Haplotype of the Lipoprotein(a) Gene Variants rs10455872 and rs3798220 Is Associated with Parameters of Coagulation, Fibrinolysis, and Inflammation in Patients after Myocardial Infarction and Highly Elevated Lipoprotein(a) Values.

Lipoprotein(a) (Lp(a)) is an independent risk factor for future coronary events. Variants rs10455872 and rs3798220 in the gene encoding Lp(a) are associated with an increased Lp(a) concentration and risk of coronary artery disease. We aimed to determine whether in high-risk coronary artery disease patients these two genetic variants and the kringle IV type 2 (KIV-2) repeats are associated with impairment of inflammatory and hemostatic parameters. Patients after myocardial infarction with elevated Lp(a) levels were included. Blood samples underwent biochemical and genetic analyses. In carriers of the AC haplotype, the concentrations of tumor necrosis factor (TNF)-α (4.46 vs. 3.91 ng/L, p = 0.046) and plasminogen activator inhibitor-1 (PAI-1) (p = 0.026) were significantly higher compared to non-carriers. The number of KIV-2 repeats was significantly associated with the concentration of high-sensitivity C-reactive protein (ρ = 0.251, p = 0.038) and overall fibrinolytic potential (r = -0.253, p = 0.038). In our patients, a direct association between the AC haplotype and both TNF-α and PAI-1 levels was observed. Our study shows that the number of KIV-2 repeats not only affects proatherosclerotic and proinflammatory effects of Lp(a) but is also associated with its antifibrinolytic properties.

Effects of proprotein convertase subtilisin-kexin type 9 inhibitors on inflammatory and hemostatic parameters in post myocardial infarction patients.

Despite progress in treatment, elevated levels of low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) (Lp(a)), represent a significant part of the residual risk. Both are associated with inflammation and the coagulation fibrinolytic system. The purpose of our research was to evaluate the effect of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on lipid parameters and indicators of inflammation, coagulation and fibrinolysis. We included 100 post myocardial infarction (MI) patients with insufficiently controlled LDL-C values despite the maximum dose of statin, and highly elevated Lp(a). Patients received alirocumab or evolocumab (150 mg sc or 140 mg sc every two weeks, respectively), or placebo for 6 months. In patients receiving PCSK9i, a significant decrease in total cholesterol (TC), LDL-C, triglycerides (TG) and Lp(a), and an increase in high density lipoprotein cholesterol (p < 0.001 for all) was found. Before treatment, the concentrations of TC, LDL-C and TG correlated with the concentrations of thrombin activatable fibrinolysis inhibitor (r = 0.41, p < 0.001; r = 0.353, p < 0.001; r = 0.311, p = 0.003, respectively), and plasminogen activator inhibitor-1 (r = 0.302, p = 0.007; r = 0.218, p = 0.049; r = 0.278; p = 0.013, respectively). The concentrations of TC and LDL-C correlated with overall fibrinolytic potential (r = -0.220, p = 0.034; r = -0.207, p = 0.047, respectively). The concentration of TG was related to the concentration of interleukin 6 (r = 0.290, p = 0.004) and interleukin 8 (r = 0.332, p = 0.001). No correlations between Lp(a) and inflammatory or hemostatic variables were found. No associations were found after treatment. Our results show that inflammatory cytokines and fibrinolytic parameters are related to LDL-C and not Lp(a) in post-MI patients before and with neither of them following PCSK9i treatment. The trial registration number: NCT04613167, Date of registration: November 3, 2020.

Smoking and Diabetes Attenuate Number of CD34+ Haematopoietic Stem Cells in Peripheral Blood of Patients with Advanced Peripheral Artery Disease.

Peripheral artery disease (PAD) is a globally prevalent problem with limited treatment options, leaving up to a fifth of patients remediless. The emergence of new studies on cell therapy in recent years offers a new promising option for their treatment. Our aim was to explore how the number of CD34+ hematopoietic cells in the peripheral blood of PAD patients is associated with patients' functional as well as atherogenic factors. We selected 30 patients with advanced PAD, recorded their performance in a walking test in standard conditions and sampled their blood for further analysis with an emphasis on CD34+ cell selection and counting. No correlation of the CD34+ cell number was confirmed with any of the observed laboratory parameters. There was an association between the claudication distance and the number of CD34+ cells (r = -0.403, p = 0.046). The number of CD34+ cells differed between patients with and without type II diabetes (p = 0.071) and between active smokers, past smokers, and non-smokers (p = 0.035; p = 0.068, p = 0.051, respectively), with both smoking and presence of diabetes type II having a negative effect on the number of CD34+ cells. Our study demonstrated a dependence of the CD34+ cell number on the patient's characteristics.

Predictors of functional and morphological arterial wall properties in coronary artery disease patients with increased lipoprotein (a) levels before and after treatment with proprotein convertase subtilisin-kexin type 9 inhibitors.

BACKGROUND: In addition to proatherogenic properties, lipoprotein (a) (Lp(a)) has also pro-inflammatory, antifibrinolytic and prothrombogenic features. The aim of the current study was to identify the predictors of functional and morphological properties of the arterial wall in patients after myocardial infarction and increased Lp(a) levels at the beginning and after treatment with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors. METHODS: Seventy-six post-myocardial infarction patients with high Lp(a) levels were included in the study. Ultrasound measurements of flow-mediated dilation of brachial artery (FMD), carotid intima-media thickness (c-IMT) and pulse wave velocity (PWV) were performed initially and after 6 months of treatment. At the same time points lipids, Lp(a), inflammatory and hemostasis markers were measured in blood samples. RESULTS: In linear regression model FMD significantly correlated with age at first myocardial infarction (ß = 0.689; p = 0.022), high-sensitivity C-reactive protein (ß = -1.200; p = 0.009), vascular cell adhesion protein 1 (VCAM-1) (ß = -0.992; p = 0.006), overall coagulation potential (ß = 1.428; p = 0.014) and overall hemostasis potential (ß = -1.473; p = 0.008). c-IMT significantly correlated with age at first myocardial infarction (ß = 0.574; p = 0.033) and Lp(a) (ß = 0.524; p = 0.040). PWV significantly correlated with systolic blood pressure (ß = 0.332; p = 0.002), tumor necrosis factor alpha (ß = 0.406; p = 0.002), interleukin-8 (ß = -0.315; p = 0.015) and plasminogen activator inhibitor 1 (ß = 0.229; p = 0.031). After treatment FMD reached statistical significance only in univariant analysis with systolic blood pressure (r = -0.286; p = 0.004) and VCAM-1 (r = -0.229; p = 0.024). PWV and c-IMT correlated with age (r = 0.334; p = 0.001 and r = 0.486; p < 0.0001, respectively) and systolic blood pressure (r = 0.556; p < 0.0001 and r = 0.233; p = 0.021, respectively). CONCLUSIONS: Our results suggest that age, systolic blood pressure, Lp(a) levels and other biochemical markers associated with Lp(a) are predictors of functional and morphological properties of the arterial vessel wall in post-myocardial patients with high Lp(a) levels initially. However, after 6 months of treatment with PCSK9 inhibitors only age and systolic blood pressure seem to be predictors of these properties. TRIAL REGISTRATION: The protocol for this study was registered with clinicaltrials.gov on November, 3 2020 under registration number NCT04613167.

Interplay between microRNAs, Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), and Lipid Parameters in Patients with Very High Lipoprotein(a) Treated with PCSK9 Inhibitors.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has an important function in the regulation of lipid metabolism. PCSK9 reduces hepatic low-density lipoprotein receptors, thereby increasing low-density lipoprotein cholesterol levels. However, its regulation remains to be elucidated, including post-transcriptional regulation by microRNAs (miRNAs). We aimed to explore the interplay between miRNAs, total serum PCSK9, and lipids during treatment with PCSK9 inhibitors. A total of 64 patients with stable coronary artery disease and very high lipoprotein(a) levels and 16 sex- and age-matched control subjects were enrolled. Patients received a PCSK9 inhibitor (evolocumab or alirocumab). Total serum PCSK9 levels were measured by immunoassay. RNA was isolated from plasma using magnetic beads, and expression of selected miRNAs was analyzed by quantitative PCR. Total serum PCSK9 levels were significantly higher in control subjects compared with patients. After 6 months of treatment with PCSK9 inhibitors, total serum PCSK9 levels increased significantly. The expression of miR-191-5p was significantly lower, and the expression of miR-224-5p and miR-483-5p was significantly higher in patients compared with control subjects. Using linear regression, the expression of miR-483-5p significantly predicted the serum PCSK9 level at baseline. After the 6-month period of therapy, the expression of miR-191-5p and miR-483-5p significantly increased. Our results support a role for miR-483-5p in regulating circulating PCSK9 in vivo. The difference in expression of miR-191-5p, miR-224-5p, and miR-337-3p between patients and control subjects suggests their possible role in the pathogenesis of coronary artery disease.

PCSK9 as an Atherothrombotic Risk Factor.

Disturbances in lipid metabolism are among the most important risk factors for atherosclerotic cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein in lipid metabolism that is also involved in the production of inflammatory cytokines, endothelial dysfunction and aherosclerotic plaque development. Studies have shown a connection between PCSK9 and various indicators of inflammation. Signalling pathways that include PCSK9 play important role in the initiation and development of atherosclerotic lesions by inducing vascular inflammation. Studies so far have suggested that PCSK9 is associated with procoagulation, enhancing the development of atherosclerosis. Experimentally, it was also found that an increased concentration of PCSK9 significantly accelerated the apoptosis of endothelial cells and reduced endothelial function, which created conditions for the development of atherosclerosis. PCSK9 inhibitors can therefore improve clinical outcomes not only in a lipid-dependent manner, but also through lipid-independent pathways. The aim of our review was to shed light on the impact of PCSK9 on these factors, which are not directly related to low-density lipoprotein (LDL) cholesterol metabolism.

Atherosclerotic Cardiovascular Disease: Risk Assessment, Prevention and Treatment Strategies.

Despite enormous advances in both surgical and pharmacological treatment, cardiovascular diseases are still the most common cause of morbidity and disability in the western world [...].

TNF-α Predicts Endothelial Function and Number of CD34+ Cells after Stimulation with G-CSF in Patients with Advanced Heart Failure.

Patients with advanced heart failure (HF) have reduced cardiac output and impaired peripheral blood flow, which diminishes endothelial shear stress and consequently flow-mediated dilatation (FMD). The aim of our study was to find out whether endothelial dysfunction is associated with the number of CD34+ cells and TNF-α levels in patients with ischemic and non-ischemic HF after stimulation with granulocyte colony-stimulating factor (G-CSF). We included 56 patients with advanced HF (LVEF < 35%). Eighteen patients (32.14%) had ischemic and 38 (67.86%) patients had non-ischemic HF. FMD of the brachial artery was performed before the patients underwent 5-day bone marrow stimulation with daily subcutaneous injections of G-CSF (5 µg/kg bid). On the fifth day peripheral blood CD34+ cell count was measured. No statistically significant differences were found between the patient groups in NT-proBNP levels ((1575 (425−2439) vs. 1273 (225−2239)) pg/mL; p = 0.40), peripheral blood CD34+ cell count ((67.54 ± 102.32 vs. 89.76 ± 71.21) × 106; p = 0.32), TNF-α ((8.72 ± 10.30 vs. 4.96 ± 6.16) ng/mL; p = 0.13) and FMD (6.7 ± 5.4 vs. 7.2 ± 5.9%; p = 0.76). In a linear regression model, only FMD (p = 0.001) and TNF-α (p = 0.003) emerged as statistically significant predictors of CD34+ cells counts. Our study suggests that TNF-α is a good predictor of impaired endothelial function and of CD34+ cells mobilization after G-CSF stimulation in patients with advanced HF of ischemic and non-ischemic origin.

Gene Expression Profiling of Markers of Inflammation, Angiogenesis, Coagulation and Fibrinolysis in Patients with Coronary Artery Disease with Very High Lipoprotein(a) Levels Treated with PCSK9 Inhibitors.

Besides lipids, inflammation, angiogenesis, coagulation and fibrinolysis play very important roles in coronary artery disease (CAD). We measured gene expression of the inflammatory markers interleukin (IL)-1ß (IL1B) and interferon (IFN)-γ (IFNG), vascular endothelial growth factor-A (VEGF-A) (VEGFA), and coagulation and fibrinolysis markers tissue factor (TF) (F3) and plasminogen activator inhibitor-1 (PAI-1) (SERPINE) in healthy controls and CAD patients with high lipoprotein(a) (Lp(a)). The aim of our study was to identify, first, if there is a difference in these markers between controls and patients; secondly, if these markers are associated with lipids; and third, what the influence of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors is on these markers. We included 124 subjects, 27 controls and 97 patients with CAD (30 in placebo and 67 in the PCSK9 group). Blood samples were collected for lipid and gene measurement. The results showed higher expression of IL1B (p < 0.0001), VEGFA (p < 0.0001), and F3 (p = 0.018) in controls in comparison with patients. Significant correlations were observed between IL1B and lipids. Treatment with PCSK9 inhibitors increased VEGFA (p < 0.0001) and F3 (p = 0.001), and decreased SERPINE (p = 0.043). The results of our study underpin the importance of IL-1ß, VEGF-A and TF in CAD as well as the effect of PCSK9 treatment on these markers.

Non-Lipid Effects of PCSK9 Monoclonal Antibodies on Vessel Wall.

Elevated low density lipoprotein (LDL) cholesterol and lipoprotein(a) (Lp(a)) levels have an important role in the development and progression of atherosclerosis, followed by cardiovascular events. Besides statins and other lipid-modifying drugs, PCSK9 monoclonal antibodies are known to reduce hyperlipidemia. PCSK9 monoclonal antibodies decrease LDL cholesterol levels through inducing the upregulation of the LDL receptors and moderately decrease Lp(a) levels. In addition, PCSK9 monoclonal antibodies have shown non-lipid effects. PCSK9 monoclonal antibodies reduce platelet aggregation and activation, and increase platelet responsiveness to acetylsalicylic acid. Evolocumab as well as alirocumab decrease an incidence of venous thromboembolism, which is associated with the decrease of Lp(a) values. Besides interweaving in haemostasis, PCSK9 monoclonal antibodies play an important role in reducing the inflammation and improving the endothelial function. The aim of this review is to present the mechanisms of PCSK9 monoclonal antibodies on the aforementioned risk factors.

Pharmacologic modulation of intracellular Na+ concentration with ranolazine impacts inflammatory response in humans and mice.

Changes in Ca2+ influx during proinflammatory stimulation modulates cellular responses, including the subsequent activation of inflammation. Whereas the involvement of Ca2+ has been widely acknowledged, little is known about the role of Na+. Ranolazine, a piperazine derivative and established antianginal drug, is known to reduce intracellular Na+ as well as Ca2+ levels. In stable coronary artery disease patients (n = 51) we observed reduced levels of high-sensitive C-reactive protein (CRP) 3 mo after the start of ranolazine treatment (n = 25) as compared to the control group. Furthermore, we found that in 3,808 acute coronary syndrome patients of the MERLIN-TIMI 36 trial, individuals treated with ranolazine (1,934 patients) showed reduced CRP values compared to placebo-treated patients. The antiinflammatory effects of sodium modulation were further confirmed in an atherosclerotic mouse model. LDL-/- mice on a high-fat diet were treated with ranolazine, resulting in a reduced atherosclerotic plaque burden, increased plaque stability, and reduced activation of the immune system. Pharmacological Na+ inhibition by ranolazine led to reduced express of adhesion molecules and proinflammatory cytokines and reduced adhesion of leukocytes to activated endothelium both in vitro and in vivo. We demonstrate that functional Na+ shuttling is required for a full cellular response to inflammation and that inhibition of Na+ influx results in an attenuated inflammatory reaction. In conclusion, we demonstrate that inhibition of Na+-Ca2+ exchange during inflammation reduces the inflammatory response in human endothelial cells in vitro, in a mouse atherosclerotic disease model, and in human patients.

Influence of lipid-lowering drugs on inflammation: what is yet to be done?

Atherosclerosis is a chronic inflammatory disease that is associated with risk of cardiovascular events. The best-characterised and well-standardised clinical indicator of inflammation is C-reactive protein. Current evidence-based drug therapies for prevention and treatment of cardiovascular diseases are mainly focused on reduction of low-density lipoprotein cholesterol. However, these drugs do not provide sufficient protection against recurrent cardiovascular events. One of the possible mechanisms behind this recurrence might be the persistence of residual inflammation. For the most commonly used lipid-lowering drugs, the statins, their reduction of cardiovascular events goes beyond lowering of low-density lipoprotein cholesterol. Here, we review the effects of these lipid-lowering drugs on inflammation, considering statins, ezetimibe, fibrates, niacin, proprotein convertase subtilisin/kexin type 9 inhibitors, bempedoic acid, ethyl eicosapentaenoic acid and antisense oligonucleotides. We focus in particular on C-reactive protein, and discuss how the effects of the statins might be related to reduced rates of cardiovascular events.

The Influence of Treatment with PCSK9 Inhibitors and Variants in the CRP (rs1800947), TNFA (rs1800629), and IL6 (rs1800795) Genes on the Corresponding Inflammatory Markers in Patients with Very High Lipoprotein(a) Levels.

Chronic inflammation contributes significantly to the development and progression of atherosclerosis. However, the factors that lead to an inflammatory imbalance towards a proinflammatory state are not yet fully understood. The CRP rs1800947, TNFA rs1800629, and IL6 rs1800795 polymorphisms may play a role in the pathogenesis of atherosclerosis and were therefore selected to investigate the influence of genetic variability on the corresponding plasma levels after treatment with a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. A group of 69 patients with stable coronary artery disease after myocardial infarction before the age of 50 years and very high lipoprotein(a) levels were enrolled in the study. All patients received a PCSK9 inhibitor (evolocumab or alirocumab). Genotyping was performed using TaqMan assays (CRP rs1800947, TNFA rs1800629, and IL6 rs1800795). Consistent with previous studies, no significant change in levels of inflammatory biomarkers was observed after 6 months of treatment with PCSK9 inhibitors. We also did not detect any significant association between single nucleotide polymorphisms CRP rs1800947, TNFA rs1800629, and IL6 rs1800795 and plasma levels of high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-α (TNF-α), or interleukin 6 (IL6), respectively, at enrollment. However, the difference in IL6 levels after treatment with PCSK9 inhibitors was statistically significant (p = 0.050) in patients with IL6-74CC genotype, indicating the possible role of the IL6 rs1800795 polymorphism in modulating inflammation.

Smoking and diabetes attenuate beneficial effects of PSCK9 inhibitors on arterial wall properties in patients with very high lipoprotein (a) levels.

Background and aims: Elevated lipoprotein (a) (Lp(a)) and low-density lipoprotein cholesterol levels (LDL-C) are significant residual risk factors for cardiovascular events. Treatment with protein convertase subtilisin kexin type 9 (PCSK9) inhibitors reduces the levels of both. Less is known about effects of PCSK9 inhibitors on functional and morphological properties of the arterial wall. The aim of the present study was to determine whether other factors besides decreased LDL-C and Lp(a) are associated with functional (flow-mediated dilation [FMD]) and morphological (carotid intima-media thickness [c-IMT], pulse-wave velocity [PWV]) changes of the arterial wall properties in patients with coronary artery disease (CAD) treated with alirocumab and evolocumab. Methods: One hundred patients with CAD after myocardial infarction before 55 years and with high Lp(a) were randomised to lipid-lowering therapies without PCSK9 inhibitors (control; N = 31), or with alirocumab 150 mg SC (N = 35) or evolocumab 140 mg SC (N = 34), every 2 weeks. All patients underwent blood sampling for biochemical analyses and ultrasound measurements for FMD, c-IMT and PWV. Results: There were no significant changes in FMD for the control (10.7% ± 6.6%-11.1% ± 4.4%, p = 0.716) and alirocumab (10.7% ± 5.9%-11.2% ± 5.3%, p = 0.547) groups, while evolocumab promoted significant increase (11.2% ± 6.8%-14.1% ± 6.6%, p < 0.0001). Only in non-smokers and non-diabetics significant improvements in FMD (p < 0.0001) after treatment with PCSK9 inhibitors were observed. Conclusion: These data show that for patients with CAD and high Lp(a) levels, beneficial effects of PCSK9 inhibitors on the arterial wall properties can be attenuated by specific risk factors, such as smoking and diabetes.

LPA Genotypes and Haplotypes Are Associated with Lipoprotein(a) Levels but Not Arterial Wall Properties in Stable Post-Coronary Event Patients with Very High Lipoprotein(a) Levels.

Lipoprotein(a) [Lp(a)] levels are an independent risk factor for coronary artery disease (CAD). Two single-nucleotide polymorphisms (rs10455872, rs3798220) and number of KIV-2 repeats in the gene encoding Lp(a) (LPA) are associated with Lp(a) and CAD. Our aim was to investigate whether in patients with stable CAD and high Lp(a) levels these genetic variants are associated with increased Lp(a) and arterial wall properties. Blood samples underwent biochemical and genetic analyses. Ultrasound measurements for the functional and morphological properties of arterial wall were performed. Genotypes of rs10455872 and haplotypes AT and GT showed significant association with Lp(a) levels. Patients with GG showed significantly higher Lp(a) levels compared with those with AG genotype (2180 vs. 1391 mg/L, p = 0.045). Patients with no AT haplotype had significantly higher Lp(a) compared to carriers of one AT haplotype (2158 vs. 1478 mg/L, p = 0.023) or two AT haplotypes (2158 vs. 1487 mg/L, p = 0.044). There were no significant associations with the properties of the arterial wall. Lp(a) levels significantly correlated also with number of KIV-2 repeats (r = -0.601; p < 0.0001). In our patients, these two LPA polymorphisms and number of KIV-2 repeats are associated with Lp(a), but not arterial wall properties.

Lipoprotein(a)-The Crossroads of Atherosclerosis, Atherothrombosis and Inflammation.

Increased lipoprotein(a) (Lp(a)) levels are an independent predictor of coronary artery disease (CAD), degenerative aortic stenosis (DAS), and heart failure independent of CAD and DAS. Lp(a) levels are genetically determinated in an autosomal dominant mode, with great intra- and inter-ethnic diversity. Most variations in Lp(a) levels arise from genetic variations of the gene that encodes the apolipoprotein(a) component of Lp(a), the LPA gene. LPA is located on the long arm of chromosome 6, within region 6q2.6-2.7. Lp(a) levels increase cardiovascular risk through several unrelated mechanisms. Lp(a) quantitatively carries all of the atherogenic risk of low-density lipoprotein cholesterol, although it is even more prone to oxidation and penetration through endothelia to promote the production of foam cells. The thrombogenic properties of Lp(a) result from the homology between apolipoprotein(a) and plasminogen, which compete for the same binding sites on endothelial cells to inhibit fibrinolysis and promote intravascular thrombosis. LPA has up to 70% homology with the human plasminogen gene. Oxidized phospholipids promote differentiation of pro-inflammatory macrophages that secrete pro-inflammatory cytokines (e. g., interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor-α). The aim of this review is to define which of these mechanisms of Lp(a) is predominant in different groups of patients.

Stem Cell Therapy for Chronic and Advanced Heart Failure.

PURPOSE OF REVIEW: The purpose of this review is to discuss recent advances in the field of cell therapy in patients with heart failure with reduced ejection fraction (HFrEF) of ischemic (iCMP) and nonischemic (dCMP) etiology, heart failure with preserved ejection fraction (HFpEF), and in advanced heart failure patients undergoing mechanical circulatory support (LVAD). RECENT FINDINGS: In HFrEF patients (iCMP and dCMP cohorts), autologous and/or allogeneic cell therapy was shown to improve myocardial performance, patients' functional capacity, and neurohumoral activation. In HFpEF patient population, the concept of cell therapy in novel and remains largely unexplored. However, initial data are very encouraging and suggest at least a similar benefit in improvements of myocardial performance (also diastolic function of the left ventricle), exercise capacity, and neurohumoral activation. Recently, cell therapy was explored in the sickest population of advanced heart failure patients undergoing LVAD support also showing a potential benefit in promoting myocardial reverse remodeling and recovery. In the past decade, several cell therapy-based clinical trials showed promising results in various chronic and advanced heart failure patient cohorts. Future cell treatment strategies should aim for more personalized therapeutic approaches by defining optimal stem cell type or their combination, dose, and delivery method for an individual patient adjusted for patient's age and stage/duration of heart failure.

Long-Term Effects of Angiotensin Receptor-Neprilysin Inhibitors on Myocardial Function in Chronic Heart Failure Patients with Reduced Ejection Fraction.

BACKGROUND: We sought to evaluate the long-term effects of angiotensin receptor blocker-neprilysin inhibitor (ARNI) therapy on reverse remodeling of the failing myocardium in HFrEF patients. METHODS: We performed a prospective non-randomized longitudinal study on 228 HFrEF patients treated with ARNI at our center. Prior to ARNI introduction all patients received stable doses of ACEI/ARB for at least six months. Clinical, biochemical and echocardiography data were obtained at ARNI introduction and 12-month follow-up. Results At follow-up, we found significant improvements in LVEF (29.7% ± 8% vs. 36.5% ± 9%; p < 0.001), LVOT-VTI (14.8 ± 4.2 cm vs. 17.2 ± 4.2 cm; p < 0.001), TAPSE (1.7 ± 0.5 cm vs. 2.1 ± 0.6 cm; p < 0.001) and LV-EDD (6.5 ± 0.8 cm vs. 6.3 ± 0.9 cm; p = 0.001). NT-proBNP serum levels also decreased significantly (1324 (605, 3281) pg/mL vs. 792 (329, 2022) pg/mL; p = 0.001). A total of 102 (45%) of patients responded favorably to ARNI (ΔLVEF < +5%; Group A) and 126 (55%) patients achieved ΔLVEF ≥ +5% (Group B). The two groups differed significantly in age, heart failure etiology, baseline LVEF and baseline NT-proBNP. On multivariable analysis, nonischemic heart failure, LVEF < 30% and NT-proBNP < 1500 pg/mL emerged as independent correlates of favorable response to ARNI therapy. CONCLUSION: ARNI therapy appears to improve echocardiographic parameters of left and right ventricular function in HFrEF patients above the effect of pre-existing optimal medical management. These effects may be particularly pronounced in patients with nonischemic heart failure, LVEF < 30% and lower degree of neurohumoral activation.

Lipoprotein(a) in atherosclerosis: from pathophysiology to clinical relevance and treatment options.

Lipoprotein(a) (Lp(a)) was discovered more than 50 years ago, and a decade later, it was recognized as a risk factor for coronary artery disease. However, it has gained importance only in the past 10 years, with emergence of drugs that can effectively decrease its levels. Lp(a) is a low-density lipoprotein (LDL) with an added apolipoprotein(a) attached to the apolipoprotein B component via a disulphide bond. Circulating levels of Lp(a) are mainly genetically determined. Lp(a) has many functions, which include proatherosclerotic, prothrombotic and pro-inflammatory roles. Here, we review recent data on the role of Lp(a) in the atherosclerotic process, and treatment options for patients with cardiovascular diseases. Currently 'Proprotein convertase subtilisin/kexin type 9' (PCSK9) inhibitors that act through non-specific reduction of Lp(a) are the only drugs that have shown effectiveness in clinical trials, to provide reductions in cardiovascular morbidity and mortality. The effects of PCSK9 inhibitors are not purely through Lp(a) reduction, but also through LDL cholesterol reduction. Finally, we discuss new drugs on the horizon, and gene-based therapies that affect transcription and translation of apolipoprotein(a) mRNA. Clinical trials in patients with high Lp(a) and low LDL cholesterol might tell us whether Lp(a) lowering per se decreases cardiovascular morbidity and mortality.KEY MESSAGESLipoprotein(a) is an important risk factor in patients with cardiovascular diseases.Lipoprotein(a) has many functions, which include proatherosclerotic, prothrombotic and pro-inflammatory roles.Treatment options to lower lipoprotein(a) levels are currently scarce, but new drugs are on the horizon.