Francesca Tarantini

Maine Medical Center, Portland, Maine, United States

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Publications (89)

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    Maria Raffaella Ambrosio · Claudia Di Serio · Giovanna Danza · [...] · Francesca Tarantini
    [Show abstract] [Hide abstract] ABSTRACT: Background Carbonic anhydrase IX is a member of α-carbonic anhydrases that is preferentially expressed in solid tumors. It enables bicarbonate transport across the plasma membrane, neutralizing intracellular pH and conferring to cancer cells a survival advantage in hypoxic/acidic microenvironments. Overexpression of carbonic anhydrase IX in cancer tissues is regulated by hypoxia inducible factor 1α − mediated transcription and the enzyme is considered a marker of tumor hypoxia and poor outcome. The role of carbonic anhydrase IX in prostate cancer has not been fully clarified and controversy has arisen on whether this enzyme is overexpressed in hypoxic prostate cancer tissues. Methods We analyzed the expression of carbonic anhydrase IX and hypoxia inducible factor 1α in two prostate cancer cell lines, LNCaP and PC-3, and in 110 cancer biopsies, by western blotting and immunocyto/histochemistry. Results In LNCaP and PC-3 cells, carbonic anhydrase IX was mostly cytoplasmic/nuclear, with very limited membrane localization. Nuclear staining became stronger under hypoxia. When we analyzed carbonic anhydrase IX expression in human prostate cancer biopsies, we found that protein staining positively correlated with hypoxia inducible factor 1α and with Gleason pattern and score, as well as with the novel grading system proposed by the International Society of Urological Pathology for prostate cancer. Once more, carbonic anhydrase IX was mainly cytoplasmic in low grade carcinomas, whereas in high grade tumors was strongly expressed in the nucleus of the neoplastic cell. An association between carbonic anhydrase IX expression level and the main clinic-pathological features involved in prostate cancer aggressiveness was identified. Conclusions There was a statistically significant association between carbonic anhydrase IX and hypoxia inducible factor 1α in prostate cancer tissues, that identifies the enzyme as a reliable marker of tumor hypoxia. In addition, carbonic anhydrase IX expression positively correlated with prostate cancer grading and staging, and with outcome, suggesting that the protein may be an independent prognosticator for the disease. The nuclear translocation of the enzyme in hypoxic cancer cells may epitomize a biological switch of the tumor towards a less favorable phenotype.
    Full-text Article · Dec 2016 · Diagnostic Pathology
  • [Show abstract] [Hide abstract] ABSTRACT: Amyloidosis prognosis is often related to the onset of heart failure and a worsening that is concomitant with kidney–liver dysfunction; thus the Model for End-stage Liver disease (MELD) may be an ideal instrument to summarize renal–liver function. Our aim has been to test the MELD score as a prognostic tool in amyloidosis. We evaluated 128 patients, 46 with TTR-related amyloidosis and 82 with AL amyloidosis. All patients had a complete clinical and echocardiography evaluation; overall biohumoral assessment included troponin I, NT-proBNP, creatinine, total bilirubin and INR ratio. The study population was dichotomized at the 12 cut-off level of MELD scores; those with MELD score >12 had a lower survival compared to controls in the study cohort (40.7 vs 66.3 %; p = 0.006). Either as a continuous and dichotomized variable, MELD shows its independent prognostic value at multivariable analysis (HR = 1.199, 95 % CI 1.082–1.329; HR = 2.707, 95 % CI 1.075–6.817, respectively). MELD shows a lower prognostic sensitivity/specificity ratio than troponin I and NT-proBNP in the whole study population and AL subgroup, while in TTR patients MELD has a higher sensitivity/specificity ratio compared to troponin and NT-proBNP (ROC analysis-AUC: 0.853 vs 0.726 vs 0.659). MELD is able to predict prognosis in amyloidosis. A MELD score >12 selects a subgroup of patients with a higher risk of death. The predictive accuracy seems to be more evident in TTR patients in whom currently no effective scoring systems have been validated.
    Article · Aug 2016 · Internal and Emergency Medicine
  • Alessandra Pratesi · Paolo Valoti · Samuele Baldasseroni · [...] · Francesca Tarantini
    Article · Apr 2016 · Internal and Emergency Medicine
  • [Show abstract] [Hide abstract] ABSTRACT: Objectives: Adiponectin (AD) promotes insulin sensitivity and has anti-atherogenic properties. However, the role of AD on clinical outcomes in coronary artery disease (CAD) is controversial. We analyzed whether AD was an independent predictor of all-cause mortality and hospitalization in patients with CAD. Method: We prospectively enrolled 138 patients with stable CAD, with or without type 2 diabetes and with or without left ventricular dysfunction. A telephone follow-up was conducted to register long term outcomes. Sensitivity/specificity ratio for AD was investigated with ROC analysis and the independent role of AD on outcome was evaluated with Cox regression model of analysis. The survival rate was represented by Kaplan Meyer curves. Results: Of 138 patients, 61 had type 2 diabetes and 71 left ventricular systolic dysfunction (EF<40%). Median time of follow-up was 1384days; mortality rate was 18.8% (26 deaths) and hospitalization rate was 47.1% (65 events). Mean concentration of AD was 9.87±7.53ng/ml; the analysis of the ROC curve identified an AD cut-off level of 13.2ng/ml (AUC 0.779; p<0.0001). Patients with AD >13.2ng/ml had a significantly higher risk of death (HR=6.50; 95% CI: 2.40-17.70), but not of cardiovascular hospitalization (HR=0.87; 95% CI: 0.31-2.44). AD predictivity remained significant also in patients with type 2 diabetes and with left ventricular systolic dysfunction. Conclusion: In stable CAD, an AD value of >13.2ng/ml independently predicts a 6-fold increased risk of all-cause mortality.
    Article · Apr 2016 · Diabetes research and clinical practice
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    Full-text Dataset · Apr 2016
  • [Show abstract] [Hide abstract] ABSTRACT: We present the case of an elderly woman which demonstrates how AF therapy in aged individuals is particularly challenging for the presence of complex conditions. The rhythm- or the rate control strategy must be carefully chosen based on individual risk profile. Oral anticoagulant therapy must be wisely managed to maximize benefits-in terms of stroke and dementia control-and to reduce complications.
    Article · Aug 2015 · Aging - Clinical and Experimental Research
  • [Show abstract] [Hide abstract] ABSTRACT: Transient FGF stimulation of various cell types results in FGF memory - a sustained blockage of efficient proliferative response to FGF and other growth factors. FGF memory establishment requires HDAC activity, indicating its epigenetic character. FGF treatment stimulates proinflammatory NFκB signaling, which is also critical for FGF memory formation. The search for FGF-induced mediators of FGF memory revealed that FGF stimulates HDAC-dependent expression of the inflammatory cytokine IL1α. Similarly to FGF, transient cell treatment with recombinant IL1α inhibits the proliferative response to further FGF and EGF stimulation, but does not prevent FGF receptor-mediated signaling. Interestingly, like cells pretreated with FGF1, cells pretreated with IL1α exhibit enhanced restructuring of actin cytoskeleton and increased migration in response to FGF stimulation. IRAP, a specific inhibitor of IL1 receptor, and a neutralizing anti-IL1α antibody prevent the formation of FGF memory and rescue an efficient proliferative response to FGF restimulation. A similar effect results following treatment with the anti-inflammatory agents aspirin and dexamethasone. Thus, FGF memory is mediated by proinflammatory IL1 signaling. It may play a role in the limitation of proliferative response to tissue damage and prevention of wound-induced hyperplasia. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Article · Jul 2015 · Journal of Cellular Physiology
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    Maura Lodovici · Elisabetta Bigagli · Francesca Tarantini · [...] · Laura Raimondi
    [Show abstract] [Hide abstract] ABSTRACT: Increased reactive oxygen species (ROS) levels produced by hyperglycemia and angiotensin-II (AT-II) are considered among the pathogenic factors in the malignant transformation of diabetic renal cells. We aimed to investigate the potential role of AT-II in the increased cancer risk seen in diabetes; measuring oxidative damage to renal DNA and protective antioxidant defenses, including adiponectin (Adp) and plasma antioxidant capacity by the Ferric Reducing Ability of Plasma (FRAP) method. In the kidney of streptozotocin (STZ)-induced (55 mg/kg) diabetic rats either treated or not treated for 3 weeks with losartan, an AT-II type 1 receptor antagonist (20 mg/kg/day); we measured 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) levels, as an index of oxidative DNA damage, circulating Adp and FRAP. Diabetic rats showed significantly higher 8-oxodGuo levels in renal DNA (8.48 ± 0.98 × 10(-6) dG, mean ± SEM n = 11) than normoglycemic ones (1.18 ± 0.04 × 10(-6) dG, mean ± SEM, n=7) and lower plasma Adp and FRAP levels in comparison to normoglycemics. The treatment of diabetic rats with losartan significantly (P < 0.01) reduced 8-oxodGuo levels (5.4 ± 0.58 × 10(-6) dG, mean ± SEM n=9) in renal DNA and conserved FRAP values. Moreover, an inverse correlation was found between 8-oxodGuo in kidney DNA and circulating Adp levels in normoglycemic and diabetic rats. Losartan treatment preserves FRAP levels, reduces DNA oxidative injury and thus the carcinogenesis risk. Furthermore, our results indicate that Adp plasma levels are a further marker of oxidative injury to the kidney and confirm that it is an important part of the plasma antioxidant defense. © 2015 by the Society for Experimental Biology and Medicine.
    Full-text Article · Feb 2015 · Experimental Biology and Medicine
  • Article · Jan 2015
  • [Show abstract] [Hide abstract] ABSTRACT: Background and aims Atrial fibrillation (AF) is the most common arrhythmia in elderly people, yet oral anticoagulation is underused in the aged. We tried to determine whether new oral anticoagulants (NOA) have greater psychological tolerability than warfarin. Methods Age-, gender-matched groups of AF patients receiving NOA (N = 15) or warfarin (N = 15) were assessed with the Anti-Clot Treatment Scale (ACTS) and the Perceived Stress Scale (PSS). Results Patients were old (81 ± 9 years). NOA group showed greater psychological satisfaction, with lower therapy-related burden (ACTS burdens: 16.3 ± 4.5 vs. 32.9 ± 10.2, p < 0.001) and higher awareness of benefits (ACTS benefits: 13.0 ± 1.3 vs. 10.8 ± 1.9, p = 0.001). Even stress was lower (PSS: 13.1 ± 4.0 vs. 17.1 ± 4.2, p = 0.013). The multivariate analysis confirmed these findings, showing that higher levels of anxiety and depression could justify more stress in warfarin patients. Conclusions The results of this preliminary study show that NOA have an improved psychological impact compared with warfarin in elderly patients.
    Article · Jun 2014 · Aging - Clinical and Experimental Research
  • [Show abstract] [Hide abstract] ABSTRACT: FGF applied as a single growth factor to quiescent mouse fibroblasts induces a round of DNA replication, however continuous stimulation results in arrest in the G1 phase of the next cell cycle. We hypothesized that FGF stimulation induces the establishment of cell memory, which prevents the proliferative response to repeated or continuous FGF application. When a 2-5 day quiescence period was introduced between primary and repeated FGF treatments, fibroblasts failed to efficiently replicate in response to secondary FGF application. The establishment of "FGF memory" during the first FGF stimulation did not require DNA synthesis, but was dependent on the activity of FGF receptors, MEK, p38 MAPK and NFκB signaling, and protein synthesis. While secondary stimulation resulted in strongly decreased replication rate, we did not observe any attenuation of morphological changes, Erk1/2 phosphorylation and cyclin D1 induction. However, secondary FGF stimulation failed to induce the expression of cyclin A, which is critical for the progression from G1 to S phase. Treatment of cells with a broad range histone deacetylase inhibitor during the primary FGF stimulation rescued the proliferative response to the secondary FGF treatment suggesting that the establishment of "FGF memory" may be based on epigenetic changes. We suggest that "FGF memory" can prevent the hyperplastic response to cell damage and inflammation, which are associated with an enhanced FGF production and secretion. "FGF memory" may present a natural obstacle to the efficient application of recombinant FGFs for the treament of ulcers, ischemias and wounds. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    Article · May 2014 · Journal of Cellular Biochemistry
  • [Show abstract] [Hide abstract] ABSTRACT: ABSTRACT Introduction: Atrial fibrillation (AF) is often associated with heart failure. Several studies have demonstrated that resumption of sinus rhythm (SR) improves cardiac output in the long-term. Aims of this study were to evaluate the acute variations of left ventricular (LV) performance, following successful external cardioversion (ECV) of persistent AF using longitudinal strain (LSt) analysis, and the influence of inflammation. Materials and Methods: We enrolled 48 patients with AF (age: 73 ± 12 years, men: 83.3%). A standard transthoracic echocardiographic evaluation was performed before the procedure and 6 h later; this included the analysis of LV endocardial peak LSt, a measure of myocardial deformation. In the last 32 patients, plasma concentration of interleukin-6 (IL-6) was also determined. Results: Restoration of SR led to the decrease of heart rate (HR) (74 ± 21 vs 64 ± 10 bpm, P < 0.001) and LV end-systolic volume (30 ± 16 vs 27 ± 17 mL/m2, P = 0.001), and to the increase of LV end-diastolic volume (LVEDV) (56 ± 20 vs 60 ± 21 mL/m2, P = 0.036) and ejection fraction (EF) (48 ± 10 vs 57 ± 11%, P < 0.001). Peak LSt improved in 43 (89.6%) patients (-12.9 ± 3.3 vs -18.0 ± 4.7%, P < 0.001). Multivariate analysis (R = 0.729, P < 0.001) showed that strain changes were directly correlated with basal HR and the appearance of atrial mechanical activity and inversely correlated with corrected thyroid dysfunction, LVEDV and the presence of a permanent pacemaker. Higher levels of IL-6 negatively affected LV performance improvement. Conclusions: Effective ECV of AF determines a significant and fast improvement of LV performance,which is readily captured by LSt analysis. Inflammatory status may impact the response to SR restoration.
    Article · Apr 2014
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    [Show abstract] [Hide abstract] ABSTRACT: Abstract Aim: In AL amyloidosis, the importance of right ventricle (RV) involvement has recently been underlined and its role in predicting prognosis has been emphasized. Little is known about the relationship between RV involvement, N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin levels. Aim of our study was to clarify the relationship between NT-proBNP and troponin and RV involvement and analyze their independent value as predictors of RV dysfunction. Methods and Results: We examined 76 consecutive patients with biopsy-proven AL amyloidosis. Each patient received complete clinical evaluation, troponin I, NT-proBNP assay and comprehensive echocardiographic evaluation. Considering a tricuspidal annulus plane systolic excursion (TAPSE) value <16 mm, 23 patients (30%) presented RV systolic dysfunction, whereas 53 (70%) did not. Patient with reduced TAPSE had thicker left ventricle (LV) walls and RV free walls, reduced LV fractional shortening, impaired LV diastolic function and worse LV and RV myocardial performance index. For RV dysfunction the best predictive value for NT-proBNP was identified as 2977 ng/l with sensitivity and specificity of 87% and 84%, respectively; best cut-off for troponin I was identified as 0.085 ng/l, with sensitivity and specificity of 85% and 90% respectively. At multivariable logistic regression analysis, both NT-proBNP and troponin I emerged as independent predictors of RV dysfunction presence but troponin appears to have a higher predictive power. Conclusion: Our study demonstrated that cut-off values of 2977 ng/ml for NT-proBNP and 0.085 ng/l for troponin were able to identify a subgroup of AL patients with RV dysfunction. Troponin I is more accurate and seems to be the best biohumoral marker of RV dysfunction.
    Full-text Article · Feb 2014 · Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis
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    Samuele Baldasseroni · Alessandra Pratesi · Francesco Orso · [...] · Francesca Tarantini
    [Show abstract] [Hide abstract] ABSTRACT: Background: Epicardial adipose tissue (EAT) is a visceral fat that fulfills two important functions: lipid-storage and secretion of adipokines with pro-inflammatory and pro-atherogenic properties. It has been suggested that EAT may affect the pathogenesis of atherosclerosis and the clinical course of coronary artery disease (CAD). In patients with obesity, diabetes and metabolic syndrome, the epicardial adipose tissue is enlarged. Little is known about the role of EAT in left ventricular dysfunction. Aim of this study was to evaluate the ability of insulin resistance to predict EAT thickness in patients with significant CAD and systolic dysfunction. Methods: We enrolled 114 subjects diagnosed with CAD by angiography. The majority underwent revascularization after an acute coronary syndrome. Patients were considered affected by significant left ventricular dysfunction when EF was < or = 40%. Three indexes of insulin resistance, the HOMA IR index, the insulin sensitivity QUICKI index, and the novel adiponectin/resistin index (ADIPO-IRAR) were calculated and correlated to EAT thickness. Epicardial fat was measured by echocardiography according to standardized methods. Results: Subjects with diabetes and with a history of hypercholesterolemia had thicker EAT compared to controls. Potassium levels and all three indexes of insulin resistance were the best independent predictors of EAT in the study population as a whole and in the subset of patients with left ventricular dysfunction. In the latter group the novel ADIPO-IRAR index displayed the strongest predictivity. Conclusion: Insulin resistance is an independent predictor of EAT thickness in patients affected by CAD, also in the presence of significant left ventricular dysfunction.
    Full-text Article · Dec 2013 · Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace / Fondazione clinica del lavoro, IRCCS [and] Istituto di clinica tisiologica e malattie apparato respiratorio, Università di Napoli, Secondo ateneo
  • [Show abstract] [Hide abstract] ABSTRACT: Atrial fibrillation (AF) is the most frequent arrhythmia in elderly patients. Aims of this study were to evaluate the predictors of arterial stiffness after external cardioversion (ECV) of AF and to establish whether a link exists between vascular properties and left atrial diameter (LAD). We studied 33 patients (age 73 ± 12 years). After 5 h from ECV of persistent AF, an echocardiogram was recorded and arterial stiffness was evaluated with cardio-ankle vascular stiffness index (CAVI). In multivariate analysis (R = 0.538, p = 0.006), CAVI (mean 9.60 ± 1.63) increased with age (p = 0.018) and with an AF length ≤3 months (p = 0.022). LAD was significantly related to CAVI (p = 0.007) even after adjustment for interventricular septum thickness (p = 0.018) (R = 0.574, p = 0.002). In patients with AF, immediately after ECV, arterial stiffness is associated with age and AF length, and could represent an important factor for left atrium remodeling and, therefore, for AF maintenance.
    Article · Nov 2013 · Aging - Clinical and Experimental Research
  • Samuele Baldasseroni · Alessandra Pratesi · Francesco Orso · [...] · Francesca Tarantini
    [Show abstract] [Hide abstract] ABSTRACT: Patients affected by coronary artery disease (CAD) have a high prevalence of depressive disorders. It has been suggested that depressive symptoms significantly reduce exercise stress test performance in CAD patients, whereas their influence on functional capacity tests, such as the 6-minute walking test (6WT), has been less investigated. The aim of this study was to evaluate the correlation between depressive symptoms and 6WT in patients with CAD and the role of age on this relationship. We enrolled 148 CAD patients. Global functional capacity was measured with 6WT and the presence of depressive symptoms with the 30-item Geriatric Depression Scale (GDS). GDS score was analysed as a continuous variable or categorized as depression absent (score <10), probable (10-14), or present (≤15). A significant inverse correlation was observed between GDS score and distance walked at 6WT. Patients positive for depressive symptoms (probable or present) had a significantly worse performance compared to those with GDS score <10. In multivariable analysis adjusted for indexes of cardiovascular disease severity and comorbidity, the presence of depressive symptoms proved to be an independent predictor of distance walked at 6WT; the predictivity of depressive symptoms on 6WT was age dependent. Depressive symptoms negatively affect 6WT performance among older CAD subjects. Non-cardiovascular parameters, such as psycho-affective disorders, must be taken into account for the interpretation of 6WT performance in old age.
    Article · Jun 2013
  • Giovanna Danza · Claudia Di Serio · Maria Raffaella Ambrosio · [...] · Francesca Tarantini
    [Show abstract] [Hide abstract] ABSTRACT: Prostate cancer is still the second cause of cancer-related death among men. Although patients with metastatic presentation have an ominous outcome, the vast majority of PCs are diagnosed at an early stage. Nonetheless, even among patients with clinically localized disease the outcome may vary considerably. Other than androgen sensitivity, little is known about which other signaling pathways are deranged in aggressive, localized cancers. The elucidation of such pathways may help to develop innovative therapies aimed at specific molecular targets. We report that in a hormone-sensitive prostate cancer cell line, LNCaP, Notch3 was activated by hypoxia and sustained cell proliferation and colony formation in soft agar. Hypoxia also modulated cellular cholesterol content and the number and size of lipid rafts, causing a coalescence of small rafts into bigger clusters; under this experimental condition Notch3 migrated from the non-raft into the raft compartment where it co-localized with the γ-secretase complex. We also looked at human prostate cancer biopsies and found that expression of Notch3 positively correlated with Gleason score and with expression of carbonic anhydrase IX, a marker of hypoxia. In conclusion, hypoxia triggers the activation of Notch3 which, in turn, sustains proliferation of prostate cancer cells. Notch3 pathway represents a promising target for adjuvant therapy in patients with prostate cancer. © 2013 Wiley Periodicals, Inc.
    Article · Jun 2013 · International Journal of Cancer
  • S. Baldasseroni · A. Pratesi · F. Orso · [...] · F. Tarantini
    Article · Jan 2013
  • Alessandra Pratesi · Francesca Tarantini · Mauro Di Bari
    [Show abstract] [Hide abstract] ABSTRACT: Tropism and efficiency of skeletal muscle depend on the complex balance between anabolic and catabolic factors. This balance gradually deteriorates with aging, leading to an age-related decline in muscle quantity and quality, called sarcopenia: this condition plays a central role in physical and functional impairment in late life. The knowledge of the mechanisms that induce sarcopenia and the ability to prevent or counteract them, therefore, can greatly contribute to the prevention of disability and probably also mortality in the elderly. It is well known that skeletal muscle is the target of numerous hormones, but only in recent years studies have shown a role of skeletal muscle as a secretory organ of cytokines and other peptides, denominated myokines (IL6, IL8, IL15, Brain-derived neurotrophic factor, and leukaemia inhibitory factor), which have autocrine, paracrine, or endocrine actions and are deeply involved in inflammatory processes. Physical inactivity promotes an unbalance between these substances towards a pro-inflammatory status, thus favoring the vicious circle of sarcopenia, accumulation of fat - especially visceral - and development of cardiovascular diseases, type 2 diabetes mellitus, cancer, dementia and depression, according to what has been called "the diseasome of physical inactivity".
    Article · Jan 2013 · Clinical Cases in Mineral and Bone Metabolism
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    Samuele Baldasseroni · Alessandro Antenore · Claudia Di Serio · [...] · Francesca Tarantini
    [Show abstract] [Hide abstract] ABSTRACT: Background Several peptides, named adipokines, are produced by the adipose tissue. Among those, adiponectin (AD) is the most abundant. AD promotes peripheral insulin sensitivity, inhibits liver gluconeogenesis and displays anti-atherogenic and anti-inflammatory properties. Lower levels of AD are related to a higher risk of myocardial infarction and a worse prognosis in patients with coronary artery disease. However, despite a favorable clinical profile, AD increases in relation to worsening heart failure (HF); in this context, higher adiponectinemia is reliably related to poor prognosis. There is still little knowledge about how certain metabolic conditions, such as diabetes mellitus, modulate the relationship between AD and HF. We evaluated the level of adiponectin in patients with ischemic HF, with and without type 2 diabetes, to elucidate whether the metabolic syndrome was able to influence the relationship between AD and HF. Results We demonstrated that AD rises in patients with advanced HF, but to a lesser extent in diabetics than in non-diabetics. Diabetic patients with reduced systolic performance orchestrated a slower rise of AD which began only in face of overt HF. The different behavior of AD in the presence of diabetes was not entirely explained by differences in body mass index. In addition, NT-proBNP, the second strongest predictor of AD, did not differ significantly between diabetic and non-diabetic patients. These data indicate that some other mechanisms are involved in the regulation of AD in patients with type 2 diabetes and coronary artery disease. Conclusions AD rises across chronic heart failure stages but this phenomenon is less evident in type 2 diabetic patients. In the presence of diabetes, the progressive increase of AD in relation to the severity of LV dysfunction is hampered and becomes evident only in overt HF.
    Full-text Article · Dec 2012 · Cardiovascular Diabetology