The Complex Mechanisms and the Potential Effects of Statins on Vascular Calcification: A Narrative Review.

Vascular calcification (VC) is a complex process of calcium deposition on the arterial wall and atherosclerotic plaques and involves interaction between vascular smooth muscle cells, inflammatory and VC mediators. The latter are independent predictors of cardiovascular morbidity and mortality and potential targets of pharmaceutical therapy. This paper is a narrative review of the complex mechanisms of VC development and in this context the potential anti-atherosclerotic effects of statins. At the initial stages of atherosclerosis VC correlates with atherosclerosis burden and in the long-term with cardiovascular morbidity and mortality. A plethora of animal and clinical studies have proposed statins as the cornerstone of primary and secondary prevention of atherosclerotic cardiovascular disease. Based on coronary computed tomography data, high doses of statins may have negligible or even positive effects on the progression of coronary artery calcification. Growing data support an increase in atherosclerotic plaque calcification in peripheral arteries (e.g., carotids), after long-term, statin-therapy. Despite the paradox of increasing VC, those effects of statins have been associated with higher plaque stability, reducing the risk of consequent adverse events. Statins seem to promote a "favorable" atherosclerotic calcification, suppressing atherosclerotic lesion expansion and their vulnerability. More studies are required to clarify the underlying mechanisms.

The Anti-Atherosclerotic Effects of Endothelin Receptor Antagonist, Bosentan, in Combination with Atorvastatin-An Experimental Study.

Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male ApoE-/- mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin, and mice were randomized into four groups: (1) control/COG: no intervention; (2) ΒOG: bosentan 100 mg/kg/day per os; (3) ATG: atorvastatin 20 mg/kg/day per os; and (4) BO + ATG: combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMP-2, -3, -9), and TIMP-1 were determined. The percentage of lumen stenosis was significantly lower across all treated groups: BOG: 19.5 ± 2.2%, ATG: 12.8 ± 4.8%, and BO + ATG: 9.1 ± 2.7% compared to controls (24.6 ± 4.8%, p < 0.001). The administration of both atorvastatin and bosentan resulted in significantly higher collagen content and thicker fibrous cap versus COG (p < 0.01). All intervention groups showed lower relative intra-plaque concentrations of MCP-1, MMP-3, and MMP-9 and a higher TIMP-1concentration compared to COG (p < 0.001). Importantly, latter parameters presented lower levels when bosentan was combined with atorvastatin compared to COG (p < 0.05). Bosentan treatment in diabetic, atherosclerotic ApoE-/- mice delayed the atherosclerosis progression and enhanced plaques' stability, showing modest but additive effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.

Altered Arterial Stiffness, Ventricular-Arterial Coupling and Troponin Levels in Patients with Systemic Lupus Erythematosus.

Introduction: Systemic Lupus Erythematosus (SLE) is an autoimmune disease associated with an increased risk of cardiovascular diseases (CVDs), leading to elevated mortality rates among patients. We aimed to evaluate the levels of cardio-ankle vascular index (CAVI), global longitudinal strain (GLS), ventricular-arterial coupling (VAC), and high-sensitivity cardiac troponin I (hsTnI) in SLE patients and to explore their relationship with clinical parameters. Methods: This cross-sectional study enrolled 82 SLE patients without evident cardiac or kidney impairment and 41 age- and sex-matched healthy controls. We comparatively evaluated CAVI, GLS, VAC, and hsTnI between SLE patients and controls, and we assessed their association among SLE patients with disease activity based on the SELENA-SLEDAI Activity Index. Multivariate regression analysis was performed to identify independent predictors of CAVI and hsTnI within the SLE cohort. Results: In comparison to healthy controls, SLE patients presented with significantly higher CAVI, GLS, and hsTnI levels, while VAC was significantly reduced (p < 0.001). Furthermore, SLE patients with active disease (SELENA-SLEDAI ≥ 4) exhibited higher levels of CAVI and troponin than those with inactive disease (p < 0.001). SLEDAI was an independent predictor of CAVI, while VAC and SLEDAI were independent determinants of hsTnI in the SLE cohort. Conclusions: SLE patients displayed abnormal levels of CAVI, VAC, GLS, and troponin compared to healthy individuals. Our findings implicate the potential of those CV novel CVD risk factors to refine screening and therapeutic strategies for this specific population.

The anti-inflammatory effects of aerobic exercise training in patients with type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a low-grade, chronic inflammatory disease, associated with increased cardiovascular risk. The purpose of this systematic review/ meta-analysis was to evaluate the effects of aerobic exercise training (AET) on inflammatory markers in T2DM patients. METHODS: The literature search was conducted utilizing PubMed, Web of Science, Embase, and the Cochrane Library from their inception up to April 2022. We screened only for randomized controlled trials (RCTs) investigating the effects of AET on C-reactive protein (CRP) and adipokines: adiponectin, resistin, interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-a), along with changes in anthropometric indices and glycemic control in adult T2DM patients. Pooled post-exercise weighted mean differences (WMDs) with 95% Confidence Intervals (CIs) were calculated for all outcomes of interest between exercise-treated patients and controls. RESULTS: Twenty-six RCTs involving 1239 T2DM patients were retrieved from the databases for meta-analysis. The cumulative results showed that post-AET inflammatory markers were lower in exercise-treated patients compared to controls regarding CRP (mg/L): WMD: -0.91; 95%CIs: -1.43, -0.40; p < 0.001 resistin (mg/ml): (WMD: -2.08; 95%CIs: -3.32, -0.84; p < 0.001); TNF-a (pg/ml): (WMD: -2.70; 95%CIs: -4.26, -1.14; p < 0.001), and IL-6 (pg/ml): (WMD: -1.05; 95%CIs: -1.68, -0.43; p < 0.001). Those effects were accompanied by significant amelioration of fasting glucose (mg/dl) (WMD: -13.02; 95%CIs: -25.39, -0.66; p = 0.04), HbA1c (%) (WMD: -0.51; 95%CIs: -0.73, -0.28, p < 0.001), and fat mass (%) (WMD: -3.14; 95%CI: -4.71, -1.58; p < 0.001). Our meta-analysis demonstrated less-consistent results for adiponectin (µg/ml), (WMD: 1.00; 95%CI: -0.12, 2.12; p = 0.08) and body-mass index (kg/m2) (WMD: -1.34; 95%CI: -2.76, 0.08; p = 0.06) tending to differ between AET and control group. CONCLUSIONS: AET can significantly reduce the inflammatory burden in T2DM patients. by ameliorating the circulating levels of CRP, resistin, TNF-a and IL-6, even without accompanied significant weight-loss. The clinical impact of those anti-inflammatory effects of AET needs to be determined.

How to Use Statins in Secondary Prevention of Atherosclerotic Diseases: from the Beneficial Early Initiation to the Potentially Unfavorable Discontinuation.

Statins, a class of lipid-lowering drugs, reduce morbidity and mortality in patients with established atherosclerosis-related cardiovascular disease. Early initiation of statin therapy after admission for acute coronary syndromes (ACS), stroke, or transient ischemic attack (TIA) is associated with improved cardiovascular outcomes. Moreover, high-dose statin treatment prior to coronary or carotid revascularization has been shown to reduce cardiovascular events in these patients. However, many patients may be undertreated, and a residual cardiovascular risk remains in current clinical practice. Despite the beneficial role of statins, their discontinuation rate among patients is still elevated leading to severe adverse cardiovascular events due to atherosclerotic plaque destabilization. In this review, we summarized the impact of statin treatment among patients, focusing on the initiation time-points as well as the potential harm derived by their discontinuation.

Systemic Lupus Erythematosus and Pulmonary Hypertension.

Pulmonary Hypertension (PH) is a common manifestation in patients with Systemic Lupus Erythematosus (SLE) and varies from asymptomatic to life-threatening disease. PH can result not only from immune system dysregulation, but also from various conditions, including cardiorespiratory disorders and thromboembolic diseases. Most commonly, SLE-related PH presents with non-specific symptoms, such as progressive dyspnea on exertion, generalized fatigue and weakness and eventually dyspnea at rest. Prompt diagnosis of SLE-related PH and early identification of the underlying pathogenetic mechanisms is demanded in order to introduce targeted therapy to prevent irreversible pulmonary vascular damage. In most cases the management of PH in SLE patients is similar to idiopathic pulmonary arterial hypertension (PAH). Furthermore, specific diagnostic tools like biomarkers or screening protocols, to establish early diagnosis seem to be not available yet. Although, the survival rates for patients with SLE-related PH vary between studies, it is evident that PH presence negatively affects the survival of SLE patients.

Bio-Actives from Natural Products with Potential Cardioprotective Properties: Isolation, Identification, and Pharmacological Actions of Apigenin, Quercetin, and Silibinin.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. As a result, pharmaceutical and non-pharmaceutical interventions modifying risk factors for CVDs are a top priority of scientific research. Non-pharmaceutical therapeutical approaches, including herbal supplements, have gained growing interest from researchers as part of the therapeutic strategies for primary or secondary prevention of CVDs. Several experimental studies have supported the potential effects of apigenin, quercetin, and silibinin as beneficial supplements in cohorts at risk of CVDs. Accordingly, this comprehensive review focused critically on the cardioprotective effects/mechanisms of the abovementioned three bio-active compounds from natural products. For this purpose, we have included in vitro, preclinical, and clinical studies associated with atherosclerosis and a wide variety of cardiovascular risk factors (hypertension, diabetes, dyslipidemia, obesity, cardiac injury, and metabolic syndrome). In addition, we attempted to summarize and categorize the laboratory methods for their isolation and identification from plant extracts. This review unveiled many uncertainties which are still unexplored, such as the extrapolation of experimental results to clinical practice, mainly due to the small clinical studies, heterogeneous doses, divergent constituents, and the absence of pharmacodynamic/pharmacokinetic analyses.

Exercise training inhibits atherosclerosis progression and reduces VE-cadherin levels within atherosclerotic plaques in hypercholesterolemic mice.

Vascular endothelial-cadherin (VE-cadherin), matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) have emerged as key-factors of atherogenesis. The aim of this study was to evaluate the effects of exercise training (ET) on those key-factors in relation to the progression of atherosclerotic lesions in hypercholesterolemic mice. Thirty male, apoE knockout (apoE-/-) mice were randomly assigned to the following equivalent groups: 1) CO-control: High-fat diet (HFD) administration for 12 weeks. 2) EX-exercise: HFD administration as in CO, and during the last 4 weeks (9th -12th week) ET on treadmill (5sessions/week, 60min/session). At the end of study, blood samples were obtained and all mice were sacrificed. Aortic roots were excised and analysed regarding the percentage of aortic stenosis, and the relative concentrations of collagen, elastin, VE-cadherin, MMP-8,-9 and TIMP-1,-2 within the atherosclerotic lesions. Aortic stenosis was significantly lower in the EX than the CO group (39.63 ± 7.22% vs 62.04 ± 8.55%; p < 0.001), along with considerable increase in fibrous cap thickness and of collagen and elastin contents within plaques (p < 0.05). Compared to controls, exercised-treated mice showed reduced intra-plaque relative concentrations of VE-cadherin (15.09 ± 1.89% vs 23.49 ± 3.01%, p < 0.001), MMP-8 (8.51 ± 2.24% vs 18.51 ± 4.08%, p < 0.001) and MMP-9 (12.1 ± 4.86% vs 18.88 ± 6.23%, p < 0.001). Inversely, the relative concentrations of TIMP-1 and TIMP-2 in the ET group were considerably higher by 62.5% and 31.2% than in the EX group (p < 0.05), respectively. Finally, body weight and lipids concentrations did not differ between groups at the end of the study (p > 0.05). ET treatment induced regression of established atherosclerotic lesions in apoE-/- mice and improved their stability. Those effects seemed to be mediated by favourable modification of VE-cadherin, MMPs and TIMPs.

The effects of exercise training on cardiac matrix metalloproteinases activity and cardiac function in mice with diabetic cardiomyopathy.

AIM: To evaluate the effects of exercise training (ET) on cardiac extracellular matrix (ECM) proteins homeostasis and cardiac dysfunction in mice with diabetic cardiomyopathy. METHODS: Thirty-six male C57BL/6 mice were randomized into 3 groups for 8 weeks (12mice/group): Diabetic control-DC: Diabetes was induced by single streptozotocin injection (200 mg/kg i.p.); Diabetic exercise-DE: Diabetic mice underwent ET program on motorized-treadmill (6-times/week, 60min/session); Non-diabetic control-NDC: Vehicle-treated, sedentary, non-diabetic mice served as controls. Before euthanasia, all groups underwent transthoracic echocardiography (TTE). Post-mortem, left-ventricle (LV) samples were histologically analysed for ECM proteins (collagen, elastin), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). RESULTS: DC group showed significantly higher cardiac contents of collagen and MMP-9 and lower elastic concentration than NDC (p < 0.001). The implementation of ET completely outweighed those diabetes-induced changes (DE vs NDC, p > 0.05). TIMP-1 levels significantly increased across all groups (DC: 18.98 ± 3.47%, DE: 24.24 ± 2.36%, NDC: 46.36 ± 5.91%; p < 0.05), while MMP-9/TIMP-1 ratio followed a reverse pattern. ET tended to increase MMP-2 concentrations versus DC (p = 0.055), but did not achieve non-diabetic levels (p < 0.05). TIMP-2 cardiac concentrations remained unaltered throughout the study (p > 0.05). Importantly, ET ameliorated both LV end-systolic internal diameter (LVESD) (p < 0.001) and the percentage of LV fractional shortening (FS%) (p = 0.006) compared to DC. Despite that favorable effect, the cardiac function level of DE group remained worse than NDC group (%FS: p = 0.002; LVESD: p < 0.001). CONCLUSION: Systemic ET may favorably change ECM proteins, MMP-9 and TIMP-1 cardiac concentrations in mice with diabetic cardiomyopathy. Those results were associated with partial improvement of echocardiography-assessed cardiac function, indicating a therapeutic effect of ET in diabetic cardiomyopathy.

Assessment of acute heart failure prognosis: the promising role of prognostic models and biomarkers.

Numerous models and biomarkers have been proposed to estimate prognosis and improve decision-making in patients with acute heart failure (AHF). The present literature review provides a critical appraisal of externally validated prognostic models in AHF, combining clinical data and biomarkers. We perform a literature review of clinical studies, using the following terms: "acute heart failure," "acute decompensated heart failure," "prognostic models," "risk scores," "mortality," "death," "hospitalization," "admission," and "biomarkers." We searched MEDLINE and EMBASE databases from 1990 to 2020 for studies documenting prognostic models in AHF. External validation of each prognostic model to another AHF cohort, containing at least one biomarker, was prerequisites for study selection. Among 358 initially screened studies, 9 of them fulfilled all searching criteria. The majority of prognostic models were simplified, including a narrow number of variables (up to 10), with good performance regarding calibration and discrimination (c-statistics > 0.65). Unfortunately, the derived and validated cohorts showed a wide variety in patients' characteristics (e.g., cause of AHF and therapy). Moreover, the prognostic models used various time-points and a plethora of combinations of variables determining different cut-off values. Although the application of valid prognostic models in AHF population is quite promising, a precise methodological approach should be set for the derivation and validation of prognostic models in AHF with unified characteristics to establish an effective performance in clinical practice.

Association of serum levels of osteopontin and osteoprotegerin with adverse outcomes after endovascular revascularisation in peripheral artery disease.

BACKGROUND: Osteoprotegerin (OPG) and osteopontin (OPN) are vascular calcification inhibitors with a known role in the atherosclerotic and inflammatory process. We investigated their relationship with adverse outcomes (restenosis/adverse cardiovascular events) after endovascular revascularisation of patients with peripheral arterial disease (PAD). METHODS: 203 consecutive patients were enrolled in the PAD group (PADG) and 78 age and sex-matched subjects with less than two cardiovascular risk factors served as control group (COG). PADG underwent standard medical assessment at baseline and 12 months after the procedure. During follow up major adverse cardiovascular events (MACEs) including arterial restenosis with need for reintervention were documented and the PADG was divided accordingly into two subgroups. RESULTS: During 12-month follow-up, 82 MACE were recorded (MACE subgroup). The rest of 124 PAD patients remained free of MACE (non-MACE subgroup). At baseline, OPG (9.89 ± 2.85 ng/ml vs 3.47 ± 1.95 ng/ml, p < 0.001) and OPN (79.99 ± 38.29 ng/ml vs 35.21 ± 14.84 ng/ml, p < 0.001) levels were significantly higher in PADG compared to COG, as well as in MACE subgroup compared to non-MACE subgroup (13.29 ± 3.23 ng/ml vs 10.86 ± 3 ng/ml and 96.45 ± 40.12 ng/ml vs 78.1 ± 38.29 ng/ml, respectively). An independent association of PAD with OPG and OPN was found in the whole patient cohort. Although OPG and OPN were significantly related to MACE incidence in the univariate analysis, multiple logistic regression analysis failed to detect any independent predictor of MACE within the PADG. CONCLUSION: Baseline high OPG and OPN levels were independently associated with PAD presence. Even higher levels of those biomarkers were detected among PAD patients with MACE, however, their prognostic role should be further clarified.

Prognostic role of inflammatory cytokines and novel adipokines in acute myocardial infarction: An updated and comprehensive review.

Acute myocardial infarction (AMI) is one of the major causes of morbidity and mortality worldwide. The inflammation response during and after AMI is common and seems to play a key role in the peri-AMI period, related with ischaemia-reperfusion injury, adverse cardiac remodelling, infarct size and poor prognosis. In this article, we provide an updated and comprehensive overview of the most important cytokines and adipokines involved in the complex pathophysiology mechanisms in AMI, summarizing their prognostic role post-AMI. Data so far support that elevated levels of the major proinflammatory cytokines TNFα, IL-6 and IL-1 and the adipokines adiponectin, visfatin and resistin, are linked to high mortality and morbidity. In contrary, there is evidence that anti-inflammatory cytokines and adipokines as IL-10, omentin-1 and ghrelin can suppress the AMI-induced inflammatory response and are correlated with better prognosis. Mixed data make unclear the role of the novel adipokines leptin and apelin. After all, imbalance of pro-inflammatory and anti-inflammatory cytokines may result in worst AMI prognosis. The incorporation of these inflammation biomarkers in established prognostic models could further improve their prognostic power improving overall the management of AMI patients.

Plasma nesfatin-1 and DDP-4 levels in patients with coronary artery disease: Kozani study.

BACKGROUND: Nesfatin-1, a novel adipokine and dipeptidyl peptidase-4 (DPP4), a mam malian serine protease, are potent factors of atherosclerosis. In the present cross-sectional study, we investigated whether the plasma nesfatin-1 and DPP4 is associated with the prevalence and severity of coronary artery disease (CAD) with and without diabetes mellitus (DM). METHODS: We consecutively enrolled a total of 240 patients with significant CAD (previous revascularization or angiographically-proven coronary artery stenosis > 50%) presented with either unstable angina (UA, N = 76) or stable chronic CAD (SCAD, N = 165). 85 patients with at least 2 classical cardiovascular risk factors but without significant CAD served as controls. The severity of CAD was assessed using coronary angiography by the Gensini score. Clinical parameters, glycemic and lipid profile, high-sensitivity CRP (hsCRP), nesfatin-1 and DPP4 levels were assayed. RESULTS: No differences were found for age, sex, hypertension and diabetes distribution between groups. Low nesfatin-1 levels were found in both CAD groups (UA & SCAD) with respect to controls. The difference between UA and SCAD groups was marginally non-significant. There was a significant increase of DPP4 along UA to SCAD and control groups. Differences between groups remained unchanged in non-diabetic participants. Nesfatin-1 significantly correlated to hsCRP (r = - 0.287, p = 0.036), HOMA-IR (r = - 0.587, p = 0.007) and hyperlipidemia (r = - 0.331, p = 0.034). DPP4 was significantly associated with hs-CRP (r = 0.353 p < 0.001) and FPG (r = 0.202, p = 0.020) in univariate analysis, but those correlations were lost in multiple regression analysis. There was a negative correlation between nesfatin-1 and the severity of CAD, quantified by the Gensini score (r = - 0.511, p < 0.001), but no association was found for DPP4. CONCLUSIONS: Serum DPP4 levels are increased in patients with CAD, while serum nesfatin-1 levels have a negative association with both the incidence and the severity of CAD. These results are independent of the presence of diabetes mellitus. In addition, both peptides have a strong association with hsCRP. Trial registration ClinicalTrials.gov Identifier: NCT00306176.

The prognostic role of RBP-4 and adiponectin in patients with peripheral arterial disease undergoing lower limb endovascular revascularization.

BACKGROUND: RBP4 is an adipokine with an established role in atherosclerosis, while adiponectin has unique anti-inflammatory properties. We investigated the association of RBP4 and adiponectin with the presence of symptomatic peripheral artery disease (PAD) and their possible prognostic role in major adverse cardiovascular events (MACE). METHODS: We enrolled 168 consecutive patients with symptomatic, established PAD, requiring revascularization by endovascular means of any or both of their lower limbs. 88 age- and sex-matched subjects with less than 2 classical cardiovascular risk factors served as controls. Clinical parameters, glycemic and lipid profile, RBP4 and adiponectin levels were assayed. The occurrence of MACE was recorded during the 6-month follow-up and patients were assigned to MACE and non-MACE subgroups. RESULTS: The presence of symptomatic PAD was significantly correlated with age, diabetes, hsCRP, RBP4 and low adiponectin levels (p < 0.05). After adjustment for age, RBP4 (ß = 0.498, p < 0.001), and adiponectin (ß = -0.288, p < 0.001) levels remained as independent predictors of PAD presence in the whole study cohort. At baseline, MACE subgroup appeared with higher RBP-4 and hsCRP serum levels than non-MACE subgroup (p < 0.001), but no differences were detected for adiponectin (p = 0.758). Serum RBP4 levels remained independent predictor of MACE (ß = 0.455, p < 0.001) after adjustment for traditional cardiovascular risk factors. CONCLUSIONS: High RBP4 and low adiponectin serum levels are independently associated with PAD presence. In addition, RBP4 is an independent predictor of MACE incidence in symptomatic PAD patients.

The interplay between statins and adipokines. Is this another explanation of statins' 'pleiotropic' effects?

Statin therapy comprises an integral part of secondary and to a lesser extent of primary cardiovascular disease prevention. This is attributed not only to their lipid-lowering properties, but as well to a plethora of pleiotropic actions. Recently, the cytokines secreted by adipose tissue, the so-called adipokines, have been proved to play a critical role in various pathophysiological functions, among which inflammation and atherosclerosis development and vulnerability. The aim of this literature review was to summarize the effects of statins and the underlying mechanisms on the circulating levels of the most common adipokines regulating atherosclerosis process, as a part of their pleiotropic function. Up to now, robust evidence implicates a significant statin-induced reduction of pro-inflammatory adipokines IL-6, TNF-a and visfatin. Weak evidence from limited, small and mostly non-randomized studies suggest increased levels of anti-inflammatory adipokines apelin, vaspin and omentin-1 after statin therapy. In the rest of most known adipokines, statins have shown either controversial (adiponectin, retinol binding protein-4 and fetuin-A) or negligible effects (leptin and resistin) on their circulating levels. Therefore, statins may favourably alter the balance of inflammatory/anti-inflammatory adipokines, implicating a novel atheroprotective mechanism. However, the interplay between statins and adipokines is still not fully elucidated and its potential clinical relevance is warranted.

Omentin-1 and vaspin serum levels in patients with pre-clinical carotid atherosclerosis and the effect of statin therapy on them.

BACKGROUND: Omentin-1 and vaspin are novel adipokines, and their association with atherosclerosis is still under investigation. The present study aimed to assess the relationship of those adipokines with preclinical, non-significant carotid atherosclerosis and the impact of statin therapy on their levels, suggesting a link between adiposity and atherosclerosis. METHODS: Eighty-four statin-free subjects with non-significant, preclinical carotid atherosclerosis and elevated LDL- cholesterol levels (>130 mg/dl) were recruited to receive atorvastatin (from 10 to 80 mg per day) (atorvastatin group - AG group). Forty-six age- and gender-matched healthy individuals, without any chronic disease served as controls (control group - CG). Clinical parameters, metabolic profile, serum omentin-1, vaspin concentrations and ultrasound measurements of carotid thickening were obtained at the beginning and after 12 months. RESULTS: At baseline, AG showed lower omentin-1 and vaspin serum levels than CG (p ≤ 0.001). Along the entire study population at baseline, omentin-1 levels were independently related to LDL-cholesterol, while vaspin levels were independently associated with hsCRP and the presence of carotid atherosclerosis (p < 0.05). Within AG, 12-months atorvastatin treatment significantly increased omentin-1 (from 202.79 ± 91.41 ng/ml to 262.56 ± 101 ng/ml, p < 0.001) and vaspin concentrations (from 1.29 ± 0.51 ng/ml to 1.70 ± 0.5 ng/ml, p = 0.002). In standard multiple regression analysis, the presence of carotid atherosclerosis related to baseline vaspin levels (ß = -0.232, p < 0.001), while the atorvastatin-induced increase of vaspin was independently associated with hsCRP reduction (ß = -0.198, p = 0.045). CONCLUSION: Low omentin-1 and vaspin serum levels associated with preclinical, non-significant carotid atherosclerosis. Notably, atorvastatin administration significantly increased both adipokines, but the underlying mechanisms and the clinical impact of those changes requires further investigation.

The cardiovascular-protective properties of saffron and its potential pharmaceutical applications: A critical appraisal of the literature.

Saffron, the dried stigma of Crocus sativus L., is used in traditional medicine for its healing properties and the treatment of various pathological conditions. The present literature review aimed to summarize and evaluate the preclinical and clinical data regarding the protective effects and mechanisms of saffron and its main components (crocin, crocetin, safranal) on cardiovascular risk factors and diseases. Many in vitro and animal studies have been conducted implicating antioxidant, hypolipidemic, anti-diabetic, and antiinflammatory impact of saffron and its constituents. Notably, there is evidence of direct atherosclerosis regression and stabilization in valid atherosclerosis-prone animal models. However, current clinical trials have shown mostly weak effects of saffron and its constituents on cardiovascular risk factors: (a) Modest lowering of fasting blood glucose, without significant reduction of HbA1c in type 2 diabetic patients, (b) moderate/controversial hypolipidemic effects, (c) negligible hypotensive effect, and (d) inconsistent modification of metabolic syndrome parameters. There are important drawbacks in clinical trial design, including the absence of pharmacokinetic/pharmacodynamic tests, the wide variance of doses and cohorts' characteristics, the small number of patients, the short duration. Therefore, large, properly designed, high-quality clinical trials, focusing on specific conditions are required to evaluate the biological/pharmacological activities and firmly establish the clinical efficacy of saffron and its possible therapeutic uses in cardiovascular diseases.

The impact of oral anti-diabetic medications on heart failure: lessons learned from preclinical studies.

The prevalence of heart failure (HF) in the diabetic population has rapidly increased over the past 2 decades, triggering research about the impact of oral anti-diabetic medications on it. Unfortunately, not all success at the bench in preclinical experiments has translated to success at the bedside. On the other hand, recent promising clinical data from oral SGLT2 inhibitors mainly lack mechanistic explanation from experimental studies. Hence, it is critical to understand the lessons learned from prior translational studies to gain a better knowledge of the mechanisms of oral anti-diabetic drugs in HF. This review aims to summarize the results from preclinical studies regarding the interaction between oral anti-diabetic medications and heart failure development and/or exacerbation. Although there is a wide spectrum of controversial results, the underlying hope is that the clinical success rate will improve and the adverse events during ineffective targeted therapy will be limited.

Influenza infection and heart failure-vaccination may change heart failure prognosis?

The interaction of influenza infection with the pathogenesis of acute heart failure (AHF) and the worsening of chronic heart failure (CHF) is rather complex. The deleterious effects of influenza infection on AHF/CHF can be attenuated by specific immunization. Our review aimed to summarize the efficacy, effectiveness, safety, and dosage of anti-influenza vaccination in HF. In this literature review, we searched MEDLINE and EMBASE from January 1st 1966 to December 31st, 2016, for studies examining the association between AHF/CHF, influenza infections, and anti-influenza immunizations. We used broad criteria to increase the sensitivity of the search. HF was a prerequisite for our search. The search fields used included "heart failure," "vaccination," "influenza," "immunization" along with variants of these terms. No restrictions on the type of study design were applied. The most common clinical scenario is exacerbation of pre-existing CHF by influenza infection. Scarce evidence supports a potential positive association of influenza infection with AHF. Vaccinated patients with pre-existing CHF have reduced all-cause morbidity and mortality, but effects are not consistently documented. Immunization with higher antigen quantity may confer additional protection, but such aggressive approach has not been generally advocated. Further studies are needed to delineate the role of influenza infection on AHF/CHF pathogenesis and maintenance. Annual anti-influenza vaccination appears to be an effective measure for secondary prevention in HF. Better immunization strategies and more efficacious vaccines are urgently necessary.

Changes in Arterial Stiffness and N-terminal pro-brain natriuretic peptide Levels after Endovascular Repair of Descending Thoracic Aorta.

BACKGROUND: Limited data exist concerning the biomechanical and central hemodynamic changes induced by endograft implantation in the descending thoracic aorta. The aim of this prospective ongoing study was to evaluate changes in arterial stiffness, assessed by pulse wave velocity (PWV; m/sec), and N-terminal pro-brain natriuretic peptide (NT-proBNP; pg/mL) levels in patients undergoing endovascular repair of descending thoracic aorta (thoracic endovascular aortic repair [TEVAR]). METHODS: Twenty-seven patients with thoracic aorta pathology who underwent elective TEVAR were included in the study. Blood samples were obtained preoperatively, 24 hr, 48 hr, and 6 months postoperatively, and serum levels of NT-proBNP were measured. PWV was determined before and 6 months after TEVAR. One-way analysis of variance by ranks was used to test the alterations in PWV (from baseline to 6 months) and NT-proBNP (along the 4 phases of evaluation). Post hoc analyses were appropriately performed. RESULTS: We recorded an increase in values of NT-proBNP from baseline (median = 96.1, interquartile range [IQR] = 82.7-117.9) to 24 hr postoperative (median = 201.6, IQR = 82.8-425.9), 48 hr postoperative (median = 317.0, IQR = 102.5-1,479.5), and 6 months postoperative (median = 144, IQR = 82.8-276.4). The Kruskal-Wallis H test showed a statistically significant increase (x2(3) = 11.17, P = 0.01) in NT-proBNP from baseline (rank mean = 22.19) toward the postoperative time points of evaluation (24 hr postoperative: 35.17 [change: +12.9, P = 0.02]; 48 hr postoperative: 42.64 [change: +20.5, P < 0.001]; 6 month postoperative: 34.91 [change: +12.7, P = 0.03]). An increase in PWV values was recorded from baseline (median = 11.9, IQR = 10.0-13.5) to 6 months postoperatively (median = 13.9, IQR = 11.9-16.4). That change achieved statistically significant level [x2(1) = 4.86, P = 0.03], with an increase in mean rank PWV (+7.5). CONCLUSIONS: Implementation of thoracic stent grafts may be associated with considerable increase of both arterial stiffness and NT-proBNP serum levels along time. Those results may indicate an adverse cardiac impact of TEVAR. However, the early and long-term effects of TEVAR on cardiovascular outcomes require further investigation.