Immunoglobulins G modulate endothelial function and affect insulin sensitivity in humans.

BACKGROUND AND AIMS: Data from animals suggest that immunoglobulins G (IgG) play a mechanistic role in atherosclerosis and diabetes through endothelial dysfunction and insulin resistance. Patients with common variable immunodeficiency (CVID), who have low circulating levels of IgG and are treated with intravenous polyclonal IgG (IVIgG), may provide an ideal model to clarify whether circulating IgG modulate endothelial function and affect insulin sensitivity in humans. METHODS AND RESULTS: We studied 24 patients with CVID and 17 matched healthy controls (HC). Endothelial function was evaluated as flow mediated dilation (FMD) of the brachial artery at baseline and 1, 7, 14, and 21 days after IVIgG infusion in the CVID patients. We measured also plasma glucose, insulin, and calculated the HOMA-IR index. We also investigated the role of human IgG on the production of Nitric Oxide (NO) in vitro in Human Coronary Artery Endothelial Cells (HCAEC). Compared to HC, FMD of CVID patients was significantly impaired at baseline (9.4 ± 0.9 and 7.6 ± 0.6% respectively, p < 0.05) but rose above normal levels 1 and 7 days after IVIgG infusion to return at baseline at 14 and 21 days. Serum insulin concentration and HOMA-IR index dropped by 50% in CVID patients after IVIgG (p < 0.002 vs. baseline). In vitro IgG stimulated NO production in HCAEC. CONCLUSIONS: Reduced IgG levels are associated with endothelial dysfunction and IVIgG stimulates endothelial function directly while improving insulin sensitivity. The current findings may suggest an anti-atherogenic role of human IgG.

One-Year Clinical Outcomes of the Legflow Drug-Coated Balloon for the Treatment of Femoropopliteal Occlusions Registry.

PURPOSE: To report the 1-year outcomes of the prospective Legflow drug-coated balloon (DCB) registry, which evaluated the safety and 12-month efficacy of the Legflow balloon in the treatment of femoropopliteal disease. METHODS: The Legflow is a new generation of DCB that has a homogenous, stable surface coating incorporating 0.1-µm paclitaxel particles. From January 2014 to June 2016, 139 patients (mean age 67.1±10.8 years; 109 men) were enrolled at 4 European institutions. Seventy-nine (56.8%) patients had claudication, while 60 (43.2%) had critical limb ischemia (CLI). Mean lesion length (MLL) was 90.0±41.2 mm. Eighty (57.6%) patients were treated for de novo lesions (MLL 83.2±41.2 mm), 29 (20.9%) for postangioplasty restenosis (MLL 81.2±30.9 mm), and 30 (21.6%) for in-stent restenosis (MLL 117.0±39.5 mm). The primary outcome measure was freedom from binary restenosis as determined by a peak systolic velocity ratio ≥2.4 on duplex or >50% stenosis on digital subtraction angiography at 12 months. The secondary outcome was freedom from clinically-driven target lesion revascularization (CD-TLR) at 12 months. RESULTS: Technical success was achieved in all the 139 treated patients. During the hospital stay, 3 CLI patients died of wound-related complications and 3 CLI patients underwent urgent TLR due to early occlusion in 2 and stent thrombosis in 1. At 12 months, 4 additional patients died of cardiac disease unrelated to the procedure. Of the 132 patients available for 1-year follow-up, the primary outcome (freedom from restenosis) was obtained in 107 (81.1%) patients. Freedom from CD-TLR was obtained in 110 (83.3%). Of the 25 late restenoses >50%, only 3 asymptomatic patients did not require TLR. Freedom from CD-TLR was higher in claudicants (87.0%) than in CLI patients (78.2%, p=0.20). In patients treated for in-stent restenosis, freedom from TLR at 1 year was 89.2%. CONCLUSION: These data suggest that the use of a new generation paclitaxel-coated balloon represents a safe and effective therapeutic strategy for femoropopliteal obstructions in different clinical and anatomical settings. These data will need to be confirmed with longer-term follow-up and in randomized controlled trials.

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.

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.

Management of Transcatheter Aortic Valve Implantation and Complex Aorta Anatomy: The Importance of Pre-Procedural Planning.

Aortic stenosis is the most common primary valve lesion requiring surgery or, especially for older patients, transcatheter intervention (TAVI). We showcase a successful transfemoral TAVI procedure in a very high-risk patient and an extremely tortuous S-shaped descending aorta, characterized by heavy calcifications and multiple strong resistance points. We demonstrated that transfemoral TAVI using the "buddy stiff guidewire" technique could be a feasible, simple, quick, and easy procedure able to straighten an extremely abdominal aorta tortuosity. With all techniques available and careful pre-procedural planning, and thanks to the flexibility of new generation TAVI delivery systems, it is possible to safely perform the procedure even in the most challenging patients.

ADDED Index or Percentage Diameter of Residual Coronary Stenosis to Risk-Stratify Patients Presenting With STEMI.

BACKGROUND: We compared the prognostic value of the ADDED Index with visually estimated diameter (DS) of residual coronary stenosis (RS) in STEMI patients after successful PCI of the culprit lesion. Even though associated with a positive outcome, the functional assessment of non-culprit stenosis remains largely underused, especially in STEMI patients. The Angiography-DeriveD hEmoDynamic index (ADDED index) showed high accuracy to predict FFR and it might be used to better guide the diagnostic and therapeutic work-up of such patients. METHODS: We retrospectively included 596 patients grouped on the basis of either the ADDED Index (ADDED Negative (<2.23, n = 153) vs ADDED Positive (≥2.23, n = 129)) or the DS of the RS (RS Negative (<50%, n = 177) vs RS Positive (≥50%, n = 105)). Patients without any RS served as control (n = 314). Primary endpoints were: 1) major adverse cardiac events (MACE), composite of all-cause death, myocardial infarction (MI), clinically driven revascularizations (CDR); 2) non-culprit vessel oriented clinical events (VOCE), composite of all-cause death, non-culprit vessel related MI and CDR. RESULTS: At 24 months the rate of both MACE and VOCE was significantly higher in both the ADDED Positive and RS Positive groups. However, differently from patients in whom complete revascularization was deferred on the basis of the angiography (RS Negative), no additional risk was found for patients in the ADDED Negative group. CONCLUSIONS: In STEMI patients with MVD deferring treatment of RS on the basis of the ADDED index, rather than the visually estimated DS, is associated with a favorable clinical outcome.

Cardiovascular effects of treadmill exercise in physiological and pathological preclinical settings.

Exercise adaptations result from a coordinated response of multiple organ systems, including cardiovascular, pulmonary, endocrine-metabolic, immunologic, and skeletal muscle. Among these, the cardiovascular system is the most directly affected by exercise, and it is responsible for many of the important acute changes occurring during physical training. In recent years, the development of animal models of pathological or physiological cardiac overload has allowed researchers to precisely analyze the complex cardiovascular responses to stress in genetically altered murine models of human cardiovascular disease. The intensity-controlled treadmill exercise represents a well-characterized model of physiological cardiac hypertrophy because of its ability to mimic the typical responses to exercise in humans. In this review, we describe cardiovascular adaptations to treadmill exercise in mice and the most important parameters that can be used to quantify such modifications. Moreover, we discuss how treadmill exercise can be used to perform physiological testing in mouse models of disease and to enlighten the role of specific signaling pathways on cardiac function.

Total occlusion of the abdominal aorta in a patient with renal failure and refractory hypertension: a case report.

Total occlusion of the abdominal aorta is unusual, and potentially catastrophic. It occurs in patients with advanced atherosclerotic occlusive disease, and can cause severe ischemic manifestations, depending on the site of obstruction. Prompt and appropriate diagnostic and therapeutic approaches are important whenever this condition is suspected, in order to avoid a fatal outcome. The development of a complex network of collaterals may prevent the manifestation of acute ischemic phenomena, and cause a delay in diagnosis and treatment. Here we report the clinical case of a 59-year-old man who was referred to our Department for evaluation of renal failure and refractory hypertension. Ultrasonography and 99mTc-DTPA scintigraphy showed a shrunken, non-functioning left kidney, while CT angiography and aortography showed the complete occlusion of the aorta from below the right renal artery down to the bifurcation of both common iliac arteries, with a critical stenosis of the origin of the right renal artery, an occlusion of the left renal artery as well as of the origin of the inferior mesenteric artery. The patient was referred to the surgery department for aorto-bifemoral bypass surgery and re-implantation of the right renal artery.

Endovascular treatment of carotid artery stenosis: evidences from randomized controlled trials and actual indications.

Atherosclerotic stenosis of common and internal carotid arteries is a well-recognized risk factor for ischemic stroke, and revascularization has been proven to be the main tool of prevention, particularly for patients with stenosis-related symptoms. While for many years surgical carotid endarterectomy (CEA) has been considered the gold-standard strategy to restore vascular patency, recently the endovascular treatment through percutaneous angioplasty and stent implantation (CAS) has become a valid alternative. In the last years, interesting data about the comparison of these strategies have emerged. CAS seems to cause more peri-procedural strokes, but may also avoid many adverse events related to surgery and general anaesthesia, including peri-procedural myocardial infarction. For these reasons, it was initially considered a second-choice strategy to be adopted in patients for whom surgery was contraindicated. However, more recent trials have shown that CAS might be considered an effective alternative to CEA. Moreover, the rapid evolution of CAS technique and materials suggests its potential to improve outcome and possible superiority compared to CEA in the next future. Purpose of this review is to discuss the most recent clinical evidences concerning the treatment of carotid artery stenosis, with a special focus on the endovascular treatment.

Functionally Complete Coronary Revascularisation in Patients Presenting with ST-elevation MI and Multivessel Coronary Artery Disease.

Up to half of patients undergoing primary percutaneous coronary intervention of a culprit stenosis in the context of the ST-elevation MI may present with multivessel disease. The presence of non-culprit stenoses have been shown to affect the outcomes of these patients, and the results of the more recent randomised trials highlight the importance of complete coronary revascularisation. In this paper, the authors review the main trials published on the topic and discuss tools for the assessment of non-culprit stenoses, while considering the right time for carrying out a complete coronary revascularisation.

Prognostic Implications of Declining Hemoglobin Content in Patients Hospitalized With Acute Coronary Syndromes.

BACKGROUND: Contemporary definitions of bleeding endpoints are restricted mostly to clinically overt events. Whether hemoglobin drop per se, with or without overt bleeding, adversely affects the prognosis of patients with acute coronary syndrome (ACS) remains unclear. OBJECTIVES: The aim of this study was to examine in the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial the incidence, predictors, and prognostic implications of in-hospital hemoglobin drop in patients with ACS managed invasively stratified by the presence of in-hospital bleeding. METHODS: Patients were categorized by the presence and amount of in-hospital hemoglobin drop on the basis of baseline and nadir hemoglobin values and further stratified by the occurrence of adjudicated in-hospital bleeding. Hemoglobin drop was defined as minimal (<3 g/dl), minor (≥3 and <5 g/dl), or major (≥5 g/dl). Using multivariate Cox regression, we modeled the association between hemoglobin drop and mortality in patients with and without overt bleeding. RESULTS: Among 7,781 patients alive 24 h after randomization with available hemoglobin data, 6,504 patients (83.6%) had hemoglobin drop, of whom 5,756 (88.5%) did not have overt bleeding and 748 (11.5%) had overt bleeding. Among patients without overt bleeding, minor (hazard ratio [HR]: 2.37; 95% confidence interval [CI]: 1.32 to 4.24; p = 0.004) and major (HR: 2.58; 95% CI: 0.98 to 6.78; p = 0.054) hemoglobin drop were independently associated with higher 1-year mortality. Among patients with overt bleeding, the association of minor and major hemoglobin drop with 1-year mortality was directionally similar but had wider CIs (minor: HR: 3.53 [95% CI: 1.06 to 11.79]; major: HR: 13.32 [95% CI: 3.01 to 58.98]). CONCLUSIONS: Among patients with ACS managed invasively, in-hospital hemoglobin drop ≥3 g/dl, even in the absence of overt bleeding, is common and is independently associated with increased risk for 1-year mortality. (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox; NCT01433627).

From biodegradable polymers to bioresorbable vascular scaffolds: available evidence in the era of new-generation drug-eluting stents.

New-generation drug-eluting stents (DES) encompass a large variety of coronary devices, featuring thin struts, biocompatible durable or biodegradable polymer coatings, and limus-eluting drugs. Due to improved early and long-term outcomes among patients undergoing percutaneous coronary intervention, new-generation metallic DES are recommended in almost all patient and lesion subsets. Available evidence from randomized trials indicates a similar safety and efficacy profile between biodegradable and durable polymers new-generation DES. Recently, polymer-free DES provided promising results particularly as alternative to bare-metal stents. Ultimately, although remaining conceptually solid, bioresorbable vascular scaffolds represent an immature technology owing to increased risk of thrombosis. In this review, we summarized current evidence about contemporary coronary devices.

Akap1 Regulates Vascular Function and Endothelial Cells Behavior.

MitoAKAPs (mitochondrial A kinase anchoring proteins), encoded by the Akap1 gene, regulate multiple cellular processes governing mitochondrial homeostasis and cell viability. Although mitochondrial alterations have been associated to endothelial dysfunction, the role of mitoAKAPs in the vasculature is currently unknown. To test this, postischemic neovascularization, vascular function, and arterial blood pressure were analyzed in Akap1 knockout mice (Akap1-/- ) and their wild-type (wt) littermates. Primary cultures of aortic endothelial cells (ECs) were also obtained from Akap1-/- and wt mice, and ECs migration, proliferation, survival, and capillary-like network formation were analyzed under different experimental conditions. After femoral artery ligation, Akap1-/- mice displayed impaired blood flow and functional recovery, reduced skeletal muscle capillary density, and Akt phosphorylation compared with wt mice. In Akap1-/- ECs, a significant enhancement of hypoxia-induced mitophagy, mitochondrial dysfunction, reactive oxygen species production, and apoptosis were observed. Consistently, capillary-like network formation, migration, proliferation, and AKT phosphorylation were reduced in Akap1-/- ECs. Alterations in Akap1-/- ECs behavior were also confirmed in Akap1-/- mice, which exhibited a selective reduction in acetylcholine-induced vasorelaxation in mesenteric arteries and a mild but significant increase in arterial blood pressure levels compared with wt. Finally, overexpression of a constitutively active Akt mutant restored vascular reactivity and ECs function in Akap1-/- conditions. These results demonstrate the important role of mitoAKAPs in the modulation of multiple ECs functions in vivo and in vitro, suggesting that mitochondria-dependent regulation of ECs might represent a novel therapeutic approach in cardiovascular diseases characterized by endothelial dysfunction.

Correction: Akap1 Deficiency Promotes Mitochondrial Aberrations and Exacerbates Cardiac Injury Following Permanent Coronary Ligation via Enhanced Mitophagy and Apoptosis.

[This corrects the article DOI: 10.1371/journal.pone.0154076.].

Akap1 Deficiency Promotes Mitochondrial Aberrations and Exacerbates Cardiac Injury Following Permanent Coronary Ligation via Enhanced Mitophagy and Apoptosis.

A-kinase anchoring proteins (AKAPs) transmit signals cues from seven-transmembrane receptors to specific sub-cellular locations. Mitochondrial AKAPs encoded by the Akap1 gene have been shown to modulate mitochondrial function and reactive oxygen species (ROS) production in the heart. Under conditions of hypoxia, mitochondrial AKAP121 undergoes proteolytic degradation mediated, at least in part, by the E3 ubiquitin ligase Seven In-Absentia Homolog 2 (Siah2). In the present study we hypothesized that Akap1 might be crucial to preserve mitochondrial function and structure, and cardiac responses to myocardial ischemia. To test this, eight-week-old Akap1 knockout mice (Akap1-/-), Siah2 knockout mice (Siah2-/-) or their wild-type (wt) littermates underwent myocardial infarction (MI) by permanent left coronary artery ligation. Age and gender matched mice of either genotype underwent a left thoracotomy without coronary ligation and were used as controls (sham). Twenty-four hours after coronary ligation, Akap1-/- mice displayed larger infarct size compared to Siah2-/- or wt mice. One week after MI, cardiac function and survival were also significantly reduced in Akap1-/- mice, while cardiac fibrosis was significantly increased. Akap1 deletion was associated with remarkable mitochondrial structural abnormalities at electron microscopy, increased ROS production and reduced mitochondrial function after MI. These alterations were associated with enhanced cardiac mitophagy and apoptosis. Autophagy inhibition by 3-methyladenine significantly reduced apoptosis and ameliorated cardiac dysfunction following MI in Akap1-/- mice. These results demonstrate that Akap1 deficiency promotes cardiac mitochondrial aberrations and mitophagy, enhancing infarct size, pathological cardiac remodeling and mortality under ischemic conditions. Thus, mitochondrial AKAPs might represent important players in the development of post-ischemic cardiac remodeling and novel therapeutic targets.

Novel Molecular Approaches in Heart Failure: Seven Trans-Membrane Receptors Signaling in the Heart and Circulating Blood Leukocytes.

Heart failure (HF) is the result of molecular, cellular, and structural changes induced by cardiac load or injury. A complex network of signaling pathways have been involved in the development and progression of cardiac dysfunction. In this review, we summarize the pivotal role of seven trans-membrane receptors (7TMRs), also called G-protein-coupled receptors (GPCRs), in HF. Moreover, we will discuss the current knowledge on the potential mirroring of 7TMR signaling between circulating blood leukocytes and the heart, and the related future possibilities in the management of HF patients.

The Murine Model of Mucopolysaccharidosis IIIB Develops Cardiopathies over Time Leading to Heart Failure.

Mucopolysaccharidosis (MPS) IIIB is a lysosomal disease due to the deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU) required for heparan sulfate (HS) degradation. The disease is characterized by mild somatic features and severe neurological disorders. Very little is known on the cardiac dysfunctions in MPS IIIB. In this study, we used the murine model of MPS IIIB (NAGLU knockout mice, NAGLU(-/-)) in order to investigate the cardiac involvement in the disease. Echocardiographic analysis showed a marked increase in left ventricular (LV) mass, reduced cardiac function and valvular defects in NAGLU(-/-) mice as compared to wild-type (WT) littermates. The NAGLU(-/-) mice exhibited a significant increase in aortic and mitral annulus dimension with a progressive elongation and thickening of anterior mitral valve leaflet. A severe mitral regurgitation with reduction in mitral inflow E-wave-to-A-wave ratio was observed in 32-week-old NAGLU(-/-) mice. Compared to WT mice, NAGLU(-/-) mice exhibited a significantly lower survival with increased mortality observed in particular after 25 weeks of age. Histopathological analysis revealed a significant increase of myocardial fiber vacuolization, accumulation of HS in the myocardial vacuoles, recruitment of inflammatory cells and collagen deposition within the myocardium, and an increase of LV fibrosis in NAGLU(-/-) mice compared to WT mice. Biochemical analysis of heart samples from affected mice showed increased expression levels of cardiac failure hallmarks such as calcium/calmodulin-dependent protein kinase II, connexin43, α-smooth muscle actin, α-actinin, atrial and brain natriuretic peptides, and myosin heavy polypeptide 7. Furthermore, heart samples from NAGLU(-/-) mice showed enhanced expression of the lysosome-associated membrane protein-2 (LAMP2), and the autophagic markers Beclin1 and LC3 isoform II (LC3-II). Overall, our findings demonstrate that NAGLU(-/-) mice develop heart disease, valvular abnormalities and cardiac failure associated with an impaired lysosomal autophagic flux.

Dermcidin: a skeletal muscle myokine modulating cardiomyocyte survival and infarct size after coronary artery ligation.

AIMS: Coronary artery disease is the leading cause of death in western countries, and its association with lower extremity peripheral artery disease (LE-PAD) represents an independent predictor of worse outcome. However, the molecular mechanisms underlying these effects are currently unknown. METHODS AND RESULTS: To investigate these processes, we used in vitro approaches and several mouse models: (i) unilateral limb ischaemia by left common femoral artery ligation [peripheral ischaemia (PI), n = 38]; (ii) myocardial infarction by permanent ligation of the left descending coronary artery (MI, n = 40); (iii) MI after 5 weeks of limb ischaemia (PI + MI, n = 44); (iv) sham operation (SHAM, n = 20). Compared with MI, PI + MI hearts were characterized by a significant increase in cardiomyocyte apoptosis, larger infarct areas, and decreased cardiac function. By using a proteomic approach, we identified a ≅ 8 kDa circulating peptide, Dermcidin (DCD), secreted by ischaemic skeletal muscles, enhancing cardiomyocytes apoptosis under hypoxic conditions and infarct size after permanent coronary artery ligation. siRNA interference experiments to reduce DCD circulating levels significantly reduced infarct size and ameliorated cardiac function after MI. CONCLUSION: Our data demonstrate that chronic limb ischaemia activates detrimental pathways in the ischaemic heart through humoral mechanisms of remote organ crosstalk. Thus, DCD may represent a novel important myokine modulating cardiomyocyte survival and function.

[Novel pharmacological strategies for aortic dilation in Marfan syndrome: from mouse models to human patients]. / Nuove strategie farmacologiche per la sindrome di Marfan: dai modelli animali all'uomo.

Marfan syndrome (MS) is a congenital disorder of the connective tissue characterized by aortic dilation with frequent progression to aortic aneurysms requiring surgical intervention. Although mutations in the fibrillin-1 (FBN1) gene have been recognized as the genetic cause of MS a long time ago, only recently deeper knowledge of the molecular mechanisms underlying fibrillin-1 biology and the crucial role of transforming growth factor-ß and angiotensin II receptor type 1 antagonists have been elucidated. This review focuses on the most commonly used animal models to investigate the molecular mechanisms underlying MS, and on novel pharmacological strategies to reduce aortic dilation in MS.

Cardiac side effects of chemotherapy: state of art and strategies for a correct management.

In recent years, the development of more effective drugs has provided a better prognosis and an increase in life expectancy for patients at all-stages of cancer. On the other hand, the price for the improving effectiveness of therapies against malignant tumors is the development of severe and potentially life-threatening drug reactions. Among these, cardiac toxic effects have recently gained particular attention. The term cardiotoxicity includes many possible pathological manifestations, but the most frequent is the reduction in cardiac function, potentially leading to heart failure and death. Importantly, the development of cardiac dysfunction may occur immediately after drug administration, or after years. The purpose of this review is to discuss the clinical features of cardiotoxicity, its molecular basis and novel possible strategies to reduce the likelihood of serious cardiac complications.