Safety and possible anti-inflammatory effect of paclitaxel associated with LDL-like nanoparticles (LDE) in patients with chronic coronary artery disease: a double-blind, placebo-controlled pilot study.

Introduction: Studies in cholesterol-fed rabbits showed that anti-proliferative chemotherapeutic agents such as paclitaxel associated with solid lipid nanoparticles (LDE) have marked anti-atherosclerotic effects. In addition, association with LDE nearly abolishes paclitaxel toxicity. We investigated whether treatment with LDE-paclitaxel changes plaque progression by coronary CT angiography and is safe in patients with chronic coronary artery disease. Methods: We conducted a prospective, randomized, double-blind, placebo-controlled pilot study in patients with multi-vessel chronic coronary artery disease. Patients were randomized to receive IV infusions of LDE-paclitaxel (paclitaxel dose: 175 mg/m2 body surface) or LDE alone (placebo group), administered every 3 weeks for 18 weeks. All participants received guideline-directed medical therapy. Clinical and laboratory safety evaluations were made at baseline and every 3 weeks until the end of the study. Analysis of inflammatory biomarkers and coronary CTA was also performed at baseline and 4 weeks after treatment. Results: Forty patients aged 65.6 ± 8 years, 20 in LDE-paclitaxel and 20 in placebo group were enrolled. Among those, 58% had diabetes, 50% had myocardial infarction, and 91% were in use of statin and aspirin. Baseline demographics, risk factors, and laboratory results were not different between groups. In all patients, no clinical or laboratory toxicities were observed. From the baseline to the end of follow-up, there was a non-significant trend toward a decrease in IL-6 levels and hsCRP in the LDE-paclitaxel group (-16% and -28%, respectively), not observed in placebo. Regarding plaque progression analysis, variation in plaque parameter values was wide, and no difference between groups was observed. Conclusion: In patients with multivessel chronic coronary artery disease and optimized medical therapy, LDE-paclitaxel was safe and showed clues of potential benefits in reducing inflammatory biomarkers. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT04148833, identifier (NCT04148833).

Acute myocardial infarction preferentially alters low-abundant, long-chain unsaturated phospholipid and sphingolipid species in plasma high-density lipoprotein subpopulations.

Aim: High-density lipoprotein (HDL) particles in ST-segment elevation myocardial infarction (STEMI) are deficient in their anti-atherogenic function. Molecular determinants of such deficiency remain obscure. Methods: Five major HDL subpopulations were isolated using density-gradient ultracentrifugation from STEMI patients (n = 12) and healthy age- and sex-matched controls (n = 12), and 160 species of phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, sphingomyelin and ceramide were quantified by LC-MS/MS. Results: Multiple minor species of proinflammatory phosphatidic acid and lysophosphatidylcholine were enriched by 1.7-27.2-fold throughout the majority of HDL subpopulations in STEMI. In contrast, minor phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, sphingomyelin and ceramide species were typically depleted up to 3-fold in STEMI vs. control HDLs, while abundances of their major species did not differ between the groups. Intermediate-to-long-chain phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol species were more affected by STEMI than their short-chain counterparts, resulting in positive correlations between their fold decrease and the carbon chain length. Additionally, fold decreases in the abundances of multiple lipid species were positively correlated with the double bond number in their carbon chains. Finally, abundances of several phospholipid and ceramide species were positively correlated with cholesterol efflux capacity and antioxidative activity of HDL subpopulations, both reduced in STEMI vs controls. KEGG pathway analysis tied these species to altered glycerophospholipid and linoleic acid metabolism. Conclusions: Minor unsaturated intermediate-to-long-chain phospholipid and sphingolipid species in HDL subpopulations are most affected by STEMI, reflecting alterations in glycerophospholipid and linoleic acid metabolism with the accumulation of proinflammatory lysolipids and maintenance of homeostasis of major phospholipid species.

Two-Year Follow-Up of Chronic Ischemic Heart Disease Patients in a Specialized Center in Brazil. / Acompanhamento de Dois Anos de Pacientes com Cardiopatia Isquêmica Crônica em um Centro Especializado no Brasil.

The incidence of cardiovascular events in patients with chronic ischemic heart disease (CIHD) may vary significantly among countries. Although populous, Brazil is often underrepresented in international records. This study aimed to describe the quality of care and the two-year incidence of cardiovascular events and associated prognostic factors in CIHD patients in a tertiary public health care center in Brazil. Patients with CIHD who reported for clinical evaluation at Instituto do Coração (São Paulo, Brazil) were registered and followed for two years. The primary endpoint was a composite of myocardial infarction (MI), stroke, or death. A significance level of 0.05 was adopted. From January 2016 to December 2018, 625 participants were included in the study. Baseline characteristics show that 33.1% were women, median age 66.1 [59.6 - 71.9], 48.6% had diabetes, 83.1% had hypertension, 62.6% had previous MI, and 70.4% went through some revascularization procedure. At a median follow-up (FU) of 881 days, we noted 37 (7.05%) primary endpoints. After adjustments, age, previous stroke, and LDL-cholesterol were independently associated with the primary endpoint. Comparing baseline versus FU, participants experienced relief of angina based on the Canadian Cardiovascular Society (CCS) scale according to the following percentages: 65.7% vs. 81.7% were asymptomatic and 4.2% vs. 2.9% CCS 3 or 4 (p < 0.001). They also experienced better quality of medication prescription: 65.8% vs. 73.6% (p < 0.001). However, there was no improvement in LDL-cholesterol or blood pressure control. This study shows that CIHD patients had a two-year incidence of the primary composite endpoint of 7.05%, and the reduction of LDL-cholesterol was the only modifiable risk factor associated with prognosis.

A incidência de eventos cardiovasculares em pacientes com doença cardíaca isquêmica crônica (DCIC) pode variar significativamente entre os países. Embora populoso, o Brasil é frequentemente sub-representado nos registros internacionais. Este estudo teve como objetivo descrever a qualidade do atendimento e a incidência de eventos cardiovasculares em dois anos, além de fatores prognósticos associados em pacientes com DCIC em um centro terciário de saúde pública no Brasil. Pacientes com DCIC que compareceram para avaliação clínica no Instituto do Coração (São Paulo, Brasil) foram cadastrados e acompanhados por dois anos. O desfecho primário foi um composto de infarto do miocárdio (IM), acidente vascular encefálico ou morte. Um nível de significância de 0,05 foi adotado. De janeiro de 2016 a dezembro de 2018, 625 participantes foram incluídos no estudo. As características basais mostram que 33,1% eram mulheres, a idade mediana era de 66,1 [59,6 ­ 71,9], 48,6% tinham diabetes, 83,1% tinham hipertensão, 62,6% tinham IM prévio e 70,4% passaram por algum procedimento de revascularização. Em um acompanhamento mediano de 881 dias, 37 (7,05%) desfechos primários foram observados. Após ajustes, idade, acidente vascular encefálico prévio e colesterol LDL foram independentemente associados ao desfecho primário. Comparando a linha de base com o acompanhamento, os participantes relataram alívio da angina com base na escala da Sociedade Cardiovascular Canadense (SCC) de acordo com as seguintes porcentagens: 65,7% vs. 81,7% eram assintomáticos e 4,2% vs. 2,9% eram SCC 3 ou 4 (p < 0,001). Eles também relataram melhor qualidade na prescrição de medicamentos: 65,8% vs. 73,6% (p < 0,001). No entanto, não houve melhora no colesterol LDL ou no controle da pressão arterial. O presente estudo mostra que pacientes com DCIC apresentaram uma incidência de 7,05% do desfecho primário composto em um período de dois anos, sendo a diminuição do colesterol LDL o único fator de risco modificável associado ao prognóstico.

Insights into the Role of Inflammation in the Management of Atherosclerosis.

Atherosclerosis is the biological basis of ischemic heart disease and ischemic stroke, the leading causes of death in the world. After decades of studies, the understanding of atherosclerosis has evolved dramatically, and inflammation has been recognized as one of the most relevant pillars in all phases of atherosclerotic disease. Nevertheless, only recently, the trial CANTOS, and subsequent outcome studies with colchicine, finally provided proof-of-concept evidence that anti-inflammatory therapies were able to reduce cardiovascular events with no influence on lipid levels. These landmark studies inaugurated an era of clinical and pre-clinical studies of immunomodulatory strategies focused on reduction of cardiovascular risk. Although there are promising results in the field, selection of the most appropriate immunomodulatory therapy and identification of patients who could benefit the most, are still enormous challenges. Further research is imperative before we can finally advance towards regular use of anti-inflammatory agents to reduce atherosclerotic events in our clinical practice.

Acompanhamento de Dois Anos de Pacientes com Cardiopatia Isquêmica Crônica em um Centro Especializado no Brasil / Two-Year Follow-Up of Chronic Ischemic Heart Disease Patients in a Specialized Center in Brazil

Resumo Fundamento A incidência de eventos cardiovasculares em pacientes com doença cardíaca isquêmica crônica (DCIC) pode variar significativamente entre os países. Embora populoso, o Brasil é frequentemente sub-representado nos registros internacionais. Objetivos Este estudo teve como objetivo descrever a qualidade do atendimento e a incidência de eventos cardiovasculares em dois anos, além de fatores prognósticos associados em pacientes com DCIC em um centro terciário de saúde pública no Brasil. Métodos Pacientes com DCIC que compareceram para avaliação clínica no Instituto do Coração (São Paulo, Brasil) foram cadastrados e acompanhados por dois anos. O desfecho primário foi um composto de infarto do miocárdio (IM), acidente vascular encefálico ou morte. Um nível de significância de 0,05 foi adotado. Resultados De janeiro de 2016 a dezembro de 2018, 625 participantes foram incluídos no estudo. As características basais mostram que 33,1% eram mulheres, a idade mediana era de 66,1 [59,6 - 71,9], 48,6% tinham diabetes, 83,1% tinham hipertensão, 62,6% tinham IM prévio e 70,4% passaram por algum procedimento de revascularização. Em um acompanhamento mediano de 881 dias, 37 (7,05%) desfechos primários foram observados. Após ajustes, idade, acidente vascular encefálico prévio e colesterol LDL foram independentemente associados ao desfecho primário. Comparando a linha de base com o acompanhamento, os participantes relataram alívio da angina com base na escala da Sociedade Cardiovascular Canadense (SCC) de acordo com as seguintes porcentagens: 65,7% vs. 81,7% eram assintomáticos e 4,2% vs. 2,9% eram SCC 3 ou 4 (p < 0,001). Eles também relataram melhor qualidade na prescrição de medicamentos: 65,8% vs. 73,6% (p < 0,001). No entanto, não houve melhora no colesterol LDL ou no controle da pressão arterial. Conclusão O presente estudo mostra que pacientes com DCIC apresentaram uma incidência de 7,05% do desfecho primário composto em um período de dois anos, sendo a diminuição do colesterol LDL o único fator de risco modificável associado ao prognóstico.

Abstract Background The incidence of cardiovascular events in patients with chronic ischemic heart disease (CIHD) may vary significantly among countries. Although populous, Brazil is often underrepresented in international records. Objectives This study aimed to describe the quality of care and the two-year incidence of cardiovascular events and associated prognostic factors in CIHD patients in a tertiary public health care center in Brazil. Methods Patients with CIHD who reported for clinical evaluation at Instituto do Coração (São Paulo, Brazil) were registered and followed for two years. The primary endpoint was a composite of myocardial infarction (MI), stroke, or death. A significance level of 0.05 was adopted. Results From January 2016 to December 2018, 625 participants were included in the study. Baseline characteristics show that 33.1% were women, median age 66.1 [59.6 - 71.9], 48.6% had diabetes, 83.1% had hypertension, 62.6% had previous MI, and 70.4% went through some revascularization procedure. At a median follow-up (FU) of 881 days, we noted 37 (7.05%) primary endpoints. After adjustments, age, previous stroke, and LDL-cholesterol were independently associated with the primary endpoint. Comparing baseline versus FU, participants experienced relief of angina based on the Canadian Cardiovascular Society (CCS) scale according to the following percentages: 65.7% vs. 81.7% were asymptomatic and 4.2% vs. 2.9% CCS 3 or 4 (p < 0.001). They also experienced better quality of medication prescription: 65.8% vs. 73.6% (p < 0.001). However, there was no improvement in LDL-cholesterol or blood pressure control. Conclusion This study shows that CIHD patients had a two-year incidence of the primary composite endpoint of 7.05%, and the reduction of LDL-cholesterol was the only modifiable risk factor associated with prognosis.

Evaluation of cardiovascular risk biomarkers after moderate consumption of red wine and cachaça in a randomized crossover trial: The Wine and Cachaça Study (WICAS).

INTRODUCTION: Moderate daily consumption of alcohol (MDCA) is associated with cardiovascular risk (CVR) reduction in observational studies. Some researches have suggested that this benefit may be associated not only with red wine consumption but also with other beverages. However, there are no clinical trials evaluating the possible CVR benefit of Brazilian spirit (cachaça) in humans. METHODS: This is a prospective, randomized, crossover study including healthy individuals initially assigned to a MDCA of cachaça or red wine for a period of 4 weeks. After a one-week abstinence period, the type of drink was changed for another 4 weeks of intervention. The MDCA for both beverages was determined as a dose equivalent to 28 g of ethanol per day for men and 14 g for women. CVR biomarkers analyses were performed before and after each intervention to assess the serologic status of C-reactive protein, lipid profile, platelet aggregation and glycemic profile. This study is registered on the ISRCTN platform under number 15978506. RESULTS: Of the 42 subjects initially randomized, 2 refused to continue in the study. The median age was 44.3 ± 10.3 years and 19 were male (47.5%). Adherence to the protocol was considered ideal with 100% regular use in both interventions and only 3 individuals in each intervention group reported alcohol abuse. There was no significant variation in anthropometric measurements during the study, except for weight gain (0.7 kg) in the red wine group (p = 0.005). The median of the delta of platelet aggregation for MDCA of cachaça was 1.2% (-1.1 to 5.3) and the median of the delta to the MDCA of wine was -1.6% (-4.5 to 2) (p = 0.02). The other biomarkers didn't show any statistically significant variation. CONCLUSION: Moderate consumption of wine and cachaça was related to variation in laboratory biomarkers of CVR related to atherosclerosis. There was significant weight gain during the period of wine consumption and there was observed a difference between platelet aggregation values after both interventions.

Beyond Statins and PCSK9 Inhibitors: Updates in Management of Familial and Refractory Hypercholesterolemias.

PURPOSE OF REVIEW: Elevation in apolipoprotein B-containing lipoproteins in the blood is a cause of atherosclerosis. Statins have changed the preventive cardiology scenario, and more recently monoclonal proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors were added as robust agents to further reduce pro-atherogenic lipoproteins and therefore prevent cardiovascular events. However, despite this many dyslipidemic individuals persist with inadequate LDL-C levels and still at risk. The purpose of this review was to discuss current status and describe advances in therapies beyond statins and monoclonal PCSK9 inhibitors. RECENT FINDINGS: Ezetimibe and lomitapide have been used for many years to further reduce LDL-C and longer term data reinforce their safety. Bempedoic acid, an inhibitor of adenosine triphosphate-citrate lyase, has been shown to add LDL-C reduction on top of statins and ezetimibe, furthermore it may be an alternative for statin intolerant patients. Inclisiran is a small interfering ribonucleic acid inhibitor that reduces the hepatic production of PCSK9 that induces robust LDL-C lowering, similar to monoclonal antibodies, with the advantage of 2 or 3 injections per year. So far, no safety signs were seen with its use. Evinacumab, a monoclonal antibody that binds angiopoietin-like protein 3 (ANGPTL3), induces robust LDL-C lowering in either homozygous familial hypercholesterolemia or severe hypercholesterolemia patients with good tolerability. Many high-risk individuals persist with elevated LDL-C, newer medications further lower LDL-C on top of standard lipid-lowering therapies and are well tolerated. Ongoing clinical trials may prove if these novel medications will reduce cardiovascular events with safety.

Phospholipid transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis is directly correlated with HDL-cholesterol levels and is not associated with cardiovascular risk.

BACKGROUND AND AIMS: While low concentrations of high-density lipoprotein-cholesterol (HDL-C) represent a well-established cardiovascular risk factor, extremely high HDL-C is paradoxically associated with elevated cardiovascular risk, resulting in the U-shape relationship with cardiovascular disease. Free cholesterol transfer to HDL upon lipolysis of triglyceride-rich lipoproteins (TGRL) was recently reported to underlie this relationship, linking HDL-C to triglyceride metabolism and atherosclerosis. In addition to free cholesterol, other surface components of TGRL, primarily phospholipids, are transferred to HDL during lipolysis. It remains indeterminate as to whether such transfer is linked to HDL-C and cardiovascular disease. METHODS AND RESULTS: When TGRL was labelled with fluorescent phospholipid 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), time- and dose-dependent transfer of DiI to HDL was observed upon incubations with lipoprotein lipase (LPL). The capacity of HDL to acquire DiI was decreased by -36% (p<0.001) in low HDL-C patients with acute myocardial infarction (n = 22) and by -95% (p<0.001) in low HDL-C subjects with Tangier disease (n = 7), unchanged in low HDL-C patients with Type 2 diabetes (n = 17) and in subjects with high HDL-C (n = 20), and elevated in subjects with extremely high HDL-C (+11%, p<0.05) relative to healthy normolipidemic controls. Across all the populations combined, HDL capacity to acquire DiI was directly correlated with HDL-C (r = 0.58, p<0.001). No relationship of HDL capacity to acquire DiI with both overall and cardiovascular mortality obtained from epidemiological studies for the mean HDL-C levels observed in the studied populations was obtained. CONCLUSIONS: These data indicate that the capacity of HDL to acquire phospholipid from TGRL upon LPL-mediated lipolysis is proportional to HDL-C and does not reflect cardiovascular risk in subjects widely differing in HDL-C levels.

The Role of Statins in Current Guidelines.

PURPOSE OF REVIEW: The causal association of LDL-cholesterol (LDL-C) with atherosclerotic cardiovascular disease (ASCVD) has been demonstrated in robust experimental, epidemiological, genetic, and interventional randomized controlled trials (RCTs). The goal of this review is to show how the knowledge acquired from statin RCTs influenced and was recommended on guidelines for prevention of ASCVD during the last three decades. RECENT FINDINGS: Guideline recommendations have evolved with accruing information derived mostly from statin RCTs, and as decades passed, more intensive LDL-C lowering was recommended according to a given ASCVD risk. Recent guidelines are unanimous in recommending intensive LDL-C lowering for the highest-risk individuals; however, they differ regarding risk stratification tools, use of specific LDL-C targets, management of primary prevention individuals, and thresholds to start non-statin lipid-lowering therapies. Even considering the advent of non-statin therapies like ezetimibe and PCSK9 inhibitors, due to their efficacy, safety, and low cost, guidelines state that statins persist as the main component of ASCVD preventive strategies and should be prescribed in adequate doses to attain evidence-based LDL-C lowering.

Free cholesterol transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis underlies the U-shape relationship between HDL-cholesterol and cardiovascular disease.

BACKGROUND: Low concentrations of high-density lipoprotein cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels are equally associated with elevated cardiovascular risk, resulting in the U-shape relationship of HDL-C with cardiovascular disease. Mechanisms underlying this association are presently unknown. We hypothesised that the capacity of high-density lipoprotein (HDL) to acquire free cholesterol upon triglyceride-rich lipoprotein (TGRL) lipolysis by lipoprotein lipase underlies the non-linear relationship between HDL-C and cardiovascular risk. METHODS: To assess our hypothesis, we developed a novel assay to evaluate the capacity of HDL to acquire free cholesterol (as fluorescent TopFluor® cholesterol) from TGRL upon in vitro lipolysis by lipoprotein lipase. RESULTS: When the assay was applied to several populations markedly differing in plasma HDL-C levels, transfer of free cholesterol was significantly decreased in low HDL-C patients with acute myocardial infarction (-45%) and type 2 diabetes (-25%), and in subjects with extremely high HDL-C of >2.59 mmol/L (>100 mg/dL) (-20%) versus healthy normolipidaemic controls. When these data were combined and plotted against HDL-C concentrations, an inverse U-shape relationship was observed. Consistent with these findings, animal studies revealed that the capacity of HDL to acquire cholesterol upon lipolysis was reduced in low HDL-C apolipoprotein A-I knock-out mice and was negatively correlated with aortic accumulation of [3H]-cholesterol after oral gavage, attesting this functional characteristic as a negative metric of postprandial atherosclerosis. CONCLUSIONS: Free cholesterol transfer to HDL upon TGRL lipolysis may underlie the U-shape relationship between HDL-C and cardiovascular disease, linking HDL-C to triglyceride metabolism and atherosclerosis.

Distinct phospholipid and sphingolipid species are linked to altered HDL function in apolipoprotein A-I deficiency.

BACKGROUND: Familial apolipoprotein A-I (apoA-I) deficiency (FAID) involving low levels of both apoA-I and high-density lipoprotein (HDL) cholesterol is associated with accelerated atherosclerosis. OBJECTIVE: The objective of this study was to define distinctive patterns in the lipidome of HDL subpopulations in FAID in relationship to antiatherogenic activities. METHODS: Five HDL subfractions were isolated by ultracentrifugation from plasma of FAID Caucasian patients (n = 5) and age-matched healthy normolipidemic Caucasian controls (n = 8), and the HDL lipidome (160 molecular species of 9 classes of phospholipids and sphingolipids) was quantitatively evaluated. RESULTS: Increased concentrations of numerous molecular species of lysophosphatidylcholine (up to 12-fold), ceramides (up to 3-fold), phosphatidylserine (up to 34-fold), phosphatidic acid (up to 71-fold), and phosphatidylglycerol (up to 20-fold) were detected throughout all five HDL subpopulations as compared with their counterparts from controls, whereas concentrations of phosphatidylethanolamine species were decreased (up to 5-fold). Moderately to highly abundant, within their lipid class, species of phosphatidylcholine, sphingomyelin, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, and ceramide featuring multiple unsaturations were primarily affected by apoA-I deficiency; their HDL content, particularly that of phosphatidylcholine (34:2), was strongly correlated with HDL function, impaired in FAID. Metabolic pathway analysis revealed that sphingolipid, glycerophospholipid, and linoleic acid metabolism was significantly affected by FAID. CONCLUSION: These data reveal that altered content of specific phospholipid and sphingolipid species is linked to deficient antiatherogenic properties of HDL in FAID.

Impact of Lipoproteins on Atherobiology: Emerging Insights.

Apolipoprotein B-containing lipoproteins and low-density lipoprotein play a key role in atherosclerotic vascular disease. Modified forms of low-density lipoprotein drive inflammation, an integral aspect of plaque progression. High-density lipoprotein particles are equipped to protect low-density lipoprotein from enzymatic and nonenzymatic modification. Under normal conditions, high-density lipoproteins facilitate cholesterol efflux from tissues, preventing its accumulation with deleterious consequences. However, the high-density lipoprotein particles characteristic of dyslipidemic states associated with premature atherosclerosis are typically dysfunctional as a result of alteration in their metabolism and consequently their structure and composition. Such an effect indirectly enhances low-density lipoprotein atherogenicity.

Defective functionality of small, dense HDL3 subpopulations in ST segment elevation myocardial infarction: Relevance of enrichment in lysophosphatidylcholine, phosphatidic acid and serum amyloid A.

BACKGROUND: Low plasma levels of high-density lipoprotein-cholesterol (HDL-C) are typical of acute myocardial infarction (MI) and predict risk of recurrent cardiovascular events. The potential relationships between modifications in the molecular composition and the functionality of HDL subpopulations in acute MI however remain indeterminate. METHODS AND RESULTS: ST segment elevation MI (STEMI) patients were recruited within 24h after diagnosis (n=16) and featured low HDL-C (-31%, p<0.05) and acute-phase inflammation (determined as marked elevations in C-reactive protein, serum amyloid A (SAA) and interleukin-6) as compared to age- and sex-matched controls (n=10). STEMI plasma HDL and its subpopulations (HDL2b, 2a, 3a, 3b, 3c) displayed attenuated cholesterol efflux capacity from THP-1 cells (up to -32%, p<0.01, on a unit phospholipid mass basis) vs. CONTROLS: Plasma HDL and small, dense HDL3b and 3c subpopulations from STEMI patients exhibited reduced anti-oxidative activity (up to -68%, p<0.05, on a unit HDL mass basis). HDL subpopulations in STEMI were enriched in two proinflammatory bioactive lipids, lysophosphatidylcholine (up to 3.0-fold, p<0.05) and phosphatidic acid (up to 8.4-fold, p<0.05), depleted in apolipoprotein A-I (up to -23%, p<0.05) and enriched in SAA (up to +10.2-fold, p<0.05); such changes were most marked in the HDL3b subfraction. In vitro HDL enrichment in both lysophosphatidylcholine and phosphatidic acid exerted deleterious effects on HDL functionality. CONCLUSIONS: In the early phase of STEMI, HDL particle subpopulations display marked, concomitant alterations in both lipidome and proteome which are implicated in impaired HDL functionality. Such modifications may act synergistically to confer novel deleterious biological activities to STEMI HDL. SIGNIFICANCE: Our present data highlight complex changes in the molecular composition and functionality of HDL particle subpopulations in the acute phase of STEMI, and for the first time, reveal that concomitant modifications in both the lipidome and proteome contribute to functional deficiencies in cholesterol efflux and antioxidative activities of HDL particles. These findings may provide new biomarkers and new insights in therapeutic strategy to reduce cardiovascular risk in this clinical setting where such net deficiency in HDL function, multiplied by low circulating HDL concentrations, can be expected to contribute to accelerated atherogenesis.

HDL particle subpopulations: Focus on biological function.

Low levels of high-density lipoprotein-cholesterol (HDL-C) constitute an independent biomarker of cardiovascular morbi-mortality. However, recent advances have drastically modified the classical and limited view of HDL as a carrier of 'good cholesterol', and have revealed unexpected levels of complexity in the circulating HDL particle pool. HDL particles are indeed highly heterogeneous in structure, intravascular metabolism and biological activity. This review describes recent progress in our understanding of HDL subpopulations and their biological activities, and focuses on relationships between the structural, compositional and functional heterogeneity of HDL particles.

Defective functionality of HDL particles in familial apoA-I deficiency: relevance of alterations in HDL lipidome and proteome.

To evaluate functional and compositional properties of HDL in subjects from a kindred of genetic apoA-I deficiency, two homozygotes and six heterozygotes, with a nonsense mutation at APOA1 codon -2, Q[-2]X, were recruited together with age- and sex-matched healthy controls (n = 11). Homozygotes displayed undetectable plasma levels of apoA-I and reduced levels of HDL-cholesterol (HDL-C) and apoC-III (5.4% and 42.6% of controls, respectively). Heterozygotes displayed low HDL-C (21 ± 9 mg/dl), low apoA-I (79 ± 24 mg/dl), normal LDL-cholesterol (132 ± 25 mg/dl), and elevated TG (130 ± 45 mg/dl) levels. Cholesterol efflux capacity of ultracentrifugally isolated HDL subpopulations was reduced (up to -25%, P < 0.01, on a glycerophospholipid [GP] basis) in heterozygotes versus controls. Small, dense HDL3 and total HDL from heterozygotes exhibited diminished antioxidative activity (up to -48%, P < 0.001 on a total mass basis) versus controls. HDL subpopulations from both homozygotes and heterozygotes displayed altered chemical composition, with depletion in apoA-I, GP, and cholesteryl ester; enrichment in apoA-II, free cholesterol, and TG; and altered phosphosphingolipidome. The defective atheroprotective activities of HDL were correlated with altered lipid and apo composition. These data reveal that atheroprotective activities of HDL particles are impaired in homozygous and heterozygous apoA-I deficiency and are intimately related to marked alterations in protein and lipid composition.