Isolated Valve Amyloid Deposition in Aortic Stenosis: Potential Clinical and Pathophysiological Relevance.

Amyloid deposition within stenotic aortic valves (AVs) also appears frequent in the absence of cardiac amyloidosis, but its clinical and pathophysiological relevance has not been investigated. We will elucidate the rate of isolated AV amyloid deposition and its potential clinical and pathophysiological significance in aortic stenosis (AS). In 130 patients without systemic and/or cardiac amyloidosis, we collected the explanted AVs during cardiac surgery: 57 patients with calcific AS and 73 patients with AV insufficiency (41 with AV sclerosis and 32 without, who were used as controls). Amyloid deposition was found in 21 AS valves (37%), 4 sclerotic AVs (10%), and none of the controls. Patients with and without isolated AV amyloid deposition had similar clinical and echocardiographic characteristics and survival rates. Isolated AV amyloid deposition was associated with higher degrees of AV fibrosis (p = 0.0082) and calcification (p < 0.0001). Immunohistochemistry analysis suggested serum amyloid A1 (SAA1), in addition to transthyretin (TTR), as the protein possibly involved in AV amyloid deposition. Circulating SAA1 levels were within the normal range in all groups, and no difference was observed in AS patients with and without AV amyloid deposition. In vitro, AV interstitial cells (VICs) were stimulated with interleukin (IL)-1ß which induced increased SAA1-mRNA both in the control VICs (+6.4 ± 0.5, p = 0.02) and the AS VICs (+7.6 ± 0.5, p = 0.008). In conclusion, isolated AV amyloid deposition is frequent in the context of AS, but it does not appear to have potential clinical relevance. Conversely, amyloid deposition within AV leaflets, probably promoted by local inflammation, could play a role in AS pathophysiology.

Epicardial Adipose Tissue-Derived IL-1ß Triggers Postoperative Atrial Fibrillation.

Background and aims: Post-operative atrial fibrillation (POAF), defined as new-onset AF in the immediate period after surgery, is associated with poor adverse cardiovascular events and a higher risk of permanent AF. Mechanisms leading to POAF are not completely understood and epicardial adipose tissue (EAT) inflammation could be a potent trigger. Here, we aim at exploring the link between EAT-secreted interleukin (IL)-1ß, atrial remodeling, and POAF in a population of coronary artery disease (CAD) patients. Methods: We collected EAT and atrial biopsies from 40 CAD patients undergoing cardiac surgery. Serum samples and EAT-conditioned media were screened for IL-1ß and IL-1ra. Atrial fibrosis was evaluated at histology. The potential role of NLRP3 inflammasome activation in promoting fibrosis was explored in vitro by exposing human atrial fibroblasts to IL-1ß and IL-18. Results: 40% of patients developed POAF. Patients with and without POAF were homogeneous for clinical and echocardiographic parameters, including left atrial volume and EAT thickness. POAF was not associated with atrial fibrosis at histology. No significant difference was observed in serum IL-1ß and IL-1ra levels between POAF and no-POAF patients. EAT-mediated IL-1ß secretion and expression were significantly higher in the POAF group compared to the no-POAF group. The in vitro study showed that both IL-1ß and IL-18 increase fibroblasts' proliferation and collagen production. Moreover, the stimulated cells perpetuated inflammation and fibrosis by producing IL-1ß and transforming growth factor (TGF)-ß. Conclusion: EAT could exert a relevant role both in POAF occurrence and in atrial fibrotic remodeling.

Red Flags, Prognostic Impact, and Management of Patients With Cardiac Amyloidosis and Aortic Valve Stenosis: A Systematic Review and Meta-Analysis.

Background: Cardiac amyloidosis (CA) has been recently recognized as a condition frequently associated with aortic stenosis (AS). The aim of this study was to evaluate: the main characteristics of patients with AS with and without CA, the impact of CA on patients with AS mortality, and the effect of different treatment strategies on outcomes of patients with AS with concomitant CA. Materials and Methods: A detailed search related to CA in patients with AS and outcomes was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Seventeen studies enrolling 1,988 subjects (1,658 AS alone and 330 AS with CA) were included in the qualitative and quantitative analysis of main patients with AS characteristics with and without CA, difference in mortality, and treatment strategy. Results: The prevalence of CA resulted in a mean of 15.4% and it was even higher in patients with AS over 80 years old (18.2%). Patients with the dual diagnosis were more often males, had lower body mass index (BMI), were more prone to have low flow, low gradient with reduced left ventricular ejection fraction AS phenotype, had higher E/A and E/e', and greater interventricular septum hypertrophy. Lower Sokolow-Lyon index, higher QRS duration, higher prevalence of right bundle branch block, higher levels of N-terminal pro-brain natriuretic peptide, and high-sensitivity troponin T were significantly associated with CA in patients with AS. Higher overall mortality in the 178 patients with AS + CA in comparison to 1,220 patients with AS alone was observed [odds ratio (OR) 2.25, p = 0.004]. Meta-regression analysis showed that younger age and diabetes were associated with overall mortality in patients with CS with CA (Z-value -3.0, p = 0.003 and Z-value 2.5, p = 0.013, respectively). Finally, patients who underwent surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) had a similar overall mortality risk, but lower than medication-treated only patients. Conclusion: Results from our meta-analysis suggest that several specific clinical, electrocardiographic, and echocardiographic features can be considered "red flags" of CA in patients with AS. CA negatively affects the outcome of patients with AS. Patients with concomitant CA and AS benefit from SAVR or TAVI.

Epicardial Adipose Tissue and Postoperative Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) often occurs after cardiac surgery and is associated with increased risk of stroke and mortality. Prior studies support the important role of inflammation in the pathogenesis of postoperative atrial fibrillation (POAF). It is known that an increased volume and a pro-inflammatory phenotype of epicardial adipose tissue (EAT) are both associated with AF onset in non surgical context. In the present study, we aim to evaluate whether also POAF occurrence may be triggered by an increased production of inflammatory mediators from EAT. METHODS: The study population was composed of 105 patients, with no history of paroxysmal or permanent AF, undergoing elective cardiac surgery. After clinical evaluation, all patients performed an echocardiographic study including the measurement of EAT thickness. Serum samples and EAT biopsies were collected before surgery. Levels of 10 inflammatory cytokines were measured in serum and EAT conditioned media. After surgery, cardiac rhythm was monitored for 7 days. RESULTS: Forty-four patients (41.3%) developed POAF. As regard to cardiovascular therapy, only statin use was significantly lower in POAF patients (65.1% vs. 84.7%; p-0.032). Levels of Monocyte Chemoattractant Protein-1 (MCP-1), in both serum and EAT, were significantly higher in POAF patients (130.1 pg/ml vs. 68.7 pg/ml; p = <0.001; 322.4 pg/ml vs. 153.4 pg/ml; p = 0.028 respectively). EAT levels of IL-6 were significantly increased in POAF patients compared to those in sinus rhythm (SR) (126.3 pg/ml vs. 23 pg/ml; p = <0.005). CONCLUSION: Higher EAT levels of IL-6 and MCP-1 are significantly associated with the occurrence of POAF. Statin therapy seems to play a role in preventing POAF. These results might pave the way for a targeted use of these drugs in the perioperative period.

The role of inflammation and metabolic risk factors in the pathogenesis of calcific aortic valve stenosis.

Given the epidemiologic increase of aged population in the world, aortic stenosis (AS) represents now the most common valvular heart disease in industrialized countries. It is a very challenging disease, representing an important cause of morbidity, hospitalization and death in the elderly population. It is widely recognized that AS is the result of a very complex active process, driven by inflammation and involving multifactorial pathological mechanisms promoting valvular calcification and valvular bone deposition. Several evidence suggest that epicardial adipose tissue (EAT), the visceral fat depot of the heart, represents a direct source of cytokines and could mediate the deleterious effects of systemic inflammation on the myocardium. Importantly, obesity and metabolic disorders are associated with chronic systemic inflammation leading to a significant increase of EAT amount and to a pro-inflammatory phenotypic shift of this fat depot. It has been hypothesized that the EAT inflammatory state can influence the structure and function of the heart, thus contributing to the pathogenesis of several cardiac diseases, including calcific AS. The current review will discuss the recently discovered mechanisms involved in the pathogenesis of AS, with particular attention to the role of inflammation, metabolic risk factors and pro-fibrotic and pro-osteogenic signal pathways promoting the onset and progression of the disease. Moreover, it will be explored the potential role of EAT in the AS pathophysiology.

Renal function and cardiac adrenergic impairment in patients affected by heart failure.

Although in heart failure (HF) there is a strict correlation between heart and kidney, no data are available on the potential relationship in HF between renal dysfunction (RD) and the impaired sympathetic innervation. Aim of the present study was to assess the relationship between RD and cardiac sympathetic innervation in HF patients with reduced ejection fraction. Two hundred and sixty-three patients with mild-to-severe HF underwent iodine-123 meta-iodobenzylguanidine myocardial scintigraphy to assess sympathetic innervation, evaluating early and late heart-to-mediastinum (H/M) ratios and washout rate. In all patients, glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was assessed. A direct association was found between EPI-eGFR and late H/M (r = .215; P < .001). Dividing the population into moderate-to-severe eGFR reduction and normal-to-mildly reduced eGFR (cutoff ≤ 60 mL·min-1·1.73 m-2), a statistically significant reduction of late H/M value was found in patients with RD compared to patients with preserved eGFR (P = .030). By multivariable linear regression analysis, eGFR resulted in the prediction of impaired late H/M in patients with RD (P = .005). Patients with RD and HF show more impaired cardiac sympathetic activity than HF patients with preserved renal function, and reduced eGFR is a predictor of reduced late H/M.

Beyond chronic kidney disease: the diagnosis of Renal Disease in the Elderly as an unmet need. A position paper endorsed by Italian Society of Nephrology (SIN) and Italian Society of Geriatrics and Gerontology (SIGG).

The dramatic increase in prevalence of chronic kidney disease (CKD) with ageing makes the recognition and correct referral of these patients of paramount relevance in order to implement interventions preventing or delaying the development of CKD complications and end-stage renal disease. Nevertheless, several issues make the diagnosis of CKD in the elderly cumbersome. Among these are age related changes in structures and functions of the kidney, which may be difficult to distinguish from CKD, and multimorbidity. Thus, symptoms, clinical findings and laboratory abnormalities should be considered as potential clues to suspect CKD and to suggest screening. Comprehensive geriatric assessment is essential to define the clinical impact of CKD on functional status and to plan treatment. Correct patient referral is very important: patients with stage 4-5 CKD, as well as those with worsening proteinuria or progressive nephropathy (i.e. eGFR reduction > 5 ml/year) should be referred to nephrologist. Renal biopsy not unfrequently may be the key diagnostic exam and should not be denied simply on the basis of age. Indeed, identifying the cause(s) of CKD is highly desirable to perform a targeted therapy against the pathogenetic mechanisms of CKD, which complement and may outperform in efficacy the general measures for CKD.

Statin therapy modulates thickness and inflammatory profile of human epicardial adipose tissue.

BACKGROUND: Epicardial adipose tissue (EAT) thickness and pro-inflammatory status has been shown to be associated with several cardiac diseases, including aortic stenosis (AS). Thus, cardiac visceral fat could represent a potential new target for drugs. In the present study we evaluate the effect of statin therapy on EAT accumulation and inflammation. METHODS: Echocardiographic EAT thickness was assessed in 193 AS patients taking (n.87) and not taking (n.106) statins, undergoing cardiac surgery. To explore the association between statin therapy and EAT inflammation, EAT biopsies were obtained for cytokines immunoassay determination in EAT secretomes. An in vitro study was also conducted and the modulation of EAT and subcutaneous adipose tissue (SCAT) secretomes by atorvastatin was assessed in paired biopsies. RESULTS: Statin therapy was significantly associated with lower EAT thickness (p < 0.0001) and with lower levels of EAT-secreted inflammatory mediators (p < 0.0001). Of note, there was a significant correlation between EAT thickness and its pro-inflammatory status. In vitro, atorvastatin showed a direct anti-inflammatory effect on EAT which was significantly higher compared to the SCAT response to statin incubation (p < 0.0001). CONCLUSIONS: The present study indicates a robust association between statin therapy and reduced EAT accumulation in patients with AS. The present data also suggest a direct relationship between EAT thickness and its inflammatory status, both modulated by statin therapy. The in vitro results support the hypothesis of a direct action of statins on EAT secretory profile. Overall our data suggest EAT as a potential new therapeutic target for statin therapy.

Increased Epicardial Adipose Tissue Volume Correlates With Cardiac Sympathetic Denervation in Patients With Heart Failure.

RATIONALE: It has been reported that epicardial adipose tissue (EAT) may affect myocardial autonomic function. OBJECTIVE: The aim of this study was to explore the relationship between EAT and cardiac sympathetic nerve activity in patients with heart failure. METHODS AND RESULTS: In 110 patients with systolic heart failure, we evaluated the correlation between echocardiographic EAT thickness and cardiac adrenergic nerve activity assessed by (123)I-metaiodobenzylguanidine ((123)I-MIBG). The predictive value of EAT thickness on cardiac sympathetic denervation ((123)I-MIBG early and late heart:mediastinum ratio and single-photon emission computed tomography total defect score) was tested in a multivariate analysis. Furthermore, catecholamine levels, catecholamine biosynthetic enzymes, and sympathetic nerve fibers were measured in EAT and subcutaneous adipose tissue biopsies obtained from patients with heart failure who underwent cardiac surgery. EAT thickness correlated with (123)I-MIBG early and late heart:mediastinum ratio and single-photon emission computed tomography total defect score, but not with left ventricular ejection fraction. Moreover, EAT resulted as an independent predictor of (123)I-MIBG early and late heart:mediastinum ratio and single-photon emission computed tomography total defect score and showed a significant additive predictive value on (123)I-MIBG planar and single-photon emission computed tomography results over demographic and clinical data. Although no differences were found in sympathetic innervation between EAT and subcutaneous adipose tissue, EAT showed an enhanced adrenergic activity demonstrated by the increased catecholamine levels and expression of catecholamine biosynthetic enzymes. CONCLUSIONS: This study provides the first evidence of a direct correlation between increased EAT thickness and cardiac sympathetic denervation in heart failure.

ß Adrenergic Receptor Kinase C-Terminal Peptide Gene-Therapy Improves ß2-Adrenergic Receptor-Dependent Neoangiogenesis after Hindlimb Ischemia.

After hindlimb ischemia (HI), increased catecholamine levels within the ischemic muscle can cause dysregulation of ß2-adrenergic receptor (ß2AR) signaling, leading to reduced revascularization. Indeed, in vivo ß2AR overexpression via gene therapy enhances angiogenesis in a rat model of HI. G protein-coupled receptor kinase 2 (GRK2) is a key regulator of ßAR signaling, and ß adrenergic receptor kinase C-terminal peptide (ßARKct), a peptide inhibitor of GRK2, has been shown to prevent ßAR down-regulation and to protect cardiac myocytes and stem cells from ischemic injury through restoration of ß2AR protective signaling (i.e., protein kinase B/endothelial nitric oxide synthase). Herein, we tested the potential therapeutic effects of adenoviral-mediated ßARKct gene transfer in an experimental model of HI and its effects on ßAR signaling and on endothelial cell (EC) function in vitro. Accordingly, in this study, we surgically induced HI in rats by femoral artery resection (FAR). Fifteen days of ischemia resulted in significant ßAR down-regulation that was paralleled by an approximately 2-fold increase in GRK2 levels in the ischemic muscle. Importantly, in vivo gene transfer of the ßARKct in the hindlimb of rats at the time of FAR resulted in a marked improvement of hindlimb perfusion, with increased capillary and ßAR density in the ischemic muscle, compared with control groups. The effect of ßARKct expression was also assessed in vitro in cultured ECs. Interestingly, ECs expressing the ßARKct fenoterol, a ß2AR-agonist, induced enhanced ß2AR proangiogenic signaling and increased EC function. Our results suggest that ßARKct gene therapy and subsequent GRK2 inhibition promotes angiogenesis in a model of HI by preventing ischemia-induced ß2AR down-regulation.

Assessing Nephrological Competence among Geriatricians: A Proof of Concept Internet Survey.

Chronic kidney disease (CKD) is highly prevalent in the elderly and negatively impacts survival and health status. Thus, nephrological competence is mandatory for a skilled geriatrician. The present study aimed to assess nephrological competence in a sample of geriatricians recruited through a web survey. To this aim, a 12-items questionnaire was produced by an expert panel of nephrologists and geriatricians and was available online for members of the Italian Society of Gerontology and Geriatrics (SIGG). Two-hundred-eighty-seven geriatricians volunteered to fill in the questionnaire. The majority of them indirectly estimated the glomerular filtration rate (GFR) using mainly the Cockroft-Gault (C-G) formula. Selected nephrological exams, such as urinary Na and serum D-vitamin measurements, did not qualify as routine exams although the majority of geriatricians supplemented their patients with fat-soluble secosteroids. Ten percent of geriatricians asked for nephrological consultation only for stage 5 CKD patients and 30,9% only for stage 4 or 5. Erythropoietin supplementation was common practice for the majority of geriatricians, while only one third of them systematically used a procedure intended to prevent the contrast induced nephropathy (CIN). Finally, an alleged 50% adherence to the international guidelines for the management of CKD patients emerged from the questionnaire. Overall, results from this survey strongly recommend promoting nephrological education among geriatricians. Didactic standards for in training geriatricians need to be updated and the cooperation between geriatrics and nephrological societies promoted.

Impact of an Innovative Educational Strategy on Medication Appropriate Use and Length of Stay in Elderly Patients.

UNLABELLED: To evaluate the impact of an educational strategy on potentially inappropriate medications (PIMs) and length of stay in hospitalized elderly patients. DESIGN: An open study, with two cross-sectional surveys interspersed with an educational program (PRE phase and POST phase), has been performed in order to compare the PIMs number before and after the introduction of an educational strategy. The study included 2 phases: PRE, in which patients were enrolled as control group; POST, in which an educational strategy on the PIMs use was introduced among physicians, and patients were enrolled as intervention group. SETTING: Italian residential rehabilitation Centre. Inclusion criteria were ≥ 2 active chronic diseases and the current use of ≥ 4 medications. The educational strategy consisted of a 3-day course on strategies to prevent PIMs and a computerized tool running on a Personal Digital Assistant (PDA) device to check for PIMs. OUTCOMES: The primary was the PIMs number, the secondary the length of stay. RESULTS: A total of 790 patients, 450 controls and 340 cases, were enrolled. According to the Beers criteria, 52.3% of the study population received ≥ 1 PIMs, 18.73% ≥ 2, and 2.4% ≥ 4 PIMs. A significant reduction of PIMs (P = 0.020) and length of stay (P < 0.0001) were seen in the intervention group. At multivariate analysis, PIMs significantly correlated with age, drugs number, and the intervention, and the length of stay significantly correlated with disease count, comorbidities, and intervention. These data suggest that our educative instrument may be useful in reducing the PIMs number and length of hospitalization in elderly with a high number of drugs and comorbidities.

Transradial approach for the endovascular treatment of type I endoleak after aortic aneurysm repair: a case report.

BACKGROUND: Endovascular repair of aortic aneurysms (EVAR) is obtained through the positioning of an aortic stent-graft, which excludes the aneurysmatic dilation. Type I endoleak is the most common complication, and it is caused by an incompetent proximal or distal attachment site, causing the separation between the stent-graft and the native arterial wall, and in turn creating direct communication between the aneurysm sac and the systemic arterial circulation. Endoleak occurrence is associated with high intrasac pressures, and requires a quick repair to prevent abdominal aortic aneurysm rupture. CASE PRESENTATION: We report the first case of a 80-year-old man undergoing percutaneous closure of a peri-graft endoleak (type I) by transcatheter embolization through radial arterial access. CONCLUSION: The transradial approach has been shown to be a safe and effective alternative to the traditional transfemoral approach. A decrease in vascular complications and improved patient comfort are the primary benefits of this technique in patients with previous EVAR.

Risk of acute myocardial infarction after transurethral resection of prostate in elderly.

BACKGROUND: Benign prostatic hyperplasia is a frequent disease among elderly, and is responsible for considerable disability. Benign prostatic hyperplasia can be clinically significant due to lower urinary tract symptoms that take place because the gland is enlarged and obstructs urine flow. Transurethral resection of the prostate remains the gold standard treatment for patients with moderate or severe symptoms who need active treatment or who either fail or do not want medical therapy. Moreover, perioperative and postoperative surgery complications as cardiovascular ones still occur. The incidence of acute myocardial infarction in patients undergoing transurethral resection of the prostate is controversial. The first studies showed an increase in mortality and relative risk of death from myocardial infarction in transurethral resection of the prostate group vs open prostatectomy but these results are in contrast with more recent data. DISCUSSION: Given the conflicting evidence of the studies in the literature, in this review we are going to discuss the factors that may influence the risk of myocardial infarction in elderly patients undergoing prostate surgery. We analyzed the possible common factors that lead to the development of myocardial infarction and benign prostatic hyperplasia (cardiovascular and metabolic), the stressor factors related to prostatectomy (surgical and haemodynamic) and the risk factors specific of the elderly population (comorbidity and therapies). SUMMARY: Although transurethral resection of the prostate is considered at low risk for severe complications, there are several reports indicating that cardiovascular events in elderly patients undergoing this surgical operation are more common than in the general population. Several cardio-metabolic, surgical and aging-related factors may help explain this observation but results in literature are not concord, especially due to the fact that most data derive from retrospective studies in which selection bias cannot be excluded. Subsequently, further studies are necessary to clarify the incidence of acute myocardial infarction in old people.

Vascular endothelial growth factor blockade prevents the beneficial effects of ß-blocker therapy on cardiac function, angiogenesis, and remodeling in heart failure.

BACKGROUND: Impaired angiogenesis in the post-myocardial infarction heart contributes to the progression to heart failure. The inhibition of vascular endothelial growth factor (VEGF) signaling has been shown to be crucial for the transition from compensatory hypertrophy to cardiac failure. Importantly, ß-adrenergic receptor blocker therapy has been also shown to improve myocardial perfusion by enhancing neoangiogenesis in the failing heart. METHODS AND RESULTS: Eight weeks from surgically induced myocardial infarction, heart failure rats were randomized to receive bisoprolol (B) or vehicle. At the end of a 10-week treatment period, echocardiography revealed reduced cardiac diameters and improved cardiac function in B-treated compared with vehicle-treated rats. Moreover, B treatment was associated with increased cardiac angiogenesis and in vivo coronary perfusion and reduced cardiac fibrosis. Importantly, 2 weeks after B treatment was started, increased cardiac VEGF expression and Akt and endothelial NO synthase activation were observed by comparing B-treated with drug-untreated failing hearts. To test whether the proangiogenic effects of B act via activation of VEGF pathway, rats were intravenously injected with adenoviral vector encoding a decoy VEGF receptor (Ad-Flk) or a control adenovirus (Ad-C), at the start of the treatment with B. After 10 weeks, histological analysis revealed reduced capillary and coronary perfusion in B-treated plus Ad-Flk rats compared with B-treated plus Ad-C rats. Moreover, VEGF inhibition counteracted the positive effects of B on cardiac function and remodeling. CONCLUSIONS: ß-Blockade promotes cardiac angiogenesis in heart failure via activation of VEGF signaling pathway. ß-Blocker-induced enhancement of cardiac angiogenesis is essential for the favorable effects of this therapy on cardiac function and remodeling.

GRK2 blockade with ßARKct is essential for cardiac ß2-adrenergic receptor signaling towards increased contractility.

BACKGROUND: ß1- and ß2-adrenergic receptors (ARs) play distinct roles in the heart, e.g. ß1AR is pro-contractile and pro-apoptotic but ß2AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes ßAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (ßarr) binding. We posited herein that GRK2 blockade might enhance the pro-contractile signaling of the ß2AR subtype in the heart. We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on ß2AR signaling under normal conditions and in heart failure (HF). RESULTS: We crossed ß1AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the ßARKct, a known GRK2 inhibitor, and studied the offspring under normal conditions and in post-myocardial infarction (MI). ßARKct expression in vivo proved essential for ß2AR-dependent contractile function, as ß2AR stimulation with isoproterenol fails to increase contractility in either healthy or post-MI B1KO mice and it only does so in the presence of ßARKct. The main underlying mechanism for this is blockade of the interaction of phosphodiesterase (PDE) type 4D with the cardiac ß2AR, which is normally mediated by the actions of GRK2 and ßarrs on the receptor. The molecular "brake" that PDE4D poses on ß2AR signaling to contractility stimulation is thus "released". Regarding the other beneficial functions of cardiac ß2AR, ßARKct increased overall survival of the post-MI B1KO mice progressing to HF, via a decrease in cardiac apoptosis and an increase in wound healing-associated inflammation early (at 24 hrs) post-MI. However, these effects disappear by 4 weeks post-MI, and, in their place, upregulation of the other major GRK in the heart, GRK5, is observed. CONCLUSIONS: GRK2 inhibition in vivo with ßARKct is absolutely essential for cardiac ß2AR pro-contractile signaling and function. In addition, ß2AR anti-apoptotic signaling in post-MI HF is augmented by ßARKct, although this effect is short-lived.

Prothymosin alpha protects cardiomyocytes against ischemia-induced apoptosis via preservation of Akt activation.

The human prothymosin alpha (PTα) gene encodes a 12.5 kDa highly acidic nuclear protein that is widely expressed in mammalian tissues including the heart and importantly, is detectable also in blood serum. During apoptosis or necrosis, PTα changes its nuclear localization and is able to exert an important cytoprotective effect. Since the role of PTα in the heart has never been evaluated, the aim of the present study was to investigate the effects of PTα on cardiomyocytes during ischemic injury. Our data show that seven after myocardial infarction (MI), PTα expression levels are significantly increased both in blood serum and in cardiac tissue, and notably we observe that PTα translocates from the nuclei to cytoplasm and plasma membrane of cardiomyocytes following MI. Furthermore, in vitro experiments in cardiomyocytes, confirm that after 6 h of simulated ischemia (SI), PTα protein levels are upregulated compared to normoxic cells. Importantly, treatment of cardiomyocytes with a recombinant PTα (rPTα), during SI results in a significant decrease in the apoptotic response and in a robust increase in cell survival. Moreover, these effects are accompanied to a significant preservation of the activated levels of the anti-apoptotic serine-threonine kinase Akt. Consistent with our in vitro observation, rPTα-treated MI mice exhibit a strong reduction in infarct size at 24 h, compared to the MI control group and at the molecular level, PTα treatment induces activation of Akt. The present study provides for the first time the demonstration that PTα offers cardioprotection against ischemic injury by an Akt-dependent mechanism.

Oral anticoagulation therapy in heart failure patients in sinus rhythm: a systematic review and meta-analysis.

BACKGROUND: Heart failure (HF) patients show high morbidity and mortality rate with increased risk of malignant arrhythmia and thromboembolism. Anticoagulation reduces embolic event and death rates in HF patients with atrial fibrillation, but if antithrombotic therapy is beneficial in patients with HF in sinus rhythm is still debated. METHODOLOGY AND PRINCIPAL FINDINGS: We conducted a systematic review of prospective, randomized controlled trials (RCTs) to assess the efficacy and safety of oral anticoagulant therapies (OATs) compared to antiplatelet treatment in HF patients in sinus rhythm. MEDLINE, Web of Science, CENTRAL and Scopus databases were searched up to May 2012. Four RCTs were identified and a total of 3663 patients were included in the meta-analysis. Patients with both ischemic and non-ischemic HF were included. There was no significant difference in mortality (odds ratio (OR) 1.01, 95% confidence interval (CI) 0.86 to 1.19) between OATs group and antiplatelet drug group. OATs have reduced ischemic stroke risk (OR 0.49, 95% CI 0.32 to 0.74), but have increased major bleeding risk (OR 2.01, 95% CI 1.40 to 2.88) compared to antiplatelet treatment. CONCLUSION: In HF patients in sinus rhythm OATs do not show a better risk-benefit profile compared to antiplatelet treatment in cardioembolism prevention. Warfarin and aspirin seem to be similar in reducing mortality. Warfarin reduces the incidence of ischemic stroke, but increases major bleedings. Thus, it is possible to speculate that aspirin prescription be indicated in patients with high risk of bleeding, whereas warfarin could be preferred in patients with high thromboembolic risk.

Statins and the elderly: recent evidence and current indications.

Cardiovascular disease (CVD) is estimated to remain as the main cause of death in developed nations over the next 30 years, with increased prevalence in the older population. This is because the observed decline in the incidence of CVD owing to improvements in prevention has now been counterbalanced by the increased shift toward an older and thus more fragile population. Statin treatment reduces cardiovascular morbidity and mortality in middle-aged adults. However, few studies have included older individuals, particularly those aged 80 years or over. The adverse effects associated with high doses of statins and their interactions with other drugs may give rise to more problems in the elderly population. Evidence remains limited regarding the overall benefit of starting statin therapy in adults aged 80 and over; so that clinical judgment remains necessary in making the decision to use them. In this review, we present available evidence from randomized clinical trials, as well as relative community and post-approval data directly applicable to the management of CVD in the elderly, in both primary and secondary prevention. Also discussed is the latest evidence regarding the putative protective effects of statins on senile dementia and the relationship between statin treatment and cancer.