Cholesterol Levels


Introduction

Lipids circulate in the blood as lipoproteins and are composed of unesterified cholesterol, triglycerides, phospholipids, and proteins. The 5 major types of lipoproteins in the blood include chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Each class of lipoprotein has a role in transporting cholesterol and triglycerides to specific destinations in the body.

Cholesterol levels are critical in the development of cardiovascular diseases (CVDs). Elevated serum lipids, including cholesterol and triglycerides—a condition known as hyperlipidemia—significantly increase the risk of atherosclerotic CVD (ASCVD). Clinically, obtaining a lipid profile is essential for screening, diagnosing, and managing these conditions. In this discussion, we will cover the indications for testing, the significance of lipid profiles, and related healthcare considerations. Typically, a lipid profile or lipid panel includes the following components:

  • Total cholesterol
  • HDL cholesterol (HDL-C)
  • LDL cholesterol (LDL-C)
  • Triglycerides

Specimen Collection

Cholesterol levels are measured from serum. A nonfasting lipid test can be performed at any time without fasting, while a fasting lipid test requires a 12-hour fast, with water being the only exception. Total and HDL cholesterol (HDL-C) are measured directly from serum. 

The Friedewald equation, developed in the 1960s, has been widely used to estimate LDL-C for both research and clinical purposes.[1] The equation is expressed as: LDL-C = (Total cholesterol) − (HDL-C) − (Triglycerides/5), in mg/dL. The equation assumes a fixed factor of 5 for the ratio of fasting triglyceride levels (up to 4.5 mmol/L) to VLDL-C (TG: VLDL-C).[1] Optimizing LDL-C levels has been the primary focus for current guidelines from organizations such as the European Society of Cardiology, the European Atherosclerosis Society,[2] and the American Heart Association and American College of Cardiology.[3]

The Friedewald equation has several limitations:[4]

  • The estimated LDL-C level is inaccurate in patients with hypertriglyceridemia (up to 4.5mmol/L or 400 mg/dL), where ultracentrifugal single-spin analysis or immunoprecipitation techniques are warranted.
  • The equation underestimates LDL-C levels in patients with lower LDL-C (<25 mg/dL or 0.6 mmol/L).
  • The equation underestimates IDL and some VLDL remnants, which are considered atherogenic.

In a comprehensive cross-sectional analysis, Martin et al proposed a novel calculation that is more accurate than the Friedewald equation, regardless of whether the blood samples are obtained from fasting or nonfasting individuals.[5]Fasting Versus Nonfasting Lipid ProfilesWhile fasting LDL-C remains the standard for initiating lipid-lowering therapy, an ongoing debate exists among healthcare specialists regarding the use of fasting versus nonfasting lipid profiles. The rationale behind this discussion stems from the fact that triglyceride levels can be affected by recent food intake and the limitations inherent in the Friedewald equation.[6][7]

Nonfasting lipid profiles offer several advantages, including greater clinical accessibility and simplicity for both patients and healthcare providers. In contrast, fasting lipid profiles require patients to make an additional visit, which can be inconvenient for both patients and clinicians. Moreover, the accuracy of fasting lipid profiles relies on patient compliance.Many current guidelines propose that nonfasting LDL-C holds similar significance to fasting LDL-C.[8][9] However, a fasting lipid panel is strongly recommended for patients with type 2 diabetes, obesity, those taking medications that may affect lipid levels (such as thiazides and beta-blockers),[10] and individuals with excessive intake of alcohol.[11] Apolipoproteins 

As per the joint American College of Cardiology Foundation/American Heart Association 2010 guidelines, the measurement of apolipoproteins, lipid particle size, and density is not recommended for cardiovascular risk assessment (Level III).

Indications

Indications for screening or obtaining a lipid profile vary between adults and children, as mentioned below. 

  • The National Health and Nutrition Examination Survey (NHANES) from 1999 to 2006 reported a 20% prevalence of dyslipidemia among adolescents, with higher lipid levels observed in those with elevated BMI.[12] Among adolescents with dyslipidemia, only 0.8% may require pharmacological treatment.[13] The 2011 guidelines from the United States National Heart, Lung, and Blood Institute (NHLBI) recommend screening all children for dyslipidemia to identify those with familial hypercholesterolemia, as these patients are at increased risk for morbidity and early mortality.[14] For children with cardiovascular risk factors such as hypertension, obesity, diabetes, or a family history of cardiovascular disease, a fasting lipid test is recommended. In contrast, a non-fasting lipid test is preferred for those without known cardiovascular risks.
  • In adults, the most common indications for lipid profile testing include:[15][16]
    • Screening due to a family history of lipid disorders, such as familial hypercholesterolemia.
    • Assessing the 10-year risk of CVDs using tools such as the 2008 Framingham General Cardiovascular Risk Score or the JBS3 Risk Score.
    • Pancreatitis.
    • Managing ASCVDs. 
    • Evaluating the need for lipid-lowering therapy.

Potential Diagnosis

DyslipidemiasPrimary disorders of lipid metabolism, such as familial hypercholesterolemia, chylomicronemia, familial combined hyperlipidemia, and familial dysbetalipoproteinemia, are classified according to the Fredrickson phenotype.[17] Secondary dyslipidemia can result from conditions such as diabetes mellitus, hypothyroidism, obstructive liver diseases, chronic renal failure, and the use of certain medications. Drugs that can increase LDL-C levels include retinoids, cyclosporine A, and phenothiazines, while drugs that can decrease HDL-C levels include progestins, androgens, beta-blockers, and anabolic steroids.Based on the types of lipid abnormalities, dyslipidemias can be categorized into high total cholesterol, high LDL-C, high non–HDL-C, high triglycerides, and low HDL-C. According to the Adult Treatment Panel III (ATP III) guidelines, the standard lipid levels are as follows:[18]

  • Fasting triglyceride levels
    • Normal: Less than 150 mg/dL 
    • Hypertriglyceridemia: 150 to 499 mg/dL
    • Very high or severe hypertriglyceridemia: Greater than 500 mg/dL
  • LDL-C levels
    • Optimal: Less than 100 mg/ dL
    • Near optimal/above optimal: 100 to 129 mg/dL
    • Borderline high: 130 to 159 mg/dL
    • High: 160 to 189 mg/dL
    • Very high: Greater than 190 mg/dL 
  • HDL-C levels 
    • Low: Less than 40 mg/dL
    • High: Greater than or equal to 60 mg/dL

Metabolic Syndrome 

There are 5 definitions of the metabolic syndrome, as mentioned below.

  • The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), 2005
  • International Diabetes Federation(IDF), 2006
  • European Group for the Study of Insulin Resistance (EGIR), 1999
  • World Health Organization (WHO), 1999
  • American Association of Clinical Endocrinologists (AACE), 2003

Among these, the NCEP Adult Treatment Panel III  definition is the most widely used. Metabolic syndrome is diagnosed when 3 or more of these parameters are abnormal—triglycerides, HDL-C, glucose, blood pressure (for hypertension), and obesity.

  • HDL-C: Less than 1.0 mmol/L (40 mg/dL) in men and less than 1.3 mmol/L (50 mg/dL) in women, or individuals receiving pharmaceutical treatment for low HDL-C, such as niacin or fibrates.
  • Triglycerides: Greater than or equal to 1.7 mmol/L (150 mg/dL) or drug treatment with niacin or fibrates for elevated triglycerides.
  • Glucose: Greater than or equal to 5.6 mmol/L (100 mg/dL), or individuals on drug treatment for elevated blood glucose.
  • Obesity: Waist circumference greater than or equal to 102 cm in men and 88 cm in women.
  • Blood pressure: Greater than or equal to 130/85 mm Hg, or individuals on drug treatment for hypertension.

Atherosclerotic Cardiovascular Disease

  • Coronary heart disease presents as myocardial infarction, angina pectoris, heart failure, or coronary death.
  • Cerebrovascular disease presents as stroke or transient ischemic attack.
  • Peripheral artery disease presents as intermittent claudication.
  • Aortic atherosclerosis and thoracic or abdominal aortic aneurysm.

The above-mentioned conditions are often collectively referred to as "CVD."

Atherosclerosis is the primary culprit in most cases of coronary heart disease.[19] Lipids and lipoproteins are well-established risk factors for developing ASCVD. Large clinical trials have demonstrated that lipid-lowering therapy can significantly reduce the risk of ASCVD events.[20][21]

Several factors are considered in a 10-year cardiovascular risk assessment, including:

  • Age (between 20 and 79)
  • Sex
  • Race
  • Systolic blood pressure  
  • Diastolic blood pressure  
  • Total cholesterol
    • LDL-C
    • HDL-C
  • History of diabetes
  • Current hypertension, statin, and aspirin treatment

The 10-year risk for ASCVD is categorized as follows:

  • Low-risk: Less than 5%
  • Borderline risk: 5% to 7.4%
  • Intermediate risk: 7.5% to 19.9%
  • High risk: Greater than or equal to 20%

Risk-enhancing factors such as a family history of premature ASCVD, metabolic syndrome, chronic kidney disease, premature menopause, chronic inflammatory disorders, high-risk ethnic groups (eg, South Asian), persistent elevations of LDL-C greater than or equal to 160 mg/dL or triglycerides greater than or equal to 175 mg/dL, high-sensitivity C-reactive protein greater than or equal to 2.0 mg/L, and ankle-brachial index less than 0.9. 

Normal and Critical Findings

For dyslipidemia, obtaining a detailed family history is crucial. Identifying family members with abnormal cholesterol deposits in the skin or eyes, premature coronary heart disease, or elevated cholesterol during childhood helps establish a diagnosis. A physical examination of the patient should include attention to abnormal cholesterol deposits in the skin or eyes, such as tendon xanthomata, which are commonly found in the Achilles tendons and the dorsum of their hands, and xanthelasma, which are soft, yellow plaques often present on the eyelids. A fasting lipid profile typically reveals most abnormalities. However, evaluation for secondary causes of hyperlipidemia is also warranted. The clinician may offer genetic testing for LDLR, APOB, and PCSK9 gene mutations, although the benefits of such testing are not yet well-established.

Patient Safety and Education

First and foremost, educating individuals about a heart-healthy lifestyle is essential. LDL-C is a significant contributor to the development of ASCVD, with a target level of 50 to 70 mg/dL recommended to prevent plaque formation in the blood vessels. According to current guidelines, patients should undergo a 10-year risk assessment, and those with a risk greater than 10% should be strongly considered for statin therapy. While low levels of HDL-C are associated with an increased risk of CVD, recent studies have shown that HDL-C–raising therapies do not provide clinical benefit. Therefore, routine use of such treatments is not recommended.

Clinical Significance

Primary prevention recommendations for adults aged 40 to 75 with an LDL-C level of 70 to 189 mg/dL focus on managing high LDL-C and low HDL-C levels, which are risk factors for coronary heart disease.[22][23] Large clinical trials have demonstrated that lowering LDL-C levels significantly reduces cardiovascular events and mortality rates. However, current consensus guidelines do not recommend targeting HDL-C for primary prevention of coronary artery disease.[24] Nevertheless, recent studies have suggested that serum cholesterol efflux capacity may have prognostic value in patients with CAD.[25]

According to the 2018 Guideline on the Management of Blood Cholesterol,[26] clinicians should aim to lower LDL-C levels by more than 50% using maximally tolerated statin therapy in individuals with ASCVD. For very high-risk ASCVD patients who are already on statin therapy but have an LDL-C level of more than 70 mg/dL, clinicians should consider adding nonstatin therapy, such as ezetimibe. Furthermore, for individuals on maximally tolerated statin therapy along with ezetimibe, a PCSK9 inhibitor should be considered.

Ezetimibe is preferred over initiating a PCSK9 inhibitor due to its cost and greater convenience. High-intensity statin therapy should be initiated regardless of the 10-year ASCVD risk in individuals with severe hypercholesterolemia (LDL-C level ≥190 mg/dL). Moderate-intensity statin therapy should be initiated in diabetic patients aged 40 to 75 with an LDL-C level greater than or equal to 70 mg/dL, regardless of their 10-year ASCVD risk. For nondiabetic patients with an LDL-C level greater than or equal to 70 mg/dL and a 10-year ASCVD risk of more than 7.5%, moderate-intensity statin therapy should be considered. 

Statin Intensity 

Moderate-intensity statin therapy is expected to reduce LDL-C levels by 30% to 50% with the following regimens:

  • Lovastatin 40 mg daily
  • Pravastatin 40 mg daily
  • Simvastatin 40 mg daily
  • Atorvastatin 10 to 20 mg daily
  • Rosuvastatin 5 to 10 mg daily
  • Pitavastatin 4 mg

High-intensity statin therapy is expected to achieve an LDL-C reduction of 50% or more with the following regimens: 

  • Atorvastatin 40 to 80 mg
  • Rosuvastatin 20 to 40 mg

In most cases, it is not recommended to intensify statin therapy for patients already on moderate-intensity statins. The efficacy of statin therapy should be evaluated six to eight weeks after initiation. Statin therapy management should be adjusted if statin-induced muscle adverse events, elevated aminotransferase levels, or renal dysfunction, such as proteinuria, develop. However, routine monitoring of serum creatine kinase levels is not currently recommended for patients on statins. For medical practitioners, it is advisable to consider obtaining a baseline CK level before initiating statin therapy. Educating patients on lifestyle modifications, medication compliance, and the importance of promptly recognizing and reporting any new onset of muscle discomfort or weakness is crucial. 


Details

Author

Yi Lee

Updated:

7/24/2023 9:39:46 PM

References


[1]

Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical chemistry. 1972 Jun:18(6):499-502     [PubMed PMID: 4337382]


[2]

Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Ž, Riccardi G, Taskinen MR, Tokgozoglu L, Monique Verschuren WM, Vlachopoulos C, Wood DA, Luis Zamorano J, Additional Contributor, Cooney MT. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Revista espanola de cardiologia (English ed.). 2017 Feb:70(2):115. doi: 10.1016/j.rec.2017.01.002. Epub     [PubMed PMID: 29389351]


[3]

Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18:139(25):e1082-e1143. doi: 10.1161/CIR.0000000000000625. Epub 2018 Nov 10     [PubMed PMID: 30586774]


[4]

Meeusen JW, Snozek CL, Baumann NA, Jaffe AS, Saenger AK. Reliability of Calculated Low-Density Lipoprotein Cholesterol. The American journal of cardiology. 2015 Aug 15:116(4):538-40. doi: 10.1016/j.amjcard.2015.05.013. Epub 2015 May 21     [PubMed PMID: 26059865]


[5]

Martin SS, Blaha MJ, Elshazly MB, Toth PP, Kwiterovich PO, Blumenthal RS, Jones SR. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA. 2013 Nov 20:310(19):2061-8. doi: 10.1001/jama.2013.280532. Epub     [PubMed PMID: 24240933]


[6]

Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation. 1979 Sep:60(3):473-85     [PubMed PMID: 222498]


[7]

Kolovou GD, Anagnostopoulou KK, Daskalopoulou SS, Mikhailidis DP, Cokkinos DV. Clinical relevance of postprandial lipaemia. Current medicinal chemistry. 2005:12(17):1931-45     [PubMed PMID: 16101498]


[8]

Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007 Jul 18:298(3):299-308     [PubMed PMID: 17635890]


[9]

Duerden M, O'Flynn N, Qureshi N. Cardiovascular risk assessment and lipid modification: NICE guideline. The British journal of general practice : the journal of the Royal College of General Practitioners. 2015 Jul:65(636):378-80. doi: 10.3399/bjgp15X685933. Epub     [PubMed PMID: 26120133]


[10]

Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, Herink M, Ito MK. Medication Induced Changes in Lipid and Lipoproteins. Endotext. 2000:():     [PubMed PMID: 26561699]


[11]

Doran B, Guo Y, Xu J, Weintraub H, Mora S, Maron DJ, Bangalore S. Prognostic value of fasting versus nonfasting low-density lipoprotein cholesterol levels on long-term mortality: insight from the National Health and Nutrition Examination Survey III (NHANES-III). Circulation. 2014 Aug 12:130(7):546-53. doi: 10.1161/CIRCULATIONAHA.114.010001. Epub 2014 Jul 11     [PubMed PMID: 25015340]

Level 3 (low-level) evidence

[12]

Ford ES, Li C, Zhao G, Mokdad AH. Concentrations of low-density lipoprotein cholesterol and total cholesterol among children and adolescents in the United States. Circulation. 2009 Mar 3:119(8):1108-15. doi: 10.1161/CIRCULATIONAHA.108.816769. Epub 2009 Feb 16     [PubMed PMID: 19221218]


[13]

Gooding HC, Rodday AM, Wong JB, Gillman MW, Lloyd-Jones DM, Leslie LK, de Ferranti SD. Application of Pediatric and Adult Guidelines for Treatment of Lipid Levels Among US Adolescents Transitioning to Young Adulthood. JAMA pediatrics. 2015 Jun:169(6):569-74. doi: 10.1001/jamapediatrics.2015.0168. Epub     [PubMed PMID: 25845026]


[14]

Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. 2011 Dec:128 Suppl 5(Suppl 5):S213-56. doi: 10.1542/peds.2009-2107C. Epub 2011 Nov 14     [PubMed PMID: 22084329]


[15]

D'Agostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, Kannel WB. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008 Feb 12:117(6):743-53. doi: 10.1161/CIRCULATIONAHA.107.699579. Epub 2008 Jan 22     [PubMed PMID: 18212285]


[16]

JBS3 Board. Joint British Societies' consensus recommendations for the prevention of cardiovascular disease (JBS3). Heart (British Cardiac Society). 2014 Apr:100 Suppl 2():ii1-ii67. doi: 10.1136/heartjnl-2014-305693. Epub     [PubMed PMID: 24667225]

Level 3 (low-level) evidence

[17]

Fredrickson DS. An international classification of hyperlipidemias and hyperlipoproteinemias. Annals of internal medicine. 1971 Sep:75(3):471-2     [PubMed PMID: 5568160]


[18]

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001 May 16:285(19):2486-97     [PubMed PMID: 11368702]


[19]

Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. The New England journal of medicine. 1996 Oct 3:335(14):1001-9     [PubMed PMID: 8801446]


[20]

Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet (London, England). 2010 Nov 13:376(9753):1670-81. doi: 10.1016/S0140-6736(10)61350-5. Epub 2010 Nov 8     [PubMed PMID: 21067804]

Level 1 (high-level) evidence

[21]

LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK, Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. The New England journal of medicine. 2005 Apr 7:352(14):1425-35     [PubMed PMID: 15755765]


[22]

Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986 Nov 28:256(20):2823-8     [PubMed PMID: 3773199]


[23]

Gregg EW, Cheng YJ, Cadwell BL, Imperatore G, Williams DE, Flegal KM, Narayan KM, Williamson DF. Secular trends in cardiovascular disease risk factors according to body mass index in US adults. JAMA. 2005 Apr 20:293(15):1868-74     [PubMed PMID: 15840861]


[24]

Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, Baigent C. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet (London, England). 2012 Aug 11:380(9841):581-90. doi: 10.1016/S0140-6736(12)60367-5. Epub 2012 May 17     [PubMed PMID: 22607822]

Level 1 (high-level) evidence

[25]

Zhang J, Xu J, Wang J, Wu C, Xu Y, Wang Y, Deng F, Wang Z, Chen X, Wu M, Chen Y. Prognostic Usefulness of Serum Cholesterol Efflux Capacity in Patients With Coronary Artery Disease. The American journal of cardiology. 2016 Feb 15:117(4):508-514. doi: 10.1016/j.amjcard.2015.11.033. Epub 2015 Dec 2     [PubMed PMID: 26718234]


[26]

Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. 2019 Jun 25:73(24):e285-e350. doi: 10.1016/j.jacc.2018.11.003. Epub 2018 Nov 10     [PubMed PMID: 30423393]

Level 1 (high-level) evidence