Mean pulmonary artery pressure estimated by echocardiogram rapidly exceeds 20 mmHg from the normal range in patients with connective tissue disease.

Earlier intervention for pulmonary hypertension (PH) has been reported to improve the prognosis of patients with connective tissue disease (CTD). However, it is not fully elucidated how rapidly PH develops in patients showing normal mean pulmonary arterial pressure (mPAP) at the index investigation. We evaluated 191 CTD patients with normal mPAP retrospectively. The mPAP was estimated by the formerly defined method employing echocardiography (mPAPecho). We investigated predictive factors that predict increasing mPAPecho at follow-up transthoracic echocardiography (TTE) using uni- and multi variable analysis. The mean age was 61.5 years old, and 160 patients were female. The percentage of patients in whom mPAPecho exceeded 20 mmHg at follow-up TTE was 38%. Multivariable analysis revealed that acceleration time/ejection time (AcT/ET) measured at the right ventricular outflow tract at initial TTE was independently associated with the consequent increase of mPAPecho at the follow-up TTE. When using 0.43 of best cutoff value in AcT/ET calculated by receiver operating characteristic analysis, the change in mPAPecho in patients with low AcT/ET was significantly higher than in those with high AcT/ET (3.05 mmHg in patients with AcT/ET < 0.43 and 1.00 mmHg in patients with AcT/ET ≥ 0.43, p < 0.001). Thirty-eight percent of CTD patients who show the normal estimated mPAP by TTE develop gradual elevation of mPAP to the level to consider early intervention within 2 years. AcT/ET at initial TTE can predict increasing mPAP at follow-up TTE.

Plasma renin activity variation following admission predicts patient outcome in acute decompensated heart failure with reduced and mildly reduced ejection fraction.

Plasma renin activity (PRA) level at admission is reported to be a prognostic predictor of acute decompensated heart failure (ADHF) patients. Although PRA is affected during hospitalization by several factors including fluid volume and drug titration, whether the changes in PRA levels during hospitalization (ΔPRA) are associated with prognosis of ADHF patients are largely unknown. PURPOSE: Investigate the predictive impact of ΔPRA on the prognosis of ADHF patients with reduced ejection fraction (HFrEF) and mildly reduced ejection fraction (HFmrEF). METHODS: Retrospectively analyzed consecutive 116 HFrEF and HFmrEF patients admitted for ADHF. PRA measurements were acquired at admission and at discharge. The primary outcome was a composite of cardiovascular death and HF re-hospitalization. RESULTS: Out of 116 patients, 85 had PRA measurements both at admission and at discharge. Compared to admission, PRA level was significantly higher at discharge (0.8 (IQR 0.3-2.2) to 2.8 (IQR 1.0-7.2), p < 0.001). Tertiary groups ranked by PRA level on admission showed trend of poor prognosis in order of high, mid, and low PRA level (p = 0.07). On the contrary, PRA level at discharge significantly differentiated the prognosis and was poor in order of high, low, and mid (p = 0.026). Next, when the participants were divided into tertiary groups ranked by ΔPRA, prognosis worsened in the order of "minimal", "decreasing", and the "increasing" tier. Cubic splines analysis also indicate a similar tendency. CONCLUSIONS: In ADHF patients with HFrEF and HFmrEF, patients with minimal ΔPRA showed the better prognosis over the those with either increasing or decreasing.

Urine albumin-to-creatinine ratio on admission predicts early rehospitalization in patients with acute decompensated heart failure.

Detecting high-risk patients for early rehospitalization is crucial in heart failure patient care. An association of albuminuria with cardiovascular events is well known. However, its predictive impact on rehospitalization for acute decompensated heart failure (ADHF) remains unknown. In this study, 190 consecutive patients admitted due to ADHF between 2017 and April 2019 who underwent urinalysis were enrolled. Among them, 140 patients from whom urine albumin-to-creatinine ratio (UACR) was measured with spot urine samples on admission were further analyzed. The association between UACR and rehospitalization due to HF during 1 year after discharge was evaluated. The mean age of 140 participants was 77.6 years and 55% were men. Only 18% (n = 25) of patients presented with normoalbuminuria (UACR < 30 mg/g∙creatinine), whereas 59% (n = 83) and 23% (n = 32) showed microalbuminuria (UACR 30-300 mg/g·creatinine) and macroalbuminuria (UACR > 300 mg/g·creatinine), respectively. The level of UACR on admission was correlated with the risk of subsequent rehospitalization due to HF (p = 0.017). The receiver operating characteristic analysis indicated that the best cut-off values for the UACR and B-type natriuretic peptide (BNP) levels to predict ADHF rehospitalization were 50 mg/g·creatinine and 824 pg/ml, respectively. When the patients were divided into four groups using both cut-off values, the individual predictive impacts of UACR and BNP on rehospitalization were comparable. Patients with both elevated UACR and BNP levels had a higher rate of HF rehospitalization than those with elevated BNP levels alone (p < 0.05). The combination of both values enabled more accurate prediction of HF rehospitalization than BNP levels alone. In conclusion, UACR could be a new useful biomarker to predict HF rehospitalization in patients with ADHF, especially in combination with the levels of BNP, and should be further evaluated in a prospective study.

Efficacy and Safety of Early Initiation of Eplerenone Treatment in Patients with Acute Heart Failure (EARLIER trial): a multicentre, randomized, double-blind, placebo-controlled trial.

AIMS: A mineralocorticoid receptor antagonist (MRA) is effective in patients with chronic heart failure; however, the effects of the early initiation of an MRA in patients with acute heart failure (AHF) have not been elucidated. METHODS AND RESULTS: In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, we focused on the safety and effectiveness of the treatment with eplerenone, a selective MRA in 300 patients with AHF, that is, 149 in the eplerenone group and 151 in the placebo group in 27 Japanese institutions. The key inclusion criteria were (i) patients aged 20 years or older and (ii) those with left ventricular ejection fraction of ≤40%. The primary outcome was a composite of cardiac death or first re-hospitalization due to cardiovascular disease within 6 months. The mean age of the participants was 66.8 years, 27.3% were women, and the median levels of brain natriuretic peptide were 376.0 pg/mL. The incidences of the primary outcome were 19.5% in the eplerenone group and 17.2% in the placebo group [hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.642-1.855]. In prespecified secondary outcomes, HR for the composite endpoint, cardiovascular death, or first re-hospitalization due to heart failure within 6 months was 0.55 (95% CI: 0.213-1.434). The safety profile for eplerenone was as expected. CONCLUSION: The early initiation of eplerenone in patients with AHF could safely be utilized. The reduction of the incidence of a composite of cardiovascular death or first re-hospitalization for cardiovascular diseases by eplerenone is inconclusive because of inadequate power.

Effect of Oral Qing-Dai Medication on Pulmonary Arterial Pressure Levels in Patients With Ulcerative Colitis.

BACKGROUND: Qing-Dai (QD) treatment of patients with ulcerative colitis (UC) sometimes causes pulmonary arterial hypertension (PAH). However, the relationship of QD treatment to pulmonary arterial systolic pressure (PASP) in patients with UC has not been clarified.Methods and Results:The 27 patients with UC who were screened for PAH by transthoracic echocardiography (TTE) and underwent repeat TTE at 1 year were analyzed in this prospective observational study. Mean age was 44.0 years old, and median follow-up duration was 392. During the follow-up, 21 patients continued QD treatment (continuous group) and 6 patients discontinued the treatment (discontinuous group). In all patients, no significant difference in PASP levels between baseline and at follow-up was observed (21.4 vs. 21.3 mmHg, P=0.802). Furthermore, the mean PASP of patients in the continuous group did not differ from baseline to follow-up (21.4 mmHg to 22.6 mmHg, P=0.212); however, in the discontinuous group mean PASP was significantly decreased (21.5 mmHg to 16.8 mmHg, P=0.005). Moreover, changes in PASP from baseline to follow-up differed between the continuous and discontinuous groups (+1.1 mmHg vs. -4.7 mmHg, P=0.004). In addition, multivariable analyses revealed that only the duration of oral QD at baseline affected the increase of PASP. CONCLUSIONS: In patients with UC, QD treatment may have an undesirable association with an increase in PASP.

Manipulation of beta-adrenergic receptor in pressure-overloaded murine hearts mimics adverse and reverse cardiac remodeling.

Transverse aortic constriction (TAC) has been widely used to create pressure overload induced heart failure in mice. However, this conventional model has some limitations such as low reproducibility and long creation period of cardiac failure. In order to establish a highly reproducible cardiac failure model that mimics adverse cardiac remodeling (ACR) we combined pressure overload and beta-adrenergic receptor stimuli using isoproterenol (ISO) and explored the optimal TAC model by changing the durations of TAC and the doses of ISO. Thus we constructed a suitable model for ACR with an effective combination of 3-week TAC and subsequent one-week ISO (3 mg/kg/day) infusion. Using RNA-Seq analyses, we identified that the up-regulated genes were mainly related to fibrosis including Fbn1, C1qtnf6 and Loxl2; and that the down-regulated genes were associated with mitochondrial function including Uqcrc1, Ndufs3, and Idh2 in failing hearts of our ACR model. Next, we followed the changes in cardiac function after ceasing ISO infusion. Left ventricular function gradually recovered after cessation of ISO, suggesting cardiac reverse remodeling (CRR). Gene expression signatures of hearts, which exhibited CRR, were almost identical to that of TAC hearts without ISO. In conclusion, our new model exhibits a transition to ACR and subsequent CRR with high reproducibility. This murine model might add new insights into the experiments of heart failure technically as well as scientifically.

Reduction in Left Ventricular Ejection Fraction is Associated with Subsequent Cardiac Events in Outpatients with Chronic Heart Failure.

Left ventricular ejection fraction (LVEF) is critical for determining the prognosis and treatment of patients with heart failure (HF). However, the influence of serial LVEF changes in patients with stable chronic HF (CHF) has not yet been completely investigated. We analyzed data of 263 outpatients with CHF from the J-MELODIC study cohort and evaluated the frequency of cardiac events. We stratified patients into tertiles based on the relative difference in LVEF in 1 year and that at baseline. We found a significant difference in the cardiac event rate among the three groups (log-rank test, p = 0.042). We identified a relative 11% LVEF reduction as the optimal cutoff value based on the receiver operating characteristics analysis. LVEF (OR, 1.04; 95% CI, 1.01-1.07; p = 0.015) and E/e' (OR, 1.06; 95% CI, 1.01-1.12; p = 0.023) at baseline were predictors of >11% LVEF reduction. After adjusting the variables including age and sex, >11% LVEF reduction was an independent predictor of subsequent cardiac events (HR, 5.79; 95% CI, 2.49-13.2; p < 0.001). In conclusion, patients with 1-year relative >11% LVEF reduction may have subsequent worsening outcomes. Such patients should be carefully followed-up as high risk population for development of cardiac events.

Effects of Weight Loss in Outpatients With Mild Chronic Heart Failure: Findings From the J-MELODIC Study.

BACKGROUND: Weight loss is a strong prognostic factor in chronic heart failure (CHF); however, little is known about its effects in patients with mild CHF. Therefore, we investigated the effects of weight loss in patients with mild CHF. METHODS AND RESULTS: We analyzed a total of 242 outpatients with mild CHF from the J-MELODIC study cohort. Weight loss was defined as ≥5% weight loss in 1 year. Twenty-seven patients (11.2%) lost ≥5% weight in 1 year. Weight loss was associated with higher rates of underweight and worsening renal function in 1 year compared with the absence of ≥5% weight loss. The predictors of weight loss included edema, B-type natriuretic peptide, and diabetes mellitus at baseline. Although weight loss was significantly associated with subsequent cardiovascular death or hospitalization for HF (log-rank P = .002) and subsequent death from any cause (log-rank P = .002), underweight was not associated with these outcomes (log-rank P = .356 and P = .168, respectively). Even after adjusting for covariates, weight loss was a significant and independent risk factor for subsequent cardiovascular death or hospitalization for HF (hazard ratio 3.22, 95% confidence interval 1.10-8.41; P = .034). CONCLUSIONS: In patients with mild CHF, ≥5% weight loss was a significant predictor for subsequent cardiovascular death or hospitalization for HF.

Effects of early diuretic response to carperitide in acute decompensated heart failure treatment: A single-center retrospective study.

BACKGROUND: Diuretic response is a strong predictor of outcome for admitted patients of acute decompensated heart failure (ADHF). However, little is known about the effects of early diuretic response to carperitide. METHODS: We retrospectively analyzed records of 85 patients hospitalized for ADHF who received carperitide as initial treatment and <40 mg furosemide during the early period. The eligible patients were divided into good diuretic responder (GR) group and poor diuretic responder (PR) group on the basis of median urinary volume. RESULTS: The PR group demonstrated older age, lower body mass index (BMI), lower estimated glomerular filtration rate, and higher blood urea nitrogen (BUN) level, left ventricular ejection fraction, and ß-blockers prescribed at baseline than the GR group. The incidence of worsening renal function (WRF) was significantly higher in the PR group than in the GR group. There was no correlation between early intravenous furosemide dose and urinary volume (Spearman correlation, ρ = 0.111, p = 0.312). Multivariate analysis showed that the statistically significant independent factors associated with poor diuretic response to carperitide were BMI (Odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.68-0.94, p = 0.004) and BUN (OR = 1.07, 95%CI 1.01-1.15, p = 0.018). Kaplan-Meier analysis indicated a lower event-free rate in the PR group than in the GR group (log-rank, p = 0.007). CONCLUSIONS: BMI and BUN levels on admission were significant determinants of early poor diuretic response to carperitide. Early poor diuretic response to carperitide was associated with future poor outcomes.

Urinary composition predicts diuretic efficiency of hypertonic saline solution with furosemide therapy and heart failure prognosis.

Recently, we and other group have reported that furosemide administration along with hypertonic saline solution enhanced diuretic efficiency of furosemide. However, little is known about factors which associated with high diuretic efficiency by hypertonic saline solution with furosemide therapy. To identify predictors of diuretic efficiency in the hypertonic saline solution with furosemide therapy, we recruited 30 consecutive hospitalized heart failure (HF) patients with volume overload (77 ± 10 years, systolic blood pressure > 90 mmHg, and estimated glomerular filtration rate > 15 ml/min/1.73 m2). Hypertonic saline with furosemide solution, consisting of 500 ml of 1.7% hypertonic saline solution with 40 mg of furosemide, was administered continuously over 24 h. The patients were divided into two groups on the basis of 24-h urine volume (UV) after initiation of diuretic treatment ≥ 2000 ml (high urine volume: HUV) and < 2000 ml (low urine volume: LUV). The basal clinical characteristics of both groups were analyzed and the predictors of HUV after receiving the treatment were identified. There were not significant differences between two groups in baseline clinical characteristics and medication. Univariate logistic analysis revealed that blood urea nitrogen/creatinine ratio, urine urea nitrogen/creatinine ratio (UUN/UCre), fractional excretion of sodium, and tricuspid annular plane systolic excursion positively associated with HUV. Multivariate logistic regression analysis revealed that UUN/UCre at baseline was independently associated with HUV, and UUN/UCre best predicts HUV by the therapy with a cut-off value of 6.16 g/dl/g Cre (AUC 0.910, 95% CI 0.696-0.999, sensitivity 80%, specificity 87%). The Kaplan-Meier curves revealed significant difference for HF rehospitalization and death rate at 180 days between patients with UUN/UCre ≥ 6.16 g/dl/g Cre and those with UUN/UCre < 6.16 g/dl/g Cre (log-rank P = 0.0489). UUN/UCre at baseline strongly predicted of diuretic efficiency in the hypertonic saline solution with furosemide therapy, and was associated with HF prognosis.

Altered expression of intestinal duodenal cytochrome b and divalent metal transporter 1 might be associated with cardio-renal anemia syndrome.

The interaction among heart failure (HF), chronic kidney disease (CKD), and anemia is called cardio-renal anemia syndrome. The mechanism of anemia in cardio-renal anemia syndrome is complex and remains completely unknown. We have previously reported that impaired intestinal iron transporters may contribute to the mechanism of anemia in HF using in vivo HF model rats. In this study, we assessed intestinal iron transporters in CKD model rats to investigate the association of intestinal iron transporters in the mechanism of cardio-renal anemia syndrome. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. Sham-operated rats served as a control. After 24-week surgery, CKD rats exhibited normocytic normochromic anemia and normal serum erythropoietin levels despite of anemia. Serum iron levels were decreased in CKD rats compared with the controls. Of interest, intestinal expression of critical iron importers, such as duodenal cytochrome b (Dcyt-b) and divalent metal transporter 1 (DMT-1), was decreased in CKD rats compared with the controls. On the other hand, intestinal expression of ferroportin, an intestinal iron exporter, was not different in the control and CKD groups. Moreover, hepatic expression of hepcidin, a regulator of iron homeostasis, did not differ between the control and CKD groups. These results suggest that impaired intestinal expression of Dcyt-b and DMT-1 might be associated with the reduction of an iron uptake in CKD. Taken together, impaired these intestinal iron transporters may become a novel therapeutic target for cardio-renal anemia syndrome.

Adaptive Servo-Ventilation Treatment Increases Stroke Volume in Stable Systolic Heart Failure Patients With Low Tricuspid Annular Plane Systolic Excursion.

We hypothesized that the effects of adaptive servo-ventilation (ASV) therapy were influenced by right-sided heart performance. This study aimed to clarify the interaction between the effects of ASV and right-sided heart performance in patients with stable heart failure (HF) with reduced ejection fraction (HFrEF).Twenty-six stable HF inpatients (left ventricular ejection fraction < 0.45, without moderate to severe mitral regurgitation (MR) were analyzed. Echocardiography was performed before and after 30 minutes of ASV. ASV increased stroke volume index (SVI) in 14 patients (30.0 ± 11.9 to 41.1 ± 16.1 mL/m2) and reduced SVI in 12 patients (36.0 ± 10.1 to 31.9 ± 12.2 mL/m2). Multivariate linear regression analysis revealed that tricuspid annular plane systolic excursion (TAPSE) before ASV was an independent association factor for (SV during ASV - SV before ASV)/LVEDV × 100 (%) (%ΔSV/LVEDV). ROC analysis of TAPSE for %ΔSV/LVEDV > 0 showed that the cut-off point was 16.5 mm. All patients were divided into 2 groups according to the TAPSE value. Although no significant differences were found in the baseline characteristics and blood tests, there were significant differences in tricuspid lateral annular systolic velocity, TAPSE, right atrial area, and right ventricular (RV) area before ASV between patients with TAPSE ≤ 16.5 mm and those with TAPSE > 16.5 mm. Interestingly, ASV reduced RV area and increased TAPSE in patients with TAPSE ≤ 16.5 mm, while it reduced TAPSE in those > 16.5 mm.ASV therapy has the potential to increase SVI in stable HFrEF patients with low TAPSE.

Interleukin-18 gene deletion protects against sepsis-induced cardiac dysfunction by inhibiting PP2A activity.

BACKGROUND: Interleukin-18 (IL-18) neutralization protects against lipopolysaccharide (LPS)-induced injuries, including myocardial dysfunction. However, the mechanism is yet to be fully elucidated. The aim of the present study was to determine whether IL-18 gene deletion prevents sepsis-induced cardiac dysfunction and to elucidate the potential mechanisms underlying IL-18-mediated cardiotoxicity by LPS. METHODS AND RESULTS: Ten-week-old male wild-type (WT) and IL-18 knockout (IL-18 KO) mice were intraperitoneally administered LPS. Serial echocardiography showed better systolic pump function and less left ventricular (LV) dilatation in LPS-treated IL-18 KO mice compared with those in LPS-treated WT mice. LPS treatment significantly decreased the levels of phospholamban (PLN) and Akt phosphorylation in WT mice compared with those in saline-treated WT mice, while the LPS-induced decrease in the phosphorylation levels was attenuated in IL-18 KO mice compared with that in WT mice. IL-18 gene deletion also attenuated an LPS-induced increase of type 2 protein phosphatase 2A (PP2A) activity, a molecule that dephosphorylates PLN and Akt. There was no difference in type 1 protein phosphatase (PP1) activity. To address whether IL-18 affects PLN and Akt phosphorylation via PP2A activation in cardiomyocytes, rat neonatal cardiac myocytes were cultured and stimulated using 100ng/ml of recombinant rat IL-18. Exogenous IL-18 decreased the level of PLN and Akt phosphorylation in cardiomyocytes. PP2A activity but not PP1 activity was increased by IL-18 stimulation in cardiomyocytes. CONCLUSIONS: IL-18 plays a pivotal role in advancing sepsis-induced cardiac dysfunction, and the mechanisms underlying IL-18-mediated cardiotoxicity potentially involve the regulation of PLN and Akt phosphorylation through PP2A activity.

Right Ventricular Enlargement and Renal Function Are Associated With Smooth Introduction of Adaptive Servo-Ventilation Therapy in Chronic Heart Failure Patients.

Although adaptive servo-ventilation (ASV) therapy has beneficial effects on chronic heart failure (CHF), a relatively large number of CHF patients cannot undergo ASV therapy due to general discomfort from the mask and/or positive airway pressure. The present study aimed to clarify baseline patient characteristics which are associated with the smooth introduction of ASV treatment in stable CHF inpatients.Thirty-two consecutive heart failure (HF) inpatients were enrolled (left ventricular ejection fraction (LVEF) < 45%, estimated glomerular filtration rate (eGFR) > 10 mL/minute/1.73m2, and apnea-hypopnea index < 30/hour). After the patients were clinically stabilized on optimal therapy, they underwent portable polysomnography and echocardiography, and then received ASV therapy. The patients were divided into two groups: a smooth introduction group (n = 18) and non-smooth introduction group (n = 14). Smooth introduction of ASV treatment was defined as ASV usage for 4 hours and more on the first night. Univariate analysis showed that the smooth introduction group differed significantly from the non-smooth introduction group in age, hemoglobin level, eGFR, HF origin, LVEF, right ventricular (RV) diastolic dimension (RVDd), RV dp/dt, and RV fractional shortening. Multivariate analyses revealed that RVDd, eGFR, and LVEF were independently associated with smooth introduction. In addition, RVDd and eGFR seemed to be better diagnostic parameters for longer usage for ASV therapy according to the analysis of receiver operating characteristics curves.RV enlargement, eGFR, and LVEF are associated with the smooth introduction of ASV therapy in CHF inpatients.

Comparison of salt with low-dose furosemide and carperitide for treating acute decompensated heart failure: a single-center retrospective cohort study.

Hypertonic saline with furosemide has been proposed for a long time as an effective therapeutic option for the treatment of acute decompensated heart failure (ADHF). We previously reported the efficacy of continuous infusion of 1.7 % hypertonic saline plus low-dose furosemide in treatment for ADHF. Although this therapeutic strategy can be a useful option for effective decongestion in treatment for ADHF, there is no study that assesses the effect and safety of saline supplementation compared with standard therapy in Japan. The aim of this study was to investigate the efficacy, safety, and cost-effectiveness of 1.7 % hypertonic saline plus low-dose furosemide infusion compared with carperitide. We compared clinical outcomes, adverse events, and cost for patients receiving carperitide (carperitide group) with those for patients receiving 1.7 % hypertonic saline plus low-dose furosemide (salt group) during the initial hospitalization for ADHF. The cost analysis was performed on the basis of the previous report about cost-effectiveness of acute heart failure. A total of 175 ADHF patients received either carperitide (n = 111) or 1.7 % hypertonic saline plus low-dose furosemide infusion (n = 64) as initial treatment. There were no differences in length of hospital stay (27 ± 19 vs. 25 ± 16 day, p = 0.170) and infusion period (7.2 ± 6.1 vs. 8.4 ± 7.5 day, p = 0.474) between the two groups. The incidence of rehospitalization did not differ at 1 month (7.6 vs. 6.6 %, p = 1.000) and 1 year (36.8 vs. 37.7 %, p = 0.907) between the two groups. The Kaplan-Meier curves revealed no significant difference for 1 year all-cause mortality between the two groups (log-rank, p = 0.724). The single hospitalization cost was 95,314 yen lower and the yearly hospitalization cost 125,628 yen lower in the salt group compared with the carperitide group. Thus, intravenous 1.7 % hypertonic saline plus low-dose furosemide infusion is as effective as carperitide in terms of clinical outcome and is a cost-effective therapeutic strategy for the treatment of ADHF.

Attenuation of hypertension and renal damage in renovascular hypertensive rats by iron restriction.

Iron is a catalyst in the formation of reactive oxygen species. Oxidative stress is associated with the pathogenesis of both human and experimental animal models of renovascular hypertension. We hypothesized that iron is involved in the pathogenesis of renovascular hypertension and that iron restriction may affect the pathogenesis of renovascular hypertension via the inhibition of oxidative stress. Herein, we investigated the effect of iron restriction on hypertension and renal damage in a rat model of two-kidney one-clip (2K1C) renovascular hypertension. Renovascular hypertension was induced by 2K1C in male Sprague-Dawley rats. At the day of clipping, 2K1C rats were divided into untreated (2K1C) and dietary iron-restricted groups (2K1C+IR). The 2K1C rats showed hypertension after the day of clipping, whereas dietary iron restriction attenuated the development of hypertension. Vascular hypertrophy and the increased fibrotic area were suppressed in the 2K1C+IR group. The clipped kidney developed renal atrophy in both the 2K1C and 2K1C+IR groups after clipping. However, the unclipped kidney showed renal hypertrophy in the 2K1C and 2K1C+IR groups, and the extent was less in the 2K1C+IR group. The 2K1C rats exhibited glomerulosclerosis and tubulointerstitial fibrosis in the unclipped kidney, whereas these changes were attenuated by an iron-restricted diet. Importantly, proteinuria was decreased in the 2K1C+IR group, along with decreased urinary 8-hydroxy-2'-deoxyguanosine excretion and superoxide production of the unclipped kidney. Moreover, the expression of nuclear mineralocorticoid receptor in the unclipped kidney of the 2K1C rats was attenuated by iron restriction. These data indicate a novel effect of iron restriction on hypertension and renal damage in renovascular hypertension.

Long-term administration of tolvaptan increases myocardial remodeling and mortality via exacerbation of congestion in mice heart failure model after myocardial infarction.

BACKGROUND: In contrast to loop diuretics, tolvaptan does not cause neurohormonal activation in several animal heart failure models. However, it remains unknown whether chronic vasopressin type 2 receptor blockade exerts beneficial effects on mortality in murine heart failure after myocardial infarction (MI). In an experimental heart failure model, we tested the hypothesis that tolvaptan reduces myocardial remodeling and mortality. METHODS AND RESULTS: MI was induced in 9-week-old male C57Bl6/J by the left coronary artery ligation. In study 1, animals were randomly assigned to treatment with placebo or tolvaptan starting 14days post-MI. In study 2, animals were randomized to tolvaptan or furosemide+tolvaptan starting 14days post-MI. Interestingly, results showed lower survival rate in tolvaptan group compared to placebo. Tolvaptan group had higher serum osmolality, heavier body weight, more severe myocardial remodeling, and lung congestion at day 28 of drug administration compared to placebo. In study 2, addition of furosemide significantly reduced mortality rate seen with tolvaptan, and presented with decreased osmolality, myocardial remodeling, and lung congestion compared to tolvaptan-treated mice. Increase in proximal tubular expression of aquaporin 1, Angiotensin II, and vasopressin seen with tolvaptan treatments were normalized to basal levels, similar to levels in placebo-treated mice. CONCLUSIONS: Contrary to our hypothesis, tolvaptan was associated with increased mortality in murine heart failure after MI. This increase in lung congestion, myocardial remodeling, could be prevented by co-administration of furosemide, which resulted in normalized serum osmolality, neurohormonal activation, and renal aquaporin 1 expression, and hence decreased mortality post-MI.

Iron is associated with the development of hypoxia-induced pulmonary vascular remodeling in mice.

Several recent observations provide the association of iron deficiency with pulmonary hypertension (PH) in human and animal studies. However, it remains completely unknown whether PH leads to iron deficiency or iron deficiency enhances the development of PH. In addition, it is obscure whether iron is associated with the development of pulmonary vascular remodeling in PH. In this study, we investigate the impacts of dietary iron restriction on the development of hypoxia-induced pulmonary vascular remodeling in mice. Eight- to ten-week-old male C57BL/6J mice were exposed to chronic hypoxia for 4 weeks. Mice exposed to hypoxia were randomly divided into two groups and were given a normal diet or an iron-restricted diet. Mice maintained in room air served as normoxic controls. Chronic hypoxia induced pulmonary vascular remodeling, while iron restriction led a modest attenuation of this change. In addition, chronic hypoxia exhibited increased RV systolic pressure, which was attenuated by iron restriction. Moreover, the increase in RV cardiomyocyte cross-sectional area and RV interstitial fibrosis was observed in mice exposed to chronic hypoxia. In contrast, iron restriction suppressed these changes. Consistent with these changes, RV weight to left ventricular + interventricular septum weight ratio was increased in mice exposed to chronic hypoxia, while this increment was inhibited by iron restriction. Taken together, these results suggest that iron is associated with the development of hypoxia-induced pulmonary vascular remodeling in mice.