Publications by authors named "Michael D Shapiro"

172 Publications

Apolipoproteins in vascular biology and atherosclerotic disease.

Nat Rev Cardiol 2021 Oct 8. Epub 2021 Oct 8.

Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

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.
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http://dx.doi.org/10.1038/s41569-021-00613-5DOI Listing
October 2021

Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies.

J Am Coll Cardiol 2021 Oct;78(14):1437-1449

Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, Oregon, USA.

Background: Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9i) lower LDL-C by up to 60% and increase plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels by 10-fold.

Objectives: The authors studied the reasons behind the robust increase in plasma PCSK9 levels by testing the hypothesis that mechanisms beyond clearance via the low-density lipoprotein receptor (LDLR) contribute to the regulation of cholesterol homeostasis.

Methods: In clinical cohorts, animal models, and cell-based studies, we measured kinetic changes in PCSK9 production and clearance in response to PCSK9i.

Results: In a patient cohort receiving PCSK9i therapy, plasma PCSK9 levels rose 11-fold during the first 3 months and then plateaued for 15 months. In a cohort of healthy volunteers, a single injection of PCSK9i increased plasma PCSK9 levels within 12 hours; the rise continued for 9 days until it plateaued at 10-fold above baseline. We recapitulated the rapid rise in PCSK9 levels in a mouse model, but only in the presence of LDLR. In vivo turnover and in vitro pulse-chase studies identified 2 mechanisms contributing to the rapid increase in plasma PCSK9 levels in response to PCSK9i: 1) the expected delayed clearance of the antibody-bound PCSK9; and 2) the unexpected post-translational increase in PCSK9 secretion.

Conclusions: PCSK9 re-entry to the liver via LDLR triggers a sensing loop regulating PCSK9 secretion. PCSK9i therapy enhances the secretion of PCSK9, an effect that contributes to the increased plasma PCSK9 levels in treated subjects.
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http://dx.doi.org/10.1016/j.jacc.2021.07.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486917PMC
October 2021

A ROR2 coding variant is associated with craniofacial variation in domestic pigeons.

Curr Biol 2021 Sep 15. Epub 2021 Sep 15.

School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA. Electronic address:

Vertebrate craniofacial morphogenesis is a highly orchestrated process that is directed by evolutionarily conserved developmental pathways. Within species, canalized development typically produces modest morphological variation. However, as a result of millennia of artificial selection, the domestic pigeon displays radical craniofacial variation within a single species. One of the most striking cases of pigeon craniofacial variation is the short-beak phenotype, which has been selected in numerous breeds. Classical genetic experiments suggest that pigeon beak length is regulated by a small number of genetic factors, one of which is sex linked (Ku2 locus). However, the genetic underpinnings of pigeon craniofacial variation remain unknown. Using geometric morphometrics and quantitative trait locus (QTL) mapping on an F intercross between a short-beaked Old German Owl (OGO) and a medium-beaked Racing Homer (RH), we identified a single Z chromosome locus that explains a majority of the variation in beak morphology in the F population. Complementary comparative genomic analyses revealed that the same locus is strongly differentiated between breeds with short and medium beaks. Within the Ku2 locus, we identified an amino acid substitution in the non-canonical Wnt receptor ROR2 as a putative regulator of pigeon beak length. The non-canonical Wnt pathway serves critical roles in vertebrate neural crest cell migration and craniofacial morphogenesis. In humans, ROR2 mutations cause Robinow syndrome, a congenital disorder characterized by skeletal abnormalities, including a widened and shortened facial skeleton. Our results illustrate how the extraordinary craniofacial variation among pigeons can reveal genetic regulators of vertebrate craniofacial diversity.
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http://dx.doi.org/10.1016/j.cub.2021.08.068DOI Listing
September 2021

High-Sensitivity C-Reactive Protein Modifies the Cardiovascular Risk of Lipoprotein(a): Multi-Ethnic Study of Atherosclerosis.

J Am Coll Cardiol 2021 Sep;78(11):1083-1094

Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Department of Internal Medicine, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, USA. Electronic address:

Background: Little is known about the relationship between lipoprotein (a) [Lp(a)] and high-sensitivity C-reactive protein (hsCRP) and their joint association with atherosclerotic cardiovascular disease (ASCVD).

Objectives: The purpose of this study was to assess whether Lp(a)-associated ASCVD risk is modified by hsCRP in the context of primary prevention.

Methods: The current study included 4,679 participants from the MESA (Multi-Ethnic Study of Atherosclerosis) Apolipoprotein ancillary data set. Cox proportional hazards models and Kaplan-Meier curves were used to assess the association among Lp(a), hsCRP, and time to cardiovascular disease (CVD) events.

Results: During a mean follow-up of 13.6 years, 684 CVD events occurred. A significant interaction was observed between Lp(a) and hsCRP (P = 0.04). With hsCRP <2 mg/L, no significant CVD risk was observed at any level of Lp(a) from <50 mg/dL to >100 mg/dL. However, with hsCRP ≥2 mg/L, a significant CVD risk was observed with Lp(a) of 50-99.9 mg/dL (HR: 1.36; 95% CI: 1.02-1.81) and Lp(a) ≥100 mg/dL (HR: 2.09; 95% CI: 1.40-3.13). Isolated elevations of either Lp(a) or hsCRP were not associated with increased CVD risk. In contrast, the combination of elevated Lp(a) (≥50 mg/dL) and hsCRP (≥2 mg/L) was independently associated with significant CVD risk (HR: 1.62; 95% CI: 1.25-2.10) and all-cause mortality (HR: 1.39; 95% CI: 1.12-1.72).

Conclusions: Lp(a)-associated ASCVD risk is observed only with concomitant elevation of hsCRP. Individuals with concomitant presence of elevated Lp(a) and systemic inflammation have greater ASCVD risk and all-cause mortality, and thus may merit closer surveillance and more aggressive ASCVD risk management.
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http://dx.doi.org/10.1016/j.jacc.2021.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444216PMC
September 2021

Two Genomic Loci Control Three Eye Colors in the Domestic Pigeon (Columba livia).

Mol Biol Evol 2021 Aug 30. Epub 2021 Aug 30.

School of Biological Sciences, University of Utah, Salt Lake City, UT, 84112, USA.

The iris of the eye shows striking color variation across vertebrate species, and may play important roles in crypsis and communication. The domestic pigeon (Columba livia) has three common iris colors, orange, pearl (white), and bull (dark brown), segregating in a single species, thereby providing a unique opportunity to identify the genetic basis of iris coloration. We used comparative genomics and genetic mapping in laboratory crosses to identify two candidate genes that control variation in iris color in domestic pigeons. We identified a nonsense mutation in the solute carrier SLC2A11B that is shared among all pigeons with pearl eye color, and a locus associated with bull eye color that includes EDNRB2, a gene involved in neural crest migration and pigment development. However, bull eye is likely controlled by a heterogeneous collection of alleles across pigeon breeds. We also found that the EDNRB2 region is associated with regionalized plumage depigmentation (piebalding). Our study identifies two candidate genes for eye colors variation, and establishes a genetic link between iris and plumage color, two traits that vary widely in the evolution of birds and other vertebrates.
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http://dx.doi.org/10.1093/molbev/msab260DOI Listing
August 2021

Ten things to know about ten cardiovascular disease risk factors.

Am J Prev Cardiol 2021 Mar 23;5:100149. Epub 2021 Jan 23.

CGH Medical Center, Sterling, IL USA.

Given rapid advancements in medical science, it is often challenging for the busy clinician to remain up-to-date on the fundamental and multifaceted aspects of preventive cardiology and maintain awareness of the latest guidelines applicable to cardiovascular disease (CVD) risk factors. The "American Society for Preventive Cardiology (ASPC) Top Ten CVD Risk Factors 2021 Update" is a summary document (updated yearly) regarding CVD risk factors. This "ASPC Top Ten CVD Risk Factors 2021 Update" summary document reflects the perspective of the section authors regarding ten things to know about ten sentinel CVD risk factors. It also includes quick access to sentinel references (applicable guidelines and select reviews) for each CVD risk factor section. The ten CVD risk factors include unhealthful nutrition, physical inactivity, dyslipidemia, hyperglycemia, high blood pressure, obesity, considerations of select populations (older age, race/ethnicity, and sex differences), thrombosis/smoking, kidney dysfunction and genetics/familial hypercholesterolemia. For the individual patient, other CVD risk factors may be relevant, beyond the CVD risk factors discussed here. However, it is the intent of the "ASPC Top Ten CVD Risk Factors 2021 Update" to provide a succinct overview of things to know about ten common CVD risk factors applicable to preventive cardiology.
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http://dx.doi.org/10.1016/j.ajpc.2021.100149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315386PMC
March 2021

Closing the Glycemic Divide: The Time for Preventive Cardiology Is Now.

J Am Coll Cardiol 2021 Aug;78(5):465-467

National Center for Cardiovascular Research (CNIC), Madrid, Spain; IIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain; CIBERCV, Madrid, Spain. Electronic address: https://twitter.com/Borjaibanez1.

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http://dx.doi.org/10.1016/j.jacc.2021.05.040DOI Listing
August 2021

Discordant responses of plasma low-density lipoprotein cholesterol and lipoprotein(a) to alirocumab: A pooled analysis from 10 ODYSSEY Phase 3 studies.

Eur J Prev Cardiol 2021 Jul;28(8):816-822

Center for Preventive Cardiology, Wake Forest University Baptist Medical Center, Section on Cardiovascular Medicine, USA.

Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors consistently reduce low-density lipoprotein cholesterol (LDL-C) by 50-60% and lipoprotein(a) (Lp(a)) by 20-30%, but the mechanism of Lp(a) lowering remains unclear. If Lp(a) is cleared by the LDL receptor, similar to LDL-C, then one would expect PCSK9 inhibition to induce a concordant LDL-C/Lp(a) response in an approximately 2:1 ratio. We aim to determine the prevalence of discordant plasma LDL-C/Lp(a) response to the PCSK9 inhibitor alirocumab.

Methods: This is a post hoc, pooled analysis of 10 randomized controlled trials from the ODYSSEY Phase 3 clinical trial program for alirocumab. Patients enrolled in the trials were high cardiovascular risk and/or with heterozygous familial hypercholesterolemia. The primary end point was prevalence of discordant LDL-C/Lp(a) response to alirocumab at 24 weeks. Discordant response was defined as LDL-C reduction >35% and Lp(a) reduction ≤10%, or LDL-C reduction ≤35% and Lp(a) reduction >10%.

Results: Of the 1709 patients in the pooled study cohort, 62.4% were male, and the mean age was 59.2 (SD: 11.0) years. Baseline mean LDL-C was 126.5 (SD: 46.3) mg/dL and baseline median Lp(a) was 46.9 (interquartile range: 21.8-89.0) mg/dL. Total prevalence of discordant LDL-C/Lp(a) response was 21.5% (12.6% with LDL-C >35% reduction and Lp(a) ≤10% reduction; 8.9% with LDL-C ≤35% reduction and Lp(a) >10% reduction). Baseline Lp(a) and familial hypercholesterolemia status did not affect discordance.

Conclusion: A high prevalence of discordant LDL-C/Lp(a) response was observed with alirocumab, further suggesting that PCSK9 inhibitor therapy with alirocumab reduces plasma Lp(a) through alternative pathways to LDL receptor clearance.
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http://dx.doi.org/10.1177/2047487320915803DOI Listing
July 2021

Coronary Artery Calcification and Risk Stratification in Familial Hypercholesterolemia: Moving Forward But Not There Yet.

JACC Cardiovasc Imaging 2021 Jul 7. Epub 2021 Jul 7.

Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jcmg.2021.06.013DOI Listing
July 2021

Stroke-Related Mortality in the United States-Mexico Border Area of the United States, 1999 to 2018.

J Am Heart Assoc 2021 07 2;10(13):e019993. Epub 2021 Jul 2.

Department of Cardiovascular Medicine Mayo Clinic Rochester MN.

BACKGROUND The United States (US)-Mexico border is a socioeconomically underserved area. We sought to investigate whether stroke-related mortality varies between the US border and nonborder counties. METHODS AND RESULTS We used death certificates from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database to examine stroke-related mortality in border versus nonborder counties in California, Texas, New Mexico, and Arizona. We measured average annual percent changes (AAPCs) in age-adjusted mortality rates (AAMRs) per 100 000 between 1999 and 2018. Overall, AAMRs were higher for nonborder counties, older adults, men, and non-Hispanic Black adults than their counterparts. Between 1999 and 2018, AAMRs reduced from 55.8 per 100 000 to 34.4 per 100 000 in the border counties (AAPC, -2.70) and 64.5 per 100 000 to 37.6 per 100 000 in nonborder counties (AAPC, -2.92). The annual percent change in AAMR initially decreased, followed by stagnation in both border and nonborder counties since 2012. The AAPC in AAMR decreased in all 4 states; however, AAMR increased in California's border counties since 2012 (annual percent change, 3.9). The annual percent change in AAMR decreased for older adults between 1999 and 2012 for the border (-5.10) and nonborder counties (-5.01), followed by a rise in border counties and stalling in nonborder counties. Although the AAPC in AAMR decreased for both sexes, the AAPC in AAMR differed significantly for non-Hispanic White adults in border (-2.69) and nonborder counties (-2.86). The mortality decreased consistently for all other ethnicities/races in both border and nonborder counties. CONCLUSIONS Stroke-related mortality varied between the border and nonborder counties. Given the substantial public health implications, targeted interventions aimed at vulnerable populations are required to improve stroke-related outcomes in the US-Mexico border area.
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http://dx.doi.org/10.1161/JAHA.120.019993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403284PMC
July 2021

Polygenic Risk Scores to Identify CVD Risk and Tailor Therapy: Hope or Hype?

Curr Atheroscler Rep 2021 Jun 28;23(9):47. Epub 2021 Jun 28.

Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Purpose Of Review: The purpose of this review is to understand the conceptual basis and implications of polygenic risk scores (PRS) in assessing risk of future coronary artery disease (CAD).

Recent Findings: Genetic information from the USA and beyond has been pooled together to create population-based biobanks, composed of millions of genotyped individuals, which have helped further our understanding of the relationship between single nucleotide polymorphisms (SNPs) and CAD. Contemporary PRS composed of millions of SNPs now serve as the gold standard and have been evaluated in several cohort studies to predict risk of CAD and potentially help guide pharmacotherapy. The development of PRS has enhanced our understanding of the relationship between genes and disease, thereby facilitating CAD risk prediction. While certain constraints currently limit their utility in clinical practice, further refinement of this tool will enable clinicians to more fully understand genetic risk and improve preventive care.
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http://dx.doi.org/10.1007/s11883-021-00950-3DOI Listing
June 2021

Roadmap to a career in preventive cardiology.

Heart 2021 Sep 14;107(17):1435-1436. Epub 2021 Jun 14.

Cardiovascular Medicine, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA

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http://dx.doi.org/10.1136/heartjnl-2021-319422DOI Listing
September 2021

Inflammation and Cardiovascular Disease: The Future.

Eur Cardiol 2021 Feb 17;16:e20. Epub 2021 May 17.

Deutsches Herzzentrum München, Technische Universität München Munich, Germany.

Despite considerable advances in reducing the global burden of atherosclerotic cardiovascular disease by targeting conventional risk factors, significant residual risk remains, with low-grade inflammation being one of the strongest risk modifiers. Inflammatory processes within the arterial wall or systemic circulation, which are driven in a large part by modified lipoproteins but subsequently trigger a hypercoagulable state, are a hallmark of atherosclerotic cardiovascular disease and, in particular, its clinical complications. Extending conventional guideline-based clinical risk stratification algorithms by adding biomarkers of inflammation may refine phenotypic screening, improve risk stratification and guide treatment eligibility in cardiovascular disease prevention. The integration of interventions aimed at lowering the inflammatory burden, alone or in combination with aggressive lipid-modifying or even antithrombotic agents, for those at high cardiovascular risk may hold the potential to reduce the still substantial burden of cardiometabolic disease. This review provides perspectives on future clinical research in atherosclerosis addressing the tight interplay between inflammation, lipid metabolism and thrombosis, and its translation into clinical practice.
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http://dx.doi.org/10.15420/ecr.2020.50DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157394PMC
February 2021

Glycated Hemoglobin to Detect Subclinical Atherosclerosis in People Without Diabetes.

J Am Coll Cardiol 2021 Jun;77(22):2792-2795

Department of Medicine and Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, Texas, USA.

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http://dx.doi.org/10.1016/j.jacc.2021.04.018DOI Listing
June 2021

Natural History of Patients With Ischemia and No Obstructive Coronary Artery Disease: The CIAO-ISCHEMIA Study.

Circulation 2021 Sep 1;144(13):1008-1023. Epub 2021 Jun 1.

New York University Grossman School of Medicine (H.R.R., D.F.K., R.A., Y.L., J.S.H.).

Background: Ischemia with no obstructive coronary artery disease (INOCA) is common and has an adverse prognosis. We set out to describe the natural history of symptoms and ischemia in INOCA.

Methods: CIAO-ISCHEMIA (Changes in Ischemia and Angina over One Year in ISCHEMIA Trial Screen Failures With INOCA) was an international cohort study conducted from 2014 to 2019 involving angina assessments (Seattle Angina Questionnaire) and stress echocardiograms 1 year apart. This was an ancillary study that included patients with a history of angina who were not randomly assigned in the ISCHEMIA trial. Stress-induced wall motion abnormalities were determined by an echocardiographic core laboratory blinded to symptoms, coronary artery disease status, and test timing. Medical therapy was at the discretion of treating physicians. The primary outcome was the correlation between the changes in the Seattle Angina Questionnaire angina frequency score and changes in echocardiographic ischemia. We also analyzed predictors of 1-year changes in both angina and ischemia, and we compared CIAO participants with ISCHEMIA participants with obstructive coronary artery disease who had stress echocardiography before enrollment, as CIAO participants did.

Results: INOCA participants in CIAO were more often female (66% of 208 versus 26% of 865 ISCHEMIA participants with obstructive coronary artery disease, <0.001), but the magnitude of ischemia was similar (median 4 ischemic segments [interquartile range, 3-5] both groups). Ischemia and angina were not significantly correlated at enrollment in CIAO (=0.46) or ISCHEMIA stress echocardiography participants (=0.35). At 1 year, the stress echocardiogram was normal in half of CIAO participants, and 23% had moderate or severe ischemia (≥3 ischemic segments). Angina improved in 43% and worsened in 14%. Change in ischemia over 1 year was not significantly correlated with change in angina (ρ=0.029).

Conclusions: Improvement in ischemia and angina were common in INOCA but not correlated. Our INOCA cohort had a degree of inducible wall motion abnormalities similar to concurrently enrolled ISCHEMIA participants with obstructive coronary artery disease. Our results highlight the complex nature of INOCA pathophysiology and the multifactorial nature of angina. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02347215.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478858PMC
September 2021

Familial hypercholesterolemia related admission for acute coronary syndrome in the United States: Incidence, predictors, and outcomes.

J Clin Lipidol 2021 May-Jun;15(3):460-465. Epub 2021 Apr 29.

Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA. Electronic address:

Background: Individuals with Familial Hypercholesterolemia (FH) are at high risk for atherosclerotic cardiovascular disease (ASCVD) events.

Objectives: The purpose of this study was to evaluate the incidence, predictors, and outcomes of admissions for acute coronary syndromes (ACS) in this high-risk group.

Methods: Utilizing the National Readmission Databases, we identified individuals with or without FH admitted to participating hospitals for ACS. The primary outcome was admission for recurrent ACS at 11 month follow-up.

Results: There were a total of 1,697,513 ACS admissions from 10/2016 to 12/2017 (non-FH=1,696,979 and FH=534). Individuals with FH admitted for ACS were younger (median age 57 vs 69 y), had fewer comorbidities (hypertension 74.7% vs 79.6%; diabetes mellitus 30.5% vs 39.0%;p<0.01), were more likely to present with ST-elevation-myocardial infarction (32.8% vs 22.6%;p<0.01) and more likely to undergo multivessel percutaneous coronary intervention (11.4% vs 7.6%;p<0.01) than patients without FH. After propensity-score matching, FH patients more commonly experienced in-hospital VT arrest (11.8% vs 8.0%;p<0.01) and required more mechanical circulatory support (8.6% vs 3.3%; p<0.01). The 30-day readmission in those with FH was more frequently for cardiovascular disease (81.5% vs 46.5%; =p<0.01). At 11-month follow-up, FH patients were more likely to be readmitted with recurrent ACS compared to those without FH (hazard ratio=2.34; 95% confidence interval=1.30-4.23; p<0.01).

Conclusions: Individuals with FH admitted for ACS are younger, have fewer comorbidities, and more frequently present with STEMIs compared to those without FH. FH patients were more likely to suffer in-hospital cardiac complications and have a higher incidence of recurrent ACS.
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http://dx.doi.org/10.1016/j.jacl.2021.04.005DOI Listing
April 2021

Association Between Omega-3 Fatty Acid Levels and Risk for Incident Major Bleeding Events and Atrial Fibrillation: MESA.

J Am Heart Assoc 2021 06 27;10(11):e021431. Epub 2021 May 27.

Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology Johns Hopkins University School of Medicine Baltimore MD.

Background Randomized trials of pharmacologic strength omega-3 fatty acid (n3-FA)-based therapies suggest a dose-dependent cardiovascular benefit. Whether blood n3-FA levels also mediate safety signals observed in these trials, such as increased bleeding and atrial fibrillation (AF), remains uncertain. We hypothesized that higher baseline n3-FA levels would be associated with incident bleeding and AF events in MESA (Multi-Ethnic Study of Atherosclerosis), which included a population free of clinical cardiovascular disease at baseline. Methods and Results We examined the association between baseline plasma n3-FA levels (expressed as percent mass of total fatty acid) with incident bleeding and AF in MESA, an ongoing prospective cohort study. Bleeding events were identified from review of hospitalization (), and (), codes, and AF from participant report, discharge diagnoses, Medicare claims data, and study ECGs performed at MESA visit 5. Separate multivariable Cox proportional hazard modeling was used to estimate hazard ratios of the association of continuous n3-FA (log eicosapentaenoic acid [EPA], log docosahexaenoic acid [DHA], log [EPA+DHA]) and incident hospitalized bleeding events and AF. Among 6546 participants, the mean age was 62.1 years and 53% were women. For incident bleeding, consistent statistically significant associations with lower rates were seen with increasing levels of EPA and EPA+DHA in unadjusted and adjusted models including medications that modulate bleeding risk (aspirin, NSAIDS, corticosteroids, and proton pump inhibitors). For incident AF, a significant association with lower rates was seen with increasing levels of DHA, but not for EPA or EPA+DHA. Conclusions In MESA, higher plasma levels of n3-FA (EPA and EPA+DHA, but not DHA) were associated with significantly fewer hospitalized bleeding events, and higher DHA levels (but not EPA or EPA+DHA) with fewer incident AF events.
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http://dx.doi.org/10.1161/JAHA.121.021431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483537PMC
June 2021

Clinical and Economic Burden of Stroke Among Young, Midlife, and Older Adults in the United States, 2002-2017.

Mayo Clin Proc Innov Qual Outcomes 2021 Apr 8;5(2):431-441. Epub 2021 Apr 8.

Division of Cardiovascular Prevention and Wellness, Department of Cardiovascular Medicine, Houston Methodist DeBakey Heart and Vascular Center.

Objective: To assess trends of stroke hospitalization rates, inpatient mortality, and health care resource use in young (aged ≤44 years), midlife (aged 45-64 years), and older (aged ≥65 years) adults.

Patients And Methods: We studied the National Inpatient Sample database (January 1, 2002 to December 31, 2017) to analyze stroke-related hospitalizations. We identified data using the codes.

Results: Of 11,381,390 strokes, 79% (n=9,009,007) were ischemic and 21% (n=2,372,383) were hemorrhagic. Chronic diseases were more frequent in older adults; smoking, alcoholism, and migraine were more prevalent in midlife adults; and coagulopathy and intravenous drug abuse were more common in young patients with stroke. The hospitalization rates of stroke per 10,000 increased overall (31.6 to 33.3) in young and midlife adults while decreasing in older adults. Although mortality decreased overall and in all age groups, the decline was slower in young and midlife adults than older adults. The mean length of stay significantly decreased in midlife and older adults and increased in young adults. The inflation-adjusted mean cost of stay increased consistently, with an average annual growth rate of 2.44% in young, 1.72% in midlife, and 1.45% in older adults owing to the higher use of health care resources. These trends were consistent in both ischemic and hemorrhagic stroke.

Conclusion: Stroke-related hospitalization and health care expenditure are increasing in the United States, particularly among young and midlife adults. A higher cost of stay counterbalances the benefits of reducing stroke and mortality in older patients.
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http://dx.doi.org/10.1016/j.mayocpiqo.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105541PMC
April 2021

Association of Carotid Artery Plaque With Cardiovascular Events and Incident Coronary Artery Calcium in Individuals With Absent Coronary Calcification: The MESA.

Circ Cardiovasc Imaging 2021 04 8;14(4):e011701. Epub 2021 Apr 8.

Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison (M.C.T., J.H.S.).

Background: Absence of coronary artery calcium (CAC) identifies asymptomatic individuals at low cardiovascular disease risk. Carotid artery plaque is a marker of increased risk, but its association with cardiovascular risk and incident CAC in people without CAC is unclear.

Methods: Multi-Ethnic Study of Atherosclerosis participants with CAC score of 0 at enrollment who also underwent carotid plaque measurement using B-mode ultrasonography were prospectively followed for incident coronary heart disease, stroke, and cardiovascular disease events, and CAC (score >0 on up to 3 serial computed tomography scans). The association of carotid plaque presence and plaque score (Ln[score+1]) at baseline with cardiovascular events and incident CAC was evaluated with Cox proportional hazards regression models adjusted for demographics, risk factors, and statin use.

Results: Among these 2673 participants (58 years, 64% women, 34% White, 30% Black, 24% Hispanic, and 12% Chinese), carotid plaque at baseline was observed in 973 (36%) and the median plaque score (range, 1-12) among those with plaque was 1. A total of 79 coronary heart disease, 80 stroke, and 151 cardiovascular disease events were observed during 16.1 years of follow-up. Carotid plaque presence and plaque score were independently associated with coronary heart disease risk (HRs, 1.66 [95% CI, 1.04-2.66]; and 1.48 [95% CI, 1.01-2.17], respectively) but not with stroke and cardiovascular disease risk. A total of 973 (36.4%) participants developed CAC over the evaluation period (median 9.3 years). Carotid plaque presence and plaque score were independently associated with incident CAC (HRs, 1.34 [95% CI, 1.18-1.54]; and 1.37 [95% CI, 1.21-1.54]), respectively.

Conclusions: The presence and extent of carotid plaque are associated with long-term coronary heart disease risk and incident CAC among middle-aged asymptomatic individuals with an initial CAC score of 0.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.011701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058258PMC
April 2021

Association Between Breast Arterial Calcification on Mammography and Coronary Artery Disease: A Systematic Review and Meta-Analysis.

J Womens Health (Larchmt) 2021 Apr 7. Epub 2021 Apr 7.

Department of Cardiology, West Virginia University School of Medicine, Morgantown, West Virginia, USA.

Breast arterial calcification (BAC), which may be detected during screening mammography, is hypothesized to be a noninvasive imaging marker that may enhance cardiovascular risk assessment. In this systematic review and meta-analysis, we sought to assess the association between BAC and coronary artery disease (CAD) by conducting a meta-analysis. We conducted a literature search of PubMed, Scopus, Cochrane library, ClinicalTrials.gov, and conference proceedings, from inception through December 24, 2019. The outcome of interest was the presence of CAD in patients with BAC. This was reported as crude and adjusted odds ratio (OR). A total of 18 studies comprising 33,494 women (mean age of 60.8 ± 3.7 years, 25% with diabetes, 57% with hypertension, and 21% with history of tobacco smoking) were included in the current meta-analysis. The prevalence of BAC among study participants was 10%. There was a statistically significant association between BAC and CAD (unadjusted OR 2.14; 95% confidence interval [CI] 1.63-2.81,  < 0.001,  = 76.5%). Moreover, adjusted estimates were available from 10 studies and BAC was an independent predictor of CAD (OR 2.39; 95% CI 1.68-3.41,  < 0.001,  = 61.7%). In the meta-regression analysis, covariates included year of publication, age, hypertension, diabetes mellitus, and history of tobacco smoking. None of these study covariates explained the heterogeneity across studies. BAC detected as part of screening mammography is a promising noninvasive imaging marker that may enhance CAD risk prediction in women. The clinical value of BAC for cardiovascular risk stratification merits further evaluation in large prospective studies.
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http://dx.doi.org/10.1089/jwh.2020.8733DOI Listing
April 2021

Heart, mind, and soul: spirituality in cardiovascular medicine.

Eur Heart J 2021 08;42(31):2965-2968

Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA.

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http://dx.doi.org/10.1093/eurheartj/ehab080DOI Listing
August 2021

Preventing Diabetes and Atherosclerosis in the Cardiometabolic Syndrome.

Curr Atheroscler Rep 2021 03 9;23(4):16. Epub 2021 Mar 9.

Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Purpose Of Review: Cardiometabolic syndrome is characterized by abdominal adiposity, insulin resistance, hypertension, and dyslipidemia. There is a growing burden of cardiometabolic disease in many parts of the world. This review highlights the critical preventive and therapeutic measures that need to be implemented to reduce the impact of cardiometabolic syndrome on cardiovascular health.

Recent Findings: Recent cardiovascular outcome trials demonstrated that newer glucose-lowering medications reduce cardiovascular and renal events in patients with type 2 diabetes mellitus (T2DM). These medications should be considered in patients with T2DM and atherosclerotic cardiovascular disease (ASCVD). These novel drugs may also play a role in primary prevention of cardiovascular disease (CVD) and renal disease in high-risk patients without T2DM. To manage dyslipidemia associated with cardiometabolic syndrome, in addition to lifestyle interventions and statin therapy, ezetimibe, and proprotein convertase subtilisin/Kexin type 9 (PCSK9), inhibitors can be used to reduce the risk of major adverse cardiovascular outcomes (MACE) especially in patients with T2DM and coronary artery disease (CAD). The residual risk of MACE in such a high-risk population can be further mitigated by treatment with an omega-3 fatty acid such as icosapent ethyl. Lifestyle modifications and the use of proven pharmacological therapies are essential for the prevention and progression of diabetes and ASCVD in those with the cardiometabolic syndrome.
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http://dx.doi.org/10.1007/s11883-021-00913-8DOI Listing
March 2021

The assembled and annotated genome of the pigeon louse Columbicola columbae, a model ectoparasite.

G3 (Bethesda) 2021 02;11(2)

School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA.

The pigeon louse Columbicola columbae is a longstanding and important model for studies of ectoparasitism and host-parasite coevolution. However, a deeper understanding of its evolution and capacity for rapid adaptation is limited by a lack of genomic resources. Here, we present a high-quality draft assembly of the C. columbae genome, produced using a combination of Oxford Nanopore, Illumina, and Hi-C technologies. The final assembly is 208 Mb in length, with 12 chromosome-size scaffolds representing 98.1% of the assembly. For gene model prediction, we used a novel clustering method (wavy_choose) for Oxford Nanopore RNA-seq reads to feed into the MAKER annotation pipeline. High recovery of conserved single-copy orthologs (BUSCOs) suggests that our assembly and annotation are both highly complete and highly accurate. Consistent with the results of the only other assembled louse genome, Pediculus humanus, we find that C. columbae has a relatively low density of repetitive elements, the majority of which are DNA transposons. Also similar to P. humanus, we find a reduced number of genes encoding opsins, G protein-coupled receptors, odorant receptors, insulin signaling pathway components, and detoxification proteins in the C. columbae genome, relative to other insects. We propose that such losses might characterize the genomes of obligate, permanent ectoparasites with predictable habitats, limited foraging complexity, and simple dietary regimes. The sequencing and analysis for this genome were relatively low cost, and took advantage of a new clustering technique for Oxford Nanopore RNAseq reads that will be useful to future genome projects.
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http://dx.doi.org/10.1093/g3journal/jkab009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022949PMC
February 2021

Insights into the kinetics and dynamics of the furin-cleaved form of PCSK9.

J Lipid Res 2020 Nov 23;62:100003. Epub 2020 Nov 23.

Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health & Science University, Portland, OR, USA.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol metabolism by inducing the degradation of hepatic low density lipoprotein receptors (LDLRs). Plasma PCSK9 has 2 main molecular forms: a 62 kDa mature form (PCSK9_62) and a 55 kDa, furin-cleaved form (PCSK9_55). PCSK9_55 is considered less active than PCSK9_62 in degrading LDLRs. We aimed to identify the site of PCSK9_55 formation (intracellular vs. extracellular) and to further characterize the LDLR-degradative function of PCSK9_55 relative to PCSK9_62. Coexpressing PCSK9_62 with furin in cell culture induced formation of PCSK9_55, most of which was found in the extracellular space. Under the same conditions, we found that i) adding a cell-permeable furin inhibitor preferentially decreased the formation of PCSK9_55 extracellularly; ii) using pulse-chase analysis, we observed the formation of PCSK9_55 exclusively extracellularly in a time-dependent manner. A recombinant form of PCSK9_55 was efficiently produced but displayed impaired secretion that resulted in its intracellular trapping. However, the nonsecreted PCSK9_55 was able to induce degradation of LDLR, though with 50% lower efficiency than PCSK9_62. Collectively, our data show that 1) PCSK9_55 is formed extracellularly; 2) PCSK9_55 has a shorter half-life; 3) there is a small intracellular pool of PCSK9_55 that is not secreted; and 4) PCSK9_55 retained within the cell maintains a reduced efficiency to cause LDLR degradation.
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http://dx.doi.org/10.1194/jlr.RA120000964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890205PMC
November 2020

Precision screening for familial hypercholesterolaemia: a machine learning study applied to electronic health encounter data.

Lancet Digit Health 2019 12 21;1(8):e393-e402. Epub 2019 Oct 21.

The Familial Hypercholesterolemia Foundation, Pasadena, CA, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Background: Cardiovascular outcomes for people with familial hypercholesterolaemia can be improved with diagnosis and medical management. However, 90% of individuals with familial hypercholesterolaemia remain undiagnosed in the USA. We aimed to accelerate early diagnosis and timely intervention for more than 1·3 million undiagnosed individuals with familial hypercholesterolaemia at high risk for early heart attacks and strokes by applying machine learning to large health-care encounter datasets.

Methods: We trained the FIND FH machine learning model using deidentified health-care encounter data, including procedure and diagnostic codes, prescriptions, and laboratory findings, from 939 clinically diagnosed individuals with familial hypercholesterolaemia (395 of whom had a molecular diagnosis) and 83 136 individuals presumed free of familial hypercholesterolaemia, sampled from four US institutions. The model was then applied to a national health-care encounter database (170 million individuals) and an integrated health-care delivery system dataset (174 000 individuals). Individuals used in model training and those evaluated by the model were required to have at least one cardiovascular disease risk factor (eg, hypertension, hypercholesterolaemia, or hyperlipidemia). A Health Insurance Portability and Accountability Act of 1996-compliant programme was developed to allow providers to receive identification of individuals likely to have familial hypercholesterolaemia in their practice.

Findings: Using a model with a measured precision (positive predictive value) of 0·85, recall (sensitivity) of 0·45, area under the precision-recall curve of 0·55, and area under the receiver operating characteristic curve of 0·89, we flagged 1 331 759 of 170 416 201 patients in the national database and 866 of 173 733 individuals in the health-care delivery system dataset as likely to have familial hypercholesterolaemia. Familial hypercholesterolaemia experts reviewed a sample of flagged individuals (45 from the national database and 103 from the health-care delivery system dataset) and applied clinical familial hypercholesterolaemia diagnostic criteria. Of those reviewed, 87% (95% Cl 73-100) in the national database and 77% (68-86) in the health-care delivery system dataset were categorised as having a high enough clinical suspicion of familial hypercholesterolaemia to warrant guideline-based clinical evaluation and treatment.

Interpretation: The FIND FH model successfully scans large, diverse, and disparate health-care encounter databases to identify individuals with familial hypercholesterolaemia.

Funding: The FH Foundation funded this study. Support was received from Amgen, Sanofi, and Regeneron.
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http://dx.doi.org/10.1016/S2589-7500(19)30150-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086528PMC
December 2019

Statins and coronary artery calcium: What's the score?

Atherosclerosis 2021 01 18;316:71-72. Epub 2020 Nov 18.

Wake Forest University School of Medicine, Winston Salem, NC, United States. Electronic address:

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http://dx.doi.org/10.1016/j.atherosclerosis.2020.11.014DOI Listing
January 2021

Coronary artery calcium testing in low-intermediate risk symptomatic patients with suspected coronary artery disease: An effective gatekeeper to further testing?

PLoS One 2020 13;15(10):e0240539. Epub 2020 Oct 13.

Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240539PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553353PMC
December 2020

Children with Heterozygous Familial Hypercholesterolemia in the United States: Data from the Cascade Screening for Awareness and Detection-FH Registry.

J Pediatr 2021 02 22;229:70-77. Epub 2020 Sep 22.

Department of Pediatrics, West Virginia University, Morgantown, WV.

Objective: To describe enrollment characteristics of youth in the Cascade Screening for Awareness and Detection of FH Registry.

Study Design: This is a cross-sectional analysis of 493 participants aged <18 years with heterozygous familial hypercholesterolemia recruited from US lipid clinics (n = 20) between April 1, 2014, and January 12, 2018. At enrollment, some were new patients and some were already in care. Clinical characteristics are described, including lipid levels and lipid-lowering treatments.

Results: Mean age at diagnosis was 9.4 (4.0) years; 47% female, 68% white and 12% Hispanic. Average (SD) highest Low-density lipoprotein cholesterol (LDL-C) was 238 (61) mg/dL before treatment. Lipid-lowering therapy was used by 64% of participants; 56% were treated with statin. LDL-C declined 84 mg/dL (33%) among those treated with lipid-lowering therapy; statins produced the greatest decline, 100 mg/dL (39% reduction). At enrollment, 39% had reached an LDL-C goal, either <130 mg/dL or ≥50% decrease from pre-treatment; 20% of those on lipid-lowering therapy reached both goals.

Conclusions: Among youth enrolled in the Cascade Screening for Awareness and Detection of FH Registry, diagnosis occurred relatively late, only 77% of children eligible for lipid-lowering therapy were receiving treatment, and only 39% of those treated met their LDL-C goal. Opportunities exist for earlier diagnosis, broader use of lipid-lowering therapy, and greater reduction of LDL-C levels.
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http://dx.doi.org/10.1016/j.jpeds.2020.09.042DOI Listing
February 2021

"Cholesterol-Years" for ASCVD Risk Prediction and Treatment.

J Am Coll Cardiol 2020 09;76(13):1517-1520

Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts. Electronic address: https://twitter.com/DLBhattMD.

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http://dx.doi.org/10.1016/j.jacc.2020.08.004DOI Listing
September 2020

Racial and Geographic Disparities in Internet Use in the United States Among Patients with Atherosclerotic Cardiovascular Disease.

Am J Cardiol 2020 11 11;134:146-147. Epub 2020 Aug 11.

Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Health Policy, Quality & Informatics Program, Michael E. DeBakey VA Medical Center Health Services Research & Development Center for Innovations in Quality, Effectiveness, and Safety, Houston, Texas; Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas. Electronic address:

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http://dx.doi.org/10.1016/j.amjcard.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418766PMC
November 2020
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