Measures of high-density lipoprotein function in men and women with severe aortic stenosis

Background: Calcification of the aortic valve is a common heart valve disorder, in some cases leading to clinically impactful severe aortic stenosis (AS). Sex-specific differences in aortic valve calcification (ACV) exist, with women having a lower burden of calcification than men as measured by computed tomography; however, the pathophysiological mechanism that leads to these differences remains unclear. Methods: Using cultured human Tamm-Horsfall protein 1 (THP-1) macrophages and human aortic valve interstitial cells, the effects of high-density lipoprotein (HDL) particles isolated from the plasma of men and women with severe AS were studied for cholesterol efflux capacity (CEC). Results: HDL-CEC was assessed in 46 patients with severe AS, n = 30 men, n = 16 women. ATP-Binding Cassette A1 (ABCA1)-mediated HDL-CEC was measured from human cultured THP-1 macrophages to plasma HDL samples. Women with severe AS had more ABCA1-mediated HDL-CEC, as compared to men (8.50 ± 3.90% cpm vs. 6.80 ± 1.50% cpm, P = 0.04). HDL pre-β1 and α-particles were higher in women than in men by spectral density, (pre-β1 HDL, 20298.29 ± 1076.15 vs. 15,661.74 ± 789.00, P = 0.002, and α-HDL, 63006.35 ± 756.81 vs. 50,447.00 ± 546.52, P =0.03). Lecithin-cholesterol acyltransferase conversion of free cholesterol into cholesteryl esters was higher in women than men (16.44 ± 9.11%/h vs. 12.00 ± 8.07%/h, P = 0.03). Conclusions: Sex-specific changes in various parameters of HDL-CEC were found in patients with severe AS. Sex-based modifications in HDL functionality by HDL-CEC might account for the reduced burden of calcification in women vs. men with severe AS. Therefore, future studies should target sex-related pathways in AS to help to improve understanding and treatment of AS

Impaired ATP-binding cassette transporter A1-mediated sterol efflux from oxidized LDL-loaded macrophages

AbstractWe investigated the interaction of oxidized low density lipoprotein (OxLDL) with the ATP-binding cassette A1 (ABCA1) pathway in J774 macrophages. Cellular efflux to apolipoprotein AI (apo-AI) of OxLDL-derived cholesterol was lower than efflux of cholesterol derived from acetylated low density lipoprotein (AcLDL). ABCA1 upregulation by 8-(4-chlorophenylthio)adenosine 3′:5′-cyclic monophosphate (cpt-cAMP) or 22 (R)-hydroxycholesterol (22-OH) and 9-cis retinoic acid (9cRA) increased the efflux to apo-AI of cellular sterols derived from AcLDL, but not of those from OxLDL. AcLDL, but not OxLDL, induced ABCA1 protein content and activity in J774. However, OxLDL did not influence J774 ABCA1 upregulation by cpt-cAMP or 22-OH/9cRA. We conclude that sterols released to cells by OxLDL are available neither as substrate nor as modulator of ABCA1

In comparison to the myocardial perfusion scintigraphy, a treadmill stress test is a viable, efficient and cost effective option to predict cardiovascular events in elderly patients

OBJETIVO: Definir o valor prognóstico e a custo-efetividade do teste ergométrico (TE) em comparação à cintilografia de perfusão miocárdica com dipiridamol (DIP) em indivíduos com > 75 anos de idade. MÉTODOS: Foram avaliados, consecutiva e prospectivamente, 66 pacientes (40% homens), com média de idade de 81 ± 5 anos. Desses pacientes, 57% eram hipertensos, 38% eram dislipidêmicos e 28%, diabéticos. O protocolo de Bruce para rampa foi adaptado, obtendo-se o valor prognóstico do TE pelo escore de Duke. RESULTADOS: A duração do TE, o porcentual da freqüência cardíaca máxima preconizada e o duplo produto no pico do exercício foram, respectivamente, de 7 ± 3 minutos, 95 ± 9% e 24.946 ± 4.576 (bpm x mmHg). O TE e a DIP apresentaram resultados positivos para isquemia miocárdica similares (21% vs 15%, respectivamente). A concordância entre os testes foi de 88% (Kappa 0,63, p 75 years of age. METHODS: Consecutive and prospective assessment of 66 patients (40% male) aged 81 ± 5 years of which 57% were hypertensive, 38% had dyslipidemia and 28% were diabetics. The Bruce protocol was adapted for a tilt treadmill and the TST prognostic value was obtained using the Duke treadmill score. RESULTS: The TST duration, recommended maximum heart rate percentage and double product at peak exercise were respectively: 7 ± 3 minutes, 95 ± 9% and 24,946 ± 4,576 (bpm x mmHg). The TST and DIP presented similar positive results for myocardial ischemia (21% vs 15%, respectively). The correlation between the tests was 88% (Kappa 0.63, p<0.01). During 685 ± 120 days of follow-up, nine major events occurred: 6 deaths, 2 acute coronary syndromes and 1 myocardial revascularization. The variables associated with the major events were: age (83 ± 6 vs 80 ± 4 years; p=0.048), male gender (78% vs 33%; p=0.02), ST segment depression (1 ± 1 mm vs 0.25 ± 0.6 mm; p= 0.01), high or intermediate risk determined by the Duke treadmill score - combined in one group (44% vs 2%; p=0.001) and abnormal DIP (44% vs 10%, p= 0.02). CONCLUSION: For this elderly population, the TST was an efficient and viable option with a similar diagnostic value in comparison to the DIP. However, the TST was more accurate in the prediction of major events and offers a lower cost

Relation of Serum Vitamin D to Risk of Mitral Annular and Aortic Valve Calcium (from the Multi-Ethnic Study of Atherosclerosis)

Serum 25-hydroxyvitamin D [25(OH)D] concentration has been identified as a possible modifiable risk factor for cardiovascular disease (CVD). We hypothesized that serum 25(OH)D concentration would be associated with calcifications of the left-sided heart valves, which are markers of CVD risk. Aortic valve calcium (AVC) and mitral annular calcium (MAC) were quantified from cardiac computed tomography scans performed on 5,530 Multi-Ethnic Study of Atherosclerosis participants at the baseline examination (2000 to 2002) and at a follow-up visit at either Examination 2 (2002 to 2004) or Examination 3 (2004 to 2005). 25(OH)D was measured from serum samples collected at the baseline examination. Using relative risk regression, we evaluated the multivariable-adjusted risk of prevalent and incident AVC and MAC in this ethnically diverse population free of clinical CVD at baseline. The mean age of participants was 62 ± 10 years; 53% were women, 40% white, 26% black, 21% Hispanic, and 12% Chinese. Prevalent AVC and MAC were observed in 12% and 9% of study sample, respectively. There were no significant associations between 25(OH)D and prevalent AVC or MAC. Over a mean follow-up of 2.5 years, 4% developed incident AVC and 5% developed incident MAC. After adjusting for demographic variables, each 10 ng/ml higher serum 25(OH)D was associated with a 15% (relative risk 0.85, 95% confidence interval 0.74 to 0.98) lower risk of incident MAC but not AVC. However, this association was no longer significant after adjusting for lifestyle and CVD risk factors. Results suggest a possible link between serum 25(OH)D and the risk for incident MAC, but future studies with longer follow-up are needed to further test this association

Measures of High-Density Lipoprotein Function and Composition in Men and Women with Severe Aortic Valve Stenosis

Introduction and Hypothesis: Aortic valve calcification (AVC), is the intrinsic mechanism of valvular obstruction in severe aortic stenosis (AS), sharing similarities with atherosclerosis. There are differences in AVC by sex, with women having a lower burden of calcification than men, but the mechanism for this is unclear. Improved HDL functionality has been associated with protection against coronary artery calcification, but its relationship to AVC is less studied.Methods: We evaluated measures of high-density lipoprotein (HDL) functionality in 46 patients with severe AS, n= 30 men, n=16 women. ATP-Binding Cassette A1 (ABCA1) mediated cholesterol efflux capacity (CEC) was measured from human cultured Tamm-Horsfall protein 1 (THP-1) macrophages to apoB-depleted patient plasma samples. Lipid profile, lecithin-cholesterol acyltransferase activity (LCAT), fast protein liquid chromatography (FPLC), HDL size, and small pre-β1 and α-HDL particles, were measured in apolipoprotein B-depleted patient plasma. Proteomic analysis was used to explore sex-based differences in the HDL proteome.Results: Women with severe AS had higher ABCA1-mediated CEC, as compared to men (n=46, p=0.04). We found differences in FPLC profiles between sexes in severe AS along with a reduction in preβ and α-particles in men vs women by spectral counts, (preβ-HDL, 15661.74±789.00 vs 20298.29±1076.15, p=0.002), and (α-HDL, 50447.00± 546.52 vs 63006.35±756.81, p=0.03). Conversion of free cholesterol into cholesteryl esters by LCAT was decreased in men vs. women (12.00±8.07 %/h vs 16.44±9.11 %/h, p=0.03). We identified 108 HDL-associated proteins in a representative man and woman, of which, 15 were found only in the female sampleConclusions: Sex-specific differences in measures of HDL functionality were found in patients with severe AS. Future studies should consider whether sex-based differences in HDL functionality might account for the decreased burden of calcification in women vs. men with severe AS

Maternal Cardiovascular Outcomes of Pregnancy in Childhood, Adolescent, and Young Adult Cancer Survivors

This review focuses on the maternal cardiovascular risk and outcomes of pregnancy in childhood, adolescent, and young adult cancer survivors who are achieving survival to their prime reproductive years. Childhood, adolescent, and young adult cancer survivors are a growing population and have increasing needs for reproductive care over decades of life. Female cancer survivors have an overall higher risk of maternal cardiovascular events compared to those without a history of cancer. In female cancer survivors with normal cardiac function before pregnancy, the incidence of new heart failure during pregnancy is low. In survivors with cardiotoxicity prior to pregnancy, the risk of heart failure during and immediately after pregnancy is much higher. We recommend cardiomyopathy surveillance with echocardiography before pregnancy for all female survivors treated with anthracyclines and chest radiation. Survivors with cardiotoxicity prior to pregnancy should be cared for by an expert multidisciplinary team, including obstetrics, cardiology, anesthesia, and specialized nursing, among others