Transoesophageal echocardiography beyond the Echo-Laboratory. An expert consensus paper of the working group of echocardiography of the Hellenic Society of Cardiology.

Transoesophageal echocardiography (TOE) is a well-established and valid imaging modality, providing more accurate and of higher quality information than transthoracic echocardiography (TTE) for several specific diagnoses and recently a useful guide of an increasing number of catheter-based and surgical interventions. The present paper represents an effort by the Echocardiography Working Group (WG) of the Hellenic Society of Cardiology to state the essential steps of the TOE exam performed beyond the echo lab: a) in the operating rooms intraoperatively during either transcatheter interventions, or cardiothoracic surgery and b) in the intensive care unit for critically ill patients' monitoring. This paper includes information and tips and tricks about the pre-procedural evaluation, the procedural echocardiographic guidance and post - procedural evaluation of the result and potential complications.

Targeting the interaction of pleiotrophin and VEGFA165 with protein tyrosine phosphatase receptor zeta 1 inhibits endothelial cell activation and angiogenesis.

Protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) is a transmembrane tyrosine phosphatase (TP) that serves as a receptor for pleiotrophin (PTN) and vascular endothelial growth factor A 165 (VEGFA165) to regulate endothelial cell migration. In the present work, we identify a PTN peptide fragment (PTN97-110) that inhibits the interaction of PTN and VEGFA165 with PTPRZ1 but not VEGF receptor 2. This peptide abolishes the stimulatory effect of PTN and VEGFA165 on endothelial cell migration, tube formation on Matrigel, and Akt activation in vitro. It also partially inhibits VEGFA165-induced VEGF receptor 2 activation but does not affect ERK1/2 activation and cell proliferation. In vivo, PTN97-110 inhibits or dysregulates angiogenesis in the chick embryo chorioallantoic membrane and the zebrafish assays, respectively. In glioblastoma cells in vitro, PTN97-110 abolishes the stimulatory effect of VEGFA165 on cell migration and inhibits their anchorage-independent growth, suggesting that this peptide might also be exploited in glioblastoma therapy. Finally, in silico and experimental evidence indicates that PTN and VEGFA165 bind to the extracellular fibronectin type-III (FNIII) domain to stimulate cell migration. Collectively, our data highlight novel aspects of the interaction of PTN and VEGFA165 with PTPRZ1, strengthen the notion that PTPRZ1 is required for VEGFA165-induced signaling, and identify a peptide that targets this interaction and can be exploited for the design of novel anti-angiogenic and anti-glioblastoma therapeutic approaches.

Transcatheter mitral valve-in-valve replacement transeptally using a novel balloon-expandable device.

We describe a patient with symptomatic severe mitral regurgitation, due to a failed 33-mm Epic (St. Jude Medical, St. Paul, MN) bioprosthetic heart valve surgically implanted 10-year before. For this specific purpose, we implanted a novel balloon-expandable transcatheter heart valve, the MyVal (Meril Life Science, Vapi, India). To the best of our knowledge, this is the second case describing the implantation of MyVal in a degenerative, surgically placed bioprosthesis.

Nickel Hypersensitivity to Atrial Septal Occluders: Smoke Without Fire?

Nickel is one of the most common contact allergens worldwide; it is used as the main component of the devices used for atrial septal defects (ASDs) and patent foramen ovale (PFO) closure. Developing nickel hypersensitivity after PFO/ASD occlusion is significantly rarer described in medical literature than typical nickel contact sensitization. The exact pathophysiological mechanism of this "device syndrome" remains unknown, and many question the real incidence or even the existence of this clinical entity. Nevertheless, it has been associated with a wide spectrum of symptoms, including chest pain, migraines, palpitation, and dyspnea. Skin patch tests are the first-line approach to diagnose nickel hypersensitivity. However, diagnostic criteria for the device syndrome have not been developed, and diagnosis in reported cases is established by a process of elimination. Management-drug therapy (corticosteroids, clopidogrel, etc.) or even surgical explantation in severe cases-of patients developing such clinical manifestations after percutaneous PFO/ASD occlusion is empirical. Undoubtedly, endocardiac device-related nickel hypersensitivity requires more focused research to discover the underlying mechanism as well as to develop reliable prognostic tests for detecting high-risk patients and preventing severe nickel hypersensitivity reactions.

Long-term clinical outcomes of coronary artery bypass graft surgery compared to those of percutaneous coronary intervention with second generation drug eluting stents in patients with stable angina and an isolated lesion in the proximal left anterior descending artery.

OBJECTIVES: We compared the long-term outcomes of percutaneous coronary intervention with second-generation drug-eluting stents (PCI-DES) and coronary artery bypass graft surgery (CABG) with the left internal mammary artery in stable angina patients with isolated single-vessel proximal left anterior descending artery (pLAD) disease. BACKGROUND: Long-term outcomes of second-generation PCI-DES and CABG in isolated pLAD lesions have not been extensively studied. METHODS: We included 631 PCI-DES patients and 379 CABG patients. Unadjusted and adjusted hazard ratios (HRs) were derived for major adverse cardiac events (MACEs), their components (cardiac death, nonfatal myocardial infarction [MI] not attributed to a non-target vessel, target-lesion revascularization), and patient-related outcome (PRO, composed of all-cause mortality, any MI, any revascularization). RESULTS: In the unadjusted and adjusted analyses, no significant difference was observed between the two groups at follow-up (mean:4.6 ± 2.5 years) for MACEs (HR: 1.45, 95% CI: 0.92-2.28, p = .11; HR:1.43, 95% CI: 0.91-2.26, p = .13), PRO (HR: 1.18, 95%CI: 0.86-1.61, p = .30; HR: 1.18, 95% CI: 0.86-1.62, p = .31), cardiac death (HR: 0.97, 95% CI: 0.46-2.05, p = .93; HR: 0.79, 95% CI: 0.36-1.72, p = .56) and MI (HR: 1.43, 95% CI: 0.49-4.13, p = .51; HR: 1.57, 95% CI: 0.53-4.64, p = .42). Compared with CABG, PCI-DES had a borderline significantly greater risk of repeat revascularization (HR: 1.99, 95% CI: 1.00-3.94, p = .05; HR: 1.95, 95% CI: 0.98-3.9, p = .06). Angina recurred more often after PCI (p < .001), whereas more arrhythmias developed after CABG (p = .02). PCI-DES resulted in fewer in-hospital complications (p < .001) and shorter hospitalizations (p < .001). CONCLUSIONS: The long-term clinical outcomes of second-generation PCI-DES and CABG in patients with stable angina and isolated pLAD disease were comparable.

Cardiovascular Effects of Biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

The risk of cardiovascular (CV) disease is increased among patients with systemic autoimmune rheumatic diseases and remains an underserved area of medical need. Although traditional risk factors for CV disease, such as hypertension, smoking, dyslipidemia and obesity contribute to endothelial dysfunction in rheumatoid arthritis (RA), they are not enough on their own to explain the observed excess CV risk. Rather, systemic inflammation seems to play a pivotal role in both disease states. Considering the inflammatory process in autoimmune diseases, scientific interest has focused on recently introduced biologic disease-modifying agents (bDMARDS) such as inhibitors of Tumor Necrosis Factor- α (ΤΝF-α), Interleukins -1 (IL-1) and -6 (IL-6). Despite the widespread use of bDMARDS in RA and other chronic autoimmune inflammatory diseases, their precise impact on CV disease and outcome remains to be elucidated, while prospective randomized control trials assessing their impact on hard CV endpoints are scarce. In this review, we summarize current knowledge concerning the effect of bDMARDs on CV outcome and on the risk of developing CV disease in patients with systemic autoimmune rheumatic diseases.

Transfemoral transcatheter aortic valve replacement in the presence of a mitral prosthesis.

PURPOSE: In the current case series, we present our experience with the self-expanding CoreValve or Evolut R (Medtronic Inc.) in patients with severe symptomatic aortic valve stenosis and concomitant mitral valve prosthesis. METHODS: Twelve patients with previous mitral valve prosthesis underwent transcatheter aortic valve replacement for severe symptomatic aortic valve stenosis and/or aortic valve regurgitation. All patients underwent evaluation with an echocardiogram, computed tomography and coronary angiogram. After the index intervention and before discharge all patients underwent transthoracic echocardiography. All outcomes were defined according to the Valve Academic Research Consortium-2 criteria. RESULTS: Eleven patients underwent transcatheter aortic valve replacement for severe symptomatic aortic valve stenosis and one patient for severe aortic valve regurgitation. There was immediate improvement of patients' hemodynamic status; no cases of procedural death, stroke, myocardial infarction, or urgent cardiac surgery occurred. There was no 30-day mortality and all patients improved, with 91.6% in functional New York Heart Association class I-II. CONCLUSION: The current study demonstrates that in patients with severe aortic valve stenosis or regurgitation and mitral valve prosthesis, the implantation of a self-expanding aortic valve via the transfemoral route is safe and feasible, with maintained long-term results.

Management of patients with concomitant coronary and carotid artery disease.

Introduction: Ideal management of concomitant carotid and coronary artery occlusive disease remains under investigation. Although researchers have advocated the potential benefits of varying treatment strategies based on either concomitant or staged surgical treatment, there is no consensus in treatment guidelines. With emerging data suggesting favorable outcome of carotid artery stenting (CAS) compared to carotid endarterectomy (CEA) in patients with critical coronary artery disease, physicians must consider these diverging therapeutic options. Areas covered: This review presents current evidence regarding the prevalence of carotid stenosis in patients with coronary artery disease, the common pathophysiologic links with an emphasis on the diverse mechanisms of stroke in the coronary artery bypass grafting (CABG) setting and discusses the contemporary registries and observational studies comparing outcomes of various revascularization strategies in high-risk patients. Authors conducted a literature search in two bibliographic databases including papers published from 1983 until 2018 (PubMed, Scopus). Expert opinion: Symptoms should drive the need to intervene on carotid stenosis in patients undergoing coronary revascularization. Carotid artery stenting has gained significant ground, especially among those individuals considered of high surgical risk. PCI may be considered as an alternative option for the management of severe concurrent coronary disease.

Inhibition of Aortic Valve Calcification by Local Delivery of Zoledronic Acid-an Experimental Study.

The aim of this study was to evaluate in an experimental model of aortic valve (AV) stenosis the effectiveness of zoledronate on the inhibition of calcification. Sixteen New Zealand rabbits were placed on vitamin D-enriched diet for 3 weeks. All animals underwent PET/CT at baseline and before euthanasia to assess calcification. Thereafter, the AVs of eight animals were treated with local delivery of 500 µg/l zoledronate. A placebo mixture was administered in the remaining eight animals. Standardized uptake values were corrected for blood pool activity, providing mean tissue to background ratios (TBRmean). In the zoledronate group, there was no progression of AV calcification (TBRmean 1.20 ± 0.12 vs 1.17 ± 0.78,p = 0.29), while AV calcification progressed in the placebo group (1.22 ± 0.15 vs 1.53 ± 0.23,p = 0.006). Ascending aorta (AA) calcification progressed in both zoledronate and placebo groups. Histology confirmed the results of the PET/CT. Inhibition of AV calcification by local delivery of zoledronate is feasible and effective.

The requirement of extracorporeal circulation system for transluminal aortic valve replacement: Do we really need it in the catheterization laboratory?

Transcatheter aortic valve replacement (TAVR) is the mainstay for treating high-risk patients with aortic stenosis. As the TAVR procedures worldwide keep increasing, it is inevitable that more issues and complications will arise. Such a complication that merits attention is the conversion of TAVR into open-heart surgery and the necessity this complication creates to have an extracorporeal circulation system in the catheterization laboratory. This review contains an analysis of all major randomized trials and registries on the number and cause of TAVR procedures that ended up in open-heart surgery and presents data to challenge the prerequisite of extracorporeal circulation system in the cath laboratory. © 2015 Wiley Periodicals, Inc.

Vascular inflammation and metabolic activity in hematopoietic organs and liver in familial combined hyperlipidemia and heterozygous familial hypercholesterolemia.

BACKGROUND: Familial dyslipidemias of either heterozygous (heFH) or combined (FCH) type lead to accelerated atherogenesis and increased cardiovascular risk. OBJECTIVE: The aim of this study was to investigate in statin-naïve adult patients with familial dyslipidemias whether inflammatory activation and liver, spleen and bone marrow metabolic activity differ compared with normolipidemic subjects and between dyslipidemic groups. METHODS: Fourteen patients with FCH, 14 with heFH, and 14 normolipidemic individuals were enrolled. Serum lipids, high-sensitivity C-reactive protein, and fibrinogen levels were measured, followed by 18F-fluorodeoxyglucose positron-emission tomography/computed tomography imaging. Radiotracer uptake in the aortic wall, spleen, bone marrow, and liver was quantified as tissue-to-background ratio (TBR). RESULTS: Patients with heFH had significantly higher low-density lipoprotein levels compared with those with FCH and controls (P < .001). However, aortic TBRs were higher in FCH compared with heFH patients and controls (P = .02 and P < .001, respectively). FCH patients exhibited higher FDG uptake in the spleen compared with controls (P = .05). In addition, FCH exhibited higher bone marrow FDG uptake compared with heFH patients and controls (P = .03 and P = .02, respectively). FCH had higher liver uptake compared with heFH patients and controls (P < .001 for both). Significant correlations were observed between inflammatory biomarkers and imaging indices as well as between aortic TBR and FDG uptake of hematopoietic organs and liver. CONCLUSIONS: Systemic, as well as vascular inflammation and spleen, bone marrow, and hepatic metabolic activity are increased in patients with FCH despite lower levels of low-density lipoprotein.

Bevacizumab increases the incidence of cardiovascular events in patients with metastatic breast or colorectal cancer.

INTRODUCTION: The effect of systemic administration of bevacizumab in cancer patients over a 5-year period after the beginning of chemotherapy treatment and comparison with a control group. METHODS: The study population consists of adult patients with metastatic breast or colorectal cancer who had not previously received antineoplasmatic treatment. Patients were stratified into two groups according to treatment: one group was treated with conventional chemotherapy plus bevacizumab and the other group was treated with conventional chemotherapy alone. The two groups did not differ in their cardiovascular history or demographic characteristics. RESULTS: Fatal outcomes were more frequent in the bevacizumab group in total as well as in different periods of follow up. However, a statistically significant difference was noted at 12 months (P-value 0.007) for new deaths and at 24 (p-value 0.001) and 60 months (p-value 0.004) for all deaths. Moreover, patients who experienced a cardiovascular or thromboembolic event belonged exclusively to the bevacizumab group. At the 5-year follow-up, five patients in the bevacizumab group developed coronary artery disease (19.23%), four experienced an acute myocardial infarction (14.81%) and five patients suffered from a thromboembolic event (17.86%). CONCLUSIONS: The addition of bevacizumab to conventional chemotherapy for metastatic breast or colorectal cancer increases the incidence of cardiovascular events, which is mainly due to the increased prevalence of myocardial infarction and thromboembolic events.

Managing the lipid profile of coronary heart disease patients.

INTRODUCTION: Lipid profile management is even more critical in patients treated for secondary prevention, since patients with established coronary heart disease are at higher risk of developing events. Current guidelines encourage lifestyle modification and patient engagement in disease prevention. However, the American College of Cardiology/American Heart Association guidelines seem to differ considerably from their predecessors, having an impact on clinical practice of lipid management. Area covered: This review article discusses and provides a summary of the current recommendations for lipid profile management in patients with coronary heart disease, with a view to present lifestyle modification and novel treatment strategies, and to indicate areas of dispute among recent guidelines. Expert commentary: Existing controversies between current guidelines concerning treatment goals and therapeutic decisions may have potential implications on the clinical management of patients. In the meantime, we eagerly wait for the results of randomized controlled trials evaluating promising, potent, safe and prolonged drugs that are in progress.

Therapeutic Applications of Calcium Metabolism Modulation in Heart Disease.

Cardiovascular disease is the leading cause of death worldwide and there is extensive research on the pathophysiology of all its clinical entities. Despite the big array of possible therapeutic modalities for cardiovascular disease, there is still a big necessity to develop novel treatments that will augment our strategies for tackling the burden of cardiovascular disease and decrease morbidity and mortality. A major player in both the physiology and pathophysiology of the cardiovascular system is calcium. Extracellular calcium is required in order to initiate cardiac muscle contraction and promote the calcium-induced calcium release mechanism from the sarcoplasmic reticulum. A lot of molecules and structures that in a direct or indirect way interact with calcium are being studied and there is a constant flow of new information that is emerging. In this review we focus on some of these calcium metabolism modulators representatives such as SERCA2a, RyR2, S100A1, phosholamban and calcineurin. We emphasize on their mechanism of action, their role in cardiovascular disease and potential therapeutic implications. We also focus on the effect the bisphosphonates might have in regression of the calcium deposition in the human arteries as well as the usage of novel biomarkers such as mircoRNAs in calcium metabolism modulation in heart disease.

Bilateral symmetry of local inflammatory activation in human carotid atherosclerotic plaques.

INTRODUCTION: Only a few studies have investigated the structural and functional characteristics of carotid arteries bilaterally. Furthermore, there is controversy as to whether inflammation in paired vascular beds is a local or systemic phenomenon. We aimed to examine, in patients with coronary artery disease, whether intra-subject left and right carotid arteries have similar inflammatory status, as determined non-invasively by microwave radiometry (MWR). METHODS: Consecutive patients (n=200) with significant coronary artery disease were evaluated via an ultrasound echo-colour Doppler (US-ECD) study of both carotid arteries and temperature measurements with MWR. During thermography, thermal heterogeneity (ΔT) was defined as the maximum temperature along the carotid artery minus the minimum temperature. RESULTS: Mean T was similar between the left and right carotid arteries (0.78 ± 0.48 vs. 0.84 ± 0.52°C, p=0.12). Mean right intima-media thickness (IMT) was greater compared to mean left IMT (2.16 ± 1.20 vs. 1.93 ± 0.94 mm, p<0.01). In all carotids, there was a correlation between left and right carotid plaque ΔT (R=0.38, p<0.001) and between left and right IMT (R=0.48, p<0.001). Independent predictors for the presence of bilateral carotid plaques were found to be the extent of coronary artery disease, high ΔT, and therapy with angiotensin II receptor blockers; predictors for the presence of high ΔT bilaterally were bilateral carotid plaques, male sex, diabetes mellitus, and hypertension. CONCLUSIONS: There is bilateral inflammatory activation in the carotid atherosclerotic lesions of patients with coronary artery disease. At this stage of carotid disease, arterial hypertension and diabetes mellitus are more strongly correlated with bilateral functional abnormalities in carotid plaques than with structural changes.