Author + information
- Erling Falk, MD, PhD∗ ()
- ↵∗Reprint requests and correspondence:
Dr. Erling Falk, Department of Cardiology, Aarhus University Hospital Skejby, Brendstrupgårdsvej 100, 8200 Aarhus, Denmark.
Atherosclerosis is an immune-inflammatory disease fueled by apolipoprotein B (apoB)–containing lipoproteins, including modified low-density lipoprotein (LDL). Immunization with LDL, oxidized LDL, or apoB-related peptides protects mice against atherosclerosis (1,2), but this approach has not been translated to humans. On the basis of the hypothesis that the same apoB-related vaccine could reduce formation and rupture of abdominal aortic aneurysm (AAA), Honjo et al. (3) report in this issue of the Journal that the apoB-related vaccine offered partial protection against experimentally-induced AAA in mice. To understand the potential implications of these findings, at least 2 critical questions need to be addressed: 1) although apoB-containing lipoproteins play a causal role in atherosclerosis, is the same true for AAA; and 2) how predictive are the results obtained in this murine model for therapeutic outcomes in patients with AAA?
Risk Factors for AAA Versus Atherosclerosis
Common among older people, AAA carries a high mortality risk due to rupture (4). Atherosclerosis of the infrarenal aorta often accompanies AAA, and the term “atherosclerotic aneurysm” was once used for AAA to imply a causal relationship. This view is no longer tenable (5–7). Although both obstructive atherosclerosis and AAA are multifactorial inflammatory diseases of the arterial wall with many common risk factors, notable differences refute the notion that AAA is atherosclerosis in disguise.
Among the traditional cardiovascular risk factors, AAA and atherosclerotic cardiovascular disease (ASCVD) share age, sex, cigarette smoking, and family history (5). However, the strength and type of relationship to AAA and ASCVD differ, with the best predictor for AAA rupture being its size (6).
Male sex is an extraordinarily strong risk factor for AAA, with a male/female ratio of up to 6:1, compared with ∼2:1 for ASCVD. Smoking is a much greater risk factor for AAA than for ASCVD (7). There is a strong dose–response relationship, with some of the acquired risk persisting even in past smokers (7). In contrast, smoking is not a proven risk factor for coronary atherosclerosis (stable angina), but is a strong and rapidly-reversible risk factor for coronary thrombosis (myocardial infarction) (7,8). Current guidelines reflect the differential effect of smoking on the vasculature: although past smokers are considered nonsmokers in ASCVD risk assessment (9), men age 65 to 75 years who have ever smoked just 100 cigarettes during a lifetime qualify for AAA screening (10).
Family history is a strong risk factor for AAA, suggesting that there is an important genetic component, with heritability of up to 70% reported in twin studies. However, compared with ASCVD, relatively few genetic markers for AAA have been identified, and together, they explain only a small proportion of observed heritability. Recent genetic evidence suggests that signaling via the interleukin-6 receptor causally relates to AAA (11), and the same may be true for the LDL receptor without necessarily implicating LDL cholesterol (12). Familial hypercholesterolemia is not a recognized risk factor for AAA.
ApoB-containing lipoproteins, including LDL, are causally related to ASCVD, whereas their role in developing AAA remains controversial (6). The same is true for blood pressure, but hypertension may provoke AAA rupture. Effects of statins and antihypertensive agents on AAA remain uncertain (6). In the Heart Protection Study, statin therapy reduced ASCVD risk substantially, but not the incidence of aneurysm repair or AAA-related death (13). Most remarkable is the inverse relationship between diabetes and AAA (14).
In terms of pathology, the late stage of AAA is characterized by accumulation of proteolytic enzymes and loss of extracellular matrix and vascular smooth muscle cells in media, angiogenesis and chronic inflammation dominated by mononuclear cells in media and adventitia, atherosclerotic changes in intima, and unorganized laminated thrombus in the aneurysm sac (15). The root cause of inflammation is unknown. Nearly all human AAAs are true aneurysm, involving all 3 layers of the aortic wall (intima, media, and adventitia).
Murine Model of AAA
A multifactorial disease of uncertain origin that develops slowly and silently over decades is difficult to model and explore experimentally. The animal model most widely used today was introduced by Daugherty et al. in 1999. They discovered that angiotensin II (Ang II) infusion in mice leads to aneurysmal dilation of the suprarenal aorta within a few days (16). Atherosclerosis, hypercholesterolemia, or hypertension is not required. Early on, macrophages infiltrate the media, which ruptures, leading to a false aneurysm accompanied by aortic dissection with intramural hemorrhage and thrombosis. Many mice die within the first week of aortic rupture (16,17), leaving the critical question: how predictive is this murine model of human AAA?
Using this model, Honjo et al. (3) tested a novel vaccination approach to prevent AAA development and rupture. They first immunized young hypercholesterolemic mice with an apoB-100 peptide (p210) known to protect mice against atherosclerosis (2). A few weeks later, Ang II was infused to induce AAA. The p210 vaccine protected against AAA formation and fatal rupture, and the beneficial effect was seen within days of Ang II infusion (most of the ruptures occurred during the first week). Elegant mechanistic studies affirmed a crucial role of CD8+ T cells in mediating the protective effects of the vaccine.
From Mice to Humans
As recognized by the authors, extrapolating from mice to humans is problematic, meaning the validity and predictiveness of these results should be considered cautiously (18). Do we understand the pathogenetic role of the therapeutic target? No, the role of apoB in human AAA is speculative. Is the mechanism of action known? Not fully, but partially in hypercholesterolemic mice with Ang II–induced AAA, as Honjo et al. (3) reported. Are these mice expected to react with a response predictive for humans? Not necessarily, given the known interspecies differences in immune systems (1). Has the treatment effect been demonstrated in other animals than mice? No, at least such evidence is not provided. Are rupture and mortality relevant endpoints for human AAA? Certainly, as AAA is usually asymptomatic unless it ruptures, and then most patients will die of internal hemorrhage. Finally, is the apoB-based vaccine safe? It is unknown, but it is inherently risky to manipulate the human immune system (6,19).
Life-threatening rupture of AAA is preventable by early detection and timely treatment of AAAs at risk of rupture. There is, however, no recognized risk-reducing treatment for the increasing number of small AAAs (<5.5 cm in diameter) detected by screening (5,6). Many of these small AAA will expand over time to a size requiring elective surgery or endovascular repair to eliminate the risk of rupture. Preventing or slowing this enlargement would reduce the need for costly and risky AAA repair. Seen in this perspective, the medical approach described by Honjo et al. (3) deserves further exploration. The clinical relevance of an apoB-based vaccine that may reduce the risk of both AAA rupture and ASCVD cannot be questioned.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Falk has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Honjo T.,
- Chyu K.-Y.,
- Dimayuga P.C.,
- et al.
- Sidloff D.,
- Stather P.,
- Dattani N.,
- et al.
- Golledge J.,
- Norman P.E.
- Norman P.E.,
- Curci J.A.
- Stone N.J.,
- Robinson J.G.,
- Lichtenstein A.H.,
- et al.
- Harrison S.C.,
- Smith A.J.,
- Jones G.T.,
- et al.
- Bradley D.T.,
- Hughes A.E.,
- Badger S.A.,
- et al.
- Heart Protection Study Collaborative Group
- Shimizu K.,
- Mitchell R.N.,
- Libby P.
- Ioannidis J.P.