-cryptoxanthin, all of which are abundant in citrus fruits, were reduced in the patients with PHQ-9 ≥10, accompanied by higher serum levels of 8-isoprostane (an oxidative stress marker). A multivariate logistic regression analysis using forward selection showed that a lowered daily intake of citrus fruits was an independent predictor of the comorbidity of moderate-to-severe depression in patients with chronic HF, after adjustment for age, gender, and the hemoglobin value. CONCLUSIONS: A lower daily consumption of citrus fruits was associated with higher prevalence of depression in patients with chronic HF. Our findings support the hypothesis that a daily consumption of citrus fruits has a beneficial effect on the prevention and treatment of depression in chronic HF patients.

Early follow-up at outpatient care after discharge improves long-term heart failure readmission rate and prognosis.

AIMS: It has been reported that congestive heart failure (CHF) readmission has not decreased in the last decade. It is also reported that CHF readmission is likely to occur shortly after discharge. We investigated whether an early follow-up at outpatient care within 2 weeks after discharge affects the long-term readmission rate and prognosis. METHODS AND RESULTS: We reviewed consecutive 1002 patients admitted to our hospital due to CHF. Two-hundred and fifty-nine patients who died in-hospital or were transferred to another hospital or readmitted within 2 weeks were excluded and 743 of discharged patients were analysed. We extracted contributing variables associated with heart failure (HF) readmission and the composite adverse outcome (all cause death or HF readmissions) by univariate and multivariate analysis. Multivariate analysis showed that the early follow-up was independently associated with freedom from HF readmission and the composite outcome. We divided these patients into two groups, with/without early follow-up and performed a propensity score-matching analysis (n = 259 each). HF readmission during 2 year follow-up was significantly less in the early follow-up group [P = 0.02, hazard ratio (HR) = 0.647, 95% confidence interval (CI) = 0.447-0.935] as well as the composite outcome was less in the early follow-up group (P = 0.01, HR = 0.643, 95% CI = 0.456-0.908). Medication adjustments were done in only 33.2% of the patients. Rates of HF readmissions were comparable regardless of whether or not medication adjustment was done at the early follow-up (P = 0.505, HR = 1.208, 95% CI = 0.692-2.106). CONCLUSIONS: The present study demonstrates that an early follow-up approach after discharge in CHF patients may improve the long-term prognosis. These results may not depend on medication adjustment but rather on modifying patient factors early after discharge.

Impact of Inadequate Calorie Intake on Mortality and Hospitalization in Stable Patients with Chronic Heart Failure.

Malnutrition is highly prevalent in patients with heart failure (HF), but the precise impact of dietary energy deficiency on HF patients' clinical outcomes is not known. We investigated the associations between inadequate calorie intake and adverse clinical events in 145 stable outpatients with chronic HF who had a history of hospitalization due to worsening HF. To assess the patients' dietary pattern, we used a brief self-administered diet-history questionnaire (BDHQ). Inadequate calorie intake was defined as <60% of the estimated energy requirement. In the total chronic HF cohort, the median calorie intake was 1628 kcal/day. Forty-four patients (30%) were identified as having an inadequate calorie intake. A Kaplan-Meier analysis revealed that the patients with inadequate calorie intake had significantly worse clinical outcomes including all-cause death and HF-related hospitalization during the 1-year follow-up period versus those with adequate calorie intake (20% vs. 5%, p < 0.01). A multivariate logistic regression analysis showed that inadequate calorie intake was an independent predictor of adverse clinical events after adjustment for various factors that may influence patients' calorie intake. Among patients with chronic HF, inadequate calorie intake was associated with an increased risk of all-cause mortality and rehospitalization due to worsening HF. However, our results are preliminary and larger studies with direct measurements of dietary calorie intake and total energy expenditure are needed to clarify the intrinsic nature of this relationship.

Clinical and Prognostic Values of ALBI Score in Patients With Acute Heart Failure.

BACKGROUND: Although liver dysfunction is one of the common complications in patients with acute heart failure (AHF), no integrated marker has been defined. The albumin-bilirubin (ALBI) score has recently been proposed as a novel, clinically-applicable scoring system for liver dysfunction. We investigated the utility of the ALBI score in patients with AHF compared to that for a preexisting liver dysfunction score, the Model of End-Stage Liver Disease Excluding prothrombin time (MELD XI) score. METHODS: We evaluated ALBI and MELD XI scores in 1,190 AHF patients enrolled in the prospective, multicentre Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure study. The associations between the two scores and the clinical profile and prognostic predictive ability for 1-year mortality were evaluated. RESULTS: The mean MELD XI and ALBI scores were 13.4±4.8 and -2.25±0.48, respectively. A higher ALBI score, but not higher MELD XI score, was associated with findings of fluid overload. After adjusting for pre-existing prognostic factors, the ALBI score (HR 2.11, 95% CI: 1.60-2.79, p<0.001), but not the MELD XI score (HR 1.02, 95% CI: 0.99-1.06, p=0.242), was associated with 1-year mortality. Likewise, area under the receiver-operator-characteristic curves for 1-year mortality significantly increased when the ALBI score (0.71 vs. 0.74, p=0.020), but not the MELD XI score (0.71 vs. 0.72, p=0.448), was added to the pre-existing risk factors. CONCLUSIONS: The ALBI score is potentially a suitable liver dysfunction marker that incorporates information on fluid overload and prognosis in patients with AHF. These results provide new insights into heart-liver interactions in AHF patients.

Plaque modification using a cutting balloon is more effective for stenting of heavily calcified lesion than other scoring balloons.

Cutting balloons (CBs) and other scoring balloons are known to be useful for plaque modification in heavily calcified lesions. There have been some reports of the efficacy of these balloons compared to conventional balloons. However, there have been no reports exploring which balloon is most effective among these three types of balloons. We, therefore, compared these three balloons with respect to effectiveness in plaque modification of calcified lesions. We retrospectively investigated 201 cases using these three balloons from April 2015 to December 2017. Of these cases, 156 with severe calcified lesions that had undergone intravascular ultrasound (IVUS) or optical frequency domain imaging (OFDI) were enrolled. The ratio of severe calcified lesion was higher in the CB group than in the groups of other balloons (p = 0.001), and IVUS and OFDI showed that a CB was more effective in plaque modification than the other balloons. The acute gain (minimum stent diameter minus minimum lumen diameter) and acute cross-sectional area (CSA) gain (minimum stent area minus minimum lumen area) were both larger in the CB group than in the others, and the stent symmetry index (minimum stent diameter/maximum stent diameter) showed that the CB group more closely approximated a perfect circle than the other groups (p = 0.0001, 0.006 and 0.002 for the acute gain, acute CSA gain and the stent symmetry index). Similar results were obtained in cases without rotational atherectomy. These data suggest that CB is more effective for plaque modification in cases of severe calcified lesions than other scoring balloons.

Specialty-Related Differences in the Acute-Phase Treatment and Prognosis in Patients With Acute Heart Failure　- Insights From REALITY-AHF.

BACKGROUND: The aim of this study was to assess specialty-related differences in the treatment for patients with acute heart failure (AHF) in the acute phase and subsequent prognostic differences. Methods and Results: We analyzed hospitalizations for AHF in REALITY-AHF, a multicenter prospective registry focused on very early presentation and treatment in patients with AHF. All patients were classified according to the medical specialty of the physicians responsible for contributed most to decisions regarding the initial diagnosis and treatment after the emergency department (ED) arrival. Patients initially managed by emergency physicians (n=614) or cardiologists (n=911) were analyzed. After propensity-score matching, vasodilators were used less often by emergency physicians than by cardiologists at 90 min after ED arrival (29.8% vs. 46.1%, P<0.001); this difference was also observed at 6, 24, and 48 h. Cardiologists administered furosemide earlier than emergency physicians (67 vs. 102 min, P<0.001). However, the use of inotropes, noninvasive ventilation, and endotracheal intubation were similar between groups. In-hospital mortality did not differ between patients managed by emergency physicians and those managed by cardiologists (4.1% vs. 3.8%, odds ratio 1.12; 95% confidence interval 0.58-2.14). CONCLUSIONS: Despite differences in initial management, no prognostic difference was observed between emergency physicians and cardiologists who performed the initial management of patients with AHF.

Efficacy and safety of the early use of V2 receptor antagonists in elderly patients with decompensated heart failure.

We recently reported that the early initiation of tolvaptan in congestive heart failure shortened the hospital stay and reduced the rate of in-hospital death. However, whether or not these results apply to elderly patients with congestive heart failure is unclear. We performed a sub-analysis of our previous study. Among the 102 patients in that study, we retrospectively analyzed the elderly patients >75 years of age treated with tolvaptan. First, we analyzed the efficacy of early tolvaptan use in these patients. We then compared the efficacy and the safety of all tolvaptan use between elderly and younger patients. There were no significant differences in the baseline clinical parameters between the early- and late-tolvaptan-use elderly patients, except for the serum blood nitrogen urea. However, the early use of tolvaptan was also associated with the earlier initiation of ambulatory cardiac rehabilitation, a shorter hospital stay, and a lower rate of in-hospital death in elderly congestive heart failure patients. Furthermore, there were no significant differences in the occurrence of worsening renal failure and hypernatremia. The early use of tolvaptan in elderly patients was also associated with a shorter hospital stay and reduced mortality. We also confirmed the safety of tolvaptan in elderly patients. It might, therefore, be beneficial to consider administering tolvaptan early in elderly patients with heart failure, just as in younger patients.

Time-to-Furosemide Treatment and Mortality in Patients Hospitalized With Acute Heart Failure.

BACKGROUND: Acute heart failure (AHF) is a life-threatening disease requiring urgent treatment, including a recommendation for immediate initiation of loop diuretics. OBJECTIVES: The authors prospectively evaluated the association between time-to-diuretic treatment and clinical outcome. METHODS: REALITY-AHF (Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure) was a prospective, multicenter, observational cohort study that primarily aimed to assess the association between time to loop diuretic treatment and clinical outcome in patients with AHF admitted through the emergency department (ED). Door-to-furosemide (D2F) time was defined as the time from patient arrival at the ED to the first intravenous furosemide injection. Patients with a D2F time <60 min were pre-defined as the early treatment group. Primary outcome was all-cause in-hospital mortality. RESULTS: Among 1,291 AHF patients treated with intravenous furosemide within 24 h of ED arrival, the median D2F time was 90 min (IQR: 36 to 186 min), and 481 patients (37.3%) were categorized as the early treatment group. These patients were more likely to arrive by ambulance and had more signs of congestion compared with the nonearly treatment group. In-hospital mortality was significantly lower in the early treatment group (2.3% vs. 6.0% in the nonearly treatment group; p = 0.002). In multivariate analysis, earlier treatment remained significantly associated with lower in-hospital mortality (odds ratio: 0.39; 95% confidence interval: 0.20 to 0.76; p = 0.006). CONCLUSIONS: In this prospective multicenter, observational cohort study of patients presenting at the ED for AHF, early treatment with intravenous loop diuretics was associated with lower in-hospital mortality. (Registry focused on very early presentation and treatment in emergency department of acute heart failure syndrome; UMIN000014105).

Early use of V2 receptor antagonists is associated with a shorter hospital stay and reduction in in-hospital death in patients with decompensated heart failure.

Tolvaptan is an oral antagonist of arginine vasopressin receptor 2 that has been approved in Japan to reduce congestive symptoms in patients with heart failure refractory to loop diuretics. However, it is unknown whether the early use of tolvaptan results in better clinical outcomes. We retrospectively analyzed 102 consecutive patients with decompensated heart failure treated with tolvaptan at our hospital. A given patient was defined as a responder when the maximum urine volume was greater than 150 % of that observed before tolvaptan use. A logistic regression analysis revealed that the early use of tolvaptan (within 3 days after admission) was an independent factor associated with tolvaptan responsiveness. There were no significant differences in the baseline clinical parameters between the early and late tolvaptan use groups. However, the early use of tolvaptan was associated with higher tolvaptan responsiveness, a shorter duration of carperitide infusion, earlier initiation of ambulatory cardiac rehabilitation, shorter hospital stay, lower rate of in-hospital death. The early use of tolvaptan was associated with a shorter hospital stay and reduced mortality in our retrospective cohort. It might therefore be beneficial to consider administering tolvaptan earlier in patients with heart failure.

Desert dust is a risk factor for the incidence of acute myocardial infarction in Western Japan.

BACKGROUND: Recently, there has been increasing concern about adverse health effects of exposure to desert dust events. However, the association between dust and the incidence of ischemic heart diseases is unknown. The aim of the present study was to elucidate whether Asian dust (AD), a windblown sand dust originating from mineral soil in China and Mongolia, is associated with the incidence of acute myocardial infarction (AMI). METHODS AND RESULTS: We investigated the data regarding hospitalization because of AMI among 3068 consecutive patients from 4 AMI centers in Fukuoka, Japan, and data for AD from April 2003 to December 2010. We applied a time-stratified case-crossover design to examine the association between AD and the incidence of AMI. Using a conditional logistic regression analysis, we estimated the odds ratios of AMI associated with AD after controlling for ambient temperature and relative humidity. The occurrence of AD events 0 to 4 days before the day of admission was significantly associated with the incidence of AMI. In particular, the occurrence of AD 4 days before admission was significantly associated with the onset of AMI. CONCLUSIONS: These data suggest that exposure to AD a few days before symptom onset is associated with the incidence of AMI.

Central neuregulin-1/ErbB signaling modulates cardiac function via sympathetic activity in pressure overload-induced heart failure.

OBJECTIVES: Neuregulin-1 (NRG-1)/ErbB signaling in the heart is reported to have a crucial role in heart failure. We recently demonstrated that NRG-1 signaling has sympathoinhibitory effects in the brain cardiovascular control center. How this central signaling impacts sympathoexcitation in heart failure, however, is unknown. Here we examined the role of central NRG-1/ErbB signaling in modulating the sympathetic nervous system in pressure overload-induced heart failure. METHODS AND RESULTS: Pressure overload-induced heart failure was induced in Wistar-Kyoto rats by banding the abdominal aorta. Rats were followed up for 15 weeks. Compared to sham-operated rats, aortic-banded rats showed left ventricle (LV) hypertrophy, LV dilation, and LV dysfunction [reducing fractional shortening (%fractional shortening), increased LV end-diastolic pressure, decreased positive and negative pressure differential (±dp/dt(max))], and increased urinary norepinephrine excretion. Aortic banding led to reduced expression of NRG-1 in the brainstem at 10 weeks after banding and reduced expression of ErbB2 at 5 weeks, but did not affect ErbB4. Central administration of recombinant NRG-1ß at 5 weeks for 2 weeks attenuated LV hypertrophy, improved LV dilatation, prevented LV dysfunction (improvement of %fractional shortening and ±dp/dt(max), and reduction of LV end-diastolic pressure), and lowered urinary norepinephrine excretion at 10 weeks, and these effects were still observed at 15 weeks. CONCLUSION: NRG-1/ErbB signaling in the brainstem is impaired during the progression of pressure overload-induced heart failure. Activation of central NRG-1 signaling improves cardiac function through sympathoinhibition. These findings provide a new treatment concept and support the benefit of NRG-1 treatment in heart failure.

Ratio of eicosapentaenoic acid to arachidonic acid is a critical risk factor for acute coronary syndrome in middle-aged older patients as well as younger adult patients.

BACKGROUND: Coronary risk factors for the onset of acute coronary syndrome (ACS), including polyunsaturated fatty acids (PUFAs), in younger adult patients may be different from those in older patients. METHODS AND RESULTS: We enrolled 578 patients who underwent coronary angiography at Fukuoka Saiseikai Hospital, and divided them into a younger adult group (YG) (<50 years, n=47) and a middle-aged older group (OG) (≥50 years, n=531). In a multivariate analysis, lower levels of high-density lipoprotein cholesterol and the ratio of eicosapentaenoic acid (EPA) to arachidonic acid (AA) (EPA/AA), and less aspirin, oral hypoglycemic agent, and calcium channel blocker (CCB) use were independent risk factors for ACS in all patients. In YG, lower levels of EPA/AA and less angiotensin II receptor blocker/angiotensin-converting enzyme inhibitor use were the independent risk factors. In OG, smoking, lower levels of EPA/AA, less aspirin and CCB use were the risk factors. While lower levels of EPA/AA was the only risk factor for ACS that was common to all patients, YG and OG, docosahexaenoic acid/AA was not associated with ACS in YG and OG. CONCLUSIONS: Lower level of EPA/AA is a common critical risk factor for ACS in middle-aged older patients as well as younger adult patients. Some of the risk factors for the onset of ACS in younger patients were different from those in older patients.

Moxonidine-induced central sympathoinhibition improves prognosis in rats with hypertensive heart failure.

OBJECTIVES: Enhanced central sympathetic outflow is an indicator of the prognosis of heart failure. Although the central sympatholytic drug moxonidine is an established therapeutic strategy for hypertension, its benefits for hypertensive heart failure are poorly understood. In the present study, we investigated the effects of central sympathoinhibition by intracerebral infusion of moxonidine on survival in a rat model of hypertensive heart failure and the possible mechanisms involved. METHODS AND RESULTS: As a model of hypertensive heart failure, we fed Dahl salt-sensitive rats an 8% NaCl diet from 7 weeks of age. Intracerebroventricular (ICV) infusion of moxonidine (moxonidine-ICV-treated group [Mox-ICV]) or vehicle (vehicle-ICV-treated group [Veh-ICV]) was performed at 14-20 weeks of age, during the increased heart failure phase. Survival rates were examined, and sympathetic activity, left ventricular function and remodelling, and brain oxidative stress were measured. Hypertension and left ventricular hypertrophy were established by 13 weeks of age. At around 20 weeks of age, Veh-ICV rats exhibited overt heart failure concomitant with increased urinary norepinephrine (uNE) excretion as an index of sympathetic activity, dilated left ventricle, decreased percentage fractional shortening, and myocardial fibrosis. Survival rates at 21 weeks of age (n = 28) were only 23% in Veh-ICV rats, and 76% (n = 17) in Mox-ICV rats with concomitant decreases in uNE, myocardial fibrosis, collagen type I/III ratio, brain oxidative stress, and suppressed left ventricular dysfunction. CONCLUSION: Moxonidine-induced central sympathoinhibition attenuated brain oxidative stress, prevented cardiac dysfunction and remodelling, and improved the prognosis in rats with hypertensive heart failure. Central sympathoinhibition can be effective for the treatment of hypertensive heart failure.

Role of hypothalamic angiotensin type 1 receptors in pressure overload-induced mineralocorticoid receptor activation and salt-induced sympathoexcitation.

Pressure overload enhances salt-induced sympathoexcitation through hypothalamic mineralocorticoid receptor (MR)-epithelial Na channel activation. Pressure overload also increases hypothalamic angiotensin type 1 receptors (AT1R). However, the role of AT1R in pressure overload-induced MR activation and salt-induced sympathoexcitation remains unknown. Therefore, the aim of the present study was to address this question. We performed aortic banding (AB) on mice from the Institute of Cancer Research. The expression of hypothalamic MR, serum/glucocorticoid-induced protein kinase-1 (SGK-1) and AT1R increased independently of plasma renin activity at 2 or 4 weeks after AB. Next, we performed AB in AT1aR-knockout (KO) mice and c57BL6/J wild-type (WT) mice. Sham-operated (Sham) mice were used as a control. Four weeks after AB (AB-KO or AB-WT), the expression of hypothalamic MR and SGK-1 increased in both AB-WT and AB-KO compared with Sham-WT and Sham-KO, respectively. The expression of AT1R was also greater in AB-WT than in Sham-WT. In addition, mice were fed a high-salt (8%) diet for an additional 4 weeks (ABH-KO and ABH-WT). High salt loading increased the urinary excretion of norepinephrine, a marker of sympathetic activity in ABH-WT, concomitant with hypothalamic MR activation, but not in ABH-KO. These results indicate that pressure overload activated hypothalamic MR independently of AT1R. After salt intake, however, AT1R was necessary to maintain hypothalamic MR activation and salt-induced sympathoexcitation.

Inhibition of neuregulin-1/ErbB signaling in the rostral ventrolateral medulla leads to hypertension through reduced nitric oxide synthesis.

BACKGROUND: We recently reported that activation of neuregulin-1 (NRG-1)/ErbB signaling in the rostral ventrolateral medulla (RVLM) of the brainstem elicits sympathoinhibition and depressor effects, and ErbB2-type ErbB receptors are involved in the neurogenic mechanisms of hypertension. Nitric oxide (NO) in the RVLM also elicits sympathoinhibition and depressor effects. NRG-1 enhances NO synthase (NOS) expression in several tissues. Here, we tested the hypothesis that ErbB2 inhibition in the RVLM contributes to increasing blood pressure via modulating the effects of NOS. METHODS: We measured the effects of chronic intracisternal infusion of an ErbB2 antagonist and local ErbB2 inhibition in the RVLM using RNA interference (ErbB2 siRNA) on blood pressure (BP), heart rate (HR), norepinephrine excretion (uNE), and NOS expression in the RVLM. The central effects of the ErbB2 antagonist or NRG-1ß were investigated with or without chronic and acute prior administration of a NOS inhibitor. RESULTS: Intracisternal infusion of the ErbB2 antagonist and ErbB2 siRNA increased BP, HR, and uNE; and reduced neuronal and endothelial NOS expression in the RVLM. Further, prior systemic administration of a NOS inhibitor abolished the pressor response to intracisternal infusion of an ErbB2 antagonist in awake rats. Prior injection of a NOS inhibitor or γ-aminobutyric acid-A receptor antagonist into the RVLM attenuated the depressor response to NRG-1 in anesthetized rats. CONCLUSIONS: These findings indicate that inhibition of ErbB2 expression in the RVLM leads to hypertension, at least in part, by reducing NO synthesis and inhibiting γ-aminobutyric acid activity. NRG-1/ErbB signaling in the RVLM might exist upstream of NO synthesis.

Mineralocorticoid receptors/epithelial Na(+) channels in the choroid plexus are involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats.

Increase in cerebrospinal fluid (CSF) Na(+) concentration ([Na(+)]) precedes hypertension and is a key step in the development of salt-induced hypertension. In the choroid plexus (CP), epithelial Na(+) channels (ENaCs) have an important role in Na(+) transport from the blood into the CSF. However, it remains unknown whether the mineralocorticoid receptors (MR)/ENaCs pathway in the CP of stroke-prone spontaneously hypertensive rats (SHRSP) is involved in neural mechanisms of hypertension. Therefore, we examined the role of the MR/ENaCs pathway in the CP in the development of hypertension in SHRSP associated with an increase in CSF [Na(+)]. As a marker of MR activation, serum/glucocorticoid-inducible kinase 1 (Sgk1) expression levels in the CP were measured and found to be greater in SHRSP than in Wistar-Kyoto (WKY) rats. CSF [Na(+)] levels were also higher in SHRSP than in WKY rats. In SHRSP, high-salt intake (8%) increased blood pressure and urinary norepinephrine excretion compared with those in animals fed a regular salt diet (0.5%) for 2 weeks. Furthermore, the expression levels of MR, Sgk1 and ENaCs in the CP and the increase in CSF [Na(+)] were greater in SHRSP fed a high-salt diet than in those fed a regular salt diet. These alterations were attenuated by intracerebroventricular infusion of eplerenone (10 µg kg(-1) per day), except for α-ENaC and ß-ENaC. We conclude that activation of the MR/ENaCs pathway in the CP contributes to hypertension via an increase in CSF [Na(+)], thereby exaggerating salt-induced hypertension with sympathetic hyperactivation in SHRSP.