Specific Lp(a) apheresis: A tool to prove lipoprotein(a) atherogenicity.

BACKGROUND: An elevated lipoprotein(a) (Lp(a)) level is observed in more than 30% of patients with stable ischemic heart disease (SIHD). We conducted an investigation of the effects of specific Lp(a) apheresis on the progression of atherosclerosis in SIHD patients with Lp(a) levels greater than 50 mg/dL. METHODS: We prospectively enrolled 15 patients diagnosed with SIHD based on symptom-driven coronary angiography findings, with Lp(a) ≥50 mg/dL and a low density lipoprotein cholesterol (LDL-C) ≤2.5 mmol/L, who were on long-term statin therapy. They underwent weekly Lp(a) apheresis using Lp(a) Lipopak® adsorption columns which contain monospecific sheep polyclonal antibodies against human Lp(a). Fifteen age and gender matched SIHD patients receiving atorvastatin monotherapy served as controls. At baseline and 18 months post-treatment, quantitative coronary angiography, intracoronary ultrasound with virtual histology and carotid ultrasound were performed. Lipid profile, including Lp(a), was measured at the scheduled visits, and before and after each apheresis procedure. Levels of high-sensitivity C-reactive protein (hsCRP), matrix metalloproteinases (MMP)-7 and 9, and tissue inhibitor of matrix metalloproteinases (TIMP)-1 and 2 were determined at baseline and at the end of the study period. RESULTS: Each specific Lp(a) apheresis procedure was carried out with two adsorption columns resulting in an average acute decrease in Lp(a) levels of 75% (from 110 ± 22 to 29 ± 16 mg/dL) without significant changes in other plasma components. Lp(a) reduction over the course of 18 months was associated with a decrease in the mean percent diameter stenosis of 5.05% and an increase in minimal lumen diameter of 14%; the mean total atheroma volume was reduced by 4.60 mm3 (p < 0.05 for all). There was a decrease in absolute common carotid intima-media thickness in the Lp(a) apheresis group of 0.07 ± 0.15 mm both from baseline and compared with the control group (p = 0.01). Levels of hsCRP were reduced by 40% in patients on Lp(a) apheresis without significant changes in the levels of other biomarkers at the end of the study. CONCLUSION: Reduction of the atherosclerotic burden in coronary and carotid arteries was observed in patients treated with specific Lp(a) apheresis and statin over 18 months compared with statin therapy alone. These findings support the atherogenic role of Lp(a) and reinforce the need to assess the effects of Lp(a)-lowering on cardiovascular events and mortality. Trial Registration Clinicaltrials.gov (NCT02133807).

[Degenerative Aortic Stenosis: Modern View on Development, Course, and Management].

Degenerative aortic stenosis is an acquired heart defect manifesting as progressive thickening and calcification of leaflets of originally normal tricuspid or congenital bicuspid aortic valve with development of orifice narrowing, left ventricular hypertrophy, and high risk of cardiovascular complications. In this review we present modern concepts of formation and progression of degenerative aortic stenosis and discuss optimal methods of management of this disease.

[Comparison of Atherosclerotic Lesions in Patients With Acute Myocardial Infarction and Stable Angina Pectoris Using Intravascular Ultrasound].

AIM: to compare noninfarct-related lesions in patients with acute myocardial infarction (MI) with culprit and non-culprit lesions in patients with stable angina pectoris (SAP) using intravascular ultrasound virtual histology (VH-IVUS). MATERIAL AND METHODS: Overall 70 patients were enrolled: 38 with ST elevation (STE) MI and 32 with stable angina pectoris (SAP). All patients underwent three-vessel coronary angiography and gray-scale and VH-IVUS after percutaneous coronary intervention (PCI) of infarct-related lesion in STEMI or culprit lesion in SAP. RESULTS: A total of 130 plaques were examined: 70 in patients with STEMI and 60 in patients with SAP. Noninfarct-related lesions in acute MI compared with non-culprit lesions in SAP had significantly larger plaque burden and plaque volume, smaller minimum lumen area, and more positive remodeling. STEMI, hyperlipidemia, plaque burden, and hypertension were independent predictors of unstable plaques.

[The Evolution of Views on Lipoprotein(a): From Biomarker to the Therapeutic Target].

Series of experimental, epidemiological, and genetic studies have demonstrated that elevated lipoprotein(a) [Lp(a)] level is associated with cardiovascular disease independently from traditional risk factors of atherosclerosis. This review covers the basics of Lp(a) pathogenicity in atherothrombosis and scrutinizes the biology of proinflammatory activity of the particle. We describe the evidence base around Lp(a) as an independent cardiovascular risk factor by giving an update on the results of epidemiological studies and genetic findings. We have summarized present evidence of Lp(a) lowering strategies and their impact on clinical outcomes in patients with high Lp(a) levels. We highlight a rationale for increased investigational efforts to further assess whether targeting Lp(a) levels minimizes cardiovascular risk.

[Conventional and novel cardiovascular risk factors and predisposition to the development of atherosclerosis].

This population-based cross-sectional study included 472 apparently healthy study participants with an increased risk of cardiovascular disease, including 300 patients with hypercholesterolemia. To assess the susceptibility to the development of atherosclerosis, an ultrasonic evaluation of common carotid arteries was used. It has been confirmed that there exists the geographical gradient of carotid intima-media thickness (cIMT), and it has been shown that this gradient is highly correlated th the known gradient of cardiovascular mortality. It was found that the combination of conventional cardiovascular risk factors can help explaining only 21% variability of cIMT, the marker of generalized atherosclerosis. It was found that a predisposition to atherosclerosis, as measured by a pathological increase in cIMT, should be due to the interaction not only conventional cardiovascular risk factors, but also to genetic and environmental factors.

[Transcatheter treatment of degenerative critical aortic valve stenosis in a patient with severe heart failure and chronic lymphocytic leukemia].

Surgical aortic valve replacement is the standard therapy for severe aortic valve stenosis, however one third of patients are rejected because of high surgical risk. Under medical treatment alone these patients have a very poor prognosis with a high mortality rate. We present a case of 70-year-old male patient with degenerative symptomatic critical aortic stenosis and chronic lymphocytic leukemia. Due to recurrence of leukemia, the patient was denied conventional open heart surgery. Within few months of palliative chemotherapy decompensated aortic stenosis with severe congestive heart failure developed. Such therapeutic alternative as transcatheter aortic valve implantation (TAVI) emerged as a lifesaving procedure for the patient that allowed performing full-dose chemotherapy later. We provide a comprehensive review of current indications and contraindications for TAVI.

Lowering of lipoprotein(a) level under niacin treatment is dependent on apolipoprotein(a) phenotype.

BACKGROUND: Lipoprotein(a) [Lp(a)] is a cardiovascular risk factor; in addition to being a low-density lipoprotein (LDL)-like particle, it contains highly heterogeneous apolipoprotein(a) [apo(a)]. No prior studies have evaluated extended-release (ER) niacin effect on Lp(a) level depending on apo(a) phenotype. METHODS: For this 24-week, prospective, open-label clinical trial we recruited 30 men (mean age 46.2 ± 7.5 years) with Lp(a) levels >20 mg/dL. No participant had previously received lipid lowering therapy, and started ER niacin 500 mg with stepwise dose increasing up to 1.5-2.0 g. Subjects were evaluated for Lp(a), lipids, high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2 (Lp-PLA2), and fibrinolytic markers (plasminogen activator inhibitor-1, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasmin-antiplasmin complex). Patients were divided into two groups with major low- (LMW) or high-molecular weight (HMW) apo(a) isoforms determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of plasma under reducing conditions followed by immunoblotting. RESULTS: At baseline, groups were comparable in age, lipid, inflammatory and fibrinolytic biomarkers levels. There was a significant difference in baseline Lp(a) concentrations: 92 ± 29 mg/dL versus 54 ± 46 mg/dL in LMW and HMW apo(a) groups, respectively, p < 0.01. During the course of niacin treatment Lp(a) decreased by 28% (p < 0.003), Lp-PLA2 by 22% (p < 0.001), C-reactive protein by 24% (p = 0.07) in LMW apo(a) group, whereas no changes in Lp(a) and biomarkers levels were obtained in HMW apo(a) group. CONCLUSION: High-dose ER niacin declines elevated Lp(a) level in male subjects with low- but not high-molecular weight apo(a) phenotype.

Specific Lipoprotein(a) apheresis attenuates progression of carotid intima-media thickness in coronary heart disease patients with high lipoprotein(a) levels.

BACKGROUND: To date, there have been no studies evaluating the effect of isolated lipoprotein(a) (Lp(a)) lowering therapy on carotid atherosclerosis progression. METHODS: We enrolled 30 patients who had coronary heart disease (CHD) verified by angiography, Lp(a) level ≥50 mg/dL, and low density lipoprotein cholesterol (LDL-C) level ≤2.6 mmol/L (100 mg/dL) on chronic statin therapy. Subjects were allocated in a 1:1 ratio to receive apheresis treatment on a weekly basis with immunoadsorption columns ("Lp(a) Lipopak"(®), POCARD Ltd., Russia) added to atorvastatin, or atorvastatin monotherapy. The primary efficacy end-point was the change from baseline in the mean intima-media thickness (IMT) of the common carotid arteries. RESULTS: After one month run-in period with stable atorvastatin dose, LDL-C level was 2.3 ± 0.3 mmol/L and Lp(a) - 105 ± 37 mg/dL. As a result of acute effect of specific Lp(a) apheresis procedures, Lp(a) level decreased by an average of 73 ± 12% to a mean of 29 ± 16 mg/dL, and mean LDL-C decreased by 17 ± 3% to a mean of 1.8 ± 0.2 mmol/L. In the apheresis group, changes in carotid IMT at 9 and 18 months from baseline were -0.03 ± 0.09 mm (p = 0.05) and -0.07 ± 0.15 mm (p = 0.01), respectively. In the atorvastatin group no significant changes in lipid and lipoprotein parameters as well as in carotid IMT were received over 18-month period. Two years after study termination carotid IMT increased by an average of 0.02 ± 0.08 mm in apheresis group and by 0.06 ± 0.10 mm in the control group (p = 0.033). CONCLUSION: Isolated extracorporeal Lp(a) elimination over an 18 months period produced regression of carotid intima-media thickness in stable CHD patients with high Lp(a) levels. This effect was maintained for two years after the end of study. TRIAL REGISTRATION: Clinicaltrials.gov (NCT02133807).

[Transcatheter Treatment of Degenerative Critical Aortic Valve Stenosis in a Patient With Severe Heart Failure and Chronic Lymphocytic Leukemia].

Surgical aortic valve replacement is the standard therapy for severe aortic valve stenosis, however one third of patients are rejected because of high surgical risk. Under medical treatment alone these patients have a very poor prognosis with a high mortality rate. We present a case of 70-year-old male patient with degenerative symptomatic critical aortic stenosis and chronic lymphocytic leukemia. Due to recurrence.

[Evolution of Lipoprotein(a): From Biomarker to the Therapeutic Target].

Series of experimental, epidemiological, and genetic studies have demonstrated that elevated lipoprotein(a) [Lp(a)] level is associated with cardiovascular disease independently from traditional risk factors of atherosclerosis. This review covers the basics of Lp(a) pathogenicity in atherothrombosis and scrutinizes the biology of proinflammatory activity of the particle. We describe the evidence base around Lp(a) as an independent cardiovascular risk factor by giving an update on the results of epidemiological studies and genetic findings. We have summarized present evidence of Lp(a) lowering strategies and their impact on clinical outcomes in patients with high Lp(a) levels. We highlight a rationale for increased investigational efforts to further assess whether targeting Lp(a) levels minimizes cardiovascular risk.

[Comparison of Atherosclerotic Lesions in Patients With Acute Myocardial Infarction and Stable Angina Pectoris Using Intravascular Ultrasound].

AIM: to compare noninfarct-related lesions in patients with acute myocardial infarction (MI) with culprit and non-culprit lesions in patients with stable angina pectoris (SAP) using intravascular ultrasound virtual histology (VH-IVUS). MATERIAL AND METHODS: Overall 70 patients were enrolled: 38 with ST elevation (STE) MI and 32 with stable angina pectoris (SAP). All patients underwent three-vessel coronary angiography and gray-scale and VH-IVUS after percutaneous coronary intervention (PCI) of infarct-related lesion in STEMI or culprit lesion in SAP.

[Effect of cascade plasma filtration on spectrum of subfractions of low density lipoproteins in blood plasma of patients with ischemic heart disease].

We studied effect of cascade plasma filtration on subfractions of low density lipoproteins (LDL) in 16 patients with ischemic heart disease (IHD) and hyperlipidemias refractory to drug therapy. The procedure caused 37.6 ± 1.4%, 43.1 ± 2.5%, and 50.9 ± 1.4% lowering of total, low density lipoprotein cholesterol, and apolipoprotein B-100, respectively. The use of filters led to removal of larger less atherogenic LDL-1 and LDL-2 subfractions with relative accumulation of small dense LDL-3, LDL-4, and LDL-5 subfractions. Lowering of concentrations of all LDL subfractions was caused by specific LDL apheresis by immunosorbtion in 4 patients with IHD. Removal of small dense LDL was more effective than that of large less atherogenic LDL-1 and LDL-2 subfraction. Thus we found differences in spectrum of LDL removed by cascade plasma filtration and immunosorbtion. The use of filters was associated with less effective removal of most atherogenic small dense LDL than of large LDL particles what led to redistribution of concentrations of various LDL subfractions towards atherogenic profile of lipoproteins. These results could constitute a basis for revision of methods of conduct of cascade plasma filtration procedures in patients with IHD.

[Value of the spectral analysis of radiofrequency intravascular ultrasound data in the evaluation of nonsignificant coronary lesions in chronic CHD patients].

Plaque complication depends on its composition and phenotype rather than on the degree of stenosis. Plaque rupture predominantly occurs in areas with large lipid core rich in cholesterol and thin fibrous cap. Features of unstable atheromas are mostly described in patients with acute coronary syndromes (ACS). The aim of our study was to assess the plaque characterization and arterial remodeling process in non-significant stenoses of patients with chronic coronary heart disease (CHD) using intravascular ultrasound (IVUS) radiofrequency (RF) data. Methods. The study included 22 stable patients (68% men, mean age 54+/-6 years) with CHD and clinical indications for coronary angiography (CAG). Diameter stenosis of the target coronary artery for IVUS procedure had to be less than 60%. Thin-cap fibroatheroma (TCFA) was defined as plaque burden >40% and amount of NC >10% without detectable overlying fibrous cap segment. Results. Sample size calculations based on the IVUS evaluation showed 54 atheromas in 29 target arteries. Features of vulnerability determined as TCFA were detected in 14 (26%) lesions. Compared with stable lesions VPs were associated with a greater plaque burden (48.5+/-8.0 mm2 vs 55.8+/-9.3 mm2, p=0.03), larger quantity of necrotic core (37.1+/-9.1% vs 24.0+/-12.6%, p=0.0045) and calcium content (22.7+/-8.5% vs 5.6+/-5.2%, p<0.000l), and less fibrous component (34.8+/-7.0% vs 60.4+/-12.4%, p<0.0001), respectively. Significant correlation was obtained between positive remodeling (defined as remodeling index >1.05) and NC percent area (r=0.389. p=0.005). Conclusion. In chronic CHD patients about 25% of atherosclerotic lesions responsible for less than 60% stenosis could be classified as vulnerable plaques. These borderline lesions contain more necrotic and calcium components compared with stable plaques, and are associated with positive arterial remodeling.

[Pleiotropic effects of nicotinic acid therapy in men with coronary heart disease and elevated lipoprotein(a) levels].

PURPOSE: To assess effects of niacin on risk factors of atherosclerosis in men with coronary heart disease (CHD) and high lipoprotein(a) [Lp(a)] levels. MATERIAL AND METHODS: Sixty men (mean age 54+/-6 years) with angiographic evidence of CHD were randomized into two groups. Active group (n=30) received extended release nicotinic acid 1500 mg, control group consisted of remaining 30 patients. All patients received basic therapy with atorvastatin 10-40 mg qd. Blood samples were collected for total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), Lp(a), lipoprotein-associated phospholipase A2 (Lp-PL-2), high-sensitivity C-reactive protein (hsCRP), complex of tissue-type plasminogen activator with plasminogen activator inhibitor type 1 (tPA/PAI-1). Carotid intima media thickness (CIMT) was measured at baseline and after 6-months therapy. RESULTS: There was no statistically significant difference between the groups in the clinical and biochemical characteristics. During the study lipid profile data were within the target levels. In the active group median percent decrease of Lp(a) level was 23% (from 84+/-40 to 67+/-25 mg/dl after 6 weeks and up to 65+/-37 mg/dl after 6 months of treatment, p<0.01); LDL-C, TG, tPA/PAI-1, and Lp-PL-2 mass levels decreased by 25, 20, 25, and 32%, respectively; HDL-C increased by 16% (p<0.05 vs baseline, respectively). Nicotinic acid treatment produced statistically significant reduction nicotinic acid of the mean CIMT (right: 0.83+/-0.16 vs 0.77+/-0.17 mm, p<0.05; left: 0.88+/-0.21 vs 0.82+/-0.17, p<0.05). In control group no changes of CIMT or blood tests were observed. CONCLUSION: In men with CHD and Lp(a) excess of addition to atorvastatin results in regression of CIMT on an average of 0.06 mm in 6 months. Such rapid and significant effect on the arterial wall structure can be attributed to the complex influence of nicotinic acid on Lp(a), lipids, Lp-PL-2 and thrombogenic factors. This is the first study providing the evidence of using Lp(a) as one of therapeutic targets in patients with high Lp(a) levels for achieving beneficial effect on a surrogate marker of atherosclerosis.