Michael D. Shapiro

Dual-Energy X-Ray Absorptiometry for Quantification of Visceral Fat

Obesity is the major risk factor for metabolic syndrome and through it diabetes as well as cardiovascular disease. Visceral fat (VF) rather than subcutaneous fat (SF) is the major predictor of adverse events. Currently, the reference standard for measuring VF is abdominal X‐ray computed tomography (CT) or magnetic resonance imaging (MRI), requiring highly used clinical equipment. Dual‐energy X‐ray absorptiometry (DXA) can accurately measure body composition with high‐precision, low X‐ray exposure, and short‐scanning time. The purpose of this study was to validate a new fully automated method whereby abdominal VF can be measured by DXA. Furthermore, we explored the association between DXA‐derived abdominal VF and several other indices for obesity: BMI, waist circumference, waist‐to‐hip ratio, and DXA‐derived total abdominal fat (AF), and SF. We studied 124 adult men and women, aged 18–90 years, representing a wide range of BMI values (18.5–40 kg/m2) measured with both DXA and CT in a fasting state within a one hour interval. The coefficient of determination (r2) for regression of CT on DXA values was 0.959 for females, 0.949 for males, and 0.957 combined. The 95% confidence interval for r was 0.968 to 0.985 for the combined data. The 95% confidence interval for the mean of the differences between CT and DXA VF volume was −96.0 to −16.3 cm3. Bland‐Altman bias was +67 cm3 for females and +43 cm3 for males. The 95% limits of agreement were −339 to +472 cm3 for females and −379 to +465 cm3 for males. Combined, the bias was +56 cm3 with 95% limits of agreement of −355 to +468 cm3. The correlations between DXA‐derived VF and BMI, waist circumference, waist‐to‐hip ratio, and DXA‐derived AF and SF ranged from poor to modest. We conclude that DXA can measure abdominal VF precisely in both men and women. This simple noninvasive method with virtually no radiation can therefore be used to measure VF in individual patients and help define diabetes and cardiovascular risk.

From Lipids to Inflammation: New Approaches to Reducing Atherosclerotic Risk

The introduction of statins ≈ 30 years ago ushered in the era of lipid lowering as the most effective way to reduce risk of atherosclerotic cardiovascular disease. Nonetheless, residual risk remains high, and statin intolerance is frequently encountered in clinical practice. After a long dry period, the field of therapeutics targeted to lipids and atherosclerosis has entered a renaissance. Moreover, the demonstration of clinical benefits from the addition of ezetimibe to statin therapy in subjects with acute coronary syndromes has renewed the enthusiasm for the cholesterol hypothesis and the hope that additional agents that lower low-density lipoprotein will decrease risk of atherosclerotic cardiovascular disease. Drugs in the orphan disease category are now available for patients with the most extreme hypercholesterolemia. Furthermore, discovery and rapid translation of a novel biological pathway has given rise to a new class of cholesterol-lowering drugs, the proprotein convertase subtilisin kexin-9 inhibitors. Trials of niacin added to statin have failed to demonstrate cardiac benefits, and 3 cholesterol ester transfer protein inhibitors have also failed to reduce atherosclerotic cardiovascular disease risk, despite producing substantial increases in HDL levels. Although the utility of triglyceride-lowering therapies remains uncertain, 2 large clinical trials are testing the influence of omega-3 polyunsaturated fatty acids on atherosclerotic events in hypertriglyceridemia. Novel antisense therapies targeting apolipoprotein C-III (for triglyceride reduction) and apo(a) (for lipoprotein(a) reduction) are showing a promising trajectory. Finally, 2 large clinical trials are formally putting the inflammatory hypothesis of atherosclerosis to the test and may open a new avenue for cardiovascular disease risk reduction.

Recommended practices for computerized clinical decision support and knowledge management in community settings: a qualitative study

BackgroundThe purpose of this study was to identify recommended practices for computerized clinical decision support (CDS) development and implementation and for knowledge management (KM) processes in ambulatory clinics and community hospitals using commercial or locally developed systems in the U.S.MethodsGuided by the Multiple Perspectives Framework, the authors conducted ethnographic field studies at two community hospitals and five ambulatory clinic organizations across the U.S. Using a Rapid Assessment Process, a multidisciplinary research team: gathered preliminary assessment data; conducted on-site interviews, observations, and field surveys; analyzed data using both template and grounded methods; and developed universal themes. A panel of experts produced recommended practices.ResultsThe team identified ten themes related to CDS and KM. These include: 1) workflow; 2) knowledge management; 3) data as a foundation for CDS; 4) user computer interaction; 5) measurement and metrics; 6) governance; 7) translation for collaboration; 8) the meaning of CDS; 9) roles of special, essential people; and 10) communication, training, and support. Experts developed recommendations about each theme. The original Multiple Perspectives framework was modified to make explicit a new theoretical construct, that of Translational Interaction.ConclusionsThese ten themes represent areas that need attention if a clinic or community hospital plans to implement and successfully utilize CDS. In addition, they have implications for workforce education, research, and national-level policy development. The Translational Interaction construct could guide future applied informatics research endeavors.

Treatment Gaps in Adults with Heterozygous Familial Hypercholesterolemia in the United States: Data from the CASCADE-FH Registry

Background— Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. Methods and Results— We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08–2.82) and hypertension (2.48; 1.92–3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86–28.86) and use of >1 LDL-lowering medication (1.80; 1.34–2.41). Conclusions— FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.

PCSK9 Association With Lipoprotein(a)

RATIONALE Lipoprotein(a) [Lp(a)] is a highly atherogenic low-density lipoprotein-like particle characterized by the presence of apoprotein(a) [apo(a)] bound to apolipoprotein B. Proprotein convertase subtilisin/kexin type 9 (PCSK9) selectively binds low-density lipoprotein; we hypothesized that it can also be associated with Lp(a) in plasma. OBJECTIVE Characterize the association of PCSK9 and Lp(a) in 39 subjects with high Lp(a) levels (range 39-320 mg/dL) and in transgenic mice expressing either human apo(a) only or human Lp(a) (via coexpression of human apo(a) and human apolipoprotein B). METHODS AND RESULTS We show that PCSK9 is physically associated with Lp(a) in vivo using 3 different approaches: (1) analysis of Lp(a) fractions isolated by ultracentrifugation; (2) immunoprecipitation of plasma using antibodies to PCSK9 and immunodetection of apo(a); (3) ELISA quantification of Lp(a)-associated PCSK9. Plasma PCSK9 levels correlated with Lp(a) levels, but not with the number of kringle IV-2 repeats. PCSK9 did not bind to apo(a) only, and the association of PCSK9 with Lp(a) was not affected by the loss of the apo(a) region responsible for binding oxidized phospholipids. Preferential association of PCSK9 with Lp(a) versus low-density lipoprotein (1.7-fold increase) was seen in subjects with high Lp(a) and normal low-density lipoprotein. Finally, Lp(a)-associated PCSK9 levels directly correlated with plasma Lp(a) levels but not with total plasma PCSK9 levels. CONCLUSIONS Our results show, for the first time, that plasma PCSK9 is found in association with Lp(a) particles in humans with high Lp(a) levels and in mice carrying human Lp(a). Lp(a)-bound PCSK9 may be pursued as a biomarker for cardiovascular risk.

Targeting PCSK9 for therapeutic gains.

Even though it is only a little over a decade from the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a plasma protein that associates with both hypercholesterolemia and low cholesterol syndromes, a rich literature has developed describing its unique physiology and the impact of antagonism of this molecule on cholesterol metabolism for therapeutic purposes. Indeed, the PCSK9 story is unfolding rapidly, with many answers and more questions. This review summarizes the most recent data from phase II/III clinical trials of PCSK9 inhibition with the three leading antibodies, highlights the clinical significance of the ongoing studies, and suggests future areas of investigation based on recent basic science discoveries on the physiology of PCSK9.

Clinical decision support in small community practice settings: a case study

Using an eight-dimensional model for studying socio-technical systems, a multidisciplinary team of investigators identified barriers and facilitators to clinical decision support (CDS) implementation in a community setting, the Mid-Valley Independent Physicians Association in the Salem, Oregon area. The team used the Rapid Assessment Process, which included nine formal interviews with CDS stakeholders, and observation of 27 clinicians. The research team, which has studied 21 healthcare sites of various sizes over the past 12 years, believes this site is an excellent example of an organization which is using a commercially available electronic-health-record system with CDS well. The eight-dimensional model proved useful as an organizing structure for the evaluation.

PCSK9 and Atherosclerosis - Lipids and Beyond

Even though it is only a little over a decade from the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a plasma protein that associates with both high and low cholesterol syndromes, a rich body of knowledge has developed, and drugs inhibiting this target have been approved in many markets. While the majority of research in recent years has focused on the impact of therapeutic antagonism of this molecule, important lines of investigation have emerged characterizing its unique physiology as it relates to cholesterol metabolism and atherosclerosis. The PCSK9 story is unfolding rapidly but is far from complete. One chapter that is of particular interest is the possible direct link between PCSK9 and atherosclerosis. This review specifically examines this relationship drawing from data produced from experimental models of plaque biology and inflammation, atherosclerosis imaging studies, and observational epidemiology.

Triglycerides, atherosclerosis, and cardiovascular outcome studies: Focus on omega-3 fatty acids

OBJECTIVE To provide an overview of the roles of triglycerides and triglyceride-lowering agents in atherosclerosis in the context of cardiovascular outcomes studies. METHODS We reviewed the published literature as well as ClinicalTrials.gov entries for ongoing studies. RESULTS Despite improved atherosclerotic cardiovascular disease (ASCVD) outcomes with statin therapy, residual risk remains. Epidemiologic data and recent genetic insights provide compelling evidence that triglycerides are in the causal pathway for the development of atherosclerosis, thereby renewing interest in targeting triglycerides to improve ASCVD outcomes. Fibrates, niacin, and omega-3 fatty acids (OM3FAs) are three classes of triglyceride-lowering drugs. Outcome studies with triglyceride-lowering agents have been inconsistent. With regard to OM3FAs, the JELIS study showed that eicosapentaenoic acid (EPA) significantly reduced major coronary events in statin-treated hypercholesterolemic patients. Regarding other agents, extended-release niacin and fenofibrate are no longer recommended as statin add-on therapy (by some guidelines, though not all) because of the lack of convincing evidence from outcome studies. Notably, subgroup analyses from the outcome studies have generated the hypothesis that triglyceride lowering may provide benefit in statin-treated patients with persistent hypertriglyceridemia. Two ongoing OM3FA outcome studies (REDUCE-IT and STRENGTH) are testing this hypothesis in high-risk, statin-treated patients with triglyceride levels of 200 to 500 mg/dL. CONCLUSION There is consistent evidence that triglycerides are in the causal pathway of atherosclerosis but inconsistent evidence from cardiovascular outcomes studies as to whether triglyceride-lowering agents reduce cardiovascular risk. Ongoing outcomes studies will determine the role of triglyceride lowering in statin-treated patients with high-dose prescription OM3FAs in terms of improved ASCVD outcomes. ABBREVIATIONS AACE = American Association of Clinical Endocrinologists ACCORD = Action to Control Cardiovascular Risk in Diabetes AIM-HIGH = Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes apo = apolipoprotein ASCEND = A Study of Cardiovascular Events in Diabetes ASCVD = atherosclerotic cardiovascular disease BIP = Bezafibrate Infarction Prevention CHD = coronary heart disease CI = confidence interval CV = cardiovascular CVD = cardiovascular disease DHA = docosahexaenoic acid DO-IT = Diet and Omega-3 Intervention Trial EPA = eicosapentaenoic acid FIELD = Fenofibrate Intervention and Event Lowering in Diabetes GISSI-HF = GISSI-Heart Failure HDL-C = high-density-lipoprotein cholesterol HPS2-THRIVE = Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events HR = hazard ratio JELIS = Japan Eicosapentaenoic Acid Lipid Intervention Study LDL = low-density lipoprotein LDL-C = low-density-lipoprotein cholesterol MI = myocardial infarction OM3FAs = omega-3 fatty acids VITAL = Vitamin D and Omega-3 Trial.

Apolipoprotein B-containing lipoproteins and atherosclerotic cardiovascular disease

Cholesterol-rich, apolipoprotein B (apoB)-containing lipoproteins are now widely accepted as the most important causal agents of atherosclerotic cardiovascular disease. Multiple unequivocal and orthogonal lines of evidence all converge on low-density lipoprotein and related particles as being the principal actors in the genesis of atherosclerosis. Here, we review the fundamental role of atherogenic apoB-containing lipoproteins in cardiovascular disease and several other humoral and parietal factors that are required to initiate and maintain arterial degeneration. The biology of foam cells and their interactions with high-density lipoproteins, including cholesterol efflux, are also briefly reviewed.