cholesterol – The Early Career Voice

PCSK9: From Bench to Bedside

February 14, 2022February 4, 2022 Devika Aggarwal, MBBS

(Image by sinclair.sharon28 from Creative Commons)

The proatherogenic role of low-density lipoprotein (LDL) cholesterol is well established and reduction of LDL cholesterol is one of the central pillars of management and prevention of atherosclerotic cardiovascular disease. The prevention of atherosclerotic events directly correlates with the reduction in LDL cholesterol and growing evidence supports the notion that the lower the LDL, the better the outcome.¹ Statins are the backbone of lipid-lowering therapy and are indispensable for primary and secondary prevention. Despite trials showing no significant difference versus placebo in terms of serious adverse events, statin intolerance is commonly encountered in clinical practice.² Additionally, patients on intensive statin therapy can have significant residual risk that can be minimized by additional lipid-lowering interventions.³ Hence, there was an urgent need for new strategies to lower LDL cholesterol levels.

In 2003, Abifadel and colleagues first reported a gain-of-function mutation in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene in a French family with autosomal dominant hypercholesterolemia, ⁴ a condition associated with significantly increased LDL cholesterol levels and risk of cardiovascular disease. Studies in mice subsequently delineated the underlying pathway: the PCSK9 gene encodes its namesake protein produced primarily in the liver.⁵ This protein binds to LDL receptors on the surface of hepatocytes, leading to their internalization and degradation. Reduced uptake of LDL particles by the hepatocytes leads to higher circulating levels of LDL cholesterol, increasing the risk of atherogenesis. Similar mechanisms are reported in humans. An analysis from the longitudinal Atherosclerosis Risk in Communities (ARIC) database showed that genetic variations in PCSK9 associated with lower levels of LDL cholesterol attenuated the risk of coronary heart disease.⁶ Studies also showed a reduction in triglyceride levels in patients with loss-of-function of PCSK9.⁷

These findings inspired the research and development of therapies targeting the PCSK9 pathway to achieve a reduction in LDL cholesterol levels. In 2009, Chan and colleagues developed a neutralizing antibody to PCSK9 that showed a significant reduction in LDL cholesterol in mice and monkeys.⁸ Within a decade of the discovery of the PCSK9 pathway, the race for human trials was on. In 2012, REGN727, a human monoclonal antibody, now known as alirocumab (Praluent®, by Regeneron and Sanofi) was shown to safely reduce LDL cholesterol levels.⁹ Similar results were seen with AMG145, later named evolocumab (Repatha®, by Amgen).¹⁰ Additional studies confirmed the ability of the two drugs to reduce LDL cholesterol by upto 60% without any serious adverse events. This led to FDA approval for both alirocumab and evolocumab as adjunct therapies to reduce LDL cholesterol in patients with (1) familial hypercholesterolemia and (2) established cardiovascular disease in 2015. Importantly, large randomized placebo-controlled trials, including the FOURIER and ODYSSEY trials, have shown remarkable reductions in the incidence of the composite clinical outcome of cardiovascular death, myocardial infarction, stroke, and hospitalization for acute coronary syndrome.^11,12 Initial concerns of neurocognitive impairment with PCSK9 inhibitors have been allayed. The clinical use of PCSK9 inhibitors has been reassuring in terms of both safety and efficacy. The primary limitations to their use are high cost and the need for twice weekly or monthly subcutaneous injections. While the reduction in annual costs from around $14,000 to $5,800 is encouraging, high co-pays and frequent need for prior authorization continue to prevent many patients from reaping the benefits of PCSK9 inhibitors.

The recent FDA approval of inclisiran (Leqvio®, Novartis) was met with enthusiasm throughout the medical community, and rightly so. Inclisiran is a novel small interfering RNA (siRNA) based therapy that blocks the synthesis of PCSK9 from the liver. The ORION trials showed a 50% reduction in LDL cholesterol levels as compared to placebo in patients with atherosclerotic cardiovascular disease on maximally tolerated statin therapy.¹³ A major advantage of inclisiran is the biannual dosing as compared with the every 2-4 week dosing with PCSK9 inhibitors. Novartis, the company behind the drug is proposing a ‘buy-and-bill’ model where the drug will be administered in the office, which will likely improve adherence.¹⁴ The convenience factor might just provide inclisiran leverage over existing therapies. Many real-world challenges still need to be addressed including long-term safety data and ensuring cost-effective and equitable distribution of this potentially life-saving drug. Despite these concerns, the approval of inclisiran is an important landmark in the field of cardiovascular disease prevention. The trajectory of PCSK9 from a newly discovered molecule to a novel siRNA-based therapy in 20 years is inspiring and reinforces the importance of basic science and translational research.\

References:

Koskinas KC, Siontis GCM, Piccolo R, et al. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur Heart J. 2018;39(14):1172-1180. doi:10.1093/eurheartj/ehx566
Tobert JA, Newman CB. Statin tolerability: In defence of placebo-controlled trials. Eur J Prev Cardiol. 2016;23(8):891-896. doi:10.1177/2047487315602861
Reith C, Armitage J. Management of residual risk after statin therapy. Atherosclerosis. 2016;245:161-170. doi:10.1016/j.atherosclerosis.2015.12.018
Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154-156. doi:10.1038/ng1161
Wiciński M, Żak J, Malinowski B, Popek G, Grześk G. PCSK9 signaling pathways and their potential importance in clinical practice. EPMA J. 2017;8(4):391-402. doi:10.1007/s13167-017-0106-6
Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272. doi:10.1056/NEJMoa054013
Handelsman Y, Lepor NE. PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review. J Am Heart Assoc. 2018;7(13):e008953. doi:10.1161/JAHA.118.008953
Chan JCY, Piper DE, Cao Q, et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci U S A. 2009;106(24):9820-9825. doi:10.1073/pnas.0903849106
Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366(12):1108-1118. doi:10.1056/NEJMoa1105803
Dias CS, Shaywitz AJ, Wasserman SM, et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol. 2012;60(19):1888-1898. doi:10.1016/j.jacc.2012.08.986
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664
Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107. doi:10.1056/NEJMoa1801174
Ray KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020;382(16):1507-1519. doi:10.1056/NEJMoa1912387
Pricey Inclisiran Is Rolling Out: a ‘Buy-and-Bill’ Model May Smooth Its Path. TCTMD.com. Accessed February 3, 2022. https://www.tctmd.com/news/pricey-inclisiran-rolling-out-buy-and-bill-model-may-smooth-its-path

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

Elevated Lipoprotein A, are we ready to intervene?

January 19, 2022January 11, 2022 Reza Mohebi, MD

Lipid abnormalities can be classified into four clinical groups:1) elevated triglycerides, 2) low high-density lipoprotein cholesterol (HDL-C),3) elevated low-density lipoprotein cholesterol (LDL-C), and 4) elevated lipoprotein A. Lipoprotein A disorder has been the least lipid abnormality studied from a clinical standpoint. Although many mendelian and genome-wide association studies have shown an association between elevated lipoprotein A and risk of incident atherosclerotic cardiovascular disease (ASCVD), the causality relationship still lacks the final corroboration of a randomized Lp(a) lowering intervention clinical trial¹.

In 1963, for the first time, Kare Berg described the existence of Lp(a). Lp(a) consisted of apolipoprotein (a) bound to apolipoprotein B-100, an apolipoprotein also found on LDL-C particles. Distinct from other lipoproteins greatly affected by diet and genetics, Lp (a) is determined by more than 90% by individuals’ genetics. Lp(a) is synthesized in hepatocytes and is released into blood circulation. Plasma concentrations of Lp(a) are inversely associated with the size of apolipoprotein(a). It is postulated that small isoforms can be synthesized faster than large ones, and apolipoprotein(a) size can account for up to 70% influence on Lp(a) blood concentration. Other known factors include single nucleotide polymorphisms, sex hormones, inflammatory mediators, and dietary factors².

Many medications have been tested to lower Lp(a) concentration. A large-scale meta-analysis of 5,256 patients (1,371 on placebo and 3,885 on statin) enrolled in a randomized clinical trial showed that most statins significantly increase Lp(a) concentration by 8-24%³. Niacin may lower Lp(a) concentration by 20-30%. However, studies did not show any significant reduction in risk of ASCVD event, once niacin was added to the medication list of patients already receiving a statin. Estrogen can also lower Lp(a) concentration by 20%; however, the usage is limited due to concern about increasing the risk of thrombotic events. Proprotein convertase subtilisin Kexin type 9 inhibitors (PCSK9 inhibitors) have been shown to lower Lp(a) concentrations. In 2 major PCSK-9 inhibitors clinical trials- FOURIER and ODYSSEY OUTCOME- the fourth quartile of Lp(a) in the treatment arm was associated with a 25% increase risk of major adverse cardiovascular events. This implies the presence of residual risk of ASCVD despite very low LDL-C⁴. In a recent sub-analysis of ODYSSEY OUTCOME trial, alirocumab reduced Lp(a) concentration. Each 5mg/dl decrease in Lp(a) by alirocumab resulted in a 2.5% reduction in risk of cardiovascular events⁵. It should be noted that none of the above medications have primarily been initially designed to test the hypotheses of the beneficial effect of medication on Lp(a) concentration.

Genetic studies have shed light on the role of each allele on Lp(a) concentrations and have provided a base for pharmacological intervention. Antisense oligonucleotides (ASO) have revolutionized the treatment of Lp(a). ASOs are short DNA fragments designed complementary for a target messenger RNA. LPA gene transcribes the two alleles of apolipoprotein(a) mRNA. ASO like Pelacarsen binds to the mRNA and generates the mRNA-ASO complex. Hepatocytes recognized this complex as foreign objects, and RNase H1 cleaves the sense strand. Four clinical trials have been conducted to assess the efficacy of ASOs to lower Lp(a) concentrations. All the clinical trials have shown promising results, from 40% to up to 90% reduction in Lp(a) depending on the type of ASO, dosage, and frequency of administrations⁶.

Currently, the pivotal phase 3 of Lp(a)HORIZON⁷ (ClinicalTrials.gov Identifier: NCT04023552) randomized controlled trial is enrolling up to 8280 individuals, aged >18 years with Lp(a) ≥ 70 mg/dl and with a history of myocardial infarction, ischemic stroke, or symptomatic peripheral artery disease. Participants are double blindly randomized to receive TQJ230 80 mg injected monthly subcutaneously or placebo and will be followed for the primary outcome of MACE (CV death, non-fatal MI, non-fatal stroke, and urgent coronary revascularization). The estimated primary completion date is May 29, 2025. So, we need to be patient and wait to see if the causal relationship between Lp(a) and ASCVD will be established by 2025.

References:

Miksenas H, Januzzi JL, Jr. and Natarajan P. Lipoprotein(a) and Cardiovascular Diseases. JAMA. 2021;326:352-353.
Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017;69:692-711.
Tsimikas S, Gordts P, Nora C, Yeang C and Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J. 2020;41:2275-2284.
Ruscica M, Greco MF, Ferri N and Corsini A. Lipoprotein(a) and PCSK9 inhibition: clinical evidence. Eur Heart J Suppl. 2020;22:L53-L56.
Szarek M, Bittner VA, Aylward P, Baccara-Dinet M, Bhatt DL, Diaz R, Fras Z, Goodman SG, Halvorsen S, Harrington RA, Jukema JW, Moriarty PM, Pordy R, Ray KK, Sinnaeve P, Tsimikas S, Vogel R, White HD, Zahger D, Zeiher AM, Steg PG, Schwartz GG and Investigators OO. Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial. Eur Heart J. 2020;41:4245-4255.
Tsimikas S, Moriarty PM and Stroes ES. Emerging RNA Therapeutics to Lower Blood Levels of Lp(a): JACC Focus Seminar 2/4. J Am Coll Cardiol. 2021;77:1576-1589.
Assessing the Impact of Lipoprotein (a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD (Lp(a)HORIZON). https://clinicaltrialsgov/ct2/show/NCT04023552. 2019.

Channeling Health Care Delivery and Implementation Science in Cardiology for Improved Outcomes

November 14, 2021November 15, 2021 Olubadewa Fatunde, MD MPH

The opening session for AHA21 was nothing sort of inspirational. In the opening session, a quote by Dr. Keith Ferdinand, Professor of Medicine and Chair of Preventative Cardiology at Tulane University, really stuck with me. The topic was how is the field of medicine adjusting in the midst of the challenges faced and inequities uncovered by the COVID pandemic? The simple answer: while positive strides have been made, there is much room for improvement. He then went on to expound about the importance of implementation science, as the best science in the world will do you no good if patients are unable to implement physical activity/dietary guidelines, understand when to take the appropriate medications, or receive preventive vaccines in time.

From the American experience with COVID, part of the difficulty in reaching the average American seems to be the emotional gap between patients and either healthcare institutions or providers. The weight evidence from the trials on COVID vaccines are clear on the efficacy and safety, particularly of the mRNA vaccines. However, delivering the messaging in a way the public will accept remains frustrating in many parts of the country. As a result, only 59% of the US population is fully vaccinated, while 68% have received at least one dose, ranking 51^st in the world (1). The way we consume information is drastically different from earlier decades. In 2020, a Pew Research poll revealed more than eight-in-ten U.S. adults (86%) received news from a digital device compared to TV (68%), with those under 50 heavily skewed towards digital news consumption.(2) In this same poll, approximately 50% of adults consumed news from social media.(2, 3) In contrast, in 2015, 75% of American adults had a PCP, dropping to 64% among 30-year-olds.(4) During the last true global pandemic, that PCP was more likely to make a house call rather than see a patient 1 to 4 times a year.

The common thread for successful interventions seems to be meeting people where they are. Several panelists on the FIT session on navigating misinformation on social media, noted that as many receive news on socia media, they were motivated to explain new studies and correct misinformation on those platforms where people are likely to spend time and digest information. Admittedly, this effect is hard to measure, and many studies thus far are qualitative in nature. More concretely, two exciting trials presented at #AHA21 seem to shed some light on how we can mobilize these neural structures to improve the rates of uptake of proven behavioral & therapeutic modalities, to yield the morbidity and mortality benefits. Simply, how do we get patients to successfully take their indicated medications?

Dr. Jiang He of Tulane University presented the results of the China Rural Hypertension Control Project, an intervention in rural China utilizing nonphysician community health workers (CHW) supervised by local primary care physicians. These CHW—village doctors—were provided with basic medical training (e.g. standardized BP measurement) and tasked to deliver protocolized antihypertensive medications and counsel patients on medication adherence and lifestyle modification (5, 6). Patients were followed monthly and received discounted or free medications and home BP monitors. After 18 months, this cluster-randomized trial, yielded a 37.1% increase in achievement of goal BP control (< 130/80 mm Hg) of subjects living in intervention villages (57%) compared with those living in control villages (19.9%) (P < 0.001). The average drop in BP in the intervention group was greater by 15/7 mm Hg. (6) The use of community health workers is not a new phenomenon in developing countries. They are often trusted community members who receive training to help address community problems. The first use of CHW with no prior formal training to address problems with rural health was in China in the 1930s.(7) This model later spread to Latin America and Southeast Asia in the 1960s with varying levels of success. Certain countries—including Brazil, Bangladesh, and Kenya—have learned from these early struggles to build sustainable successful CHW models (7-9). Our colleagues in infectious disease have successfully integrated CHW to help tackle lack of adherence to Tuberculosis medications causing resistance, by CHW directly observing patients taking their medicines (DOTS).(10) In the US, CHW was recognized as a standard job classification by the US Department of Labor (US Bureau of Labor Statistics, 2010) for the first time in the 2010 census and continue to be underutilized. If the work of Dr. He and colleagues, can be translated to a form suitable to the US health system, this can hold great promise for prevention of the myriad problems stemming from uncontrolled hypertensions.

Dr. Alexander Blood, of Brigham and Women’s Hospital, provides a glimpse of what this may look like. Based on prior work led by Dr. Benjamin Scirica at the same institution(11), the program uses “navigators” to communicate with patients (via phone, text, and email), pharmacists to prescribe and adjust medication as necessary, as well as an algorithm to help educate patients, integrate data, and coordinate care. (12, 13) As a result, systolic blood pressure was reduced by 10 mm Hg and LDL cholesterol by 45 mg/dL in approximately 10,000 participants enrolled. In an interview with TCTMD, Dr. Blood compared this program to Warfarin management, where the physician writes the initial prescription and the Pharmacy and Warfarin clinic maintain patient’s INR on a weekly basis. It is unlikely that quarterly or biannual visits will yield effective control in patients with poor health literacy. For patients that needed higher intensity care, they were referred to their physician (12, 13). An important aspect of this trial is the results were consistent in populations typically underserved by the medical system–Blacks, Hispanics, and non-English speaking populations. Dr. Blood noted, “…if you structure the way you’re reaching out to patients, engaging them, and communicating with them—if you’re intentional and equitable in the way you make that type of outreach—it’s possible to engage, enroll, and help patients reach maintenance at similar rates across these subpopulations that are traditionally underserved in medicine.” (12)

In summary, while amazing new discoveries & technologies continue to reshape what is possible in cardiology, it is equally important to apply the same ingenuity to scaling up what we already know works and meet people where they are, in order to guide them to best health that science can offer.

References:

Hannah Ritchie EM, Lucas Rodés-Guirao, Cameron Appel, Charlie Giattino, Esteban Ortiz-Ospina, Joe Hasell, Bobbie Macdonald, Diana Beltekian and Max Roser (2020) – “Coronavirus Pandemic (COVID-19)”. Published online at OurWorldInData.org. Retrieved from: ‘https://ourworldindata.org/coronavirus’ [Online Resource]. [Available from: https://ourworldindata.org/covid-vaccinations?country=USA.
Shearer E. More than eight-in-ten Americans get news from digital devices2021. Available from: https://www.pewresearch.org/fact-tank/2021/01/12/more-than-eight-in-ten-americans-get-news-from-digital-devices/.
Shearer E, Mitchell A. News Use Across Social Media Platforms in 20202021. Available from: https://www.pewresearch.org/journalism/2021/01/12/news-use-across-social-media-platforms-in-2020/.
Levine DM, Linder JA, Landon BE. Characteristics of Americans With Primary Care and Changes Over Time, 2002-2015. JAMA Intern Med. 2020;180(3):463-6.
Sun Y, Li Z, Guo X, Zhou Y, Ouyang N, Xing L, et al. Rationale and Design of a Cluster Randomized Trial of a Village Doctor-Led Intervention on Hypertension Control in China. Am J Hypertens. 2021;34(8):831-9.
Neale T. Village-Level Intervention Nets Big BP Control Gains in Rural China. TCTMD. 2021. https://www.tctmd.com/news/village-level-intervention-nets-big-bp-control-gains-rural-china [Accessed November 14, 2021]
Perry H. A Brief History of Community Health Worker Programs. https://www.mchip.net/: USAID; 2013. p. 14.
Lehmann U, Sanders D. Community health workers: What do we know about them? The state of the evidence on programmes, activities, costs and impact on health outcomes of using community health workers. School of Public Health, University of the Western Cape, Evidence and Information for Policy DoHRfH; 2007.
Rosenthal EL, Wiggins N, Ingram M, Mayfield-Johnson S, De Zapien JG. Community health workers then and now: an overview of national studies aimed at defining the field. J Ambul Care Manage. 2011;34(3):247-59.
Farmer P, Kim JY. Community based approaches to the control of multidrug resistant tuberculosis: introducing “DOTS-plus”. BMJ. 1998;317(7159):671-4.
Scirica BM, Cannon CP, Fisher NDL, Gaziano TA, Zelle D, Chaney K, et al. Digital Care Transformation: Interim Report From the First 5000 Patients Enrolled in a Remote Algorithm-Based Cardiovascular Risk Management Program to Improve Lipid and Hypertension Control. Circulation. 2021;143(5):507-9.
O’Riordan M. Pharmacist-Led Intervention Slashes LDL and BP in 10,000 Patients. TCTMD. 2021. https://www.tctmd.com/news/pharmacist-led-intervention-slashes-ldl-and-bp-10000-patients?utm_source=TCTMD&utm_medium=email&utm_campaign=Newsletter111321 [Accessed November 14, 2021]
Blood AJ CC, Gordon WJ, et al. Digital care transformation: report from the first 10,000 patients enrolled in a remote algorithm-based cardiovascular risk management program to improve lipid and hypertension control. Presented at: AHA 2021. November 13, 2021.

Diet, Fat, and Healthy Heart

July 16, 2021July 7, 2021 Huan Wang, PhD

What type of milk do you prefer? Most people will give you their answers quickly without much hesitation. Besides taste and flavor, whether to choose whole milk (~3.5% fat), reduced-fat milk (2% fat) or skim milk (0% fat) depends mostly on how much fat do you prefer in your diet. Reduced fat milk and skim milk have become the poster children for heart beneficial diets in the past decades. The long-held belief that fat is bad for your heart originates from a famous epidemiology study conducted by Ancel Keys and colleagues¹.

Ancel Keys’ Seven Countries Studies influenced dietary recommendation on fat for decades. Keys believed that fatty foods such as dairy products and red meat are the culprit for coronary heart disease. He studied diet, lifestyle, and incidence of coronary heart diseases in about 13,000 adult men in Finland, Greece, Italy, Japan, the Netherlands, the United States, and Yugoslavia¹, and found that countries with diets high in saturated fat including the United States have the highest blood cholesterol levels and heart-attack death rates. Based on Keys’ studies and other similar findings, the United States and the United Kingdom introduced dietary guidelines which recommend reducing consumption of saturated fat to about 10% of total energy intake, to lower cholesterol in the blood and therefore decrease the risks of a heart attack. A low-fat diet has been associated with good health practices ever since. Here is a twist to this story, Keys didn’t include France, where the nation’s high-fat diet doesn’t correlate with the occurrence of heart diseases. It turns out to be the opposite.

Not all fat is created equal. Let’s take milk fat for example. Milk fat contains a variety of fats such as saturated fat, unsaturated fat, and trans-fat. Generally, trans-fat is considered as “bad” fat in processed foods and fried foods, however, naturally found trans-fat in milk is beneficial. Another example is cholesterol. It’s taken for granted to associate dysregulated blood cholesterol levels with dietary cholesterol intake. In fact, it’s not cholesterol itself that causes high blood cholesterol levels, but rather the lipoproteins that move cholesterol in and out of cells. Broadly, there are the “good” cholesterol– high-density lipoprotein (HDL) and the “bad” cholesterol– low-density and very-low-density lipoproteins (LDL and VLDL). Seventy percent of milk fat is saturated fat, and saturated fats in milk raise both HDL (good) and LDL (bad) cholesterol. The net effect of milk fat might be neutral. Processed foods, fried foods and stick margarine have lots of trans-fats from production and are known for raising LDL cholesterol and lowering HDL cholesterol.

The “good” and “bad” cholesterol levels are considered as the golden standard for cardiovascular risk prediction. However, recent research shows that high HDL levels in some cases associated with higher risks in heart disease². The plot is thickened. It turns out that some people with a genetic mutation in HDL receptor gene fail to transport cholesterol outside of blood, therefore results in higher level of fats in the body despite having high levels of HDL cholesterols in the circulation. In conclusion, blindly relying on fat content in the Nutrition label is simply not enough.

Now, let’s go back to the milk choice question one more time. Not only we need to consider what type of fat in cow milk, but we also need to look at other factors too. Sugar is often ignored when it comes to buying milk. Reduced fat and skim milk contain slightly more carbohydrates than whole fat milk does. If your goal is to lose weight by reducing fat content in your milk, you might get disappointed. The relationship between milk fat and weight management is still not clear. An epidemiology study shows that women who consumed more than 1 serving of whole fat milk per day were 15% less likely to gain weight compared to those who drink low fat milk³. Also recent research show that consuming saturated fat does not directly cause heart disease⁴. Therefore, how much you eat doesn’t necessarily translate to how much will end up in your body. It depends on how you body metabolizes it, what’s your genetic makeup and what else in your diet potentially positively or negatively contribute to the net outcomes. Last not the least, even not all fat creates equal, trans-fat from fried foods and processed foods are still universally considered bad for your health. Try to avoid those if it’s possible.

REFERENCE

Keys A. Seven Countries. Harvard University Press; 2013.
Zanoni P, Khetarpal SA, Larach DB, Hancock-Cerutti WF, Millar JS, Cuchel M, DerOhannessian S, Kontush A, Surendran P, Saleheen D, Trompet S, Jukema JW, De Craen A, Deloukas P, Sattar N, et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science. 2016;351(6278):1166 LP – 1171.
Rosell M, Håkansson NN, Wolk A. Association between dairy food consumption and weight change over 9 y in 19 352 perimenopausal women. The American Journal of Clinical Nutrition. 2006;84(6):1481–1488.
Weinberg SL. The diet–heart hypothesis: a critique. Journal of the American College of Cardiology. 2004;43(5):731–733.
“The facts on fats infographic” [Image] (2017). American Heart Association. https://www.heart.org/en/healthy-living/healthy-eating/eat-smart/fats/the-facts-on-fats

New Cholesterol Guidelines From A Neurologist’s Perspective

November 15, 2018March 28, 2019 Siddharth Sehgal, MD

The American Heart Association’s annual premier conference “Scientific Sessions 2018” concluded on Monday. This meeting showcases the latest advancements and discoveries in the field of cardiovascular medicine and is attended by clinicians and researchers from across the world.

Being a vascular neurologist, I have attended the International Stroke Conference organized by the AHA several times, however, this was my first time attending Scientific Sessions. I was able to attend the conference via Live Streaming while sitting in my office in Burlington, Massachusetts.

There are a lot of overlaps between cerebrovascular and cardiovascular disease and I was particularly interested in attending the sessions pertaining to stroke prevention and brain health. One of the most anticipated presentations was the release and discussion of the new AHA/ACC Cholesterol Clinical Practice Guidelines.

Some key takeaways from the updated guidelines:

The guidelines continue to underscore the role of lifestyle and dietary habits in addition to lipid lowering medication use to treat cholesterol disorders. There is emphasis on the concept of shared decision making with the patient which should include discussion of their individual risk and the treatment options to reduce that risk.
Addition of Ezitimibe and subsequently PCSK-9 inhibitors is now recommended in patients who cannot achieve target LDL levels despite maximum tolerated statin doses. There is some concern about the cost effectiveness of PCSK-9 inhibitors, but these medications are expected to become cheaper in the future.
Risk enhancing factors are introduced as part of a personalized approach to risk assessment prior to initiating statin therapy. These include persistent elevation of LDL>160 mg/dL, history of pre-eclampsia, family history of premature atherosclerotic cardiovascular disease, history of chronic kidney disease and chronic inflammatory disease, among others.
There is a recommendation for expanding use of calcium score as part of the risk assessment, especially in patients where risk benefit analysis is uncertain.

In addition to the guidelines for medications and lifestyle changes to treat cholesterol disorders, I especially enjoyed Dr. Laurence Sperling’s talk about the safety of statins.

Patients should be prescribed statins again at a lower dose or modified drug regimen if the reason for discontinuation was mild side effect symptoms. Although rare, but some patients do develop severe myopathy with statin use. These patients should be prescribed alternate non-statin therapies to achieve the target cholesterol levels. There has not been any proven benefit of Co Q10 to prevent or treat statin associated muscle symptoms. Despite the increased risk of diabetes mellitus with statins, it is recommended to continue the drug in patients who may be at risk or develop new onset DM. These patients should be counseled about the net clinical benefit of these drugs for long term cardiovascular event prevention. It appears reasonable to initiate statin therapy in the presence of an appropriate indication despite a history of stable liver disease. In patients without hepatic disorders, there is no clinical benefit of routine creatine kinase and liver enzyme measurements.

Very often patients have questions and concerns about initiating and continuing their statin medication. I believe that these data and recommendations further reinforce my personal practice to encourage patients to continue their statin medication as the risk benefit ratio remains favorable despite mild side effects.

Metformin: A diabetes medication with cardiovascular protective effects

July 19, 2018 Dalia Gaddis, PhD

What if a diabetes medication can improve cardiovascular events? Since patients with type II diabetes are more prone to cardiac events, the use of diabetes medication to help reduce cardiovascular burden would definitely be beneficial. One of such medications is the drug, Metformin.

Metformin, also know with the trade name of Glucophage, is the first-line of treatment for type II diabetes. It is also often prescribed to patients with metabolic syndrome and patients with polycystic ovarian syndrome to control insulin resistance. Metformin works by increasing insulin sensitivity and decreasing glucose production by the liver. While its molecular mechanism of action is not completely understood, one way metformin exerts its effects is through regulating AMP-activated protein kinase (AMPK), an enzyme that plays an important role in insulin signaling and detecting cellular energy levels. By regulating AMPK, metformin also lowers inflammation and thus there is an emerging body of evidence suggesting that metformin regulates the immune system and reduces inflammation and can potentially protect against diseases such as inflammatory bowel disease and atherosclerosis.

Until recently, there has been associations that metformin may protect against cardiovascular disease, although exactly how was never been directly studied. A recent study by a group of researchers in Columbia University in New York, published recently in the ATVB journal, looked at the role of metformin and how it may affect cardiovascular disease. The authors show that exposure of liver cells to metformin increased the expression of ABCG5 and ABCG8, two cholesterol transporter molecules responsible for the efflux of cholesterol. The authors also saw the same effect when they gave metformin to mice fed a western diet, also know as high cholesterol, high fat diet. This increase in expression of ABCG5 and ABCG8 was accompanied by an increase in cholesterol clearance from the plasma in these treated mice. This study provides first evidence of how metformin could have a direct cardiovascular disease protective effect.

Since metformin, through regulating AMPK, has an anti-inflammatory effect, this study shows that metformin may have a combined protective impact regarding cardiovascular disease; the first through increasing cholesterol clearance and the second through reducing immune mediated inflammation, overall resulting in lower cholesterol levels and less inflammatory mediators responsible for atherosclerosis progression and thus reducing cardiovascular disease risk. It would be interesting to see if patients who are taking metformin for diabetes treatment have a decrease in cardiovascular events in a controlled manner. Finally, this study highlights the potential of a drug like metformin, not only as a diabetes medication but as a cardiovascular protective drug as well.

Dalia Gaddis is a postdoctoral fellow at the La Jolla Institute for Allergy and Immunology. She has a Ph.D. in microbiology and immunology. She is currently working on understanding the interactions between the immune system and atherosclerosis development.

The Liver’s New Job: Making An Immune Response Towards Cholesterol!

March 19, 2018 Dalia Gaddis, PhD

If you think the liver’s only relationship with cholesterol is to control its metabolism and excretion, think again. It turns out the liver is also involved in the immune response towards cholesterol particularly in situations where cholesterol is increased, a recent study published in the Circulation Research journal shows.

In a previous post, I wrote about how complex the relationship between heart disease and the immune system is. While most studies that examine the role of the immune system in atherosclerosis focus on immune cells from the blood, lymphoid organs, or look at the immune cells in the aortic walls, there are very few studies that looked at the contribution of the immune system in the liver to atherosclerosis development.

As an immunological site, the liver plays an important role in preventing autoimmunity and defending against invaders. Being the largest solid organ in the body, with its rich blood flow and its proximity to the digestive system, the liver is a crucial organ in cholesterol metabolism. The liver is also filled with macrophages, an immune cell that, among its many jobs, specializes in getting rid of extra cholesterol. High cholesterol levels can destroy the liver’s ability to metabolize cholesterol and result in liver failure. However, not much is known about the role of the immune cells in the liver and how do they respond to high cholesterol levels. A research group from the Cardiovascular Medicine Unit in Karolinska Institute, Sweden, examined this exact question. Their study shows that in mouse models, T cells, a type of immune cell that is involved in adaptive immunity, increases in the liver as a result of high cholesterol levels. These liver T cells can travel to the aortic vessels were atherosclerosis occurs, providing first evidence that the liver immune cells may contribute to the immune response during atherosclerosis development.

As an immunologist who studies how the immune system affects atherosclerosis development, I am constantly fascinated by new findings in this area. The study made me think of whether the liver’s immune response is responding to the excess cholesterol in the circulation or to that accumulating in the liver. As there are different types of T cells, some that promote atherosclerosis while others reduce disease progression, the study also made me wonder if these different cells generated in the liver tipped the balance in favor or against a protective immune response. Does a similar immune response happen in the liver of people with high cholesterol levels? With these new findings, the door is now open to questions that will help our understanding of the complex relationship between cholesterol, the liver, the immune system and how it all ties together to influence atherosclerosis and heart disease.

Lipid-lowering Therapy In Young Adults: Do We Need To Re-invent The Wheel Or Just Align It?

February 16, 2018 Tanja Dudenbostel, MD

Elevated cholesterol levels or hypercholesterolemia can be found for years or even decades, before individuals present with cardiovascular disease and complications such as myocardial infarction, stroke, or sudden cardiac death. The diagnosis of hypercholesterolemia and its treatment along with healthy lifestyle changes including a healthy diet and exercise as well as blood pressure control, are cornerstones of long-term cardiovascular health.¹

There has been a substantial decline in cardiovascular disease mortality in the last decade due to improved awareness, therapy for established cardiovascular disease and primary and secondary preventive interventions.1 However, this observation is absent in young adults.2 Over the last decade, unfavorable trends in coronary heart disease and related mortality in younger individuals, i.e. 35-55 year-old, have emerged.²

We have previously shown that there is a phenotype of young adults with premature hypertension and development of resistant hypertension in their 30s.³ This phenotype has been characterized in a cross-sectional study of 2068 patients seen in a university referral clinic for resistant hypertension. In this study 45% of consecutively seen patients were younger than 55 years of age. Amongst them, 23% had high lipids, 25% were obese, 19% had diabetes, and 13% had obstructive sleep apnea. Cardiovascular events such a s history of myocardial infarction, stroke, or heart failure were prevalent were found in >20%. The majority of these predominately obese, resistant hypertensive individuals have excessive aldosterone, cortisol and sodium levels, conditions that are associated with increased cardiovascular morbidity and mortality, independent of blood pressure levels.

Lipid-lowering drugs, so-called statins, have been shown to reduce cardiovascular disease and mortality. Lipid lowering with statins in patients with hypercholesterolemia has a proven survival benefit for both primary prevention (ie, in patients without clinical evidence of coronary disease) and secondary prevention (ie, in patients with established coronary disease), even when serum cholesterol concentrations are “normal” for the population or borderline high. The mechanisms by which lipid-lowering therapy is beneficial are incompletely understood since absolute levels of cholesterol before or during treatment only explain parts while cholesterol-independent effects have been also described.1 Among the non-lipid mechanisms that may be involved are plaque stabilization, reduced inflammation, improvement of endothelial and arterial function, and decreased blood clotting.

In 2013 the American College of Cardiology and American Heart Association developed a new guideline for the management of hyperlipidemia. While previous guidelines recommended to initiate or adjust predominantly in response to lipid values these 2013 ACC/AHA guidelines target patients to fixed dose of statin therapy corresponding to atherosclerotic cardiovascular disease (ASCVD) or other risk factors. The four at-risk populations of individuals that are thought to benefit from statin therapy based on this guideline include:

Adult patients with clinical ASCV
Adult patients with primary elevations of LDL–C ≥190 mg/dL
Patients 40-75 years of age with diabetes and LDL–C 70 to 189 mg/dL without clinical ASCVD
Patients 40-75 years of age without clinical ASCVD or diabetes with LDL–C 70 to 189 mg/dL and have an estimated 10-year ASCVD risk of 7.5% or higher

In our cohort half of obese young patients under the age of 40 would per se not qualify to be treated with a statin. Patients between the ages of 40-55 are in the majority of cases not considered “eligible” since age is one of the most powerful nominators in the risk calculator and, anecdotally, when we evaluate these patients for statin eligibility for primary prevention, we usually calculate an estimated 10-year CVD risk score of <5%.

At their first visits we always discuss life style changes, since younger patients may be more motivated to eat healthier, exercise, and lose weight, but consistent, successful lifestyle changes are often difficult to accomplish.

When we consider statin treatment for primary prevention even if the ASCVD risk score is <7.5%, there are a lot of unknowns. Aside from statins being contraindicated in young women who are or want to become pregnant or are breastfeeding, it is not known if there are short-term benefits of therapy. There are few data on the safety of statins over decades of therapy and possible side effects of statin therapy could outweigh potential benefits.

Furthermore, we don’t know whether long-term treatment leads to better outcomes and who are the individuals who are going to benefit. With evolving advances in precision medicine, we may be able to “customize” primary prevention especially for this group and identify young individuals in whom premature cardiovascular events can be prevented.

However, the question remains: how can we prevent cardiovascular events in young adults?

Data of young adults who suffered a cardiovascular event will help to elucidate underlying mechanisms and optimal therapy regimens.

Premature CHD in young adults versus CHD 02012018

This problem has been recognized and resulted in the YOUNG-MI Registry, a retrospective study examining a cohort of young adults age ≤50 years with a first-time MI. The study uses electronic health records of 2 large academic centers, as well as detailed chart review of all patients, to generate high-quality longitudinal data regarding the clinical characteristics, management, and outcomes of patients who experience a myocardial infarction at a young age. Findings are thought to provide important insights regarding prevention, risk stratification, treatment, and outcomes of cardiovascular disease in this understudied population, as well as identify disparities which, if addressed, can lead to further improvement in patient outcomes.

In a recent study from this registry, Singh et al. analyzed retrospectively the statin eligibility of young adults after a myocardial infarction. In this study the statin eligibility, based on the 2013 ACC/AHA guidelines and 2016 USPSTF recommendations, for primary prevention in adults <50 years who experienced a first-time type 1 myocardial infarction were evaluated. The median age of analyzed patients was 45 years, 20% were women, the majority had at least 1 traditional cardiovascular risk factor and 57% had experienced a ST-segment elevation myocardial infarction. Surprisingly, the median estimated 10-year atherosclerotic cardiovascular disease risk score was only 4.8% (interquartile range 2.8-8.0%). Only 49% and 29% would have met criteria for statin eligibility as per the 2013 ACC/AHA guidelines and 2016 USPSTF recommendations, respectively. These findings were even more noticeable in women where 63% were not eligible for statins according to either one of the guidelines as opposed to 46% of men only. To summarize these findings, the majority of young adults who present with a heart attack would not have met current guideline-based treatment thresholds for statin therapy prior to their myocardial infarction.

It highlights the need for better risk assessment tools for young adults. Further, much more needs to be known about risk profiles, optimal prevention, and treatment to improve outcomes in these young understudied adults.

References

Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC, Jr., Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC, Jr., Tomaselli GF and American College of Cardiology/American Heart Association Task Force on Practice G. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1-45.
Ghazi L, Oparil S, Calhoun DA, Lin CP and Dudenbostel T. Distinctive Risk Factors and Phenotype of Younger Patients With Resistant Hypertension: Age Is Relevant. Hypertension. 2017;69:827-835.
Ghazi L, Dudenbostel T, Xing D, Ejem D, Turner-Henson A, Joiner CI, Affuso O, Azuero A, Oparil S, Calhoun DA, Rice M and Hage FG. Assessment of vascular function in low socioeconomic status preschool children: a pilot study. J Am Soc Hypertens. 2016.

Tanja Dudenbostel is an Internist, Hypertension Specialist within Cardiology at the University of Alabama at Birmingham where I divide my time as an Assistant Professor between clinical research and seeing patients in cardiology.

Can Increasing HDL Reduce Heart Disease? An Issue Of Constant Debate!

January 23, 2018 Dalia Gaddis, PhD

A couple of years ago I was fortunate to attend the HDL workshop that followed the ATVB council conference, which was held in San Francisco. The workshop’s main focus was to discuss and debate high-density lipoproteins (HDL), or what is commonly known as “the good cholesterol,” and how it influences heart disease.

You may ask, “HDL-cholesterol is good for your heart, so why dedicate two days to discuss what is already know?!” Here is where it gets interesting. While we look forward to lab results showing high HDL-cholesterol levels and low levels of LDL-cholesterol (bad cholesterol) as an indication of reduced risk for cardiovascular disease, the actual answer to the benefits of HDL for cardiovascular disease is far from a simple yes or no. Yes, having high HDL-cholesterol indeed reduces the risk of heart disease, but this does not hold true for patients with metabolic conditions like diabetes, or chronic inflammation like chronic kidney disease. In fact, multiple clinical studies that aimed at increasing levels of HDL-cholesterol have failed to reduce cardiovascular events. It is now becoming evident that just increasing the quantity of HDL-cholesterol alone is not sufficient to ensure cardiovascular free events.

Scientists are discovering that there is more to HDL-cholesterol than its concentration. The size of these HDL molecules, their composition, and their ability to remove lipids from the blood stream for excretion are more indicative of HDL protective function. In addition, scientists are also finding that HDL has other compelling properties that can lower cardiovascular risk indirectly. HDL can reduce inflammation, protects from cell death and promotes wound healing. HDL also had antithrombotic effects (prevents blood clots formation), all of which would decrease the possibility of a cardiovascular incident.

So why not measure for the functionality of HDL rather than its mere concentration to determine one’s risk for cardiovascular disease? This was a topic for discussion at the HDL workshop. The methods used to measure HDL functionality are far from being standardized for use in clinical settings. More work is needed to find techniques that can be used routinely and reliably across clinical laboratories.

It is worth to note that the increase in HDL-cholesterol levels that are triggered by life style changes: healthy diets and physical exercise, does in fact correlate with reduced risk of cardiovascular disease. Researchers think life style change does not only increase HDL-cholesterol but also has an effect on its function and on other metabolic parameters. So until science figures a more clinically feasible way to measure HDL functionality, it would still be a good practice to continue whatever healthy diet and exercise regimen you are on and to aim to keep those HDL-cholesterol numbers high and those LDL-cholesterol numbers low.