coronary heart disease

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Inflammation: a missing target in coronary heart disease treatment

Reza Mohebi, MD

The role of inflammation in coronary artery disease’s pathophysiology dates back to more than 100 years ago. By the end of the 18th century, Virchow described atherosclerosis as “endarteritis deformans” for the first time. Since then, many studies at the cellular level have shown that lipid accumulation in blood vessels cannot justify the development and progression of the atherosclerosis process. Today, it is established that metabolic factors in conjunction with the inflammatory process lead to the initiation and progression of atherosclerosis. Still, the interaction of innate and adaptive immune systems for the development of atherosclerosis is not fully understood.

Despite significant progress in cardiovascular disease therapies, patients with cardiovascular disease are at high risk of adverse clinical outcomes. Current treatments have focused on lowering low-density lipoprotein-cholesterol concentration, inhibiting platelet activation and coagulation cascades, controlling blood pressure and glucose levels. None of these FDA-approved therapies have targeted the inflammatory pathways involved in atherosclerosis.

Clinical studies have emerged in the cardiovascular field to target inflammation in the past five years. Canakinumab, a monoclonal antibody targeting interleukin-1β, was one of the first anti-inflammatory medications shown to lower the risk of adverse cardiovascular events. In 2017, Ridker and colleagues1 showed that canakinumab led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering among patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. Two years later, in 2019, Ridker and colleagues2 published the efficacy of low-dose methotrexate to prevent atherosclerotic events. Unlike the Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS), methotrexate-an antimetabolite medication indicated for the treatment of autoimmune diseases and a variety of cancers- not only failed to show any efficacy in lowering adverse cardiovascular events among patients with previous myocardial infarction or multivessel coronary disease but also resulted in elevations in liver enzyme levels, reductions in leukocyte counts, hematocrit levels, and a higher incidence of non–basal-cell skin cancers than placebo. The negative result implies the need for explicitly targeting the inflammatory pathways directly involved in atherosclerosis. In 2020, 2 studies evaluated the efficacy of colchicine in reducing atherosclerotic events. Both studies3, 4 showed that patients with chronic coronary artery disease who received colchicine 0.5mg daily had a lower risk of cardiovascular events compared who received placebo. Lastly, a double-blind, randomized, placebo-controlled phase 2 trial5 evaluated the efficacy of ziltivekimab-a human monoclonal IL-6 inhibitor- among chronic kidney disease patients with elevated high-sensitivity CRP. The study showed that ziltivekimab significantly reduced biomarkers of inflammation relevant to atherosclerosis. The study paves the way for conducting a large-scale cardiovascular outcomes trial to investigate the effect of ziltivekimab at high risk of cardiovascular events.

In today’s practice, monoclonal antibodies targeting interleukins are standard therapies in many medicine subspeciality like oncology (many cancers: lymphoma, leukemia), rheumatology (autoimmune disease: rheumatoid arthritis, gout), gastroenterology (Crohn’s disease), and infectious disease (COVID-19 treatment). In the cardiovascular field, although randomized trials are emerging about the efficacy of monoclonal antibodies targeting inflammatory pathways to reduce the cardiovascular risk in patients with atherosclerotic disease, still further evidence is needed. The role of inflammation in atherosclerosis is well-established, and cardiologists may need to better familiarize themselves with inflammatory pathways involved in atherosclerosis since many anti-inflammatory medications will probably be routinely prescribed in the near future to lower the elevated cardiovascular risk.

References:

  1. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ and Group CT. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377:1119-1131.
  2. Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, Mam V, Hasan A, Rosenberg Y, Iturriaga E, Gupta M, Tsigoulis M, Verma S, Clearfield M, Libby P, Goldhaber SZ, Seagle R, Ofori C, Saklayen M, Butman S, Singh N, Le May M, Bertrand O, Johnston J, Paynter NP, Glynn RJ and Investigators C. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med. 2019;380:752-762.
  3. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, Berry C, Lopez-Sendon J, Ostadal P, Koenig W, Angoulvant D, Gregoire JC, Lavoie MA, Dube MP, Rhainds D, Provencher M, Blondeau L, Orfanos A, L’Allier PL, Guertin MC and Roubille F. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381:2497-2505.
  4. Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, The SHK, Xu XF, Ireland MA, Lenderink T, Latchem D, Hoogslag P, Jerzewski A, Nierop P, Whelan A, Hendriks R, Swart H, Schaap J, Kuijper AFM, van Hessen MWJ, Saklani P, Tan I, Thompson AG, Morton A, Judkins C, Bax WA, Dirksen M, Alings M, Hankey GJ, Budgeon CA, Tijssen JGP, Cornel JH, Thompson PL and LoDoCo2 Trial I. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383:1838-1847.
  5. Ridker PM, Devalaraja M, Baeres FMM, Engelmann MDM, Hovingh GK, Ivkovic M, Lo L, Kling D, Pergola P, Raj D, Libby P, Davidson M and Investigators R. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomized, placebo-controlled, phase 2 trial. Lancet. 2021;397:2060-2069.

 

“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 health matters. If you think you are having a heart attack, stroke, or another emergency, please call 911 immediately.”
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Addressing Women’s Cardiac Risk in Primary Care: Research & Practice

Elizabeth Knight, PhD, DNP

Last month, I wrote about my roles in research, practice, and education. This month, I’ll delve into how research and practice interface around a critical health issue: coronary heart disease in women.

A study recently published in JAHA suggests that both delay between symptom onset and hospital presentation and post-PCI coronary blood flow are independently associated with excess mortality in women1.

A key finding for clinical practice is that if delay between symptom onset and hospital presentation is less than two hours, that sex difference in mortality is not significant. One takeaway is that though it’s not the only factor, delay matters— and it’s something we can target now, in primary care (where I work) and in public health.

A key point for research is that PCI doesn’t seem to improve coronary blood flow in women as much as it does in men. What does this mean?  Here’s the rub: the whole paradigm of coronary heart disease— from defining acute coronary syndrome to medical management and PCI— is based on the flawed assumption that men and women are essentially the same (as Pande & Jacobs discuss in an accompanying editorial2).

Recall that women have historically been drastically underrepresented in heart disease research, so the foundational assumptions are based on men. Though the evidence is mounting on some of the mechanisms of sex differences— microvascular disease, endothelial dysfunction, MINOCA— this hasn’t yet resulted in meaningful differences in approach to ACS treatment. Before this study’s publication, it had not been clear whether women didn’t do as well post-PCI simply because they were less likely to get in in a timely fashion, or because it didn’t work as well for them. Now we have data suggesting that both are true. Are we using a hammer when we really need a screwdriver? There is an enormous need for research in this area designed with sex differences as a presupposition and with establishing effective treatments as the goal. It will be a long road and we won’t have “the answer” tomorrow.

So as a clinician, knowing that the data isn’t there yet to show us how to improve women’s outcomes in PCI, one of the best tools I have is education and communication with my patients and fellow clinicians around treatment delay. We’ve made great progress educating patients and providers about women’s risks of heart disease (thanks in large part to AHA’s Go Red for Women campaign). Yet women still have longer delays in accessing treatment and worse outcomes in ACS than their male counterpoints.

Since heart disease is the number one killer of U.S. women and men3, preventing and detecting it are high priorities for PCPs like me. Even though short appointments and competing priorities mean finding time for prevention and risk assessment is tricky, we need to do better in our discussions around cardiac risk. We’re doing well at initiating discussions around statin prescriptions and, to a lesser extent, lifestyle measures. We need to work on discussions about symptoms of ACS and response to symptoms.

What are you doing now to improve women’s cardiovascular outcomes? Will you commit to taking one of these steps?

References:

  1. Cenko E, van der Schaar M, Yoon J, Kedev S, Vavlukis M, Vasiljevic Z, Ašanin M, Miličić D, Manfrini O, Badimon L, Bugiardini R. Sex‐specific treatment effects after primary percutaneous intervention: A study on coronary blood flow and delay to hospital presentation. J Am Heart Assoc. 2019; 8:e011190. DOI: DOI: 10.1161/JAHA.118.011190.
  2. Pande, AN & Jacobs, A. Reperfusion and time to presentation in women: Too little too late. J Am Heart Assoc. 2019; 8. DOI: 10.1161/JAHA.118.011835
  3. Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, Delling FN, Djousse L,Elkind MSV, Ferguson JF, Fornage M, Jordan LC, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, O’Flaherty M, Pandey A, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Spartano NL, Stokes A, Tirschwell DL, Tsao CW, Turakhia MP, VanWagner LB, Wilkins JT, Wong SS, Virani SS; on behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2019 update: a report from the American Heart Association [published online ahead of print January 31, 2019]. Circulation. doi: 10.1161/CIR.0000000000000659.
  4. Greenwood B, Carnahan S., & Huang L. Patient-physician gender concordance and increased mortality among female heart attack patients. PNAS August 21, 2018 115 (34) 8569-8574; published ahead of print August 6, 2018 DOI: 10.1073/pnas.1800097115

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

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:

  1. Adult patients with clinical ASCV
  2. Adult patients with primary elevations of LDL–C ≥190 mg/dL
  3. Patients 40-75 years of age with diabetes and LDL–C 70 to 189 mg/dL without clinical ASCVD
  4. 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

  1. 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.
  2. 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.
  3. 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 Headshot

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.