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.

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.

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.

Classical and Novel Lipid-Lowering Therapies for Diabetic Patients with Established Coronary Artery Disease or High Risk of Coronary Artery Disease-A Narrative Clinical Review.

Diabetic atherosclerosis is a complex process that is characterized by diffuse and unstable lesions increasing 2-4-fold the risk of adverse cardiovascular (CV) events. Diabetic dyslipidemia has a predominant role in coronary artery disease (CAD) and has been the target of classical and emerging pharmaceutical agents with established or promising CV benefits. The aim of the present narrative review was to summarize the effects of classical and novel lipid-lowering pharmaceutical agents on lipid profile and CV outcomes in diabetic patients with established CAD or high risk of CAD. Statins remain the first-line treatment for all diabetic patients since they considerably ameliorate lipid parameters and non-lipid CV risk factors, leading to reduced CV morbidity and mortality. Complementary to statins, ezetimibe exerts lipid-lowering properties with modest but significant reductions in major adverse cardiovascular events (MACEs) and CV mortality. PCSK9 inhibitors considerably reduce LDL-C levels and lower MACEs in diabetic patients. On the other hand, fibrates may confer a very modest decline in MACE incidence, while the CV impact of omega-3 fatty acids is promising but remains questionable. Bempedoic acid and inclisiran have a potential therapeutic role in the management of diabetic dyslipidemia, but this is still not adequately documented. Given the heightened CV risk among individuals with diabetes, more decisive results would be of great importance in the utility of all these drugs.

The Role of Echocardiography in the Diagnosis and Prognosis of Pulmonary Hypertension.

The right heart catheterisation constitutes the gold standard for pulmonary hypertension (PH) diagnosis. However, echocardiography remains a reliable, non-invasive, inexpensive, convenient, and easily reproducible modality not only for the preliminary screening of PH but also for PH prognosis. The aim of this review is to describe a cluster of echocardiographic parameters for the detection and prognosis of PH and analyse the challenges of echocardiography implementation in patients with suspected or established PH. The most important echocardiographic index is the calculation of pulmonary arterial systolic pressure (PASP) through the tricuspid regurgitation (TR). It has shown high correlation with invasive measurement of pulmonary pressure, but several drawbacks have questioned its accuracy. Besides this, the right ventricular outflow track acceleration time (RVOT-AT) has been proposed for PH diagnosis. A plethora of echocardiographic indices: right atrial area, pericardial effusion, the tricuspid annular plane systolic excursion (TAPSE), the TAPSE/PASP ratio, tricuspid annular systolic velocity (s'), can reflect the severity and prognosis of PH. Recent advances in echocardiography with 3-dimensional right ventricular (RV) ejection fraction, RV free wall strain and right atrial strain may further assist the prognosis of PH.

The diagnostic value of stress echocardiography with limited myocardial ischemia in high-risk patients.

BACKGROUND: The diagnostic value of limited myocardial ischemia in DSE is not well known. OBJECTIVES: We investigated whether myocardial ischemia during dobutamine stress echocardiography (DSE) in 1 apical segment of any of the ventricular walls of the left ventricle relates to the anatomical and functional stenosis of the suppling coronary artery. METHODS: Our observational, prospective study enrolled 212 patients, symptomatic or asymptomatic, with newly diagnosed limited myocardial ischemia on DSE. Almost 25% of them had already known CAD, while the rest were divided into low-risk and high-risk groups, integrating 1-2 and ≥3 classical cardiovascular risk factors, respectively. After DSE, all patients underwent invasive coronary angiography (ICA) and were followed up for one year. In coronary arteries distributing ischemic area, the calculated stenosis ≥50% and FFR<0.8 were considered anatomically and functionally significant, respectively. In the latter cases, the patients underwent coronary revascularization. RESULTS: Significant anatomical and functional stenosis of the supplying coronary artery was common among patients with already known CAD (62.5% and 44.5%, respectively) or those without CAD but a high-risk profile (60.2% and 25.6%, respectively). In logistic regression analysis, CAD revascularization was independently determined by an already known CAD, diabetes mellitus, and high-risk profile. During follow-up, 24 patients experienced ACS or new angina episodes, which were associated with diabetes and smoking in univariate analysis. CONCLUSION: Limited myocardial ischemia may implicate significant anatomical and functional coronary stenosis among individuals with a history of CAD or those without known CAD but a high-risk profile. The prognostic value of our findings requires further investigation.

Pulmonary Hypertension in Left Ventricular Valvular Diseases: A Comprehensive Review on Pathophysiology and Prognostic Value.

Left ventricular (LV) valvular diseases, make up one of the most common etiologies for pulmonary hypertension (PH), and it is not well understood how and at which degree it affects prognosis. The aim of the present study was a comprehensive review of the pathophysiologic mechanism of PH in patients with LV valvular diseases and the prognostic value of baseline and post-intervention PH in patients undergoing interventional treatment. The pathophysiology of PH in patients with LV valvular diseases involves gradual elevation of left ventricular filling pressure and left atrial pressure, which are passively transmitted to the pulmonary circulation and raise pulmonary artery systolic pressure (PASP). A long-lasting exposure to elevated PASP progressively leads to initially functional and thereafter irreversible structural changes in the pulmonary vasculature, leading up to high pulmonary vascular resistance. Surgical treatment of severe LV valvular diseases is highly effective in patients without resting PH or those with exercise-induced PH (EIPH) before intervention. In the case of pre-operative PH, successful interventional therapy decreases PASP, but the post-operative cardiac and all-cause mortality remain higher compared to patients without pre-operative PH. Hence, it is of paramount importance to detect patients with severe LV valvulopathies before the development of PH, since they will get greater benefits from early intervention.

Exercise-Induced Pulmonary Hypertension: A Valid Entity or Another Factor of Confusion?

Exercise-induced pulmonary hypertension EIPH has been defined as an increase in mean pulmonary arterial pressure (mPAP) during exercise in otherwise normal values at rest. EIPH reflects heart and/or lung dysfunction and may precede the development of manifest pulmonary hypertension (PH) in a proportion of patients. It is also associated with decreased life expectancy in patients with heart failure with reduced ejection fraction (HFrEF) or left ventricle (LV) valvular diseases. Diastolic dysfunction exacerbated during exercise relates to increased LV filling pressure and left atrial pressure (LAP). In this context backward, transmitted pressure alone or accompanied with backward blood flow promotes EIPH. The gold standard of EIPH assessment remains the right heart catheterization during exercise, which is an accurate but invasive method. Alternatively, non-invasive diagnostic modalities include exercise stress echocardiography (ESE) and cardiopulmonary exercise testing (CPET). Both diagnostic tests are performed under gradually increasing physical stress using treadmill and ergo-cycling protocols. Escalating workload during the exercise is analogous to the physiological response to real exercise. The results of the latter techniques show good correlation with invasive measurements, but they suffer from lack of validation and cut-off value determination. Although it is not officially recommended, there are accumulated data supporting the importance of EIPH diagnosis in the assessment of other mild/subclinical or probably fatal diseases in patients with latent PH or heart failure or LV valvular disease, respectively. Nevertheless, larger, prospective studies are required to ensure its role in clinical practice.

The Role of Osteopontin in Atherosclerosis and Its Clinical Manifestations (Atherosclerotic Cardiovascular Diseases)-A Narrative Review.

Atherosclerotic cardiovascular diseases (ASCVDs) are the most common and severe public health problem nowadays. Osteopontin (OPN) is a multifunctional glycoprotein highly expressed at atherosclerotic plaque, which has emerged as a potential biomarker of ASCVDs. OPN may act as an inflammatory mediator and/or a vascular calcification (VC) mediator, contributing to atherosclerosis progression and eventual plaque destabilization. In this article, we discuss the complex role of OPN in ASCVD pathophysiology, since many in vitro and in vivo experimental data indicate that OPN contributes to macrophage activation and differentiation, monocyte infiltration, vascular smooth muscle cell (VSMC) migration and proliferation and lipid core formation within atherosclerotic plaques. Most but not all studies reported that OPN may inhibit atherosclerotic plaque calcification, making it "vulnerable". Regarding clinical evidence, serum OPN levels may become a biomarker of coronary artery disease (CAD) presence and severity. Significantly higher OPN levels have been found in patients with acute coronary syndromes than those with stable CAD. In limited studies of patients with peripheral artery disease, circulating OPN concentrations may be predictive of future major adverse cardiovascular events. Overall, the current literature search suggests the contribution of OPN to atherosclerosis development and progression, but more robust evidence is required.

A new approach of statin therapy in carotid atherosclerosis: Targeting indices of plaque vulnerability on the top of lipid-lowering. A narrative review.

Novel imaging techniques and biomarkers have emerged as surrogate markers of carotid plaque vulnerability. In parallel, statin administration in patients with established carotid atherosclerosis not requiring revascularization has reduced the number of consequent cerebrovascular events. This reduction is not only attributed to the lipid-lowering properties of statins but also to their pleiotropic actions. The present literature review aimed to summarize the stabilizing effects of statins on carotid plaques based on imaging modalities and biomarkers and propose an alternative approach to their implementation. Moreover, we assessed the perioperative use of statins in patients undergoing carotid revascularization and the impact of aggressive vs. conventional statin therapy. Recent studies using: (1) ultrasound indices of plaque echogenicity; (2) fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scans for plaque inflammation assessment; or (3)magnetic resonance imaging (MRI) scans quantifying intraplaque hemorrhage, and lipid-rich necrotic core (LRNC) have shown quite promising results in evaluation of carotid plaque vulnerability. Based on those imaging modalities, a growing number of studies have demonstrated a very modest carotid plaque regression due to/induced by statins, while their stabilizing impact is disproportionally higher. Other studies assaying several biomarkers (e.g. inflammation, etc.) have confirmed a statin-induced carotid plaque stabilization. All the aforementioned benefits followed a dose-dependent pattern of statins, on top of the low-density lipoprotein cholesterol (LDL-C) target in current guidelines. In the case of symptomatic patients with carotid atherosclerosis suitable for revascularization, robust evidence implicates a significant statin-related reduction of perioperative cardiovascular risk only in patients undergoing endarterectomy.

Potential Pharmaceutical Applications of Quercetin in Cardiovascular Diseases.

Quercetin, as a member of flavonoids, has emerged as a potential therapeutic agent in cardiovascular diseases (CVDs) in recent decades. In this comprehensive literature review, our goal was a critical appraisal of the pathophysiological mechanisms of quercetin in relation to the classical cardiovascular risk factors (e.g., hyperlipidemia), atherosclerosis, etc. We also assessed experimental and clinical data about its potential application in CVDs. Experimental studies including both in vitro methods and in vivo animal models mainly outline the following effects of quercetin: (1) antihypertensive, (2) hypolipidemic, (3) hypoglycemic, (4) anti-atherosclerotic, and (5) cardioprotective (suppressed cardiotoxicity). From the clinical point of view, there are human studies and meta-analyses implicating its beneficial effects on glycemic and lipid parameters. In contrast, other human studies failed to demonstrate consistent favorable effects of quercetin on other cardiometabolic risk factors such as MS, obesity, and hypertension, underlying the need for further investigation. Analyzing the reason of this inconsistency, we identified significant drawbacks in the clinical trials' design, while the absence of pharmacokinetic/pharmacodynamic tests prior to the studies attenuated the power of clinical results. Therefore, additional well-designed preclinical and clinical studies are required to examine the therapeutic mechanisms and clinical efficacy of quercetin in CVDs.

Prevalence and Management Challenges in Central Post-Stroke Neuropathic Pain: A Systematic Review and Meta-analysis.

INTRODUCTION: Central post-stroke pain (CPSP) is defined as the neuropathic pain that arises either acutely or in the chronic phase of a cerebrovascular event and is a result of central lesions of the somatosensory tract. The aim of this systematic review and meta-analysis was to establish the prevalence of CPSP, to describe its characteristics, and to discuss the associated management challenges. METHODS: After a systematic Medline search, we identified 69 papers eligible to be included. RESULTS: The pooled prevalence of CPSP in patients with stroke at any location was 11% (95% CI 7-18%), which can increase to more than 50% in the subgroups of patients with medullary or thalamic strokes. CPSP onset coincides with stroke occurrence in 26% of patients (95% CI 18-35%); CPSP manifests within a month since symptom onset in 31% of patients (95% CI 22-42%), and occurs between the first month and the first year in 41% of patients (95% CI 33.9-49.0%). CPSP develops more than 12 months after stroke onset in 5% of patients (95% CI 3-8%). CONCLUSIONS: Clinicians should look for any evidence of central neuropathic pain for at least 12 months after stroke. Both pharmacological and non-pharmacological interventions can be used for the management of CPSP. Lamotrigine has the strongest evidence (Level II of evidence, derived from small randomized controlled trials) for being effective in the management of CPSP. Future research should focus on well-designed trials of pharmacological and non-pharmacological interventions aiming to relief CPSP, which is a very common but often neglected pain syndrome.