Clinical Impacts of Urinary Neutrophil Gelatinase-Associated Lipocalin in Patients With Chronic Kidney Disease Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Chronic kidney disease (CKD) is associated with poor prognosis in patients undergoing percutaneous coronary intervention (PCI). Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker for renal injury. However, the association between urinary NGAL concentrations and renal and cardiovascular events in patients with CKD undergoing PCI has not been elucidated. This study investigated the clinical impact of urinary NGAL concentrations on renal and cardiovascular outcomes in patients with non-dialysis CKD undergoing PCI.Methods and Results: We enrolled 124 patients with non-dialysis CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2) undergoing elective PCI. Patients were divided into low and high NGAL groups based on the median urinary NGAL concentration measured the day before PCI. Patients were monitored for renal and cardiovascular events during the 2-year follow-up period. Kaplan-Meier analyses showed that the incidence of renal and cardiovascular events was higher in the high than low NGAL group (log-rank P<0.001 and P=0.032, respectively). Multivariate Cox proportional hazards analyses revealed that urinary NGAL was an independent risk factor for renal (hazard ratio [HR] 4.790; 95% confidence interval [CI] 1.537-14.924; P=0.007) and cardiovascular (HR 2.938; 95% CI 1.034-8.347; P=0.043) events. CONCLUSIONS: Urinary NGAL could be a novel and informative biomarker for predicting subsequent renal and cardiovascular events in patients with CKD undergoing elective PCI.

Prognostic impact of polypharmacy and discharge medications in octogenarians and nonagenarian patients with acute heart failure.

With the increasing frequency of heart failure (HF) in elderly patients, polypharmacy has become a major concern owing to its adverse outcomes. However, reports on the clinical impact of polypharmacy and discharge medications in hospitalized super-aged patients with acute HF are rare. Data from 682 patients aged 80 years or older, hospitalized for treating acute HF, were analyzed. We recorded the number of medications at discharge and classified them into three groups: HF, non-HF cardiovascular, and non-cardiovascular medications. We investigated the correlation of polypharmacy, defined as daily administration of 10 or more medications at discharge, and the use of discharge medications with post-discharge prognosis. Polypharmacy was recorded in 24.3% of enrolled patients. Polypharmacy was not an independent predictor of all-cause mortality, the incidence of cardiac-related death, or HF-associated rehospitalization; however, the number of non-cardiovascular medications, multiple usage of potentially inappropriate medications, use of mineralocorticoid receptor antagonists, and doses of loop diuretics were associated with poor prognosis. Polypharmacy was significantly associated with higher mortality in patients with Barthel index ≥ 60 at discharge; hence, physical function at discharge was useful for the stratification of prognostic impacts of polypharmacy. The current study demonstrated that polypharmacy was not essentially associated with poor prognosis in super-aged patients with acute HF. Appropriate medications that consider the patient's physical function, rather than polypharmacy itself, are important for the management of HF.

Clinical features, future cardiac events, and prognostic factors following percutaneous coronary intervention in young female patients.

BACKGROUND: The proportion of young females among the patients who undergo percutaneous coronary intervention (PCI) is relatively small, and information on their clinical characteristics is limited. This study investigated the clinical characteristics and prognostic factors for future cardiac events in young females who underwent PCI. METHODS: This multicenter observational study included 187 consecutive female patients aged < 60 years who underwent PCI in seven hospitals. The primary composite endpoint was the incidence of cardiac death, nonfatal myocardial infarction, and target vessel revascularization. RESULTS: The mean patient age was 52.1 ± 6.1 years and 89 (47.6%) had diabetes, and renal dysfunction (an estimated glomerular filtration rate < 60 mL/min/1.73 m2) was observed in 38 (20.3%). During a median follow-up of 3.3 years, the primary endpoint occurred in 28 patients. The Cox proportional hazards models showed that renal dysfunction was an independent predictor for the primary endpoint (hazard ratio 3.04, 95% confidence interval 1.25-7.40, p = 0.01), as well as multivessel disease (hazard ratio 2.79, 95% confidence interval 1.12-6.93, p = 0.03). Patients with renal dysfunction had a significantly higher risk for the primary endpoint than those without renal dysfunction. CONCLUSIONS: Renal dysfunction was strongly associated with future cardiac events in young females who underwent PCI.

Long-term outcomes of percutaneous revascularization for internal mammary artery-left anterior descending artery bypass failure.

Despite the excellent long-term results of internal mammary artery (IMA)-left anterior descending (LAD) bypass, percutaneous revascularization of IMA is sometimes required for IMA-LAD bypass failure. However, its clinical outcomes have not been fully elucidated. The aim of this study was to investigate the long-term clinical outcomes, including target lesion revascularization (TLR) following contemporary percutaneous revascularization of failed IMA bypass graft. We examined data of 59 patients who had undergone percutaneous revascularization of IMA due to IMA-LAD bypass failure at nine hospitals. Patients with IMA graft used for Y-composite graft or sequential bypass graft were excluded. The incidence of TLR was primarily examined, whereas other clinical outcomes including cardiac death, myocardial infarction, and target vessel revascularization were also evaluated. Mean age of the enrolled patients was 67.4 ± 11.3 years, and 74.6% were men. Forty patients (67.8%) had anastomotic lesions, and 17 (28.8%) underwent revascularization within three months after bypass surgery. Procedural success was achieved in 55 (93.2%) patients. Stent implantation was performed in 13 patients (22.0%). During a median follow-up of 1401 days (interquartile range, 282-2521 days), TLR was required in six patients (8.5% at 1, 3, and 5 years). Patients who underwent percutaneous revascularization within 3 months after surgery tended to have a higher incidence of TLR. Clinical outcomes of IMA revascularization for IMA-LAD bypass failure were acceptable.

A Comparative Study of Three Nutritional Risk/Screening Indices for Predicting Cardiac Events and Physical Functioning Among Patients with Acute Heart Failure.

Undernutrition is very common among patients with heart failure (HF). This study evaluated the prognostic values of three nutritional risk/screening indices among patients with acute HF. We retrospectively calculated scores for 465 patients with acute HF using the Controlling Nutritional Status (CONUT) tool, the Geriatric Nutritional Risk Index (GNRI), and the Mini-Nutritional Assessment Short Form (MNA-SF). The outcomes of interest were the 1-year rate of cardiac events (cardiac-related death or HF-related readmission) and the Barthel index as an index of physical function during hospitalization. The CONUT, GNRI, and MNA-SF scores were significantly correlated, although the proportions of a normal nutritional state varied (CONUT: 18.3%, GNRI: 32.9%, and MNA-SF: 43.9%). Kaplan-Meier estimates revealed that cardiac events were more common among patients with undernutrition based on the CONUT score, and multivariable regression analysis revealed that only the CONUT score independently predicted poor outcomes. Furthermore, changes in the Barthel index during hospitalization were significantly correlated with the CONUT score but not with the GNRI and MNA-SF scores. In receiver operating characteristic analyses, the CONUT score had the most powerful predictive values on both the postdischarge incidence of cardiac events and the decline of physical function during hospitalization compared with the GNRI and the MNA-SF. These results indicate that the CONUT score might provide useful information for predicting poor outcomes in patients with acute HF.

Clinical Outcomes Following Emergent Percutaneous Coronary Intervention for Acute Total/Subtotal Occlusion of the Left Main Coronary Artery.

BACKGROUND: Data regarding the clinical features, outcomes and prognostic factors in patients presenting with acute total/subtotal occlusion of the unprotected left main coronary artery (LMCA) remain limited.Methods and Results:From a multi-center registry, 134 patients due to acute total/subtotal occlusion of the unprotected LMCA were reviewed. Emergency room (ER) status classification was defined according to the presence of cardiogenic shock and cardiopulmonary arrest (CPA) in the ER (class 1=no cardiogenic shock; class 2= cardiogenic shock but not CPA; and class 3=CPA). In-hospital mortality and cerebral performance category (CPC) as the endpoints were evaluated. One-half (67/134) of the enrolled patients presented with total occlusion of the unprotected LMCA. Regarding ER status classification, class 1, 2, and 3 were observed in 30.6%, 45.5%, and 23.9% of the patients, respectively. In-hospital mortality occurred in 73 (54.5%) patients; of the remaining patients, 52 (85.3%) could be discharged with a CPC 1 or 2. ER status classification (odds ratio 4.4 [95% confidence interval: 2.33-10.67]; P<0.001) and total occlusion of the unprotected LMCA (odds ratio 8.29 [95% confidence interval 2.93-23.46]; P<0.001) were strong predictors of in-hospital mortality. CONCLUSIONS: Acute total/subtotal occlusion involving the unprotected LMCA appeared to be associated with high in-hospital mortality. ER status classification and initial flow in the unprotected LMCA were significant predictive factors of in-hospital mortality.

Long-term renal outcomes after elective percutaneous coronary intervention in patients with advanced renal dysfunction.

The aim of the present study was to evaluate the renal outcomes, including the time course of renal function, after elective PCI in patients with advanced renal dysfunction and to assess the predictors of renal dysfunction progression. This is a subanalysis of a previous observational multicenter study that investigated long-term clinical outcomes in patients with advanced renal dysfunction (eGFR < 30 mL/min/1.73 m2), focusing on 151 patients who underwent elective PCI and their long-term renal outcomes. Renal dysfunction progression was defined as a 20% relative decrease in eGFR at 1 year from baseline or the initiation of permanent dialysis within 1 year. Progression of renal dysfunction at 1 year occurred in 42 patients (34.1%). Among patients with renal dysfunction progression, the decrease of renal function from baseline was not observed at 1 month but after 6 months of the index PCI. Baseline eGFR and serum albumin level were significant predictors of renal dysfunction progression at 1 year. Among 111 patients who had not been initiated on dialysis within 1 year, those with renal dysfunction progression had a significantly higher incidence of dialysis initiation more than 1 year after the index PCI than those with preserved renal function (p < 0.001). Among patients with advanced renal dysfunction who underwent elective PCI, 34.1% showed renal dysfunction progression at 1 year. The decrease in renal function was not observed at 1 month but after 6 months of the index PCI in patients with renal dysfunction progression. Furthermore, patients with renal dysfunction progression had poorer long-term renal outcomes.

Utility of the Nutritional Screening in Predicting Adverse Outcome of Patients With Overweight/Obesity and Acute Heart Failure.

BACKGROUND: Undernutrition is a negative predictor of adverse outcomes in patients with heart failure (HF). Despite the survival advantage of elevated body mass index (BMI) in patients with HF, BMI does not necessarily reflect a favorable nutritional status. In the present study, we investigated the clinical impact of nutritional screening in patients with HF and overweight/obesity. METHODS: We examined the data from 170 patients with overweight or obesity status (defined as BMI ≥ 25 kg/m2) who admitted for acute HF. Their controlling nutritional status (CONUT) score was calculated on admission. The CONUT score is regarded as an index of the nutritional status. RESULTS: The median duration of follow-up was 1096 days (interquartile range, 805-1096 days). Undernutrition was identified in 66.5% of the patients. Kaplan-Meier survival analysis demonstrated that patients with undernutrition had a higher incidence of all-cause death and readmission due to HF than those without undernutrition. Multivariate Cox regression analysis revealed that the CONUT score, but not BMI and the geriatric nutritional risk index, was independently correlated with poor prognosis. CONCLUSIONS: Undernutrition is highly prevalent and independently predicts poor outcomes in patients with overweight/obesity and acute HF.

Myonectin Is an Exercise-Induced Myokine That Protects the Heart From Ischemia-Reperfusion Injury.

RATIONALE: Physical exercise provides benefits for various organ systems, and some of systemic effects of exercise are mediated through modulation of muscle-derived secreted factors, also known as myokines. Myonectin/C1q (complement component 1q)/TNF (tumor necrosis factor)-related protein 15/erythroferrone is a myokine that is upregulated in skeletal muscle and blood by exercise. OBJECTIVE: We investigated the role of myonectin in myocardial ischemic injury. METHODS AND RESULTS: Ischemia-reperfusion in myonectin-knockout mice led to enhancement of myocardial infarct size, cardiac dysfunction, apoptosis, and proinflammatory gene expression compared with wild-type mice. Conversely, transgenic overexpression of myonectin in skeletal muscle reduced myocardial damage after ischemia-reperfusion. Treadmill exercise increased circulating myonectin levels in wild-type mice, and it reduced infarct size after ischemia-reperfusion in wild-type mice, but not in myonectin-knockout mice. Treatment of cultured cardiomyocytes with myonectin protein attenuated hypoxia/reoxygenation-induced apoptosis via S1P (sphingosine-1-phosphate)-dependent activation of cAMP/Akt cascades. Similarly, myonectin suppressed inflammatory response to lipopolysaccharide in cultured macrophages through the S1P/cAMP/Akt-dependent signaling pathway. Moreover, blockade of S1P-dependent pathway reversed myonectin-mediated reduction of myocardial infarct size in mice after ischemia-reperfusion. CONCLUSIONS: These data indicate that myonectin functions as an endurance exercise-induced myokine which ameliorates acute myocardial ischemic injury by suppressing apoptosis and inflammation in the heart, suggesting that myonectin mediates some of the beneficial actions of exercise on cardiovascular health.

Clinical outcomes after percutaneous coronary intervention in non-dialysis patients with acute coronary syndrome and advanced renal dysfunction.

BACKGROUND: Data about the clinical outcomes of ACS patients with advanced renal dysfunction (estimated glomerular filtration rate < 30 mL/min/1.73 m2) following percutaneous coronary intervention (PCI) are limited. METHODS: We examined the data obtained from 194 ACS patients with non-dialysis advanced renal dysfunction who underwent PCI at five hospitals. The primary composite endpoint was the incidence of major adverse cardiac and cerebrovascular events (MACCE: all-cause death, myocardial infarction, and ischemic stroke). RESULTS: Eighty patients (41.2%) were diagnosed with ST-elevation myocardial infarction (STEMI), and 117 patients (58.8%) with non-ST-elevation ACS (NSTE-ACS). Overall patients were followed for a median of 657.5 days. Cumulative incidence of MACCE at median follow-up was 32.3% (45.4% for STEMI and 23.4% for NSTE-ACS). Kaplan-Meier analysis demonstrated that patients in the STEMI group had significantly higher incidence of MACCE than those in the non-STEMI and unstable angina group (Log-rank p < 0.001). In-hospital MACCE rate was higher in the STEMI group than in the NSTE-ACS group, whereas post-discharge MACCE rate was comparable between the two groups. In the multivariate analysis, STEMI and Killip classification ≥ 2 were associated with in-hospital MACCE. On the other hand, body mass index and serum albumin at admission were independent predictors of post-discharge MACCE. CONCLUSIONS: Short- and long-term prognoses following PCI in non-dialysis patients with ACS and advanced renal dysfunction is still unfavorable. STEMI and Killip classification ≥ 2 were independent predictors for in-hospital MACCE, and body mass index and serum albumin were for post-discharge MACCE.

Influence of Preadmission Frailty on Short- and Mid-Term Prognoses in Octogenarians With ST-Elevation Myocardial Infarction.

BACKGROUND: Octogenarians, who are frequently frail, represent a large proportion of patients admitted for ST-segment elevation myocardial infarction (STEMI). We investigated the relationship between frailty, assessed by the Canadian Study of Health and Aging Clinical Frailty Scale (CFS), and short- and mid-term prognoses in octogenarian STEMI patients.Methods and Results:We used a multicenter registry data of 1,301 patients with STEMI undergoing percutaneous coronary intervention (PCI) between January 2014 and December 2016. Of them, 273 were retrospectively analyzed after categorization into 3 groups based on the preadmission CFS (CFS 1-3, 140 patients; CFS 4-5, 99 patients; and CFS 6-8, 34 patients). We evaluated the influence of CFS on overall mortality at 2 years and on non-home discharge, defined as the composite of in-hospital death and new transfer to a hospital or nursing home. During the study period (median, 565 days), the overall mortality and ratio of non-home discharge increased as CFS increased. After adjustment for multivariable analysis, the severely frail continued to be significantly associated with an increased risk of overall mortality (adjusted hazard ratio 2.37; 95% confidence interval [CI] 1.11-5.05; P=0.026) and non-home discharge (adjusted odds ratio 9.50; 95% CI 3.48-25.99; P<0.001). CONCLUSIONS: Frailty, as assessed by CFS, had an influence on short- and mid-term prognoses in octogenarian patients with STEMI.

Prognostic Impact of the Preservation of Activities of Daily Living on Post-Discharge Outcomes in Patients With Acute Heart Failure.

BACKGROUND: Hospitalization for heart failure (HF) carries a risk of impairment in physical activity. We assessed the association between changes in Barthel index (BI) during hospitalization and prognosis in patients with acute HF. Methods and Results: We evaluated the BI in 256 patients with acute HF at the time of hospital admission (pre-BI) and at discharge (post-BI). All patients were followed for 1 year after discharge. BI significantly decreased during hospitalization in enrolled patients. Patients with a post-BI <60 had longer hospital stays and higher rates of non-home discharge, and had a lower 1-year survival rate than those with a post-BI ≥60. Multivariate Cox regression analysis revealed that post-BI, not pre-BI or changes in BI, significantly correlated with all-cause death and the composite of all-cause death or rehospitalization for HF for 1 year after discharge. Patients with decreasing BI during hospitalization had significantly lower all-cause death- or HF readmission-free survival following acute HF than those having a pre-BI ≥60 and changes in BI ≥0. CONCLUSIONS: Results demonstrate that low BI at discharge and decreased BI during hospitalization predicted poor outcomes in Japanese patients with acute HF. A comprehensive approach, beginning in the acute phase, aiming to maintain patients' ability to perform activities of daily living could provide better management of HF.

C1q/TNF-related protein-1 functions to protect against acute ischemic injury in the heart.

Obesity is associated with an increased risk of cardiovascular disease. C1q/TNF-related protein (CTRP)-1 is a poorly characterized adipokine that is up-regulated in association with ischemic heart disease. We investigated the role of CTRP1 in myocardial ischemia injury. CTRP1-knockout mice showed increased myocardial infarct size, cardiomyocyte apoptosis, and proinflammatory gene expression after I/R compared with wild-type (WT) mice. In contrast, systemic delivery of CTRP1 attenuated myocardial damage after I/R in WT mice. Treatment of cardiomyocytes with CTRP1 led to reduction of hypoxia-reoxygenation-induced apoptosis and lipopolysaccharide-stimulated expression of proinflammatory cytokines, which was reversed by inhibition of sphingosine-1-phosphate (S1P) signaling. Treatment of cardiomyocytes with CTRP1 also resulted in the increased production of cAMP, which was blocked by suppression of S1P signaling. The antiapoptotic and anti-inflammatory actions of CTRP1 were cancelled by inhibition of adenylyl cyclase or knockdown of adiponectin receptor 1. Furthermore, blockade of S1P signaling reversed CTRP1-mediated inhibition of myocardial infarct size, apoptosis, and inflammation after I/R in vivo. These data indicate that CTRP1 protects against myocardial ischemic injury by reducing apoptosis and inflammatory response through activation of the S1P/cAMP signaling pathways in cardiomyocytes, suggesting that CTRP1 plays a crucial role in the pathogenesis of ischemic heart disease.

Safety and Efficacy of Long-Term Use of Tolvaptan in Patients With Heart Failure and Chronic Kidney Disease.

BACKGROUND: We assessed the long-term safety and efficacy of tolvaptan in 102 patients with heart failure (HF) and chronic kidney disease (CKD). Median follow-up duration was 1.6 years (1.0-4.4 years).Methods and Results:One patient discontinued tolvaptan because of hypernatremia. There were no changes in renal function or electrolytes during the 1-year follow-up. The cardiac-related death-free or HF-related hospitalization-free survival rate was significantly higher in patients receiving tolvaptan than in propensity score-matched patients who did not receive tolvaptan. CONCLUSIONS: In patients with HF and CKD, long-term administration of tolvaptan was well-tolerated, relatively safe and effective, suggesting its utility for long-term management of these conditions.

Adipose-derived protein omentin prevents neointimal formation after arterial injury.

Obesity is highly linked with the development of vascular diseases. Omentin is a circulating adipokine that is downregulated in patients with cardiovascular diseases. In this study, we investigated the role of omentin in regulation of vascular remodeling in response to injury. Wild-type (WT) mice were treated intravenously with adenoviral vectors encoding human omentin (Ad-OMT) or control ß-gal and subjected to arterial wire injury. Ad-OMT treatment reduced the neointimal thickening and the frequencies of bromodeoxyuridine-positive proliferating cells in injured arteries. Treatment of vascular smooth muscle cells (VSMCs) with human omentin protein at a physiologic concentration led to suppression of growth and ERK phosphorylation after stimulation with various growth factors. Omentin stimulated AMPK signaling in VSMCs, and blockade of AMPK reversed omentin-mediated inhibition of VSMC growth and ERK phosphorylation. Furthermore, fat-specific human omentin transgenic (OMT-TG) mice exhibited reduced neointimal thickening and vascular cell growth following vascular injury. AMPK activation was enhanced in injured arteries in OMT-TG mice, and administration of AMPK inhibitor reversed the reduction of neointimal hyperplasia in OMT-TG mice. These data indicate that omentin attenuates neointimal formation after arterial injury and suppresses VSMC growth through AMPK-dependent mechanisms. Thus, omentin can represent a novel target molecule for the prevention of vascular disorders.

Lipoprotein(a) levels predict adverse vascular events after acute myocardial infarction.

Lipoprotein(a) [Lp(a)], which is genetically determined, has been reported as an independent risk factor for atherosclerotic vascular disease. However, the prognostic value of Lp(a) for secondary vascular events in patients after coronary artery disease has not been fully elucidated. This 3-year observational study included a total of 176 patients with ST-elevated myocardial infarction (STEMI), whose Lp(a) levels were measured within 24 h after primary percutaneous coronary intervention. We divided enrolled patients into two groups according to Lp(a) level and investigated the association between Lp(a) and the incidence of major adverse cardiac and cerebrovascular events (MACCE). A Kaplan-Meier analysis demonstrated that patients with higher Lp(a) levels had a higher incidence of MACCE than those with lower Lp(a) levels (log-rank P = 0.034). A multivariate Cox regression analysis revealed that Lp(a) levels were independently correlated with the occurrence of MACCE after adjusting for other classical risk factors of atherosclerotic vascular diseases (hazard ratio 1.030, 95 % confidence interval: 1.011-1.048, P = 0.002). In receiver-operating curve analysis, the cutoff value to maximize the predictive power of Lp(a) was 19.0 mg/dl (area under the curve = 0.674, sensitivity 69.2 %, specificity 62.0 %). Evaluation of Lp(a) in addition to the established coronary risk factors improved their predictive value for the occurrence of MACCE. In conclusion, Lp(a) levels at admission independently predict secondary vascular events in patients with STEMI. Lp(a) might provide useful information for the development of secondary prevention strategies in patients with myocardial infarction.

Clinical benefit of tolvaptan in patients with acute decompensated heart failure and chronic kidney disease.

Tolvaptan, a vasopressin type 2 receptor antagonist, has an aquaretic effect without affecting renal function. The effects of long-term tolvaptan administration in heart failure patients with renal dysfunction have not been clarified. Here, we assessed the clinical benefit of tolvaptan during a 6-month follow-up in acute decompensated heart failure (ADHF) patients with severe chronic kidney disease (CKD; estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m(2)). We compared 33 patients with ADHF and severe CKD who were administered tolvaptan in addition to loop diuretics (TLV group), with 36 patients with ADHF and severe CKD who were administered high-dose loop diuretics (≥40 mg) alone (LD group). Alterations in serum creatinine and eGFR levels from the time of hospital discharge to 6-month follow-up were significantly different between the groups, with those in the TLV group being more favorable. Furthermore, Kaplan-Meier analysis revealed that rehospitalization for heart failure (HF) was significantly lower in the TLV group compared with the LD group. In ADHF patients with severe CKD, tolvaptan use for 6 months reduced worsening of renal function and rehospitalization rates for HF when compared with conventional diuretic therapy. In conclusion, tolvaptan could be a safe and effective agent for long-term management of HF and CKD.

Cardiac myocyte-derived follistatin-like 1 prevents renal injury in a subtotal nephrectomy model.

Heart disease contributes to the progression of CKD. Heart tissue produces a number of secreted proteins, also known as cardiokines, which participate in intercellular and intertissue communication. We recently reported that follistatin-like 1 (Fstl1) functions as a cardiokine with cardioprotective properties. Here, we investigated the role of cardiac Fstl1 in renal injury after subtotal nephrectomy. Cardiac-specific Fstl1-deficient (cFstl1-KO) mice and wild-type mice were subjected to subtotal (5/6) nephrectomy. cFstl1-KO mice showed exacerbation of urinary albumin excretion, glomerular hypertrophy, and tubulointerstitial fibrosis after subtotal renal ablation compared with wild-type mice. cFstl1-KO mice also exhibited increased mRNA levels of proinflammatory cytokines, including TNF-α and IL-6, NADPH oxidase components, and fibrotic mediators, in the remnant kidney. Conversely, systemic administration of adenoviral vectors expressing Fstl1 (Ad-Fstl1) to wild-type mice with subtotal nephrectomy led to amelioration of albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis, accompanied by reduced expression of proinflammatory mediators, NADPH oxidase components, and fibrotic markers in the remnant kidney. In cultured human mesangial cells, treatment with recombinant FSTL1 attenuated TNF-α-stimulated expression of proinflammatory cytokines. Treatment of mesangial cells with FSTL1 augmented the phosphorylation of AMP-activated protein kinase (AMPK), and inhibition of AMPK activation abrogated the anti-inflammatory effects of FSTL1. These data suggest that Fstl1 functions in cardiorenal communication and that the lack of Fstl1 production by myocytes promotes glomerular and tubulointerstitial damage in the kidney.

Omentin functions to attenuate cardiac hypertrophic response.

Cardiac hypertrophy occurs in many obesity-related conditions. Omentin is an adipose-derived plasma protein that is downregulated under obese conditions. Here, we investigated whether omentin modulates cardiac hypertrophic responses in vivo and in vitro. Systemic administration of an adenoviral vector expressing human omentin (Ad-OMT) to wild-type (WT) mice led to the attenuation of cardiac hypertrophy, fibrosis and ERK phosphorylation induced by transverse aortic constriction (TAC) or angiotensin II infusion. In cultured cardiomyocytes, stimulation with phenylephrine (PE) led to an increase in myocyte size, which was prevented by pretreatment with human omentin protein. Pretreatment of cardiomyocytes with omentin protein also reduced ERK phosphorylation in response to PE stimulation. Ad-OMT enhanced phosphorylation of AMP-activated protein kinase (AMPK) in the heart of WT mice after TAC operation. Blockade of AMPK activation by transduction with dominant-negative mutant forms of AMPK reversed the inhibitory effect of omentin on myocyte hypertrophy and ERK phosphorylation following PE stimulation. Moreover, fat-specific transgenic mice expressing human omentin showed reduced cardiac hypertrophy and ERK phosphorylation following TAC surgery compared to littermate controls. These data suggest that omentin functions to attenuate the pathological process of myocardial hypertrophy via the activation of AMPK in the heart, suggesting that omentin may represent a target molecule for the treatment of cardiac hypertrophy.

Neuron-derived neurotrophic factor functions as a novel modulator that enhances endothelial cell function and revascularization processes.

Strategies to stimulate revascularization are valuable for cardiovascular diseases. Here we identify neuron-derived neurotrophic factor (NDNF)/epidermacan as a secreted molecule that is up-regulated in endothelial cells in ischemic limbs of mice. NDNF was secreted from cultured human endothelial cells, and its secretion was stimulated by hypoxia. NDNF promoted endothelial cell network formation and survival in vitro through activation of Akt/endothelial NOS (eNOS) signaling involving integrin αvß3. Conversely, siRNA-mediated knockdown of NDNF in endothelial cells led to reduction of cellular responses and basal Akt signaling. Intramuscular overexpression of NDNF led to enhanced blood flow recovery and capillary density in ischemic limbs of mice, which was accompanied by enhanced phosphorylation of Akt and eNOS. The stimulatory actions of NDNF on perfusion recovery in ischemic muscles of mice were abolished by eNOS deficiency or NOS inhibition. Furthermore, siRNA-mediated reduction of NDNF in muscles of mice resulted in reduction of perfusion recovery and phosphorylation of Akt and eNOS in response to ischemia. Our data indicate that NDNF acts as an endogenous modulator that promotes endothelial cell function and ischemia-induced revascularization through eNOS-dependent mechanisms. Thus, NDNF can represent a therapeutic target for the manipulation of ischemic vascular disorders.