natriuretic-peptide--brain and Ischemia

B-type natriuretic peptide (BNP; 77-108 amino acids) and its N-terminal (1-76 amino acids) counterpart, NT-proBNP, are cardiac biomarkers that have been established for the assessment of left ventricular dysfunction and congestive heart failure and provide prognostic and risk stratification information for patients with acute coronary syndrome. Various automated immunoassays currently are available for the measurement of these natriuretic peptides, but there are significant analytical differences, especially between BNP and NT-proBNP.. Recently published methods and results were reviewed.. Although there are significant pre-analytical and analytical differences between the Triage BNP and Elecsys NT-proBNP and other BNP methods, they do not translate to clinically significant differences in their diagnostic and prognostic application in the assessment of systolic heart failure and risk stratification of patients with acute coronary syndrome. However, there appears to be some evidence that suggests that NT-proBNP may have an advantage in the detection of patients with mild or asymptomatic heart disease.

Topics: Biomarkers; Exercise; Heart Failure; Humans; Immunoassay; Ischemia; Multicenter Studies as Topic; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Ventricular Dysfunction, Left

We investigated the effects of transendocardial CD34(+) cell transplantation in patients with ischemic cardiomyopathy.. In a prospective crossover study, we enrolled 33 patients with ischemic cardiomyopathy with New York Heart Association class III and left ventricular ejection fraction <40%. In phase 1, patients were treated with medical therapy for 6 months. Thereafter, all patients underwent transendocardial CD34(+) cell transplantation. Peripheral blood CD34(+) cells were mobilized by granulocyte colony stimulating factor, collected via apheresis, and injected transendocardially in the areas of hibernating myocardium. Patients were followed up for 6 months after the procedure (phase 2). Two patients died during phase 1 and none during phase 2. The remaining 31 patients were 85% men, aged 57±6 years. In phase 1, we found no change in left ventricular ejection fraction (from 25.2±6.2% to 27.1±6.6%; P=0.23), N-terminal pro B-type natriuretic peptide (from 3322±3411 to 3672±5165 pg/mL; P=0.75) or 6-minute walk distance (from 373±68 to 411±116 m; P=0.17). In contrast, in phase 2 there was an improvement in left ventricular ejection fraction (from 27.1±6.6% to 34.9±10.9%; P=0.001), increase in 6-minute walk distance (from 411±116 to 496±113 m; P=0.001), and a decrease in N-terminal pro B-type natriuretic peptide (from 3672±5165 to 1488±1847 pg/mL; P=0.04). The average number of injected CD34(+) cells was 90.6±7.5×10(6). Higher doses of CD34(+) cells and a more diffuse distribution of transendocardial cell injections were associated with better clinical response.. Transendocardial CD34(+) cell transplantation may be associated with improved left ventricular function, decreased N-terminal pro B-type natriuretic peptide levels, and better exercise capacity in patients with ischemic cardiomyopathy. These effects seem to be particularly pronounced in patients receiving diffusely distributed cell injections and high-dose cell therapy.. http://www.clinicaltrials.gov. Unique identifier: NCT01350310.

Topics: Adult; Antigens, CD34; Blood Cells; Cardiomyopathies; Cross-Over Studies; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Ischemia; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Recovery of Function; Treatment Outcome

The diagnostic approach and the clinical management of patients presenting with suspected acute coronary syndrome or cardiac dysfunction are as yet challenging. Although ischemia modified albumin (IMA) and natriuretic peptides were recently proposed for detection of myocardial ischemia and cardiac dysfunction, little information is available on preanalytical and metabolic sources of variability of these markers.. To establish the influence of a regular endurance training and the relationship with conventional biochemical variables, NT-pro-brain natriuretic peptide (NT-proBNP) and IMA were assayed, along with cardiac troponin T (cTnT), lactate dehydrogenase (LDH), creatine kinase (CK), creatinine and albumin, in 35 sedentary healthy individuals and 50 male professional road cyclists, 12-24 h following the last demanding training session.. Athletes displayed higher values of both LDH (299+/-61 vs. 257+/-36 U/l, P=0.002) and CK (184+/-123 vs. 115+/-74 U/l, P=0.011), and slightly lower concentrations of creatinine (82+/-12 vs. 87+/-9 micromol/l, P=0.044). No athlete or sedentary control displayed cTnT concentrations exceeding the lower sensitivity limit of the assay. As compared to the sedentary controls, main IMA concentration was increased in athletes (100+/-13 vs. 94+/-6 KU/l, P=0.035), whereas that of NT-proBNP appeared significantly decreased (2.8+/-1.6 vs. 4.3+/-34, P=0.005). The percentage of subjects displaying values exceeding the upper reference limit for the IMA assay was significantly different between athletes and sedentary controls (50% vs. 7%; P<0.001). Pearson correlation analysis revealed an inverse association between IMA and albumin in both athletes (r=-0.640; P<0.001) and sedentary controls (r=-0.583; P=0.001).. Results of our investigation indicate that a demanding and regular aerobic training regimen, though able to trigger skeletal muscle sufferance, is not associated with any biochemical sign of severe and irreversible chronic cardiac involvement. Moreover, we suggest the adoption of specific IMA diagnostic thresholds following patients' stratification according to serum albumin concentration and physical activity.

Topics: Adult; Albumins; Exercise; Humans; Ischemia; Male; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Protein Precursors

Lebetin 2 (L2), a natriuretic-like peptide (NP), exerts potent cardioprotection in myocardial infarction (MI), with stronger effects than B-type natriuretic peptide (BNP). To determine the molecular mechanisms underlying its cardioprotection effect, we used molecular modeling, molecular docking and molecular dynamics (MD) simulation to describe the binding mode, key interaction residues as well as mechanistic insights into L2 interaction with NP receptors (NPRs). L2 binding affinity was determined for human, rat, mouse and chicken NPRs, and the stability of receptor-ligand complexes ascertained during 100 ns-long MD simulations. We found that L2 exhibited higher affinity for all human NPRs compared to BNP, with a rank preference for NPR-A > NPR-C > NPR-B. Moreover, L2 affinity for human NPR-A and NPR-C was higher in other species. Both docking and MD studies revealed that the NPR-C-L2 interaction was stronger in all species compared to BNP. Due to its higher affinity to human receptors, L2 could be used as a therapeutic approach in MI patients. Moreover, the stronger interaction of L2 with NPR-C could highlight a new L2 signaling pathway that would explain its additional effects during cardiac ischemia. Thus, L2 is a promising candidate for drug design toward novel compounds with high potency, affinity and stability.

Topics: Animals; Humans; Ischemia; Mice; Molecular Docking Simulation; Natriuretic Peptide, Brain; Peptides; Rats; Snakes; Viper Venoms

Among changes in demographics, aging is the most relevant cardiovascular risk factor. The prevalence of peripheral artery disease (PAD) is high in elderly patients and is associated with a worse prognosis. Despite optimal treatments, mortality in the high-risk population of octo- and nonagenarians with PAD remains excessive, and predictive factors need to be identified. The objective of this study was to investigate predictors of mortality in octo- and nonagenarians with PAD.. Cases of treated octo- and nonagenarians, including the clinical characteristics and markers of myocardial injury and heart failure, were studied retrospectively with respect to all-cause mortality. Hazard ratios [HR] were calculated and survival was analyzed by Kaplan-Meyer curves and receiver operating characteristic curved were assessed for troponin-ultra and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and chronic limb-threatening ischemia (CLTI).. A total of 123 octo- and nonagenarians admitted for PAD were eligible. The troponin level was the major predictor of all-cause mortality (HR: 4.6, 95% confidence interval [CI]: 1.4-15.3), followed by the NT-proBNP level (HR: 3.9, 95% CI 1.8-8.8) and CLTI (HR: 3.1, 95% CI 1.6-5.9). Multivariate regression revealed that each increment of 1 standard deviation in log troponin and log NT-proBNP was associated with a 2.7-fold (95% CI 1.8-4.1) and a 1.9-fold (95% CI 1.2-2.9) increased risk of all-cause death. Receiver operating characteristic curve analysis using a combination of all predictors yielded an improved area under the curve of 0.888. In a control group of an equal number of younger individuals, only NT-proBNP (HR: 4.2, 95% CI 1.2-14.1) and CLTI (HR: 6.1, 95% CI 1.6-23.4) were predictive of mortality.. Our study demonstrates that cardiovascular biomarkers and CLTI are the primary predictors of increased mortality in elderly PAD patients. Further risk stratification through biomarkers in this high-risk population of octo- and nonagenarians with PAD is necessary.

Topics: Age Factors; Aged; Aged, 80 and over; Aging; Biomarkers; Chronic Disease; Female; Humans; Ischemia; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peripheral Arterial Disease; Prognosis; Retrospective Studies; Risk Assessment; Risk Factors; Troponin

Myocardial infarction followed by adverse left ventricular (LV) remodeling is the most frequent proximate cause of heart failure. Hydrogen sulfide (H2S) is an important endogenous modulator of diverse physiological and pathophysiological processes. Its role in post-ischemic ventricular remodeling and the associated neurohormonal responses has not been defined. Here, we aimed at evaluating whether the slow-releasing water-soluble H2S donor GYY4137 (GYY) exerts cardioprotective effects and modulates the neurohormonal response to cardiac ischemic injury.. Treatment for 2 or 7 days with GYY (100 mg/Kg/48 h, IP) after acute myocardial infarction (MI) in rats preserved LV dimensions and function in vivo, compared to untreated infarcted (MI), placebo- and dl-propargylglycine- (PAG, an inhibitor of endogenous H2S synthesis) treated animals (n=9/group/time-point). LV dimensions and function in GYY-treated animals were comparable to healthy sham-operated rats. GYY-treated hearts had significantly less LV fibrosis than MI, placebo and PAG hearts. A higher density of blood vessels was found in the LV scar area of GYY-treated animals compared to all other infarcted groups. Despite preserved LV structure and function, treatment with GYY increased the levels of the natriuretic peptides ANP and BNP in association with enhanced cyclic GMP levels, paralleled by higher cGMP-dependent protein kinase type I (cGKI) protein levels.. Our data suggest that the slow-releasing H2S donor, GYY4137, preserves cardiac function, attenuates adverse remodeling and may exert post-ischemic cardioprotective (pro-angiogenic, anti-apoptotic, anti-hypertrophic and anti-fibrotic) effects in part through enhanced early post-ischemic endogenous natriuretic peptide activation.

Topics: Animals; Atrial Natriuretic Factor; Cardiotonic Agents; Humans; Hydrogen Sulfide; Ischemia; Morpholines; Myocardial Infarction; Natriuretic Peptide, Brain; Organothiophosphorus Compounds; Rats; Ventricular Dysfunction, Left; Ventricular Remodeling

We investigated whether the pathways linked to Toll-like receptors 2 and 4 (TLRs) are involved in renal ischemia-reperfusion (I/R)-induced cardiac hypertrophy. Wild type (WT) C57BL/6J, TLR2-/- and TLR4-/- mice were subjected to left kidney ischemia for 60 min followed by reperfusion for 5, 8, 12 and 15 days. Proton density magnetic resonance showed alterations in the injured kidney from WT mice, together with signs of parenchymal edema and higher levels of vimentin mRNA, accompanied by: (i) small, but significant, increase in serum urea after 24 h, (ii) 100% increase in serum creatinine at 24 h. A serum peak of inflammatory cytokines occurred after 5 days of reperfusion. Heart weight/body weight and heart weight/tibia length ratios increased after 12 and 15 days of reperfusion, respectively. Cardiac hypertrophy markers, B-type natriuretic peptide (BNP) and α-actin, left ventricle mass, cardiac wall thickness and myocyte width increased after 15 days of reperfusion, together with longer QTc and action potential duration. Cardiac TLRs, MyD88, HSP60 and HSP70 mRNA levels also increased. After 15 days of reperfusion, absence of TLRs prevented cardiac hypertrophy, as reflected by similar values of left ventricular cardiac mass and heart weight/body weight ratio compared to the transgenic Sham. Renal tissular injury also ameliorated in both knockout mice, as revealed by the comparison of their vimentin mRNA levels with those found in the WT on the same day after I/R. The I/R TLR2-/- group had TNF-α, IFN-γ and IL-1β levels similar to the non-I/R group, whereas the TLR4-/- group conserved the p-NF-κB/NF- κB ratio contrasting with that found in TLR2-/-. We conclude: (i) TLRs are involved in renal I/R-induced cardiac hypertrophy; (ii) absence of TLRs prevents I/R-induced cardiac hypertrophy, despite renal lesions seeming to evolve towards those of chronic disease; (iii) TLR2 and TLR4 selectively regulate the systemic inflammatory profile and NF- κB activation.

Topics: Actins; Animals; Cardiomegaly; Chaperonin 60; Cytokines; Heart; HSP70 Heat-Shock Proteins; Ischemia; Kidney; Kidney Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Myocardium; Natriuretic Peptide, Brain; Reperfusion Injury; Toll-Like Receptor 2; Toll-Like Receptor 4; Vimentin

Atherosclerotic peripheral arterial disease (PAD) is one of the most prevalent, morbid, and mortal diseases. The aim of this study was to evaluate mortality rates of patients with atherosclerotic PAD stratified according to age and diabetes and to determine predictors of death.. We studied 487 patients with symptomatic PAD consecutively admitted to the hospital. This cohort included the following four patient subgroups: (1) 216 patients with PAD <75 years of age without diabetes mellitus; (2) 115 patients with PAD < 75 years of age with diabetes mellitus; (3) 102 patients with PAD ≥ 75 years of age without diabetes mellitus; and (4) 54 patients with PAD ≥ 75 years of age with diabetes mellitus. Control subjects without atherosclerotic disease were matched to the patients with PAD in a 1:1 design by sex, age (± 2 years), and diabetes mellitus status. Outcome measure was all-cause mortality at 5 years.. Mortality rates at 5 years were 10% in nondiabetic patients with PAD < 75 years of age (vs 5% in control subjects; risk ratio [RR], 2.15; 95% confidence interval [CI], 1.60-4.34); 23% in diabetic patients with PAD < 75 years of age (vs 7% in control subjects; RR, 3.53; 95% CI, 1.80-6.91); 38% in nondiabetic patients with PAD ≥ 75 years of age (vs 22% in control subjects; RR, 2.08; 95% CI, 1.26-3.44); and 52% in diabetic patients with PAD ≥ 75 years of age. Applying multivariate Cox proportional hazards regression analyses (with cardiovascular risk factors, coexisting atherosclerotic disease, clinical stage of PAD, and several biochemical markers as predictor variables), we found the following independent predictors of outcome: in the 216 nondiabetic patients with PAD < 75 years of age, high-sensitivity C-reactive protein (hs-CRP) (RR, 3.04; 95% CI, 1.48-6.26); in the 115 diabetic patients with PAD < 75 years of age, amino-terminal pro-B-type natriuretic peptide (NT-proBNP) (RR, 2.63; 95% CI, 1.65-4.19); in the 102 nondiabetic patients with PAD ≥ 75 years of age, critical limb ischemia (RR, 3.70; 95% CI, 1.82-7.52) and NT-proBNP (RR, 1.93; 95% CI, 1.32-2.82); and in the 54 diabetic patients with PAD ≥ 75 years of age, hs-CRP (RR, 2.61; 95% CI, 1.45-4.67) and NT-proBNP (RR, 3.31; 95% CI, 1.96-5.60).. Mortality rates at 5 years varied considerably among patients with PAD stratified according to age and diabetes. Predictors of death differed among the four patient subgroups in this study and included critical limb ischemia, hs-CRP, and NT-proBNP. Our results might help to develop future strategies for optimized treatment of hospitalized patients with symptomatic PAD.

Topics: Age Factors; Aged; Aged, 80 and over; Austria; Biomarkers; C-Reactive Protein; Case-Control Studies; Comorbidity; Critical Illness; Diabetes Mellitus; Female; Humans; Ischemia; Kaplan-Meier Estimate; Male; Middle Aged; Mortality; Multivariate Analysis; Natriuretic Peptide, Brain; Odds Ratio; Patient Admission; Peptide Fragments; Peripheral Arterial Disease; Proportional Hazards Models; Prospective Studies; Risk Factors; Time Factors

To evaluate the correlation between the dimensions of ischemic and hemorrhagic lesions detected by diffusion MRI and the changes in lesion dimensions with serum NT-proBNP levels in mild and moderate head trauma.. 30 patients were assessed in our study. A control group of 10 individuals with no trauma history was formed in order to establish normal serum NT-proBNP values. Patients underwent brain diffusion MRI 24 and 48 hours following admittance. Their plasma NT-proBNP levels were checked at the same stages.. The correlation between the values of 24th and 48th hour Intra-axial hemorrhage (IAHEM) and Intra-axial ischemia (IAISC) and the values of 24th and 48th hour NT-proBNP was established as statistically significant.. It was observed that the serum NT-proBNP values could be higher in patients with wide intra-axial lesion following head trauma than patients with smaller intra-axial lesions. In addition, the fact that it has been established that the serum NT-proBNP values of patients with increasing cerebral parenchymal lesion dimensions on the advancing hours after the trauma increase suggests that serum NTproBNP values may be significant in the follow-up of the dimensions of cerebral parenchymal damage.

Topics: Adult; Cerebral Hemorrhage; Craniocerebral Trauma; Diffusion Magnetic Resonance Imaging; Female; Humans; Ischemia; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Young Adult

The goal of this study was to analyze differences in risk factors, including the level of brain natriuretic peptide (BNP) and the distribution of lesions, between cases of critical limb ischemia (CLI) and intermittent claudication (IC) among patients with peripheral arterial disease.. Risk factors and clinical characteristics were prospectively investigated in 817 consecutive patients, including 185 patients with CLI and 632 patients with IC.. The patients in the CLI group were older than those in the IC group (p＜0.001). The prevalence of diabetes and cerebral infarction and the proportion of women were higher in the CLI group (p＜0.05). The plasma BNP levels in the CLI group were higher than those observed in the IC group (333±538 vs. 136±354 pg/mL, p＜0.001). In contrast, the levels of homocysteine and fibrinogen were higher and the levels of albumin and the estimated glomerular filtration rate were lower in the CLI group (p＜0.05). According to a multiple logistic analysis, the BNP level, diabetes, female gender, the albumin level, body mass index (BMI) and ankle-brachial pressure index (ABI) were associated with CLI (p＜0.05). Aortoiliac artery lesions were less common, whereas femoropopliteal and below-the-knee (BK) lesions were more common, in the CLI group (p＜0.05). The number of affected BK arteries was also higher in the CLI group (p＜0.001). Correlations were found between the presence of aortoiliac lesions and smoking and a low HDL cholesterol level, while femoropopliteal lesions were found to correlate with age, BMI and hypertension and BK lesions were found to correlate with diabetes, age, female gender and BMI (p＜0.05). The plasma BNP level correlated with the number of affected BK arteries (p＜0.05).. A high BNP level, diabetes, female gender, a low albumin level, ABI and BMI are risk factors for CLI. In this study, differences in the levels of anatomical lesions and correlated risk factors were found between the CLI and IC groups.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Angiography; Ankle Brachial Index; Asian People; Body Mass Index; Cholesterol; Female; Fibrinogen; Glomerular Filtration Rate; Homocysteine; Humans; Intermittent Claudication; Ischemia; Japan; Leg; Male; Middle Aged; Natriuretic Peptide, Brain; Peripheral Arterial Disease; Prevalence; Risk Factors; Sex Factors; Smoking

Myocardial perfusion imaging (MPI) can detect myocardial perfusion abnormalities but many examinations are without pathological findings. This study examines whether circulating biomarkers can be used as screening modality prior to MPI.. 243 patients with an intermediate risk of CAD or with known CAD with renewed suspicion of ischemia were referred to MPI. Blood samples were analyzed for N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), YKL-40, IL-6, matrix metalloproteinase 9 (MMP-9) and high sensitive C-reactive protein (hsCRP). Patients with myocardial perfusion defects had elevated levels of NT-proBNP (p<0.0001), YKL-40 (p = 0.03) and IL-6 (p = 0.03) but not of hsCRP (p = 0.58) nor of MMP-9 (p = 0.14). The NT-proBNP increase was observed in both genders (p<0.0001), whereas YKL-40 (p = 0.005) and IL-6 (p = 0.02) were elevated only in men. A NT-proBNP cut off-concentration at 25 ng/l predicted a normal MPI with a negative predictive value >95% regardless of existing CAD.. 20-25% of patients suspected of CAD could have been spared a MPI by using a NT-proBNP cut-off concentration at 25 ng/l with a negative predictive value >95%. NT-proBNP has the potential use of being a screening marker of CAD before referral of the patient to MPI.

Topics: Adipokines; Aged; Biomarkers; Chitinase-3-Like Protein 1; Coronary Artery Disease; Female; Glycoproteins; Humans; Inflammation; Interleukin-6; Ischemia; Lectins; Male; Middle Aged; Myocardial Perfusion Imaging; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Risk; Sex Factors

To test the hypothesis that B-type natriuretic peptide (BNP) acts as a potent vasculogenic agent by enhancing the number, proliferation, adhesion, and migration of endothelial progenitor cells (EPCs).. BNP is a neurohormonal peptide that predicts outcome and used for treatment in chronic heart failure patients. It has been shown to promote angiogenesis in experimental animals. EPCs have been demonstrated to contribute to postnatal angiogenesis and vasculogenesis.. The number of EPC colony forming units (CFU) and levels of N-terminal ProBNP were assayed in patients with severe, yet controlled, New York Heart Association (NYHA) II-IV heart failure. The in vitro effects of BNP on early EPC-CFU numbers, proliferation, migration, adhesive, and vascular tube formation capacities were studied using human and murine systems. The effects of in vivo BNP administration on Sca-1/Flk-1 progenitors and on vasculogenesis in the hindlimb ischemia model were then assayed in wild-type mice.. A significant correlation was found between circulating N-terminal ProBNP levels and EPC-CFU numbers. We observed a dose-dependent effect of BNP on the numbers of CFU and proliferation capacity of human EPCs as well as on their adhesive, migratory, and tube formation properties, in vitro. Systemic BNP administration to mice led to a significant increase in bone marrow Sca-1/Flk-1 EPCs and improvement in blood flow and capillary density in the ischemic limbs of mice.. BNP promotes vessel growth by increasing the number of endothelial progenitors and enhancing their functional properties. These provasculogenic properties of BNP could account for some of its beneficial effects in chronic heart failure patients and may be harnessed for the purpose of improving collateral formation in ischemic subjects.

Topics: Animals; Ataxin-1; Ataxins; Bone Marrow Cells; Cell Adhesion; Cell Count; Cell Movement; Collagen; Colony-Forming Units Assay; Drug Combinations; Endothelial Cells; Heart Failure; Humans; Ischemia; Laminin; Mice; Natriuretic Peptide, Brain; Neovascularization, Pathologic; Neovascularization, Physiologic; Nerve Tissue Proteins; Nuclear Proteins; Peptide Fragments; Phosphatidylinositol 3-Kinases; Proteoglycans; Stem Cells; Vascular Endothelial Growth Factor Receptor-1

Cardiac atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) modulate blood pressure and volume by activation of the receptor guanylyl cyclase-A (GC-A) and subsequent intracellular cGMP formation. Here we report what we believe to be a novel function of these peptides as paracrine regulators of vascular regeneration. In mice with systemic deletion of the GC-A gene, vascular regeneration in response to critical hind limb ischemia was severely impaired. Similar attenuation of ischemic angiogenesis was observed in mice with conditional, endothelial cell-restricted GC-A deletion (here termed EC GC-A KO mice). In contrast, smooth muscle cell-restricted GC-A ablation did not affect ischemic neovascularization. Immunohistochemistry and RT-PCR revealed BNP expression in activated satellite cells within the ischemic muscle, suggesting that local BNP elicits protective endothelial effects. Since within the heart, BNP is mainly induced in cardiomyocytes by mechanical load, we investigated whether the natriuretic peptide/GC-A system also regulates angiogenesis accompanying load-induced cardiac hypertrophy. EC GC-A KO hearts showed diminished angiogenesis, mild fibrosis, and diastolic dysfunction. In vitro BNP/GC-A stimulated proliferation and migration of cultured microvascular endothelia by activating cGMP-dependent protein kinase I and phosphorylating vasodilator-stimulated phosphoprotein and p38 MAPK. We therefore conclude that BNP, produced by activated satellite cells within ischemic skeletal muscle or by cardiomyocytes in response to pressure load, regulates the regeneration of neighboring endothelia via GC-A. This paracrine communication might be critically involved in coordinating muscle regeneration/hypertrophy and angiogenesis.

Topics: Animals; Cardiomegaly; Cell Adhesion Molecules; Cell Movement; Cell Proliferation; Cells, Cultured; Coronary Vessels; Endothelial Cells; Female; Guanylate Cyclase; Hindlimb; Ischemia; Male; Mice; Microfilament Proteins; Natriuretic Peptide, Brain; Neovascularization, Physiologic; p38 Mitogen-Activated Protein Kinases; Phosphoproteins; Reperfusion; RNA, Messenger

Atrial and brain natriuretic peptides (ANP and BNP, respectively) function via guanylyl cyclase (GC)-A, resulting in diuresis, natriuresis, and blood vessel dilation. Here, we investigated the role of endogenous ANP/BNP-GC-A signaling on reparative vascular remodeling using a hind-limb ischemia model.. In GC-A-deficient mice (GC-A-KO), hind-limb ischemia resulted in autoamputation or severe ulcers in 60% of mice (6/10) during the 28-day observation period. In wild-type (WT) mice, partial amputation or mild ulcers were detected in only 20% of mice (2/10). Laser Doppler perfusion imaging revealed that the recovery of blood flow in the ischemic limb was significantly inhibited in GC-A-KO mice compared with WT mice. Immunostainings with anti-PECAM-1 antibody demonstrated that, in GC-A-KO, the capillary density of the ischemic tissue was significantly diminished compared to WT. Furthermore, bone marrow transplantation showed the predominant role of GC-A on local ischemic tissue rather than on vascular progenitor cells mobilized from bone marrow during vascular remodeling. In cultured human endothelial cells, ANP treatment significantly stimulated mRNA expressions of vascular endothelial growth factor and endothelial nitric oxide synthase via Erk1/2-dependent mechanism.. These results suggest that endogenous ANP and BNP play important roles in reparative vascular remodeling in ischemic tissue.

Topics: Animals; Atrial Natriuretic Factor; Blood Vessels; Cell Adhesion Molecules; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Hindlimb; Humans; Ischemia; Male; Mice; Microfilament Proteins; Natriuretic Peptide, Brain; Nitric Oxide Synthase Type III; Phosphoproteins; Receptors, Atrial Natriuretic Factor; Regeneration; Regional Blood Flow; RNA, Messenger; Vascular Endothelial Growth Factor A

The prognostic value of cardiac troponins and natriuretic peptide in acute ischemic stroke is uncertain. We measured cardiac troponin T (cTnT), cardiac troponin I (cTnI), and N-terminal pro-brain natriuretic peptide (NT-proBNP) at admission in acute ischemic stroke patients without evident myocardial damage.. In 174 consecutive patients with MRI-confirmed ischemic stroke, serial measurements of cTnT, cTnI, and NT-proBNP were performed at 3 different time points in the hyperacute phase (at admission, on days 1 and 2). Relation of laboratory values to risk factors, stroke subtype classification, and clinical outcome after 3 months was analyzed.. The highest proportion of raised parameters was found at day 2 for cTnI in 8 of 103 (7.8%), at day 3 for cTnT in 8 of 174 (4.6%), and NT-proBNP in 114 of 174 (65.5%) patients. Proportion of patients with good outcome was significantly reduced in the group with highest NT-proBNP quartile. However, using multivariate regression analysis, no significant relation to morbidity and mortality was found for cTnT, cTnI, or NT-proBNP. Significant impact on the outcome was detected for lesion size, insular involvement, sex, age, and stroke severity.. NT-proBNP is raised in nearly two thirds of acute stroke patients, whereas elevated cardiac troponins are found only in a small number of acute ischemic stroke patients. Neither NT-proBNP nor cardiac troponins influence clinical outcome if other risk factors are considered.

Topics: Age Factors; Aged; Brain Ischemia; Electrocardiography; Female; Humans; Ischemia; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Prospective Studies; Protein Structure, Tertiary; Regression Analysis; Risk Factors; Sex Factors; Stroke; Time Factors; Treatment Outcome; Troponin I; Troponin T

Natriuretic peptides (NPs), which consist of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP, respectively), are characterized as cardiac or vascular hormones that elicit their biological effects by activation of the cGMPcGMP-dependent protein kinase (cGK) pathway. We recently reported that adenoviral gene transfer of CNP into rabbit blood vessels not only suppressed neointimal formation but also accelerated reendothelialization, a required step for endothelium-dependent vasorelaxation and antithrombogenicity. Accordingly, we investigated the therapeutic potential of the NPscGMPcGK pathway for vascular regeneration. In transgenic (Tg) mice that overexpress BNP in response to hindlimb ischemia, neovascularization with appropriate mural cell coating was accelerated without edema or bleeding, and impaired angiogenesis by the suppression of nitric oxide production was effectively rescued. Furthermore, in BNP-Tg mice, inflammatory cell infiltration in ischemic tissue and vascular superoxide production were suppressed compared with control mice. Ischemia-induced angiogenesis was also significantly potentiated in cGK type I Tg mice, but attenuated in cGK type I knockout mice. NPs significantly stimulated capillary network formation of cultured endothelial cells by cGK stimulation and subsequent Erk12 activation. Furthermore, gene transfer of CNP into ischemic muscles effectively accelerated angiogenesis. These findings reveal an action of the NPscGMPcGK pathway to exert multiple vasculoprotective and regenerative actions in the absence of apparent adverse effects, and therefore suggest that NPs as the endogenous cardiovascular hormone can be used as a strategy of therapeutic angiogenesis in patients with tissue ischemia.

Topics: Animals; Atrial Natriuretic Factor; Blood Vessels; Cells, Cultured; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Gene Expression; Gene Transfer Techniques; Humans; Inflammation; Ischemia; Mice; Mice, Knockout; Mice, Transgenic; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Neovascularization, Physiologic; Regeneration