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"Shapiro, Michael"
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Apolipoproteins in vascular biology and atherosclerotic disease
Apolipoproteins are important structural components of plasma lipoproteins that influence vascular biology and atherosclerotic disease pathophysiology by regulating lipoprotein metabolism. Clinically important apolipoproteins related to lipid metabolism and atherogenesis include apolipoprotein B-100, apolipoprotein B-48, apolipoprotein A-I, apolipoprotein C-II, apolipoprotein C-III, apolipoprotein E and apolipoprotein(a). Apolipoprotein B-100 is the major structural component of VLDL, IDL, LDL and lipoprotein(a). Apolipoprotein B-48 is a truncated isoform of apolipoprotein B-100 that forms the backbone of chylomicrons. Apolipoprotein A-I provides the scaffolding for lipidation of HDL and has an important role in reverse cholesterol transport. Apolipoproteins C-II, apolipoprotein C-III and apolipoprotein E are involved in triglyceride-rich lipoprotein metabolism. Apolipoprotein(a) covalently binds to apolipoprotein B-100 to form lipoprotein(a). In this Review, we discuss the mechanisms by which these apolipoproteins regulate lipoprotein metabolism and thereby influence vascular biology and atherosclerotic disease. Advances in the understanding of apolipoprotein biology and their translation into therapeutic agents to reduce the risk of cardiovascular disease are also highlighted.In this Review, Mehta and Shapiro discuss the mechanisms by which apolipoproteins regulate lipoprotein metabolism and thereby influence vascular biology and atherosclerotic disease. Advances in the understanding of apolipoprotein biology and their translation into therapeutic agents to reduce the risk of cardiovascular disease are also highlighted.
Journal Article
IL-6 and Cardiovascular Risk: A Narrative Review
Purpose of Review
The objective of this narrative review is to summarize data from recently published prospective observational studies that analyze the association between circulating interleukin-6 (IL-6) levels and cardiovascular clinical or imaging endpoints.
Recent Findings
Higher levels of IL-6 are associated with a higher risk of cardiovascular death, major adverse cardiovascular events, myocardial infarction, stroke, peripheral artery disease, and heart failure. Imaging studies have also shown an association between IL-6 and carotid intima-media thickness progression, carotid plaque progression, severity, and vulnerability. These observations have been consistent across a wide range of study populations and after adjusting for traditional and emerging risk factors including high-sensitivity C-reactive protein.
Summary
Robust epidemiologic evidence supports IL-6 as a central mediator of cardiovascular risk along with human genetic studies and mechanistic experiments. Ongoing clinical studies are testing the therapeutic hypothesis of IL-6 inhibition in patients with atherosclerotic cardiovascular disease or heart failure.
Journal Article
Coronary artery calcium testing in low-intermediate risk symptomatic patients with suspected coronary artery disease: An effective gatekeeper to further testing?
Computed tomography for quantification of coronary artery calcium (CAC) is a simple non-invasive tool to assess atherosclerotic plaque burden. CAC is highly correlated with coronary atherosclerosis and is a robust predictor of cardiovascular outcomes. Recently, the 2018 ACC/AHA Cholesterol Guidelines endorsed the use of CAC scores in asymptomatic, intermediate risk individuals where the decision to initiate stain therapy is uncertain. However, whether quantification of CAC may play a role in the assessment of symptomatic individuals remains a matter of debate. In this review, we examine the evidence for the use of CAC in low-intermediate risk patients with chest pain. This appraisal places a particular focus on the growing body of literature supporting the negative predictive value of a CAC score of zero to rule out significant coronary artery disease in those without high-risk features. We also evaluate current guidelines, limitations, and future research directions for CAC scoring in this important subgroup of patients.
Journal Article
Acknowledging Individual Responsibility while Emphasizing Social Determinants in Narratives to Promote Obesity-Reducing Public Policy: A Randomized Experiment
This study tests whether policy narratives designed to increase support for obesity-reducing public policies should explicitly acknowledge individual responsibility while emphasizing social, physical, and economic (social) determinants of obesity. We use a web-based, randomized experiment with a nationally representative sample of American adults (n = 718) to test hypotheses derived from theory and research on narrative persuasion. Respondents exposed to narratives that acknowledged individual responsibility while emphasizing obesity's social determinants were less likely to engage in counterargument and felt more empathy for the story's main character than those exposed to a message that did not acknowledge individual responsibility. Counterarguing and affective empathy fully mediated the relationship between message condition and support for policies to reduce rates of obesity. Failure to acknowledge individual responsibility in narratives emphasizing social determinants of obesity may undermine the persuasiveness of policy narratives. Omitting information about individual responsibility, a strongly-held American value, invites the public to engage in counterargument about the narratives and reduces feelings of empathy for a character that experiences the challenges and benefits of social determinants of obesity.
Journal Article
Small Interfering RNA Therapeutic Inclisiran: A New Approach to Targeting PCSK9
Hypercholesterolemia is a leading cause of cardiovascular disease and mortality in men and women throughout the USA and abroad. The development of statins (HMG-CoA reductase inhibitors) to lower plasma atherogenic cholesterol levels and improve cardiovascular outcomes represents one of the greatest contributions to clinical science in the twentieth century, although residual risk remains even among statin-treated patients. Our understanding of lipid metabolism took a giant leap forward in 2003 with the discovery of proprotein convertase subtilsin/kexin type 9 (PCSK9), a low abundance circulating protein with an outsized effect on the regulation of plasma cholesterol levels. Evolocumab and alirocumab represent the first two US Food and Drug Administration-approved fully human monoclonal antibodies that target PCSK9, which not only lower low-density lipoprotein (LDL) cholesterol to unprecedented levels, but also further improve important cardiovascular outcomes. Small interfering RNA (siRNA) molecules now represent the next generation of drugs designed to antagonize PCSK9. Inclisiran is a siRNA specific for PCSK9 that prevents translation of PCSK9 messenger RNA, leading to decreased concentrations of the protein and lower concentrations of LDL cholesterol. The ORION clinical development program includes several completed and ongoing clinical trials designed to evaluate the safety and efficacy of inclisiran and test its ability to improve hard cardiovascular outcomes. This review discusses the mechanisms of action of inclisiran, examines the current evidence, and provides a comparison of similarities and differences relative to the PCSK9 inhibitors.
Journal Article
The Role of Sleep in Cardiovascular Disease
Purpose of Review
Sleep is an important component of cardiovascular (CV) health. This review summarizes the complex relationship between sleep and CV disease (CVD). Additionally, we describe the data supporting the treatment of sleep disturbances in preventing and treating CVD.
Recent Findings
Recent guidelines recommend screening for obstructive sleep apnea in patients with atrial fibrillation. New data continues to demonstrate the importance of sleep quality and duration for CV health.
Summary
There is a complex bidirectional relationship between sleep health and CVD. Sleep disturbances have systemic effects that contribute to the development of CVD, including hypertension, coronary artery disease, heart failure, and arrhythmias. Additionally, CVD contributes to the development of sleep disturbances. However, more data are needed to support the role of screening for and treatment of sleep disorders for the prevention of CVD.
Journal Article
A copy number variant is associated with a spectrum of pigmentation patterns in the rock pigeon (Columba livia)
Rock pigeons (Columba livia) display an extraordinary array of pigment pattern variation. One such pattern, Almond, is characterized by a variegated patchwork of plumage colors that are distributed in an apparently random manner. Almond is a sex-linked, semi-dominant trait controlled by the classical Stipper (St) locus. Heterozygous males (ZStZ+ sex chromosomes) and hemizygous Almond females (ZStW) are favored by breeders for their attractive plumage. In contrast, homozygous Almond males (ZStZSt) develop severe eye defects and often lack plumage pigmentation, suggesting that higher dosage of the mutant allele is deleterious. To determine the molecular basis of Almond, we compared the genomes of Almond pigeons to non-Almond pigeons and identified a candidate St locus on the Z chromosome. We found a copy number variant (CNV) within the differentiated region that captures complete or partial coding sequences of four genes, including the melanosome maturation gene Mlana. We did not find fixed coding changes in genes within the CNV, but all genes are misexpressed in regenerating feather bud collar cells of Almond birds. Notably, six other alleles at the St locus are associated with depigmentation phenotypes, and all exhibit expansion of the same CNV. Structural variation at St is linked to diversity in plumage pigmentation and gene expression, and thus provides a potential mode of rapid phenotypic evolution in pigeons.
Journal Article
Lipoprotein(a) Reduction in Persons with Cardiovascular Disease
Elevated levels of lipoprotein(a) in the plasma are a risk factor for cardiovascular disease, and lowering levels can be achieved with antisense oligonucleotide targeting
LPA
messenger RNA, which encodes lipoprotein(a). This trial tested whether the same effect can be achieved in persons with established cardiovascular disease.
Journal Article
Metabolic dysfunction-associated fatty liver disease and implications for cardiovascular risk and disease prevention
The newly proposed term “metabolic dysfunction-associated fatty liver disease” (MAFLD) is replacing the old term “non-alcoholic fatty liver disease” (NAFLD) in many global regions, because it better reflects the pathophysiology and cardiometabolic implications of this common liver disease. The proposed change in terminology from NAFLD to MAFLD is not simply a single-letter change in an acronym, since MAFLD is defined by a set of specific and positive diagnostic criteria. In particular, the MAFLD definition specifically incorporates within the classification recognized cardiovascular risk factors. Although convincing evidence supports a significant association between both NAFLD and MAFLD, with increased risk of CVD morbidity and mortality, neither NAFLD nor MAFLD have received sufficient attention from the Cardiology community. In fact, there is a paucity of scientific guidelines focusing on this common and burdensome liver disease from cardiovascular professional societies. This Perspective article discusses the rationale and clinical relevance for Cardiologists of the newly proposed MAFLD definition.
Journal Article