Geriatric nutritional risk index as readmission predictor in older adults with heart failure irrespective of ejection fraction.

Objectives: Malnutrition is associated with an increased risk of hospital readmission for heart failure in patients with acute decompensated heart failure (ADHF). Therefore, evaluation of the nutritional status in patients with ADHF may be important. The geriatric nutritional risk index (GNRI), the controlling nutritional status (CONUT) score, and the prognostic nutritional index (PNI) are widely used objective indexes for evaluation of the nutritional status. The present study was performed to determine the best nutritional index for predicting the prognosis in older adults with ADHF. Methods: We retrospectively studied 167 older adults (>65 years of age) who were admitted with ADHF from January 2012 to December 2015 and discharged alive. The objective nutritional status was evaluated using the GNRI, CONUT score, and PNI at admission. The endpoint of this study was unplanned hospitalization for worsening heart failure (WHF) within 1 year after discharge. Results: During the follow-up period, 58 patients were readmitted for WHF. In the multivariate Cox analysis, only the GNRI (p<0.0001) was independently associated with readmission for WHF among the three nutritional indexes. Kaplan-Meier analysis revealed that patients in the low-GNRI group (<90 as determined by receiver operating characteristic curve analysis) had a significantly greater risk of 1-year hospital readmission for WHF (p<0.0001; hazard ratio, 6.1; 95% confidence interval, 3.5-10.5). Conclusion: Among the objective nutritional indexes, the GNRI is the best predictor of readmission for WHF within 1 year after discharge in older adults with ADHF.

Long-Term Outcomes and Clinical Predictors of Mortality Following Occurrence of Stent Thrombosis.

Background Stent thrombosis (ST) remains a significant medical issue. In particular, longer-term mortality and clinical predictors after ST occurrence have yet to be elucidated. Methods and Results This was a multicenter, retrospective, observational study. A total of 187 definite ST cases from January 2008 to December 2017 were enrolled, and the long-term clinical outcomes were investigated. The primary outcome measure was the cumulative mortality after ST occurrence. In addition, independent predictors of mortality were assessed. Among the stent types causing ST, bare-metal stent, first-generation drug-eluting stent, second-generation drug-eluting stent, and third-generation drug-eluting stent comprised 31.0%, 19.3%, 36.9%, and 6.4% of cases, respectively. Median duration from stent implantation to ST was 680.5 (interquartile range, 33.8-2450.5) days. Cumulative mortality was 14.6%, 17.4%, 21.2%, 24.4%, and 33.8% at 1, 2, 3, 5 and 10 years, respectively. The cumulative mortality did not significantly differ by type of stent, and mortality of late ST was higher than that of early ST and very late ST; however, it did not reach statistical significance after the multivariate analysis. Independent predictors of mortality were hemodialysis (hazard ratio [HR], 7.80; 95% CI, 3.07-19.81; P<0.001), culprit lesions in the left main trunk (HR, 8.14; 95% CI, 1.71-38.75; P=0.008), culprit lesions in the left coronary artery (HR, 2.77; 95% CI, 1.10-6.96; P=0.030), and peak creatine kinase (HR, 1.017; 95% CI, 1.011-1.022; P<0.001). Conclusions The 10-year cumulative mortality after ST reached 33.8%. Close follow-up is thus mandatory for patients with ST, especially with hemodialysis, culprit lesions in the left main trunk and left coronary artery, and high peak creatine kinase.

Aortic Mural Thrombus in the Non-atherosclerotic Aorta of Patients with Multiple Hypercoagulable Factors.

An aortic mural thrombus (AMT) on a non-atherosclerotic wall is a rare but important cause of arterial thromboembolism. We herein report two cases of AMT in the thoracic aorta. Both showed multiple hypercoagulable factors (case 1: protein S deficiency and positive finding of anti-cardiolipin antibody; case 2: protein C deficiency, gastric cancer, and cisplatin-based chemotherapy) and were successfully treated with anticoagulation. Hypercoagulable states, including malignancy, can influence the formation of AMT; therefore, the accurate assessment of a hypercoagulable condition is necessary when we encounter patients with AMT.

Novel risk stratification with time course assessment of in-hospital mortality in patients with acute heart failure.

BACKGROUND: Patients with acute heart failure (AHF) show various clinical courses during hospitalization. We aimed to identify time course predictors of in-hospital mortality and to establish a sequentially assessable risk model. METHODS AND RESULTS: We enrolled 1,035 consecutive AHF patients into derivation (n = 597) and validation (n = 438) cohorts. For risk assessments at admission, we utilized Get With the Guidelines-Heart Failure (GWTG-HF) risk scores. We examined significant predictors of in-hospital mortality from 11 variables obtained during hospitalization and developed a risk stratification model using multiple logistic regression analysis. Across both cohorts, 86 patients (8.3%) died during hospitalization. Using backward stepwise selection, we identified five time-course predictors: catecholamine administration, minimum platelet concentration, maximum blood urea nitrogen, total bilirubin, and C-reactive protein levels; and established a time course risk score that could sequentially assess a patient's risk status. The addition of a time course risk score improved the discriminative ability of the GWTG-HF risk score (c-statistics in derivation and validation cohorts: 0.776 to 0.888 [p = 0.002] and 0.806 to 0.902 [p<0.001], respectively). A calibration plot revealed a good relationship between observed and predicted in-hospital mortalities in both cohorts (Hosmer-Lemeshow chi-square statistics: 6.049 [p = 0.642] and 5.993 [p = 0.648], respectively). In each group of initial low-intermediate risk (GWTG-HF risk score <47) and initial high risk (GWTG-HF risk score ≥47), in-hospital mortality was about 6- to 9-fold higher in the high time course risk score group than in the low-intermediate time course risk score group (initial low-intermediate risk group: 20.3% versus 2.2% [p<0.001], initial high risk group: 57.6% versus 8.5% [p<0.001]). CONCLUSIONS: A time course assessment related to in-hospital mortality during the hospitalization of AHF patients can clearly categorize a patient's on-going status, and may assist patients and clinicians in deciding treatment options.

Contrast-free diagnosis and treatment of coronary artery disease guided by integrated cardiac imaging: concept and first clinical experience.

The use of iodinated contrast media (ICM) remains a potential hazard for patients undergoing diagnostic cardiac imaging and percutaneous coronary intervention. In particular patients with history of prior adverse reaction to a contrast agent are at a high risk in case of re-exposure, even if designated premedication is administered. Based on a patient with recurrent angina pectoris and history of systemic anaphylactic reaction to ICM, we describe the logical stepwise approach from diagnostic imaging to safe and successful imaging guided percutaneous coronary intervention without the use of contrast agent.

A novel homemade snare, safe, economical and size-adjustable.

AIMS: Snaring has recently been reported as being effective in catching the retrograde guidewire (GW) in retrograde percutaneous coronary intervention (PCI) for chronic total occlusion. However, commercially available snares and previously reported homemade snares have a number of drawbacks, such as additional cost, limited size adjustability, risk of vessel injury and difficult handling. We report here a novel method to create easily an inexpensive, safe and size-adjustable snare. METHODS AND RESULTS: Our newly developed homemade snare consists of a conventional 0.014" GW, a PCI balloon, and a guiding catheter (GC). In most cases, no extra cost is needed. As the snare is created by the soft wire tip, vascular injury is negligible. To adjust the size of the snare loop, the snare wire is simply pulled backwards and pushed forwards. Using this snare technique, we succeeded in the total revascularisation of a CTO in the left main trunk with a retrograde approach. CONCLUSIONS: We report a novel method to create easily an inexpensive, safe and size-adjustable snare, and demonstrate its use in a retrograde CTO intervention. In some cases where a conventional snare is indicated, such as removal of intravascular iatrogenic foreign bodies, this novel homemade snare would be preferable because of its advantages.

Carotid intima-media thickness, but not visceral fat area or adiponectin, correlates with intracoronary stenosis detected by multislice computed tomography in people with type 2 diabetes and hypertension.

We investigated the relationship between intracoronary stenosis detected by multislice computed tomography and various clinical parameters in type 2 diabetic patients with hypertension treated with candesartan (n=42). The results showed that carotid intima-media thickness, but not visceral fat area or adiponectin, correlated significantly with intracoronary stenosis (p<0.05).

Clinical significance of high-molecular weight form of adiponectin in male patients with coronary artery disease.

BACKGROUND: It has been reported previously that the measurement of plasma total adiponectin level is clinically useful to estimate the risk of coronary artery disease (CAD). Here, the relevance of high molecular weight (HMW) adiponectin with risk factors for atherosclerosis is investigated METHODS AND RESULTS: A total of 186 consecutive male CAD patients participated in the study and were categorized into quartiles based on their total adiponectin level. The interquartile cut-off points were 4.0, 5.5 and 7.0 microg/ml. The HMW adiponectin levels were significantly lower in the quartile of lower total adiponectin levels both in non-diabetic and diabetic patients. In contrast, low molecular weight adiponectin levels (which were calculated as the Total - HMW) were constant. In univariate analysis, total adiponectin correlated negatively with body mass index and hemoglobin (Hb) A1c, and HMW adiponectin correlated negatively with HbA1c in non-diabetic patients. On the other hand, total and HMW adiponectin correlated positively with high-density lipoprotein-cholesterol (HDL-C) in diabetic patients. Multiple regression analysis revealed that HMW adiponectin correlated negatively with HbA1c in non-diabetic patients, and total and HMW adiponectin correlated positively with HDL-C in diabetic patients. CONCLUSIONS: Change in the HMW isoform reflects a change in total adiponectin level. Measurement of total and HMW adiponectin were equally useful in assessing metabolic risk in CAD patients.

Adiponectin accumulates in myocardial tissue that has been damaged by ischemia-reperfusion injury via leakage from the vascular compartment.

OBJECTIVES: Adiponectin, a circulating adipocyte-derived hormone, exerts beneficial actions on hearts subjected to ischemia-reperfusion injury. Adiponectin exists in plasma as three different oligomeric forms: trimer, hexamer and high molecular weight. This study investigated the expression and myocardial accumulation of adiponectin in a murine model of ischemia-reperfusion injury. METHODS: Wild-type and adiponectin deficient mice were subjected to left anterior descending artery ligation followed by reperfusion. Plasma adiponectin levels were analyzed by ELISA and adiponectin in heart was determined by immunohistochemical, Western blot and real-time PCR analyses. RESULTS: Plasma adiponectin levels declined after myocardial ischemia-reperfusion injury due to reductions in high molecular weight and, to a lesser extent, trimer and hexamer isoforms. Adiponectin protein was detected in injured but not sham-operated heart, and this was accompanied by a negligible increase in adiponectin transcript in the myocardium. Systemic delivery of adiponectin to adiponectin knockout (APN-KO) mice led to the accumulation of adiponectin in ischemia-reperfusion-injured, but not-uninjured hearts at levels comparable to wild-type suggesting that cardiac expression of adiponectin does not appreciably contribute to its accumulation in the infarcted heart. The serum half-life of adiponectin was 7.4+/-0.3 h in ischemia-reperfusion and 9.7+/-0.5 h in sham-operated mice (P>0.05), whereas the half-life of adiponectin in the damaged heart was 26.9+/-2.2 h (P<0.05). CONCLUSIONS: These data show that adiponectin accumulates in the heart following ischemic damage primarily through leakage from the vascular compartment, and that adiponectin has a longer half-life in damaged heart tissue than in plasma.

Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate, on adiponectin level.

OBJECTIVE: Adiponectin is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule. We previously found peroxisome proliferators response element in adiponectin promoter region, suggesting that peroxisome proliferator-activated receptor (PPAR) ligands elevate adiponectin. Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease. Effect of fibrates on adiponectin has not been clarified, whereas thiazolidinediones enhance adiponectin. Thus, we explored the possibility and mechanism that fibrates enhance adiponectin in humans, mice, and cells. METHODS AND RESULTS: Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The Bezafibrate Infarction Prevention study. Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes. Fibrates, bezafibrate and fenofibrate, significantly elevated adiponectin levels in wild-type mice and 3T3-L1 adipocytes. Such an effect was not observed in PPARalpha-deficient mice and adipocytes. Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha-RNAi. CONCLUSIONS: Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes.

Adiponectin and renal function, and implication as a risk of cardiovascular disease.

The relation among adiponectin, renal function, and incident cardiovascular disease (CVD) in patients with different degrees of renal dysfunction was investigated. In total, 150 subjects were included in this study and followed prospectively for a mean of 32 months. At baseline, median adiponectin levels for chronic kidney disease (CKD) stages 1, 2, 3, 4 and 5, as estimated by creatinine clearance (> or =90, 60 to 90, 30 to 60, <30 ml/min), were 3.06, 4.04, 6.43, and 11.9 microg/ml, respectively (p for trend <0.01), and a significant association between adiponectin and CKD stages was also confirmed in multivariate regression analysis (F = 6.2, p <0.001). During follow-up, 31 subjects developed CVD, including myocardial infarction, angina pectoris, stroke, and transient ischemic attack. Gender-specific median values of adiponectin were used to separate the higher group from the lower group, and the Kaplan-Meier curve showed a significantly lower event-free survival rate in the lower adiponectin group (<4.39 microg/ml in men, <6.84 microg/ml in women, chi-square 4.88, p <0.03). The risk factor-adjusted Cox regression showed that an increase in adiponectin per 1 microg/ml was associated with a decrease in the risk of CVD to 0.86 (95% confidence interval 0.75 to 0.96, p = 0.004). In the subgroup with previous ischemic heart disease (IHD; n = 65), a significantly lower event-free survival rate of IHD was also observed in the lower adiponectin group (<4.45 microg/ml in men, <4.49 microg/ml in women, chi-square 3.96, p <0.05). The relative distribution of adiponectin isoforms was examined in patients with severe CKD, and the percentage of the high-molecular-weight form in patients with IHD during follow-up (n = 3) was significantly smaller than that in those without IHD (n = 4, p <0.02). In conclusion, renal function is a significant regulator of adiponectin when categorized by CKD stage, whereas hypoadiponectinemia is a predictor of CVD, including recurrent IHD.

Adiponectin replenishment ameliorates obesity-related hypertension.

Patients with obesity are susceptible to hypertension. We have reported that the plasma adiponectin levels are decreased in obesity and that adiponectin has many defensive properties against obesity-related diseases, such as type 2 diabetes and coronary artery disease. The aim of this study was to determine the relationship between adiponectin and hypertension in mice. We measured blood pressure and heart rate directly by a catheter in the carotid artery and indirectly by automatic sphygmomanometer at the tail artery. Obese KKAy mice had significantly lower plasma adiponectin levels and higher systolic blood pressure than control C57BL/6J mice at 21 weeks of age. Adenovirus-delivered adiponectin significantly decreased blood pressure in KKAy mice. The direct role of adiponectin on blood pressure regulation under insulin resistance-free state was investigated in adiponectin-knockout (KO) mice. Adiponectin KO mice developed hypertension when maintained on a high-salt diet (8% NaCl) without insulin resistance. The hypertension of salt-fed adiponectin KO mice was associated with reduced mRNA levels of endothelial NO synthase (eNOS) and prostaglandin I(2) synthase in aorta and low metabolite levels of endothelial NO synthase and prostaglandin I(2) synthase in plasma. Adiponectin therapy lowered the elevated blood pressure and corrected the above mRNA levels to those of the wild type. Our results suggest that hypoadiponectinemia contributes to the development of obesity-related hypertension, at least in part, directly, in addition to its effect via insulin resistance, and that adiponectin therapy can be potentially useful for hypertension in patients with the metabolic syndrome.

Adiponectin-mediated modulation of hypertrophic signals in the heart.

Patients with diabetes and other obesity-linked conditions have increased susceptibility to cardiovascular disorders. The adipocytokine adiponectin is decreased in patients with obesity-linked diseases. Here, we found that pressure overload in adiponectin-deficient mice resulted in enhanced concentric cardiac hypertrophy and increased mortality that was associated with increased extracellular signal-regulated kinase (ERK) and diminished AMP-activated protein kinase (AMPK) signaling in the myocardium. Adenovirus-mediated supplemention of adiponectin attenuated cardiac hypertrophy in response to pressure overload in adiponectin-deficient, wild-type and diabetic db/db mice. In cultures of cardiac myocytes, adiponectin activated AMPK and inhibited agonist-stimulated hypertrophy and ERK activation. Transduction with a dominant-negative form of AMPK reversed these effects, suggesting that adiponectin inhibits hypertrophic signaling in the myocardium through activation of AMPK signaling. Adiponectin may have utility for the treatment of hypertrophic cardiomyopathy associated with diabetes and other obesity-related diseases.

Adiponectin as a biomarker of the metabolic syndrome.

BACKGROUND: The metabolic syndrome, a cluster of abdominal obesity, dyslipidemia, hypertension and hyperglycemia, is a common basis for atherosclerotic vascular diseases in industrial countries exposed to overnutrition. Adiponectin is an adipose-derived plasma protein with anti-atherogenic and insulin-sensitizing activities. METHODS AND RESULTS: A total of 661 Japanese adults (479 men, 53+/-10 years; 182 women 56+/-10 years) were enrolled. Plasma adiponectin concentrations correlated negatively with waist circumference, visceral fat area, serum triglyceride concentration, fasting plasma glucose, fasting plasma insulin, and systolic and diastolic blood pressure in both sexes. A positive correlation was found between plasma adiponectin and high-density lipoprotein cholesterol concentrations in both sexes. The mean number of components of the metabolic syndrome increased as the plasma adiponectin concentration decreased: 2.57+/-1.34 for men and 2.00+/-1.51 for women with adiponectin concentrations <4.0 microg/ml. In all, 52.3% of men and 37.5% of women with adiponectin concentrations <4.0 microg/ml fulfilled the criteria for metabolic syndrome. CONCLUSION: Hypoadiponectinemia is closely associated with the clinical phenotype of the metabolic syndrome and measuring the plasma concentration of adiponectin may be useful for management of the metabolic syndrome.

Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages.

BACKGROUND: Vascular inflammation and subsequent matrix degradation play an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipose-specific plasma protein, accumulated to the injured artery and attenuated vascular inflammatory response. Clinically, high plasma adiponectin level was associated with low cardiovascular event rate in patients with chronic renal failure. The present study was designed to elucidate the effects of adiponectin on matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in human monocyte-derived macrophages. METHODS AND RESULTS: Human monocyte-derived macrophages were incubated with the physiological concentrations of human recombinant adiponectin for the time indicated. Adiponectin treatment dose-dependently increased TIMP-1 mRNA levels without affecting MMP-9 mRNA levels. Adiponectin also augmented TIMP-1 secretion into the media, whereas MMP-9 secretion and activity were unchanged. Time course experiments indicated that TIMP-1 mRNA levels started to increase at 24 hours of adiponectin treatment and were significantly elevated at 48 hours. Adiponectin significantly increased interleukin-10 (IL-10) mRNA expression at the transcriptional level within 6 hours and significantly increased IL-10 protein secretion within 24 hours. Cotreatment of adiponectin with anti-IL-10 monoclonal antibody completely abolished adiponectin-induced TIMP-1 mRNA expression. CONCLUSIONS: Adiponectin selectively increased TIMP-1 expression in human monocyte-derived macrophages through IL-10 induction. This study identified, for the first time, the adiponectin/IL-10 interaction against vascular inflammation.

Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease.

OBJECTIVES: This study examined the association of mutations in adiponectin gene with the prevalence of coronary artery disease (CAD). BACKGROUND: Coronary artery disease is a major cause of mortality in the industrial countries. Adiponectin gene locus, chromosome 3q27, is the candidate site for CAD. We have reported that adiponectin has antiatherogenic and antidiabetic properties, and that the plasma levels negatively correlated with body mass index (BMI) are significantly low in patients with CAD or type 2 diabetes. METHODS: The study subjects were 383 consecutive patients with angiographically confirmed CAD and 368 non-CAD subjects adjusted for age and BMI in the Japanese population. Single nucleotide polymorphisms (SNPs) in the adiponectin gene were determined by Taqman polymerase chain reaction (PCR) method or a PCR-based assay for the analysis of restriction fragment length polymorphism. The plasma adiponectin concentration was measured by enzyme-linked immunosorbent assay. RESULTS: Among SNPs, the frequency of I164T mutation was significantly higher in CAD subjects (2.9%) than in the control (0.8%, p < 0.05). The plasma adiponectin levels in subjects carrying the I164T mutation were significantly lower than in those without the mutation, and were independent of BMI. In contrast, SNP94 and SNP276, which are reported to be associated with an increased risk of type 2 diabetes, were associated neither with CAD prevalence nor with plasma adiponectin level. Subjects with I164T mutation exhibited a clinical phenotype of the metabolic syndrome. CONCLUSIONS: The I164T mutation in the adiponectin gene was a common genetic background associated with the metabolic syndrome and CAD in the Japanese population.

Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin.

Adiponectin is an adipocyte-derived, antiatherogenic protein that is present in serum as three isoforms. Total adiponectin levels are decreased in obese or diabetic humans or animal models. This study was designed to elucidate the relative isoform distribution of adiponectin in human disease states and identify the active form of adiponectin toward vascular endothelial cells. The percentage of high molecular weight form (HMW) per total adiponectin was significantly lower in patients with coronary artery disease than control subjects, whereas the hexamer form was similar and the trimer form was significantly higher. During weight reduction in obese subjects, the HMW form increased and the trimer and hexamer forms decreased. Recombinant adiponectin dose-dependently suppressed apoptosis and caspase-3 activity in human umbilical vein endothelial cells (HUVECs). Transduction with dominant-negative AMP-activated protein kinase (AMPK) abolished the suppressive effect of adiponectin on HUVECs. Gel filtration chromatography was used to separate the adiponectin isoforms, and the antiapoptotic effect toward HUVECs was only observed with the HMW form. These data suggest that HMW adiponectin specifically confers the vascular-protective activities of this adipocytokine. The full text of this article is available online at http://circres.ahajournals.org.

Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells.

Adiponectin is an adipocyte-specific adipocytokine with anti-atherogenic and anti-diabetic properties. Here, we investigated whether adiponectin regulates angiogenic processes in vitro and in vivo. Adiponectin stimulated the differentiation of human umbilical vein endothelium cells (HUVECs) into capillary-like structures in vitro and functioned as a chemoattractant in migration assays. Adiponectin promoted the phosphorylation of AMP-activated protein kinase (AMPK), protein kinase Akt/protein kinase B, and endothelial nitric oxide synthesis (eNOS) in HUVECs. Transduction with either dominant-negative AMPK or dominant-negative Akt abolished adiponectin-induced eNOS phosphorylation as well as adiponectin-stimulated HUVEC migration and differentiation. Dominant-negative AMPK also inhibited adiponectin-induced Akt phosphorylation, suggesting that AMPK is upstream of Akt. Dominant-negative Akt or the phosphatidylinositol 3-kinase inhibitor LY294002 blocked adiponectin-stimulated Akt and eNOS phosphorylation, migration, and differentiation without altering AMPK phosphorylation. Finally, adiponectin stimulated blood vessel growth in vivo in mouse Matrigel plug implantation and rabbit corneal models of angiogenesis. These data indicate that adiponectin can function to stimulate the new blood vessel growth by promoting cross-talk between AMP-activated protein kinase and Akt signaling within endothelial cells.