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1.
Arterioscler Thromb Vasc Biol ; 36(4): 757-64, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26868212

ABSTRACT

OBJECTIVE: Circulating levels of high-sensitivity cardiac troponin T (hs-cTnT) and N terminal pro brain natriuretic peptide (NT-proBNP) are predictors of prognosis in patients with coronary artery disease (CAD). We aimed at evaluating the effect of coronary atherosclerosis and myocardial ischemia on cardiac release of hs-cTnT and NT-proBNP in patients with suspected CAD. APPROACH AND RESULTS: Hs-cTnT and NT-proBNP were measured in 378 patients (60.1±0.5 years, 229 males) with stable angina and unknown CAD enrolled in the Evaluation of Integrated Cardiac Imaging (EVINCI) study. All patients underwent stress imaging to detect myocardial ischemia and coronary computed tomographic angiography to assess the presence and characteristics of CAD. An individual computed tomographic angiography score was calculated combining extent, severity, composition, and location of plaques. In the whole population, the median (25-75 percentiles) value of plasma hs-cTnT was 6.17 (4.2-9.1) ng/L and of NT-proBNP was 61.66 (31.2-132.6) ng/L. In a multivariate model, computed tomographic angiography score was an independent predictor of the plasma hs-cTnT (coefficient 0.06, SE 0.02; P=0.0089), whereas ischemia was a predictor of NT-proBNP (coefficient 0.38, SE 0.12; P=0.0015). Hs-cTnT concentrations were significantly increased in patients with CAD with or without myocardial ischemia (P<0.005), whereas only patients with CAD and ischemia showed significantly higher levels of NT-proBNP (P<0.001). CONCLUSIONS: In patients with stable angina, the presence and extent of coronary atherosclerosis is related with circulating levels of hs-cTnT, also in the absence of ischemia, suggesting an ischemia-independent mechanism of hs-cTnT release. Obstructive CAD causing myocardial ischemia is associated with increased levels of NT-proBNP.


Subject(s)
Angina, Stable/blood , Coronary Artery Disease/blood , Myocardial Ischemia/blood , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Troponin T/blood , Angina, Stable/diagnosis , Biomarkers/blood , Chi-Square Distribution , Coronary Angiography/methods , Coronary Artery Disease/diagnosis , Echocardiography, Stress , Europe , Female , Humans , Linear Models , Magnetic Resonance Imaging , Male , Middle Aged , Multivariate Analysis , Myocardial Ischemia/diagnosis , Myocardial Perfusion Imaging , Positron-Emission Tomography , Predictive Value of Tests , Severity of Illness Index , Tomography, Emission-Computed, Single-Photon , Tomography, X-Ray Computed
2.
Exp Mol Pathol ; 102(2): 354-359, 2017 04.
Article in English | MEDLINE | ID: mdl-28274612

ABSTRACT

Suppression of tumorigenicity 2 (ST2) mediates the effect of Interleukin-33 (IL-33). Few data are reported on the relationship between IL-33/ST2 and obesity. We aimed to investigate effects of obesity on IL-33/ST2 system in heart, adipose tissue and liver in a rodent model of obesity. The relationship of cardiac expression of IL-33/ST2 system with natriuretic peptides (NPs) system and inflammatory mediators was also studied. mRNA expression of IL-33/ST2 system was evaluated in cardiac, adipose and hepatic biopsies from obese Zucker rats (O) and controls (CO). Expression levels of sST2 was significantly lower in O rats compared with CO (p<0.05) in all tissues. Besides, the mRNA levels of IL-33 decreased significant in fat of O respect to CO, while, expression levels of ST2L was significantly higher in liver of CO than in O. A strong relationship of IL-33/ST2 with NPs and classical inflammatory mediators was observed in cardiac tissue. Expression of sST2 in cardiac, adipose and liver tissue decreased in O compared with controls, suggesting an involvement for IL-33/ST2 system in molecular mechanisms of obesity. The strong relationships with NP systems and inflammatory mediators could suggest an involvement for IL-33/ST2 in molecular pathways leading to cardiac dysfunction and inflammation associated with obesity.


Subject(s)
Adipose Tissue/metabolism , Interleukin-33/metabolism , Liver/metabolism , Myocardium/metabolism , Obesity/genetics , Receptors, Interleukin-1/metabolism , Animals , Disease Models, Animal , Interleukin-33/genetics , Male , Obesity/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats, Zucker , Receptors, Interleukin-1/genetics , Transcriptome
3.
Clin Chem Lab Med ; 53(9): 1359-66, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25411996

ABSTRACT

BACKGROUND: In left ventricular assist device (LVAD) recipients, plasma levels of interleukin (IL)-6 are associated with Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles, reflecting post-operative risk. However, it is not clear how the cardiac level of IL-6, detectable on the tissue samples at the time of implantation, can contribute to predict the post-operative outcome. METHODS: In 40 LVAD recipients, blood and myocardial samples from LV-apex were collected at the time of implantation to assess plasma and cardiac IL-6 levels. Serum C-reactive protein (CRP) levels were considered as inflammatory variable routinely used in LVAD-based therapy. RESULTS: Cardiac IL-6 levels did not correlate with either plasma IL-6 levels (R=0.296, p=0.063) and tissue IL-6 mRNA expression (R=-0.013, p=0.954). Contrary to what happened for the plasma IL-6 and CRP, no differences were observed in cardiac IL-6 levels with respect to INTERMACS profiles (p=0.090). Furthermore, cardiac IL-6 concentrations, unlike IL-6 and CRP circulating levels, were not correlated with the length of intensive care unit stay and hospitalization. CONCLUSIONS: Cardiac IL-6 levels do not contribute to improve risk profile of LVAD recipients in relation to clinical inpatient post-implantation. Instead, plasma IL-6 and serum CRP concentrations are more effective in predicting the severity of the clinical course in the early phase of LVAD therapy.


Subject(s)
C-Reactive Protein/metabolism , Heart-Assist Devices , Interleukin-6/metabolism , Myocardium/metabolism , Adult , Aged , Female , Hospitalization , Humans , Intensive Care Units , Interleukin-6/blood , Male , Middle Aged , Postoperative Period , Risk Assessment , Treatment Outcome
4.
J Transl Med ; 12: 350, 2014 Dec 12.
Article in English | MEDLINE | ID: mdl-25496327

ABSTRACT

BACKGROUND: In end-stage heart failure (HF), the implantation of a left ventricular assist device (LVAD) is able to induce reverse remodeling. Cellular proteases, such as cathepsins, are involved in the progression of HF. The aim of this study was to evaluate the role of cathepsin system in HF patients supported by LVAD, in order to determine their involvement in cardiac remodeling. METHODS: The expression of cysteine (CatB, CatK, CatL, CatS) and serine cathepsin (CatG), and relative inhibitors (Cystatin B, C and SerpinA3, respectively) was determined in cardiac biopsies of 22 patients submitted to LVAD (pre-LVAD) and compared with: 1) control stable chronic HF patients on medical therapy at the moment of heart transplantation without prior LVAD (HT, n = 7); 2) patients supported by LVAD at the moment of transplantation (post-LVAD, n = 6). RESULTS: The expression of cathepsins and their inhibitors was significantly higher in pre-LVAD compared to the HT group and LVAD induced a further increase in the cathepsin system. Significant positive correlations were observed between cardiac expression of cathepsins and their inhibitors as well as inflammatory cytokines. In the pre-LVAD group, a relationship of cathepsins with dilatative etiology and length of hospitalization was found. CONCLUSIONS: A parallel activation of cathepsins and their inhibitors was observed after LVAD support. The possible clinical importance of these modifications is confirmed by their relation with patients' outcome. A better discovery of these pathways could add more insights into the cardiac remodeling during HF.


Subject(s)
Cathepsins/metabolism , Heart Failure/metabolism , Heart Ventricles/physiopathology , Heart-Assist Devices , Female , Heart Failure/surgery , Humans , Male
5.
J Clin Lab Anal ; 28(5): 374-80, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24648291

ABSTRACT

BACKGROUND: The determination of matrix metalloproteases (MMPs) is relevant in many pathophysiological conditions, especially if associated with extracellular matrix remodeling; however, the results obtained are closely linked to the method used and are not directly comparable. The aim of this study was to perform a reappraisal of quantitative gel zymography technique for MMPs in human plasma, to use for comparison with commercially available ELISA and in those experimental conditions where the MMP active form needs to be revealed. METHODS: The critical methodological parameters of zymography were checked and a comparison with a routinely used ELISA was performed. RESULTS: Sensitivity and reproducibility levels of zymography are suitable for detection of MMP-9 in human plasma, providing results closely related to those obtained by ELISA. CONCLUSIONS: Analytical parameters of zymography were suitable for detection of MMPs in human plasma. Quantitative zymography for MMPs is an alternative method for comparing the results of ELISA widely employed for MMP determination, thus reducing the discrepancies between laboratories regarding gelatinase assay.


Subject(s)
Electrophoresis, Polyacrylamide Gel/standards , Enzyme Assays/standards , Matrix Metalloproteinase 9/blood , Blood Chemical Analysis/standards , Enzyme-Linked Immunosorbent Assay/standards , Female , Humans , Logistic Models , Male , Matrix Metalloproteinases/blood , Reproducibility of Results , Sensitivity and Specificity , Time Factors
6.
Cytokine ; 63(2): 113-22, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23669252

ABSTRACT

OBJECTIVE: New device therapies have expanded the strategies for treating heart failure (HF) patients. Unloading of the heart with a left ventricular assist device (LVAD) can lead to the reversal of many remodeling changes whose underlying mechanisms are not yet completely known. Molecular analysis might play a role in obtaining further insight into the regulatory mechanisms of this process. A critical step in an RT-PCR study is the selection of reference genes for data normalization. This study aimed to determine an optimal combination of stably expressed reference genes in different regions of the human heart in order to study the effects of LVAD implants on cardiac remodeling, and in particular to check their reliability on the evaluation of pro-inflammatory cytokine expression. DESIGN AND METHODS: We validated nine of the most commonly used reference genes in human myocardium samples obtained at heart transplantation from patients with LVAD implant (n=30 from a total of six patients) and from heart transplant (HT from a total of seven patients) recipients as controls (n=35). Samples from both left (LV) and right (RV) ventricles were analyzed. The normalization strategy was tested by analyzing mRNA expression of IL-6, IL-8 and TNF-α, whose protein levels were measured by immunometric assay. RESULTS: The most stable gene combinations changed according to the experimental groups (the LVAD and HT groups and the different myocardial regions). Considering all the cardiac samples as a whole, the three most stably expressed genes were PPIA, RPL13A, and YWHAZ (M=0.70). Using the best normalization strategy, a significant increase in IL-6, IL-8 mRNA expression was observed in LVAD samples compared to HT (p<0.0001). Similar results were obtained by protein analysis. CONCLUSIONS: Our results underline the importance of always selecting reference genes for the specific system studied. The most appropriate normalization strategy is of pivotal importance for understanding the molecular mechanisms associated with the pathophysiology of HF, such as inflammation.


Subject(s)
14-3-3 Proteins/metabolism , Cyclophilin A/metabolism , Heart Transplantation , Heart-Assist Devices , Ribosomal Proteins/metabolism , 14-3-3 Proteins/genetics , Adult , Cyclophilin A/genetics , Female , Heart , Heart Failure , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Interleukin-8/genetics , Interleukin-8/metabolism , Male , Middle Aged , RNA, Messenger/biosynthesis , Ribosomal Proteins/genetics , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Ventricular Remodeling/genetics
7.
Pharmacol Res ; 70(1): 41-9, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23295943

ABSTRACT

Apoptosis is involved in both acute and chronic loss of cardiomyocytes after myocardial infarction (MI). To date, the pathophysiological significance of an apoptotic transcriptional profile activated in the post-ischemic remodeled myocardium, in the absence of hemodynamic factors secondary to left ventricular (LV) dysfunction, still remains to be determined. The mRNA expression of pro- and anti-apoptotic factors was determined in a swine model of non-reperfused MI with preserved LV ejection fraction. The extent of cell death was evaluated by histological analysis. Male adult farm pigs with MI (n=5), induced by permanent surgical ligation of the left anterior descending coronary artery and sham-operated adult farm pigs as control (n=7) were studied. Tissue samples were collected from the border (BZ) and remote zone (RZ) of the infarcted area to identify possible regional effects. After 4 weeks post-MI, the infarct size was 13±1% of the LV wall mass in absence of contractile dysfunction. In BZ, there was increased mRNA expression of Casp-3 (BZ vs Controls: 0.51±0.15 vs 1.39±0.04, p<0.001), a significant decrease in Bcl-2 (by 63%), associated with an increase in apoptotic cells, as revealed by TUNEL staining and cleaved-Casp-3 presence. In contrast, in the RZ there was a significant reduction of pro-apoptotic factors compared to BZ (by 80% for Casp-3), in presence of scattered apoptotic cells, increased gene expression of Hsp72 (1.82±0.21 vs 1.34±0.08, p=0.037) and iNOS (1.51±0.14 vs 1.19±0.05, p<0.05) compared to control. In conclusion, the LV distribution of apoptotic transcriptional profile revealed that apoptotic cell death is highly detectable in BZ, possibly explaining the local abnormalities of myocardial cell survival in a porcine model of MI with normal overall function.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Apoptosis , Myocardial Infarction/pathology , Myocardium/pathology , Stroke Volume/physiology , Ventricular Remodeling , Animals , Apoptosis/genetics , Disease Models, Animal , Electrophoresis, Agar Gel , Gene Expression Profiling , Magnetic Resonance Imaging, Cine , Male , Myocardial Contraction , Myocardial Infarction/genetics , Myocardium/enzymology , Myocardium/metabolism , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Stroke Volume/genetics , Swine , Transcription, Genetic , Ventricular Remodeling/genetics
8.
Cardiovasc Diabetol ; 11: 143, 2012 Nov 19.
Article in English | MEDLINE | ID: mdl-23164042

ABSTRACT

BACKGROUND: The role of systemic and myocardial adiponectin (ADN) in dilated cardiomyopathy is still debated. We tested the regulation of both systemic and myocardial ADN and the relationship with AMP-activated protein kinase (AMPK) activity in a swine model of non-ischemic dilated cardiomyopathy. METHODS AND RESULTS: Cardiac tissue was collected from seven instrumented adult male minipigs by pacing the left ventricular (LV) free wall (180 beats/min, 3 weeks), both from pacing (PS) and opposite sites (OS), and from five controls. Circulating ADN levels were inversely related to global and regional cardiac function. Myocardial ADN in PS was down-regulated compared to control (p < 0.05), yet ADN receptor 1 was significantly up-regulated (p < 0.05). No modifications of AMPK were observed in either region of the failing heart. Similarly, myocardial mRNA levels of PPARγ, PPARα, TNFα, iNOS were unchanged compared to controls. CONCLUSIONS: Paradoxically, circulating ADN did not show any cardioprotective effect, confirming its role as negative prognostic biomarker of heart failure. Myocardial ADN was reduced in PS compared to control in an AMPK-independent fashion, suggesting the occurrence of novel mechanisms by which reduced cardiac ADN levels may regionally mediate the decline of cardiac function.


Subject(s)
Adiponectin/metabolism , Cardiomyopathy, Dilated/metabolism , Heart Failure/metabolism , Myocardium/pathology , AMP-Activated Protein Kinases/metabolism , Adiponectin/blood , Adiponectin/genetics , Animals , Cardiac Pacing, Artificial , Cardiomyopathy, Dilated/blood , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/physiopathology , Disease Models, Animal , Down-Regulation , Heart Failure/blood , Heart Failure/genetics , Heart Failure/physiopathology , Male , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , PPAR alpha/genetics , PPAR alpha/metabolism , PPAR gamma/genetics , PPAR gamma/metabolism , Pilot Projects , RNA, Messenger/metabolism , Receptors, Adiponectin/metabolism , Stroke Volume , Swine , Swine, Miniature , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Ventricular Function, Left , Ventricular Remodeling
9.
J Nucl Cardiol ; 19(6): 1182-9, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22879076

ABSTRACT

BACKGROUND: Cardiovascular risk factors are classically associated with coronary atherosclerosis. We sought to investigate whether risk factors are also associated with left ventricular (LV) dilatation, contractile impairment and reduced myocardial blood flow (MBF) in patients with non-ischemic LV dysfunction. METHODS: We studied 81 patients (59 males, age 60 ± 9 years) with mild-to-severe LV dysfunction (mean ejection fraction 37%, range 19%-50%), no history of diabetes and normal coronary arteries. Absolute MBF was measured by positron emission tomography and (13)N-ammonia at rest and after dipyridamole (0.56 mg/kg I.V. over 4 min). RESULTS: Overt LV dysfunction (LV end-diastolic diameter >60 mm associated with LV ejection fraction <45%) was present in 42 patients (52%); severely depressed hyperemic MBF (<1.09 mL · min(-1) · g(-1)) was present in 41 patients (51%). Using multivariate logistic regression analysis, low high-density lipoprotein cholesterol (HDL-C, P < .036), newly diagnosed non-insulin-dependent diabetes or insulin-resistance (NIDD/IR, P < .019) and the use of diuretics (P = .001) were independently associated with overt LV dysfunction. Low HDL-C (P = .015) and NIDD/IR (P = .048) were also independently associated with severely depressed hyperemic MBF. CONCLUSIONS: Low HDL-C and NIDD/IR are associated with more severe LV impairment and reduced hyperemic MBF in non-ischemic LV dysfunction.


Subject(s)
Coronary Artery Disease/diagnostic imaging , Coronary Circulation , Positron-Emission Tomography , Ventricular Dysfunction, Left/diagnostic imaging , Adult , Aged , Aged, 80 and over , Algorithms , Ammonia , Analysis of Variance , Biomarkers/blood , Blood Glucose/metabolism , Cholesterol, HDL/blood , Coronary Artery Disease/blood , Coronary Artery Disease/complications , Dipyridamole , Female , Humans , Male , Middle Aged , Nitrogen Radioisotopes , Positron-Emission Tomography/methods , Predictive Value of Tests , Rest , Risk Factors , Sensitivity and Specificity , Severity of Illness Index , Vasodilator Agents , Ventricular Dysfunction, Left/blood , Ventricular Dysfunction, Left/etiology
10.
J Mater Sci Mater Med ; 23(1): 205-16, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22143909

ABSTRACT

Over the past decade, a large number of strategies and technologies have been developed to reduce heart failure progression. Among these, cardiac tissue engineering is one of the most promising. Aim of this study is to develop a 3D scaffold to treat cardiac failure. A new three-block copolymer, obtained from δ-valerolactone and polyoxyethylene, was synthesised under high vacuum without catalyst. Copolymer/gelatine blends were microfabricated to obtain a ECM-like geometry. Structures were studied under morphological, mechanical, degradation and biological aspects. To prevent left ventricular remodelling, constructs were biofunctionalises with molecularly imprinted nanoparticles towards the matrix metalloproteinase MMP-9. Results showed that materials are able to reproduce the ECM structure with high resolution, mechanical properties were in the order of MPa similar to those of the native myocardium and cell viability was verified. Nanoparticles showed the capability to rebind MMP-9 (specific rebinding 18.67) and to be permanently immobilised on the scaffold surface.


Subject(s)
Biomimetics , Myocardial Infarction/pathology , Polymers/chemistry , Tissue Scaffolds , Ventricular Remodeling , Humans , Matrix Metalloproteinase 9/metabolism , Molecular Imprinting , Spectroscopy, Fourier Transform Infrared
11.
Am J Physiol Endocrinol Metab ; 301(1): E105-12, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21505146

ABSTRACT

An impaired ability to store fatty acids (FA) in subcutaneous adipose tissue (SAT) may be implicated in the pathogenesis of obesity-related diseases via overexposure of lean tissues and production of free radicals from FA oxidation (FAO). We studied regional FA metabolism in skeletal muscle and adipose tissue in humans and investigated the long-term effects of the FAO inhibitor trimetazidine on glucose and FA metabolism. Positron emission tomography (PET) and [(11)C]palmitate were used to compare FA metabolism in SAT and skeletal muscle between eight obese and eight nonobese subjects (BMI ≥/< 30 kg/m(2)). A subgroup of nine subjects underwent a 1-mo trimetazidine administration. PET with [(11)C]palmitate and [(18)F]fluorodeoxyglucose, indirect calorimetry, and MRI before and after this period were performed to characterize glucose and FA metabolism, fat masses, skeletal muscle triglyceride, and creatine contents. Obesity was characterized by a 100% elevation in FAO and a defect in the FA esterification rate constant (P < 0.05) in skeletal muscle. FA esterification was reduced by ~70% in SAT (P < 0.001) in obese vs. control subjects. The degrees of obesity and insulin resistance were both negatively associated with esterification-related parameters and positively with FAO (P < 0.05). Trimetazidine increased skeletal muscle FA esterification (P < 0.01) and mildly upregulated glucose phosphorylation (P = 0.066). Our data suggest that human obesity is characterized by a defect in tissue FA storage capability, which is accompanied by a (potentially compensatory) elevation in skeletal muscle FAO; trimetazidine diverted FA from oxidative to nonoxidative pathways and provoked an initial activation of glucose metabolism in skeletal muscle.


Subject(s)
Fats/metabolism , Fatty Acids/metabolism , Muscle, Skeletal/metabolism , Obesity/drug therapy , Obesity/metabolism , Trimetazidine/therapeutic use , Adult , Aged , Anti-Obesity Agents/pharmacology , Anti-Obesity Agents/therapeutic use , Cross-Sectional Studies , Fluorodeoxyglucose F18/pharmacokinetics , Humans , Lipid Metabolism/drug effects , Middle Aged , Muscle, Skeletal/drug effects , Obesity/diagnostic imaging , Oxidation-Reduction/drug effects , Positron-Emission Tomography , Trimetazidine/pharmacology , Up-Regulation/drug effects , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic use , Young Adult
12.
Pharmacol Res ; 64(1): 11-24, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21440629

ABSTRACT

Heart failure (HF) is a major public health problem and the approach for an accurate individualization of HF risk and care should include a profile of laboratory data, in addition to clinical and imaging data. The possibility of identifying the most vulnerable patients is clinically important, especially considering that many therapeutic interventions are available today. This goal has not been yet reached although many novel biomarkers have been proposed and tested. The complexity of the biochemical network at the basis of HF pathophysiology clearly suggests that a single marker cannot reflect all the features of this syndrome, whereas the combined use of more indices would better characterize HF patients and create new options for their management, helping identify which patients to follow more closely. The multimarker approach, considering various biochemical pathways simultaneously, bases its robustness on a suitable choice of indices known to be individually associated with HF. The choice of biomarker combination is essential to the performance of the multimarker strategy. A major problem in selecting the biomarker profile is the proportional increase in economic burden; thus a "parsimonious" biomarker combination has to be used in a cost-effective evaluation. Statistical analysis and analytical performance of the different elements of the combination, in turn, may heavily influence results. This review summarizes the results obtained using a multimarker approach for HF risk stratification, for predicting HF incidence in a population, and evaluating the response to therapy. An insight into transcriptomic biomarkers, recently proposed for HF individual risk assessment, is also reported. A reliable selection of biomarkers for the careful management of HF patients is of pivotal importance in reducing healthcare costs without reducing patient care.


Subject(s)
Biomarkers , Heart Failure/diagnosis , Heart Failure/therapy , Animals , Drug Monitoring/methods , Heart Failure/epidemiology , Heart Failure/metabolism , Heart Failure/physiopathology , Humans , Risk Assessment/methods
13.
Pharmacol Res ; 63(3): 207-15, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20934513

ABSTRACT

The role of myocardial apoptosis during the development of heart failure (HF), in the absence of coronary artery stenosis, is still debated. The aim of the study was to evaluate whether (similar to functional impairment) the activation of myocardial apoptosis follows a regional pattern in an established model of pacing-induced HF. HF was induced in adult male minipigs by rapid and sustained left ventricular (LV) epicardial pacing (n=8; n=5 healthy controls). Progressive regional derangement of the contractile function and perfusion was assessed by magnetic resonance imaging as LV end-systolic wall thickening (LVESWT) and relative upslope of signal intensity (LVRUSI, %) in the anterior/anterior-lateral (pacing site, PS) and infero-septal LV region (opposite site, OS). LV tissue from PS and OS was analyzed for biomarkers of cell apoptosis and injury. After 21 days of LV pacing, LVESWT was lower in the PS compared to OS (7.6±3.7 vs 24.16±3.6%, p<0.05), and LV ejection fraction was 24.0±3.7 (p<0.05 vs control). The mRNA expression of caspase (Casp)-3 was significantly higher in the PS of HF hearts than in controls (1.28±0.125 vs 0.82±0.10), but not Casp-9. Bcl-2 and Hsp72 expression was significantly increased in PS compared to control (0.90±0.60 vs 0.63±0.033; 0.72±0.10 vs 0.28±0.098), in the presence of a TNF-α level increased by 50.7%. The regional myocardial apoptotic index, assessed by TUNEL, was unchanged in HF. In conclusion, the activators and inhibitors of cell apoptosis are equally expressed without affecting the survival of cardiomyocytes and the magnitude of regional myocardial dysfunction during development of non-ischemic HF.


Subject(s)
Apoptosis/physiology , Heart Failure/physiopathology , Myocardium/pathology , Myocytes, Cardiac/pathology , Myocytes, Cardiac/physiology , Severity of Illness Index , Animals , Heart Failure/pathology , Male , Swine , Swine, Miniature
14.
Circ J ; 75(10): 2387-96, 2011.
Article in English | MEDLINE | ID: mdl-21817815

ABSTRACT

BACKGROUND: Redox aminothiols have been reported to modulate the activity of recombinant metalloproteinases (MMP). The aim of the present study was to investigate the effects of myocardial redox state on the activities of MMP-2 and -9 implicated in cardiac remodeling in end-stage heart failure patients supported by left ventricular assist device (LVAD). METHODS AND RESULTS: During heart transplant (HT) surgery, myocardial specimens (MS) from right ventricular walls and LV walls were obtained from 7 LVAD recipients (LVAD group, MS n=35) and from 7 stable HT candidates on medical therapy (MT group, MS n=35). Myocardial MMP-2 and -9 activities and expression, tissue inhibitor of MMP (TIMP)-1 and -4, transforming growth factor (TGF)-ß1 and aminothiol concentrations were measured. MMP-2 and -9 activities were evaluated also by incubating MS with different amounts of reduced and oxidized glutathione (GSH). MMP-2 and -9 activities and expression were lower in the LVAD group, whereas myocardial TIMP-1 and -4 concentrations were comparable to those of MT patients. Higher GSH and TGF-ß1 concentrations were found in LVAD-recipients. Only GSH concentrations were inversely related to MMP-2 and -9 activities. In vitro, GSH had an inhibitory effect on MMP-2 and -9 activities. CONCLUSIONS: LVAD recipients show reduced myocardial MMP-2 and -9 activities and expression when compared to medically treated patients. Changes of myocardial redox state, predominantly GSH-dependent, appear to modulate MMP-2 and -9 activities by an inhibitory effect dependent on thiol content. These data support a role of GSH cycle in modulating the extracellular matrix in end-stage heart failure patients supported by LVAD.


Subject(s)
Heart-Assist Devices , Matrix Metalloproteinases/metabolism , Myocardium/metabolism , Ventricular Dysfunction, Left/therapy , Adult , Female , Glutathione/metabolism , Heart Ventricles , Humans , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Middle Aged , Oxidation-Reduction , Tissue Inhibitor of Metalloproteinase-1/metabolism , Tissue Inhibitor of Metalloproteinase-2/metabolism
15.
Cytokine ; 49(3): 325-30, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20031444

ABSTRACT

In patients with dilated cardiomyopathy (DCM) abnormal myocardial blood flow (MBF) has been associated with coronary microvascular dysfunction. The aim of this study was to test the hypothesis that osteopontin (OPN) plasma levels could be associated with the activation of the renin-aldosterone system (RAS) in these patients and be involved in mediating myocardial and coronary damage. In 66 patients with idiopathic left ventricular dysfunction of variable severity the plasma levels of OPN were correlated with biomarkers of systemic metabolism, RAS activation, myocardial dysfunction and with clinical indexes of left ventricle (LV) function and perfusion obtained by 2D-echocardiography and PET. As compared to controls, patients showed a significant increase of inflammatory markers (OPN: 508+/-30.8ng/ml vs. 426.9+/-16.4, p<0.05 and interleukin (IL)-6: 1.71+/-0.29pg/ml vs. 0.38+/-0.03pg/ml, p<0.001) and of indexes of cardiac damage. OPN levels were significantly correlated with the extent of microvascular dysfunction (MBF at rest: p=0.01; during dipyridamole: p=0.0003) and with plasma renin activity (PRA) (r=0.26, p=0.04). Both in patients with milder or more severe LV dysfunction lower MBF values were associated with higher OPN levels and PRA. These results suggest a interdependent role of RAS and vascular inflammation in cardiomyopathy.


Subject(s)
Aldosterone/metabolism , Cardiomyopathy, Dilated , Coronary Circulation , Microcirculation , Myocardium , Osteopontin/blood , Renin/metabolism , Biomarkers/blood , Cardiomyopathy, Dilated/blood , Cardiomyopathy, Dilated/pathology , Cardiomyopathy, Dilated/physiopathology , Female , Humans , Inflammation/immunology , Inflammation/pathology , Male , Middle Aged , Myocardium/cytology , Myocardium/pathology , Regional Blood Flow , Ventricular Dysfunction, Left/blood , Ventricular Dysfunction, Left/physiopathology
16.
Clin Chem Lab Med ; 48(4): 561-8, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20298133

ABSTRACT

BACKGROUND: Adiponectin, present in different multimeric forms in circulation, is increasingly used in clinical settings as a cardiometabolic marker. The development of several commercially available enzyme-linked immunosorbent assays (ELISA) has allowed for the widespread measurement of adiponectin in research as well as in clinical practice. The comparative performance of these assays is thus an issue of major relevance. METHODS: The analytical performance of four different ELISAs (LINCO, B-Bridge, SPIbio and ALPCO) was evaluated. Samples from 102 cardiac patients and 40 healthy subjects were tested using LINCO and ALPCO. The latter is able to measure the concentrations of multimers. For the multimer assay, an error propagation study was performed. A subset of subjects was tested by all four ELISAs for comparison purposes. RESULTS: Bland-Altman plots revealed differences between the results of the four ELISAs, mainly for ALPCO. However, a strong correlation between the different ELISAs (ALPCO, r=0.83; B-Bridge, r=0.98; SPIbio, r=0.91 vs. LINCO) was observed. Total adiponectin measured by LINCO showed a better association with cardiac disease [receiver-operating characteristic (ROC) curves] than total and high molecular weight adiponectin measured by ALPCO. CONCLUSIONS: The results of this study contribute to a better understanding of the methodological features of the several ELISAs, and help in the evaluation and comparison of the relative results.


Subject(s)
Adiponectin/blood , Enzyme-Linked Immunosorbent Assay/methods , Adiponectin/chemistry , Adult , Aged , Heart Diseases/diagnosis , Humans , Male , Middle Aged , Molecular Weight , Protein Multimerization , ROC Curve , Reagent Kits, Diagnostic
17.
Pacing Clin Electrophysiol ; 33(7): 865-72, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20230463

ABSTRACT

BACKGROUND: Increase in adrenomedullin (ADM) plasma levels in congestive heart failure (HF) patients is due to many cardiac and systemic factors, particularly to greater fluid retention and to activation of sympathetic nervous system. Aim of this study was to assess the role of plasma ADM levels in HF patients treated by cardiac resynchronization therapy (CRT). METHODS: 50 patients, mean age 70 years, 34 male, New York Heart Association (NYHA) Class III-IV HF, left ventricular ejection fraction (LVEF) < 35%, underwent CRT. All patients were in sinus rhythm and with complete left bundle branch block (QRS duration 138 +/- 6 msec). A complete echoDoppler exam, blood samples for brain natriuretic peptide (BNP), and ADM were obtained from 2 to 7 days before implantation. RESULTS: At 16 +/- 6 months follow-up, >or=1 NYHA Class improvement was observed in 38 patients. However, a >10% reduction in end-systolic dimensions (ESD) was reported in 21 patients (Group I): -16.6 +/- 1.8%; in the remaining 29 patients ESD change was almost negligible: -2.0 +/- 1.03% (Group II), P < 0.0001. The two groups were comparable for age, sex, cause of LV dysfunction, therapy, QRS duration at baseline, preimplantation ESD, LVEF%, and BNP. Significantly higher pre implantation ADM levels were present in Group I than in Group II (27.2 +/- 1.8 pmol/l vs 17.9 +/- 1.4, P = 0.0003). CONCLUSIONS: Significantly higher ADM levels indicate a subgroup of patients in whom reverse remodeling can be observed after CRT. Patients with lower ADM basal values before CRT could represent a group in whom the dysfunction is so advanced that no improvement can be expected.


Subject(s)
Adrenomedullin/blood , Cardiac Pacing, Artificial/methods , Heart Failure/diagnosis , Heart Failure/prevention & control , Ventricular Dysfunction, Left/diagnosis , Ventricular Dysfunction, Left/prevention & control , Aged , Aged, 80 and over , Biomarkers/blood , Female , Heart Failure/blood , Humans , Male , Middle Aged , Outcome Assessment, Health Care/methods , Reproducibility of Results , Sensitivity and Specificity , Treatment Outcome , Ventricular Dysfunction, Left/blood , Ventricular Remodeling
18.
Recenti Prog Med ; 101(9): 364-8, 2010 Sep.
Article in Italian | MEDLINE | ID: mdl-21268375

ABSTRACT

The importance of biomarker assay such as cardiac troponins and H-FABP is assuming a pivotal role not only in the diagnosis and follow-up of patients with acute coronary syndromes. Radiofrequency (RF) ablation represents a widely used method for the non pharmacologic treatment of arrhythmias.We report a case of a patient complaining of life-threatening arrhythmias treated by RF in whom temporal changes of cardiac biomarkers was determined after the procedure.


Subject(s)
Arrhythmias, Cardiac/blood , Arrhythmias, Cardiac/surgery , Catheter Ablation , Fatty Acid-Binding Proteins/blood , Aged , Biomarkers/blood , Humans , Male
19.
Recenti Prog Med ; 101(12): 475-9, 2010 Dec.
Article in Italian | MEDLINE | ID: mdl-21394984

ABSTRACT

The cardiac resynchronization therapy (CRT), based on correction of electro-mechanical dyssynchrony by biventricular pacing in patients with severe chronic HF unresponsive to optimal medical treatment and left ventricular conduction disturbances, has been developed. The determination of plasma adrenomedullin (ADM) levels before implantation could provide important additional information to reduce the high percentage (30%) of patients not responding to treatment despite the use of increasingly sophisticated methods for selecting candidates. The case described illustrates the importance of basal ADM plasma levels in predicting the clinical and functional improvement after treatment with CRT.


Subject(s)
Adrenomedullin/blood , Cardiac Resynchronization Therapy , Heart Failure/blood , Heart Failure/therapy , Aged , Female , Humans , Prognosis
20.
Cytokine ; 46(2): 228-35, 2009 May.
Article in English | MEDLINE | ID: mdl-19285424

ABSTRACT

In this study the effects of nitric oxide (NO) on intimal hyperplasia (IH) were evaluated in an ex-vivo model of human saphenous vein (SV). SV segments were cultured in conditions able to reproduce IH (FCS), or in medium alone (RPMI), or in presence of a NO donor (NO). Osteopontin (OPN) and Interleukin (IL)-6 were determined in the medium at different culture times and in the tissue, at the end of experiment. OPN and IL-6 release in medium was increased in FCS with respect to RPMI (OPN: 13.9+/-2.9 vs. 2.3+/-0.8 microg/ml, p=0.0011; IL-6: 304.2+/-64.7 vs. 42.0+/-10.1 ng/ml, p<0.0006) as well as intima thickness, that positively correlated with OPN production (r=0.81). In tissue OPN was higher in FCS (82.0+/-30.3 ng/mg protein) than in RPMI (13.8+/-4.2, p=0.0051) and at baseline (3.7+/-0.7, p=0.018). NO reduces IH progression (25%) and both OPN and IL-6 expression (OPN/GAPDH: undetectable baseline; 0.27+/-0.06 RPMI; 0.89+/-0.28 FCS; 0.09+/-0.05 NO; p=0.026 FCS vs. baseline, p=0.018 vs. RPMI, p=0.005 vs. NO). The beneficial NO effect on IH reduction appears to be mediated by the indirect inhibition of OPN production. NO could modulates the initial inflammatory signals that induces the OPN over-production with the related cascade of events leading to IH.


Subject(s)
Hyperplasia/metabolism , Nitric Oxide/metabolism , Osteopontin/metabolism , Tunica Intima/metabolism , Tunica Intima/pathology , Graft Occlusion, Vascular , Humans , Hyperplasia/pathology , Interleukin-6/metabolism , Nitric Oxide Donors/pharmacology , Nitroso Compounds/pharmacology , Osteopontin/genetics , Saphenous Vein/anatomy & histology , Saphenous Vein/drug effects , Saphenous Vein/metabolism , Saphenous Vein/pathology , Stents , Tissue Culture Techniques , Tunica Intima/anatomy & histology , Tunica Intima/drug effects
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