Endothelial ILK induces cardioprotection by preventing coronary microvascular dysfunction and endothelial-to-mesenchymal transition.

Endothelial dysfunction is an early event in coronary microvascular disease. Integrin-linked kinase (ILK) prevents endothelial nitric oxide synthase (eNOS) uncoupling and, thus, endothelial dysfunction. However, the specific role of endothelial ILK in cardiac function remains to be fully elucidated. We hypothesised that endothelial ILK plays a crucial role in maintaining coronary microvascular function and contractile performance in the heart. We generated an endothelial cell-specific ILK conditional knock-out mouse (ecILK cKO) and investigated cardiovascular function. Coronary endothelial ILK deletion significantly impaired cardiac function: ejection fraction, fractional shortening and cardiac output decreased, whilst left ventricle diastolic internal diameter decreased and E/A and E/E' ratios increased, indicating not only systolic but also diastolic dysfunction. The functional data correlated with extensive extracellular matrix remodelling and perivascular fibrosis, indicative of adverse cardiac remodelling. Mice with endothelial ILK deletion suffered early ischaemic-like events with ST elevation and transient increases in cardiac troponins, which correlated with fibrotic remodelling. In addition, ecILK cKO mice exhibited many features of coronary microvascular disease: reduced cardiac perfusion, impaired coronary flow reserve and arterial remodelling with patent epicardial coronary arteries. Moreover, endothelial ILK deletion induced a moderate increase in blood pressure, but the antihypertensive drug Losartan did not affect microvascular remodelling whilst only partially ameliorated fibrotic remodelling. The plasma miRNA profile reveals endothelial-to-mesenchymal transition (endMT) as an upregulated pathway in endothelial ILK conditional KO mice. Our results show that endothelial cells in the microvasculature in endothelial ILK conditional KO mice underwent endMT. Moreover, endothelial cells isolated from these mice and ILK-silenced human microvascular endothelial cells underwent endMT, indicating that decreased endothelial ILK contributes directly to this endothelial phenotype shift. Our results identify ILK as a crucial regulator of microvascular endothelial homeostasis. Endothelial ILK prevents microvascular dysfunction and cardiac remodelling, contributing to the maintenance of the endothelial cell phenotype.

Statins and psoriasis: Position statement by the Psoriasis Task Force of the European Academy of Dermatology and Venerology.

BACKGROUND: Psoriasis is associated with an increased mortality risk, with cardiovascular disease being the leading excess cause (in a dose-response manner with psoriasis severity). Statins have demonstrated a reduction in all-cause mortality with no excess of adverse events among the general population. The underuse of interventions in cardiovascular prevention, such as statins, for patients with psoriasis may be the result of an insufficient evaluation. OBJECTIVES: To provide the dermatologist with a tool for systematizing the treatment of dyslipidemia in psoriasis, which generally escapes the scope of dermatological practice, and to facilitate decision-making about the referral and treatment of patients. METHODS: The Psoriasis Task Force of the European Academy of Dermatology and Venereology performed this two-phase study to achieve a consensus and create recommendations on the use of statin therapy in patients with psoriasis. The first phase included a systematic review to identify a list of outline concepts and recommendations according to guidelines. The second phase consisted in a two-round Delphi study to evaluate those recommendations not literally taken from guidelines. RESULTS: A list of 47 concepts and recommendations to be followed by dermatologists involved in the treatment of patients with moderate-severe psoriasis was created. It included six main concepts about cardiovascular risk and psoriasis, six items related with the role of low-density lipoprotein cholesterol (LDL-c) and the benefits of statin treatment in psoriasis patients, eight recommendations about how cardiovascular risk should be assessed, three on the role of non-invasive cardiovascular imaging, three on LDL-c thresholds, eight key points related to statin prescription, 10 on statin treatment follow-up and three on patient referral to another specialist. CONCLUSIONS: The application of this position statement (close final list of concepts and recommendations) will help dermatologists to manage dyslipidemia and help psoriasis patients to reduce their cardiovascular risk.

Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

Oral anticoagulation and left atrial appendage closure: a new strategy for recurrent cardioembolic stroke.

BACKGROUND AND PURPOSE: There are no recommendations regarding how to treat cardioembolic recurrent strokes when patients are well anticoagulated. We evaluated the safety and efficacy of combining oral anticoagulation (OAC) with percutaneous left atrial appendage closure (LAAC) in patients with well-anticoagulated atrial fibrillation (AF) with recurrent strokes. METHODS: In an explorative, prospective, observational study, LAAC was performed in patients with AF with at least two ischaemic strokes in the previous year, despite good anticoagulation using the Amplatzer Cardiac Plug (St Jude Medical, St Paul, MN, USA) or Amulet Abbot device (Abbot Vascular, Santa Clara, CA, USA). We recorded age, type of AF, CHA2 DS2 -VASC and HAS-BLED scores, types of OAC and risk factors. After closure, treatment with aspirin (100 mg/day) was continued for 3 months in combination with indefinite OAC. Clinical status, recurrent embolisms and bleeding complications were recorded during follow-up. RESULTS: A total of 19 patients were included (mean age, 72.1 ± 9.6 years; mean CHA2 DS2 -VASC score, 5.3 ± 1.48; mean number of previous strokes, 2.78 ± 1.15). Thirteen had spontaneous echocardiographic contrast and all had dilatation of the left atrium. Eighteen patients had a multilobulated left atrial appendage, 17 with 'chicken-wing' morphology and one patient had a left atrial appendage thrombus. There were no complications during the procedure. Only one patient had a transient ischaemic attack and no major bleeding occurred during a mean follow-up of 17.4 ± 11.5 months. CONCLUSION: Combination therapy with indefinite OAC plus LAAC in patients with AF with recurrent strokes despite good anticoagulation should be considered in order to prevent a new stroke.

State of play and future direction with NOACs: An expert consensus.

Atrial fibrillation (AF) and venous thromboembolism (VTE) are cardiovascular conditions significant in contemporary practice. In both, the use of anticoagulation with vitamin K antagonists (VKAs) has been traditionally used to prevent adverse events. However, VKA therapy is associated with challenges relating to dose maintenance, the need to monitor anticoagulation, and bleeding risks. The non-vitamin K oral anticoagulants (NOACs) are becoming accepted as a clear alternative to VKA therapy for both AF and VTE management. The aim of this paper was to review contemporary evidence on the safety of NOACs in both conditions. A comprehensive literature review was conducted to explore key safety issues and expert consensus was achieved from eight professionals specialised in AF and VTE care. Consensus-based statements were formulated where available evidence was weak or contradictory. The expert statements in this paper form a key overview of the safety of NOACs compared with VKA therapy, and the comparative safety of different NOACs. It is apparent that a detailed patient work-up is required in order to identify and manage individual risk factors for bleeding and thrombosis prior to NOAC therapy. Additional measures, such as dose reductions, may also be used to maintain the safety of NOACs in practice.

Recommendations on managing lenvatinib and everolimus in patients with advanced or metastatic renal cell carcinoma.

INTRODUCTION: There are several second-line treatment options for patients with renal cell carcinoma after first-line failure of a tyrosine kinase inhibitor, especially with the recent approvals of cabozantinib, nivolumab, and the lenvatinib plus everolimus combination. A lack of reliable biomarkers and an overall lack of prospective head-to-head comparisons make it a challenge to choose a second-line treatment in the clinic. Areas covered: In this review/meta-opinion, we describe the safety profile of the lenvatinib plus everolimus combination in renal cell carcinoma. The combination of lenvatinib plus everolimus has achieved the highest rates of objective responses and the longest progression free and overall survival in cross-comparison trials. At the same time, the safety profile of this combination, including the rate of total and severe adverse events, the percentage of dose reductions required, and the rate of treatment discontinuation, was less favorable compared with available monotherapy options, suggesting that better management could help to maximize the activity of this combination while protecting patients from undue harm. Expert opinion: Herein, we aim to postulate multidisciplinary recommendations on the advice to offer to patients and caregivers before starting treatment and how to manage the combination from the perspective of daily clinical practice.

Identifying the needs for competency-based education in Europe: a needs assessment of cardiologists across 52 countries.

Objective: This international needs assessment was mandated by the European Society of Cardiology (ESC) to obtain an in-depth understanding of the current gaps and challenges of European cardiology professionals, with the aim to provide evidence for the development of needs-driven educational and professional development activities. Methods: This ethics-approved needs assessment was conducted among cardiologists from all sub-specialties across 56 countries of Europe and the Mediterranean basin. A mixed-methods research approach was used, combining qualitative in-depth interviews and focus groups with a quantitative survey. Results: Seventy-four (74) cardiologists participated in the qualitative phase and 866 completed the survey. Respondents represented 52 of the 56 targeted countries. Three themes were identified: 1) Challenges in the clinical decision-making process, 2) Challenges in establishing the patient-physician relationship, and 3) Sub-optimal team communication and collaboration. Specific gaps and causalities related to each challenge were found. Although most of the gaps were common across countries and sub-specialties, some significant differences were noted. Conclusion: The findings of this needs assessment indicate gaps and challenges in clinical practice across countries and across sub-specialities. Taking cardiology as an example, this study identifies clear areas of focus, especially around issues of collaboration and communication, for targeted competency-based education in Europe.

Ultrasound and radiology surrogate endpoints in pharmacological studies.

Cardiovascular studies investigating therapeutic intervention with clinical endpoints are costly due to the need for considerable duration and large number of patients, or both. Therefore, for evaluation of novel cardiovascular drug efficacy, surrogate endpoints are used. Cardiovascular imaging endpoints have proven their worth. Sometimes the relevance of imaging is questioned and other methods are suggested instead. There is also some confusion about the strengths of imaging endpoints. The aim of the present paper is to review ultrasound and radiology imaging techniques as surrogate endpoints in pharmacological trials.

Recommendations for transoesophageal echocardiography: update 2010.

Transoesophageal echocardiography (TOE) is a standard and indispensable technique in clinical practice. The present recommendations represent an update and extension of the recommendations published in 2001 by the Working Group on Echocardiography of the European Society of Cardiology. New developments covered include technical advances such as 3D transoesophageal echo as well as developing applications such as transoesophageal echo in aortic valve repair and in valvular interventions, as well as a full section on perioperative TOE.

Role of echocardiography in the assessment of mechanical dyssynchrony.

The aim of this paper is to summarize the current scientific evidence regarding the prognostic implications of mechanical asynchrony, the benefits of identifying mechanical asynchrony prior to cardiac resynchronization therapy by means of echocardiography to predict response to cardiac resynchronization therapy and the different described parameters for dyssynchrony evaluation and measurement.

[Albuminuria and cardiovascular risk: basal results of the KORAL-CARDIO study]. / Albuminuria y riesgo cardiovascular. Estudio KORAL-CARDIO.

BACKGROUND AND OBJECTIVES: Albuminuria is a marker of higher cardiovascular and renal risk in hypertension; it also indicates the need of a tighter control of blood pressure with drugs blocking the renin-angiotensin system. The objective of the KORAL-CARDIO study was to assess the clinical picture and management of patients with hypertension and cardiac disease and albuminuria not previously treated with angiotensin inhibitors. METHODS: A total of 2711 hypertensive patients (44% female) with ischemic or hypertensive cardiopathy or atrial fibrillation and with a positive screening test for albuminuria was included. Type 2 diabetes was also present in 42%. RESULTS: Macroalbuminuria was present in 7.2% of non diabetic and 12.7% of diabetic patients, respectively. Associated complications were: 25% and 35% body mass index over 30 kg/m2; 22% and 39% ischemic heart disease; 4% and 8% stroke; 19% and 22% atrial fibrillation; 42% and 53% high cholesterol levels; 8% and 8% grade 3 hypertension, for non-diabetics and diabetics respectively. Antihypertensive monotherapy was used in 66% of non-diabetics and in 63% of diabetics; only 7% of patients in both groups were treated with triple antihypertensive therapy. CONCLUSIONS: Cardiovascular complications are very frequently associated to albuminuria in patients with hypertension and heart disease not previously treated with angiotensin inhibitors. Blood pressure control was clearly inadequate in this group.

Myocardial contrast echocardiography in coronary artery disease.

Myocardial contrast echocardiography (MCE) allows the assessment of myocardial perfusion by imaging the coronary microcirculation. The development of new contrast agents and new diagnostic tools far assessing myocardial perfusion by means of MCE has led to a new field of applications far patients suffering from ischemic heart disease. Several studies have shown that MCE is a feasible and accurate method to evaluate patients with: a) acute coronary syndromes: MCE is useful before the epicardial reperfusion to delineate the area at risk and to assess the collateral-derived myocardial blood flow, and after the epicardial reperfusion to detect the non-reflow phenomenon; b) chronic coronary syndromes: MCE allows the detection of significant coronary stenosis by means of stress methods and methods without any stress; c) myocardial viability and hibernating myocardium: MCE helps to predict functional recovery of akinetic segments. In these settings, MCE is not only useful as a diagnostic tool but also provides prognostic information. MCE is a technique in constant development. Among the latest advances we note the development of transesophageal probes with second-harmonic image that allows assessment of myocardial perfusion in a more accurate way. This technique should introduce MCE into new clinical fields, especially the evaluation of myocardial perfusion during cardiac operations. Another recent development is in parametric imaging techniques. These consist in obtaining time curves for all the pixels in the image instead of working only with a few separate regions of interest. A parameter scan is computed far any pixel showing their value as a color overlay in the parametric image. Summarizing, we can say that MCE is crossing from the experimental laboratory to the daily clinical practice far the evaluation of ischemic heart disease. MCE provides an interesting tool that offers the potential of a complete evaluation of patients with chronic coronary artery disease. This includes both diagnostic and prognostic evaluation.

Usefulness of contrast agents in the diagnosis of left ventricular pseudoaneurysm after acute myocardial infarction.

BACKGROUND AND OBJECTIVE: The diagnosis of left ventricular pseudoaneurysm after acute myocardial infarction is usually based on echocardiography. However, this technique may have limitations in some patients, especially in cases with suboptimal acoustic window. The objective of this study was to evaluate the usefulness of contrast echocardiography in the diagnosis of left ventricular pseudoaneurysm after myocardial infarction. METHODS AND RESULTS: The study population comprises six patients in whom a two-dimensional echocardiography showed an image consistent with left ventricular pseudoaneurysm. Levovist (Schering) 4gr was administered i.v. to more clearly visualize the blood flow from the left ventricle to the left ventricular pseudoaneurysm cavity in all patients. Infarct location was anterior in five patients, and posterolateral in one. No patient had received thrombolysis or primary angioplasty during the acute phase. The transthoracic echocardiographic study showed an echo-free space adjacent to left ventricle in all patients. In four cases, the diagnosis of left ventricular pseudoaneurysm was made before contrast administration. In the remaining two patients, the definite diagnosis was made only after Levovist administration. CONCLUSION: In the diagnosis of postinfarction left ventricular pseudoaneurysm, the administration of contrast agents may be of help in the correct visualization of the blood flow from the left ventricle to the left ventricular pseudoaneurysm cavity, and may allow a definite diagnosis to be obtained in some patients.