George Latsios

Diabetes Mellitus-Associated Vascular Impairment: Novel Circulating Biomarkers and Therapeutic Approaches

It is widely accepted that diabetes mellitus (DM) impairs endothelial nitric oxide synthase activity as well as enhances the production of reactive oxygen species, thus resulting in diminished nitric oxide bioavailability and the consequent pro-atherogenetic alterations. Important biomarkers of the vasculature are related to endothelial dysfunction, to inflammatory and coagulation processes, and to oxidative stress in DM. Several therapeutic strategies might exert favorable effects on the vasculature of diabetic patients, such as insulin analogues, antihypertensive agents, statins, and hypoglycemic agents, whereas in spite of the prominent role of oxidative stress in diabetes, antioxidant therapy remains controversial. The use of specific biomarkers related to vascular function could be a useful therapeutic approach in such patients.

Transaortic transcatheter aortic valve implantation: A novel approach for the truly “no‐access option” patients

Objectives: The aim of this study was to test the safety and efficacy of the retrograde, minimally invasive, “transaortic” approach of transcatheter aortic valve implantation (TAVI) using the Medtronic CoreValve prosthesis (Medtronic, Minneapolis) as an alternative minimally invasive surgical access route. Background: TAVI is today recognized as an established percutaneous technique for patients with severe aortic valve stenosis (AS). However, as the number of patients screened for TAVI increases, many are found with absolutely no option for peripheral artery access. Methods: A new method of TAVI access, described as “transaortic” was performed in two patients A CoreValve prosthesis was implanted via the “transaortic” route. The patients were a 93‐ and a 84‐year‐old woman, both with severe PAOD. After a ministernotomy the ascending aorta was directly punctured. At the end, the access site was surgically sutured with the prepositioned sutures. The patients were at all times “off‐pump” (beating heart procedure) and without IABP. Results: TAVI was successful in both cases, leading to a fall in the transvalvular gradient and there were no cases of mortality, stroke or myocardial infarction. The patients were extubated directly after the procedure, mobilized after 4 days, and were discharged home after 7 and 9 days. Conclusions: In the rare occasion, where due to anatomical reasons transfemoral TAVI is not feasible, a minimally invasive “transaortic” approach, as described, provides an alternative option. This is especially true when the transapical route is not suitable (annulus >25 mm or contraindication to lateral thoracotomy).

“Device landing zone” calcification, assessed by MSCT, as a predictive factor for pacemaker implantation after TAVI†

Background: After trans‐catheter aortic valve implantation (TAVI), the need for postinterventional pacemaker (PM) implantation can occur in as many as 10–50% of cases, but it is not yet clear, how this need can be predicted. The aim of this study was to assess the possible predictive factors of post TAVI PM implantation based on Computed Tomography (CT) measured aortic valve calcification and its distribution. Methods: We prospectively analyzed 81 consecutive symptomatic patients with severe AS scheduled for TAVI using the CoreValve prosthesis (Medtronic, Minneapolis, USA). In all patients, a native and contrast‐enhanced multislice cardiac CT was performed preinterventionally, estimating calcification load of the native valve cusps and of the adjacent outflow tract (so called “device landing zone”, DLZ) by the Agatston Score (AgS). Objective, computer‐evaluated, preprocedural ECG‐analysis was performed with regards to pre‐existing conduction abnormalities. Transthoracic echocardiography was performed pre and post TAVI. Results: TAVI was successful in all cases. PM implantation was deemed necessary in altogether 32 patients, out of 67 without a PM pre‐TAVI (32/67, 47%). Various parameters were tested as predictors of post TAVI PM in a multivariate logistic regression analysis model. Female sex (P = 0,005) and depressed EF (P = 0,023) showed a significant correlation. PM implantation correlated also to the DLZ calcification, as assessed by CT (P = 0,004). This model leads to an AUC (area under the ROC—receiver operator characteristics—curve) of 0.83. Conclusion: Calcium amount in the CoreValve DLZ in combination with clinical data could predict the need for post TAVI PM implantation.

Circulating endothelial progenitor cells as biomarkers for prediction of cardiovascular outcomes.

Experimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulating EPC has been shown to be inversely correlated with cardiovascular risk factors and vascular function and to predict cardiovascular events independent of both traditional and non-traditional risk factors. Thus, EPCs provide a clinical advantage over the use of other biomarkers as their measurement is directly associated with endothelial function, and available evidence suggests that they are consistently and significantly associated with a spectrum of cardiovascular complications, such as acute coronary syndromes and coronary artery disease. However, many issues in the field of EPC isolation and identification, particularly in regards to the effective and unequivocal molecular characterization of these cells still remain unresolved. In addition, simple EPC counts do not adequately describe cardiovascular disease risk. This limitation is attributable to variation in the definition of EPCs, the number of existing cardiovascular risk factors in different patients as well as a difference in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets.

Acute effects of different alcoholic beverages on vascular endothelium, inflammatory markers and thrombosis fibrinolysis system

BACKGROUND & AIM Mild alcohol consumption has been associated with decreased cardiovascular risk, although the underlying mechanisms are still unclear. We compared the acute effects of several alcoholic beverages on endothelial function, inflammatory process and thrombosis/fibrinolysis system in young adults. METHODS In this randomized intervention trial, healthy young individuals with no risk factor for atherosclerosis were randomized into 5 equally sized groups and received an equal amount of alcohol (30 g), as red wine (264 ml), white wine (264 ml), beer (633 ml), whisky (79 ml) or water (250 ml). Forearm blood flow was determined by gauge-strain plethysmography, at baseline, 1 and 4 h after alcohol intake. Levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP), fibrinogen (Fib), plasminogen activator inhibitor (PAI-1), von Willebrand factor (vWF) and tissue plasminogen activator (tPA) were determined at baseline and 4 h after alcohol consumption. RESULTS Reactive hyperemia was significantly increased 1 h after beer and red wine consumption (p<0.05 for both), while it returned at baseline at 4 h (p=ns vs baseline) but remained unchanged in all the other groups. vWF was decreased in the beer and red wine groups (p<0.05 for both) only. PAI-1/tPA ratio remained unchanged only in red wine and control group. Inflammatory markers remained unchanged in all the groups. CONCLUSIONS Acute consumption of red wine or beer improves endothelial function and decreases vWF levels, suggesting that the type of beverage may differently affect endothelial function and thrombosis/fibrinolysis system in healthy adults.

Potential Pathogenic Inflammatory Mechanisms of Endothelial Dysfunction Induced by Type 2 Diabetes Mellitus

Insulin resistance and the vascular complications of diabetes include activation of the inflammation cascade, endothelial dysfunction, and oxidative stress. The comorbidities of diabetes, namely obesity, insulin resistance, hyperglycemia, hypertension and dyslipidemia collectively aggravate these processes while antihyperglycemic interventions tend to correct them. Increased C-reactive protein, interleukin 6, tumor necrosis factor alpha and especially interstitial cellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin are associated with cardiovascular and non-cardiovascular complications of both type 1 and type 2 diabetes. We sought to review the clinical implications of the inflammation theory, including the relevance of inflammation markers as predictors of type 2 diabetes in clinical studies, and the potential treatments of diabetes, inferred from the pathophysiology.

Antidepressive treatment as a modulator of inflammatory process in patients with heart failure: Effects on proinflammatory cytokines and acute phase protein levels

BACKGROUND Depression has been associated with increased inflammatory process. Although anti-depressive medication has anti-inflammatory effect in major depression, its role in patients with heart failure (HF) is unknown. In the present study we evaluated the impact of antidepressive medication on the expression of proinflammatory cytokines and acute phase response proteins, in patients with HF and major depression. METHODS The study population consisted of 250 patients with HF (154 suffering from major depression). Patients with major depression were under selective serotonin reuptake inhibitors (SSRIs, n=120) or tricyclic antidepressants (TCA) and/or serotonin/norepinephrine reuptake inhibitors (SNRIs) (n=34), for at least 6 months. RESULTS Levels of TNF-alpha, IL-6, CRP and fibrinogen were not significantly different between HF patients with depression under treatment and those without depression (p=NS for all). However, TNF-alpha and CRP levels were significantly lower in patients receiving TCA/SNRI compared to patients receiving SSRIs or those without depression (p<0.05 for all). Similarly, patients under TCA/SNRI had significantly lower heart rate compared to those treated with SSRIs or those without depression. In multivariate analysis, treatment with SNRI/TCA was an independent predictor for log(TNF-alpha) (beta=0.036(SE:0.016) and log(CRP) (beta=0.099(SE:0.048), p=0.041). CONCLUSIONS In the present study we demonstrate for the first time that treatment of patients with HF and major depression with TCAs/SNRIs, is associated with lower levels of TNF-alpha and CRP, suggesting that the type of antidepressive treatment may have a significant effect on the underlying inflammatory process.

Inflammatory and thrombotic processes are associated with vascular dysfunction in children with familial hypercholesterolemia

BACKGROUND Evidence suggests that children with familial hypercholesterolemia (FH) have endothelial dysfunction. Inflammatory and haemostatic abnormalities are associated with advanced atherosclerosis and increased cardiovascular events. However, it is unknown whether these abnormalities present in FH children and contribute to their vascular dysfunction. METHODS AND RESULTS We studied 38 children with FH (19 males, 19 females aged 14.8+/-0.9 years mean+/-S.E.) and 41 healthy children (controls; 22 males, 19 females aged 15.4+/-0.7 years). Endothelium-dependent reactive hyperemia (RH%) and endothelium-independent nitrate hyperemia dilatation (NH%) were measured by strain gauge plethysmography. Inflammatory and haemostatic parameters were assessed by ELISA. RH% and NH% were significantly reduced in FH compared to controls (91.3+/-9.3% vs. 120.4+/-10.6% and 53.6+/-3.8% vs. 74.5+/-7.4%, p<0.05 for both). Total cholesterol and lipoprotein (a) were increased in FH children compared to controls (282.3+/-8.8 mg/dl vs. 163.8+/-4.6 mg/dl and 11.0[4.6, 30.7]mg/dl vs. 5.24[2.63, 11.0]mg/dl median [IQR] respectively; p<0.001 for both). Intercellular cell adhesion molecule (ICAM-1) and interleukin 1 beta (IL-1 beta) serum levels were increased in FH compared to controls (p<0.05 and <0.001, respectively). Plasminogen activator inhibitor 1 (PAI-1) levels were also higher in FH children (p<0.001). Multivariate analysis revealed that reactive hyperemia was independently associated with nitrate-dependent reactive hyperemia (beta=0.597(0.199), p<0.01), PAI-1(beta=-6.78(2.65), p<0.05), log IL-1 beta (beta=-102.8 (30.2), p<0.01), age (beta=-5.06 (2.35), p<0.05) and FH status (beta=-25.2(10.6), p<0.05) (R(2) for the model: 0.63, p=0.001). CONCLUSIONS Inflammatory and haemostatic abnormalities are present in FH children and contribute to the endothelial dysfunction observed in these children.

Selective Serotonin Reuptake Inhibitors Modify the Effect of β-Blockers on Long-Term Survival of Patients With End-Stage Heart Failure and Major Depression

BACKGROUND Major depression (MD) is a key feature in heart failure (HF), and it is unclear whether common antidepressive medications interact with cardiovascular drugs used for the treatment of patients with MD and HF, affecting their efficacy. We examined the impact of MD on long-term survival of patients with end-stage severe HF. We also evaluated the interaction between antidepressive medication and beta-blockers on the clinical outcome of these patients. METHODS AND RESULTS The study population consisted of 250 patients with end-stage severe HF. Sixty-one percent of these patients suffered MD and were receiving selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCA). All patients were followed prospectively for 18 months. The primary end point was cardiovascular death. At baseline, patients with severe MD had higher serum interleukin 6 (P < .05) and soluble vascular cell adhesion molecule (P < .01). During the follow-up, 167 cardiovascular deaths were reported, and MD was 1 of the major predictors of cardiovascular death (P = .031), whereas treatment with angiotensin receptor inhibitors and statins were also important negative predictors of mortality (P = .036 and P = .039, respectively). Although beta-blockers had a borderline nonsignificant effect on cardiovascular mortality in the overall population, they had a striking beneficial effect among those patients with major depression receiving SSRIs (P = .006), whereas they had a negative effect on mortality in those patients receiving SNRIs/TCAs (P = .025). CONCLUSIONS MD is an independent predictor of cardiovascular death in patients with end-stage HF. beta-blockers are associated with lower cardiovascular mortality in patients with end-stage HF and depression only when they are combined with SSRIs.

Endothelial Dysfunction and Atherosclerosis: Focus on Novel Therapeutic Approaches

Endothelial dysfunction reflected by reduced nitric oxide (NO) availability is certainly the causative factor or promoting mechanism of atherosclerosis. It is necessary to detect endothelial dysfunction at an early stage using appropriate methods, and to choose a treatment for the recovery of endothelial function. There are nonpharmacological and pharmacological therapies to attain endothelial repair. The latter includes the use of renin-angiotensin system inhibitors, statins, erythropoietin, tetrahydrobiopterin, and antioxidants. The pharmacologic therapies are intended to increase NO synthase activity and NO release, inhibit NO degradation, and enhance the activity of endothelial progenitor cells. This article reviews the current knowledge of the pathophysiological events contributing to endothelial dysfunction as well as several established and novel treatment options to reverse those changes along with the discussion of recent patents.