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.

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.

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.

Effective blood hemoglobin level to predict prognosis in heart failure with preserved left ventricular ejection fraction: results of the Japanese heart failure syndrome with preserved ejection fraction registry.

High prevalence of anemia in heart failure with preserved left ventricular ejection fraction (HFpEF) has been reported. However, little is known about the association of anemia and gender with prognosis in HFpEF patients. In addition, effective blood hemoglobin (Hb) level for prognosis in HFpEF patients remains largely unknown. In this study, we investigated the association between anemia, gender, and prognosis in 535 HFpEF patients enrolled in Japanese heart failure syndrome with preserved ejection fraction registry. Furthermore, we assessed effective blood Hb level to predict prognosis in HFpEF patients. According to the World Health Organization criteria, the prevalence rate of anemia on admission was about 70% in both male and female HFpEF patients. Kaplan-Meier analysis for all-cause mortality demonstrated that anemic patients had poor prognosis compared with non-anemic patients in both male and female HFpEF patients. Interestingly, multivariate analysis revealed that blood Hb level at discharge was an independent predictor of all-cause mortality in both male and female HFpEF patients. According to survival classification and regression tree analysis, blood Hb level at discharge of 9.4 g/dL for male and 12.3 g/dL for female was more accurate cutoff value to predict all-cause mortality in HFpEF patients. Anemia was implicated in poor prognosis in both male and female HFpEF patients. In particular, blood Hb level at discharge was an independent predictor of all-cause mortality in both male and female HFpEF patients. Effective cutoff value of blood Hb level at discharge to predict all-cause mortality was lower in male than in female HFpEF patients.

Influence of dietary iron intake restriction on the development of hypertension in weanling prehypertensive rats.

Hypertension is a major public health problem leading to death. To reduce the morbidity and mortality in patients with hypertension, it is crucial to develop a novel strategy for prevention of hypertension. We have currently reported an attempt at dietary iron intake restriction as non-pharmacological treatment of hypertension in patients with hypertension. However, it remains fully unknown whether dietary iron restriction prevents the development of hypertension. We investigated the influence of dietary iron restriction on the development of hypertension in weanling pre-hypertensive model rats. 3-week-old male stroke-prone spontaneously hypertensive rats (SHR-SP) were randomly divided into two groups and were given an ad libitum normal diet or an iron-restricted diet for 12 weeks. Blood pressure was progressively increased in SHR-SP according to growth, while dietary iron restriction attenuated the development of hypertension. Proteinuria was also increased in SHR-SP according to growth, whereas dietary iron restriction suppressed the increment of proteinuria. SHR-SP exhibited glomerulosclerosis and exacerbated renal interstitial fibrosis at 15 weeks old, indicating that SHR-SP developed hypertensive nephropathy in the adult stage; however, these changes were attenuated by dietary iron restriction. Gelatin zymography showed dietary iron restriction decreased both renal MMP-2 and MMP-9 activities in SHR-SP at 15 weeks old. Of interest, dietary iron restriction suppressed renal TGFß-RI expression and Smad2 phosphorylation in SHR-SP. Furthermore, dietary iron restriction decreased renal fibrosis, renal MMP-2 and MMP-9 activities, renal TGFß-RI expression, and Smad2 phosphorylation in rats with unilateral ureteral obstruction. Dietary iron restriction prevented the development of hypertension in weanling pre-hypertensive rats.

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.

The distribution of calcified nodule and plaque rupture in patients with peripheral artery disease: an intravascular ultrasound analysis.

In addition to plaque rupture (PR), calcified nodule (CN) may also have the potential to develop into arterial thrombus in the peripheral arteries. This study evaluated the distribution of plaque ruptures and calcified nodules in the peripheral arteries and their impact on the outcome of endovascular therapy (EVT). Consecutive 159 patients who underwent EVT with intravascular ultrasound guidance were enrolled. The position of CNs and PRs were assigned to any of common iliac artery, external iliac artery, common femoral artery, and superficial femoral artery. Forty-six (29%) patients had calcified nodule and twenty-eight (18%) patients had plaque rupture somewhere in the lower limb arteries. Although calcified nodules were evenly distributed throughout the length of the arteries plaque ruptures were predominantly located in the proximal segment of the iliofemoral arteries. Stent expansion ratio was significantly smaller in the target arteries with calcified nodules than in those with plaque rupture. Multivariate logistic regression analysis identified hemodialysis as an independent clinical predictor of calcified nodule (odds ratio 8.15, 95% confidence interval 1.73-38.3; P = 0.008). CN definitely affects incomplete stent deployment in the peripheral artery contributing to adverse events, on the other hand, PR has more acceptable outcomes after stent implantation. In the clinical setting, it is important that we realize the features of peripheral artery disease and its patient characteristics which having CNs and PRs to make a strategy for revascularization.

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.

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.

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.

Morphological, Functional, and Biological Vascular Healing Response 6 Months After Drug-Eluting Stent Implantation: A Randomized Comparison of Three Drug-Eluting Stents.

OBJECTIVES: This study evaluated coronary endothelial function after the implantation of sirolimus-eluting stents (SESs), everolimus-eluting stents (EESs), and zotarolimus-eluting stents (ZES) by a different methodology, and also analyzed whether optical coherence tomography (OCT) findings represent endothelial healing after stenting. BACKGROUND: It is unclear whether OCT assessment of stent strut coverage represents endothelial healing after drug-eluting stent implantation. METHODS: Thirty patients with a left anterior descending artery lesion were randomized 1:1:1 to receive an SES, EES, or ZES. The vascular response was evaluated 6 months after stenting by three methods: the functional response by acetylcholine infusion, the morphological response by OCT, and the biological response by measuring vascular endothelial growth factor (VEGF) levels. RESULTS: The proportion of uncovered struts by OCT at 6 months was significantly higher in both SES and EES than in ZES. However, the vasomotor response was impaired and the VEGF level of the coronary sinus was significantly lower in SES than in EES and ZES. There were no relationships between the OCT findings and vasomotor response to acetylcholine and VEGF levels in all cohorts. CONCLUSIONS: The vascular response at 6 months was more preserved in ZES and EES than in SES. Our results suggest that the morphological assessment with OCT may not always be used as a surrogate for functional and biological healing response after stenting. © 2015 Wiley Periodicals, Inc.

Aortic iron overload with oxidative stress and inflammation in human and murine abdominal aortic aneurysm.

OBJECTIVE: Although iron is an essential element for maintaining physiological function, excess iron leads to tissue damage caused by oxidative stress and inflammation. Oxidative stress and inflammation play critical roles for the development of abdominal aortic aneurysm (AAA). However, it has not been investigated whether iron plays a role in AAA formation through oxidative stress and inflammation. We, therefore, examined whether iron is involved in the pathophysiology of AAA formation using human AAA walls and murine AAA models. APPROACH AND RESULTS: Human aortic walls were collected from 53 patients who underwent cardiovascular surgery (non-AAA=34; AAA=19). Murine AAA was induced by infusion of angiotensin II to apolipoprotein E knockout mice. Iron was accumulated in human and murine AAA walls compared with non-AAA walls. Immunohistochemistry showed that both 8-hydroxy-2'-deoxyguanosine and CD68-positive areas were increased in AAA walls compared with non-AAA walls. The extent of iron accumulated area positively correlated with that of 8-hydroxy-2'-deoxyguanosine expression area and macrophage infiltration area in human and murine AAA walls. We next investigated the effects of dietary iron restriction on AAA formation in mice. Iron restriction reduced the incidence of AAA formation with attenuation of oxidative stress and inflammation. Aortic expression of transferrin receptor 1, intracellular iron transport protein, was increased in human and murine AAA walls, and transferrin receptor 1-positive area was similar to areas where iron accumulated and F4/80 were positive. CONCLUSIONS: Iron is involved in the pathophysiology of AAA formation with oxidative stress and inflammation. Dietary iron restriction could be a new therapeutic strategy for AAA progression.

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.

Association of dietary iron restriction with left ventricular remodeling after myocardial infarction in mice.

Several epidemiologic studies have reported that body iron status and dietary iron intake are related to an increased risk of acute myocardial infarction (MI). However, it is completely unknown whether dietary iron reduction impacts the development of left ventricular (LV) remodeling after MI. Here, we investigate the effect of dietary iron restriction on the development of LV remodeling after MI in an experimental model. MI was induced in C57BL/6 J mice (9-11 weeks of age) by the permanent ligation of the left anterior descending coronary artery (LAD). At 2 weeks after LAD ligation, mice were randomly divided into two groups and were given a normal diet or an iron-restricted diet for 4 weeks. Sham operation without LAD ligation was also performed as controls. MI mice exhibited increased LV dilatation and impaired LV systolic function that was associated with cardiomyocyte hypertrophy and interstitial fibrosis in the remote area, as compared with the controls at 6 weeks after MI. In contrast, dietary iron restriction attenuated LV dilatation and impaired LV systolic function coupled to cardiomyocyte hypertrophy and interstitial fibrosis in the remote area. Importantly, cardiac expression of cellular iron transport proteins, transferrin receptor 1 and divalent metal transporter 1 was increased in the remote area of MI mice compared with the controls. Dietary iron restriction attenuated the development of LV remodeling after MI in mice. Cellular iron transport might play a role in the pathophysiological mechanism of LV remodeling after MI.

Impact of intravascular ultrasound findings on long-term patency after self-expanding nitinol stent implantation in the iliac artery lesion.

Although intravascular ultrasound (IVUS) predictors of stent patency for the coronary artery lesion have been established, little is known about IVUS predictors of stent patency for the aorto-iliac artery lesion. We analyzed 154 lesions of 122 patients who underwent stent implantation for iliac artery lesions. Quantitative and qualitative IVUS analyses were performed for pre- and post-procedural IVUS imaging in all lesions. Target lesion revascularization (TLR) was defined as clinically driven revascularization with >50 % angiographic stenosis of the target lesion. The mean follow-up period was 39 ± 16 months. TLRs were performed in 13 lesions (8.4 %). Post-procedural minimum stent area (MSA) was significantly smaller in the TLR group compared to the no-TLR group (16.0 ± 5.8 vs. 25.6 ± 8.5 mm(2), p < 0.001). Stent edge dissection was frequently observed in the TLR group compared to the no-TLR group (53.8 vs. 24.1 %, p = 0.04). Multivariate analysis revealed that post-procedural MSA (OR = 0.76, p < 0.01) and stent edge dissection (OR = 10.4, p < 0.01) were independent IVUS predictors of TLR. Receiver-operating characteristic analysis identified post-procedural MSA <17.8 mm(2) as the optimal cut-point for the prediction of TLR (AUC = 0.846). Post-procedural MSA and stent edge dissection could predict long-term stent patency in the iliac artery lesion. Our results propose that adequate stent enlargement without edge dissection might be important to reduce TLR in the iliac artery lesion.

Impact of spotty calcification on long-term prediction of future revascularization: a prospective three-vessel intravascular ultrasound study.

To date, there are no prospective studies on the relationship between plaque characteristics identified by 40 MHz IVUS and future adverse events. This prospective study evaluated the relationship between plaque morphology in nonculprit nonsignificant lesions, determined by 40 MHz IVUS, and long-term clinical outcomes. Consecutively, 45 patients who underwent 3-vessel intravascular ultrasound (IVUS) examinations were prospectively enrolled. Qualitative and quantitative IVUS analyses including scoring of echogenicity for assessment of plaque characterization were performed for each nonsignificant nonculprit lesion. The number, the length, the location (superficial or deep), and maximum arc were measured for each calcium deposit within plaques. Spotty calcification was defined as calcium deposits <90° and <6 mm in length. Primary end point was defined as nonsignificant nonculprit lesion-related revascularization (NNLR) during 6 years of follow-up. A total of 163 nonsignificant nonculprit lesions with mild to moderate stenosis were identified on baseline 3-vessel IVUS. Of those 163 lesions, six lesions required NNLR during the follow-up period. There were no differences in quantitative IVUS parameters including remodeling index, plaque burden, and echogenicity between lesions requiring and not requiring NNLR. However, deep spotty calcification was more frequently identified in lesions requiring NNLR than in those not requiring NNLR (33 vs. 8 %, P = 0.02). Spotty calcium deposits identified by 40 MHz IVUS predicted the need for NNLR during a 6-year follow-up period. This finding suggests that deep spotty calcium may be a surrogate marker for plaque progression and the subsequent need for revascularization in the future.

Hemodynamic response to sildenafil in patients with decompensated congestive heart failure can be predicted by deceleration time of transmitral flow.

AIM: How sildenafil acutely provides hemodynamic alterations in patients with decompensated congestive heart failure remains unknown. The aim of this study was to investigate whether myocardial and/or hemodynamic conditions affect hemodynamic response to sildenafil in patients with decompensated heart failure. METHODS AND RESULTS: Twenty-five consecutive patients with decompensated congestive heart failure were enrolled. The patients underwent echocardiography before and 1 hour after a single oral administration of sildenafil (20 mg). Sildenafil decreased pulmonary vascular resistance by 24% (P < 0.05), and increased left ventricular (LV) time-velocity integral by 17% (P < 0.05). Alteration of the ratio of peak velocity of early LV filling to early diastolic myocardial velocity (E/E'), an indicator of LV filling pressure, following administration of sildenafil, negatively associated with the deceleration time of early filling wave (DcT) at baseline. Patients with baseline DcT ≥ 200 milliseconds (n = 11) exhibited E/E' increase, whereas patients with baseline DcT <200 milliseconds (n = 14) exhibited E/E' decrease. CONCLUSIONS: Administration of sildenafil elevated LV filling pressure in decompensated heart failure patients with shortened deceleration time of early diastolic transmitral flow.

Tissue Characterization of In-Stent Neointima Using Optical Coherence Tomography in the Late Phase After Bare-Metal Stent Implantation--An Ex Vivo Validation Study.

BACKGROUND: We performed an ex vivo study to investigate optical coherence tomography (OCT) imaging for differentiating several types of neointimal tissue during the later phases after bare-metal stent (BMS) implantation as compared with histologic results. METHODS AND RESULTS: OCT imaging was performed in 6 autopsy hearts for 10 BMS with implant duration >4 years. OCT qualitative neointimal tissue characterization was based on tissue structure and classified as homogeneous pattern, heterogeneous pattern with visible struts, or heterogeneous pattern with invisible struts. Corresponding histological analyses of each 2-mm cross-section of the entire BMS were performed. Of 81 cross-sections, histological analysis revealed that the homogeneous pattern of neointima on OCT (n=39) contained smooth muscle cells with collagen, indicating high neointimal maturity. The heterogeneous patterns with visible struts (n=35) contained different tissues, including a proteoglycan-rich myxomatous matrix or dense calcified plate deposition. The heterogeneous patterns with invisible struts (n=7) included neointimal lipid/necrotic core formation, accumulation of foam cells, or microcalcification scattering. Of the 66 cross-sections containing large microvessels within the neointima on histology, only 6 (9%) were visualized by OCT. CONCLUSIONS: The present study confirmed the potential use of OCT in differentiating several types of neointima after BMS implantation. The image interpretation of OCT, based on visualization of stent struts, enables identification of several types of neointimal tissues, including in-stent fibroatheroma formation, more accurately.

Intravenous salt supplementation with low-dose furosemide for treatment of acute decompensated heart failure.

BACKGROUND: Theoretically, salt supplementation should promote diuresis through increasing the glomerular filtration rate (GFR) during treatment of acute decompensated heart failure (ADHF) even with low-dose furosemide; however, there is little evidence to support this idea. METHODS AND RESULTS: This was a prospective, randomized, open-label, controlled trial that compared the diuretic effectiveness of salt infusion with that of glucose infusion supplemented with low-dose furosemide in 44 consecutive patients with ADHF. Patients were randomly administered 1.7% hypertonic saline solution supplemented with 40 mg furosemide (salt infusion group) or glucose supplemented with 40 mg furosemide (glucose infusion group). Our major end points were 24-hour urinary volume and GFR. Urinary volume was greater in the salt infusion group than in the glucose infusion group (2,701 ± 920 vs 1,777 ± 797 mL; P < .001). There was no significant difference in the estimated GFR at baseline. Creatinine clearance for 24 h was greater in the salt infusion group than in the glucose infusion group (63.5 ± 52.6 vs 39.0 ± 26.3 mL min(-1) 1.73 m(-2); P = .048). CONCLUSIONS: Salt supplementation rather than salt restriction evoked favorable diuresis through increasing GFR. The findings support an efficacious novel approach of the treatment of ADHF.

Nuclear factor-κB-hypoxia-inducible factor-2 pathway in aortic valve stenosis.

BACKGROUND AND AIM OF THE STUDY: Valvular calcification is a prominent feature of aortic valve stenosis (AS), and calcified aortic valves share several features with bone tissue. Hypoxia-inducible factor-2 (HIF-2) is activated by nuclear factor-κB (NF-κB) and plays a critical role in an osteoblastic differentiation. The study aim was to determine whether the NF-κB-HIF-2 pathway is involved in the pathophysiology of calcified aortic valve disease. METHODS: A total of 50 specimens of aortic valve leaflets obtained from patients who had undergone aortic valve replacement for AS was examined. The aortic valve leaflets from 10 patients with annulo-aortic ectasia (AAE) served as controls. The stenotic valve leaflets were examined using immunohistochemistry to detect NF-κB, HIF-2α, vascular endothelial growth factor (VEGF), vascular endothelial cells, and collagen X. The calcification area was measured and any correlation between the calcification area and NF-κB-HIF-2 pathway was assessed. RESULTS: NF-κB and HIF-2α were expressed in the leaflets from patients with AS, but not in those from AAE controls. Both factors were expressed around massive calcified lesions, and HIF-2α was co-localized with NF-κB. VEGF, neoangiogenesis and collagen X were located in the area where HIF-2α was expressed, and correlated positively with HIF-2α expression. The calcification area correlated positively with collagen X expression. CONCLUSION: The NF-κB-HIF-2 pathway was expressed in calcified aortic valves and associated with an increased expression of VEGF and collagen X. This signaling pathway may play important roles in the pathophysiology of AS.