Traditionally held every two years in Davos, Cardiology Update has become one of the most important European cardiology congresses. This year’s topics included the role of inflammation in atherosclerosis and the presentation of the HOPE-3 trial on the effect of blood pressure and/or lipid reduction in primary prevention.
The first session of the congress, held early on Sunday morning, was devoted entirely to the topic of atherosclerosis. Prof. Peter Libby, MD (Boston/
USA) opened the meeting with his presentation on the role of inflammation in atherosclerosis. “That inflammation plays an important role in the development and progression of atherosclerosis represents nothing new,” he explained by way of introduction. Much more important in this context, however, is the question of whether targeted anti-inflammatory therapy can improve the course of cardiovascular disease. “There are basically hundreds of potential targets for such a therapy,” he further opined. In the following, he focused on interleukin 1 (IL-1).
The role of interleukin 1
The role of IL-1 in atherosclerosis has been studied for many years. As early as 1986, Prof. Libby and coworkers demonstrated that endothelial cells produce IL-1 when stimulated with a bacterial endotoxin or recombinant human tumor necrosis factor [1]. “A short time later, we found that interleukin 1 can induce its own gene expression. This means that we are dealing with a built-in amplification circuit,” he explained. Another, proinflammatory amplification circuit represented the production of IL-6 induced by IL-1. “Interleukin 6 leads to a change in protein synthesis in the liver, resulting in increased production of proteins that play a role in the body’s defense responses, including thrombosis. In particular, these are fibrinogen and plasminogen activator inhibitor-1, an important blocker of our endogenous fibrinolysis.”
As Prof. Libby further explained, the synthesis of interleukin-1-beta in particular, one of the three proteins belonging to the interleukin-1 gene family, is tightly regulated. “Interleukin-1-beta is synthesized as an inactive precursor and activated by the enzyme caspase 1 – also called interleukin-1-beta converting enzymes.” Caspase 1 itself is activated by a protein complex located inside the cell, the inflammasome. “Various factors are capable of stimulating the inflammasome. These include not only pathogens such as viruses or bacteria, but also endogenous factors such as cholesterol crystals,” Prof. Libby explained. Because of its role in the generation of interleukin-1-beta from the inactive precursor, the inflammasome also represents a potential therapeutic target. Indeed, a recently published paper demonstrated that selective inhibition of the NLRP3 inflammasome resulted in a reduction in myocardial infarct size and preserved cardiac function in animal models [2].
Therapeutic manipulation of IL-1-beta.
Prof. Libby went on to discuss the possibilities of directly influencing IL-1-beta therapeutically. One option is the selective anti-interleukin-1-beta antibody canakinumab. Canakinumab has previously been approved for the treatment of cryopyrin-associated periodic syndromes and systemic juvenile idiopathic arthritis [3]. Ridker et al. have evaluated the antibody in a placebo-controlled randomized phase IIb trial in 556 patients with well-controlled diabetes mellitus and high cardiovascular risk [4]. “Canakinumab thereby led to a dose-dependent reduction in interleukin-6, hsCRP, and fibrinogen,” he said. Based on these results, CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), a phase III study of more than 10 000 patients with stable postinfarction coronary artery disease and continued high risk, despite secondary prevention, was initiated [5]. “On the one hand, this study offers us the opportunity to test the inflammation hypothesis of atherosclerosis. On the other hand, it will potentially provide us with a new therapeutic option to help address residual risk in secondary prevention,” Prof. Libby concluded his remarks.
Blood pressure and/or lipid reduction in primary prevention.
In the session on hypertension, Prof. Salim Yusuf, MD (Hamilton/CAN), presented the results of the HOPE-3 study [6-8]. It included 12 705 patients in 21 countries with intermediate cardiovascular risk (defined as an annual risk of a major cardiovascular event of about 1%) and without cardiovascular disease and compared in a 2×2 factorial design a blood pressure lowering regimen (candesartan 16 mg plus hydrochlorothiazide 12.5 mg), lidip lowering (rosuvastatin 10 mg) and the combined treatment with placebo. “All participants further received counseling regarding lifestyle and other medications as necessary,” Prof. Yusuf explained. He also emphasized that a key concern had been to include patients of different ethnicities in the study (Table 1).
Finally, after a median follow-up of 5.6 years, no lower rate of serious cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, revascularization, heart failure) was observed in the study arm with antihypertensive therapy compared with placebo [6]. “A subgroup analysis by blood pressure tercile showed that candesartan plus hydrochlorothiazide resulted in a significantly lower rate of major cardiovascular events only in patients in the top tercile, that is, with systolic blood pressure above 143.5 mmHg,” Prof. Yusuf added. The safety of the treatment was extremely good. However, there was significantly more dizziness in the active therapy group, but no syncope or problems such as acute renal failure. And this was done without any dose titration or routine follow-up in the study.
Lipid lowering with rosuvastatin resulted in a significantly lower risk of cardiovascular event compared with placebo [7]. “In terms of time course, there was hardly any effect in the first one to two years. However, the risk then decreased, especially from the third year onward,” says Prof. Yusuf. Furthermore, all subgroups benefited, regardless of baseline LDL-C levels, blood pressure, or ethnicity. Regarding tolerability, muscle symptoms and cataract surgery occurred significantly more often with rosuvastatin.
Finally, the combination of blood pressure and lipid reduction also resulted in a significantly lower rate of cardiovascular events [8]. “In the risk of coronary heart disease, a plateau formed after about three years. Does this now mean that after a certain time we can completely suppress the progression of the disease?” asked Prof. Yusuf. He said he did not know; this would have to be investigated in more detail in other studies.
Finally, Prof. Yusuf summarized the main points of the HOPE-3 study: “We found that statins benefit all patients with intermediate risk, whereas antihypertensive therapy benefits only those with high blood pressure or at high risk. In terms of risk reduction, combination therapy achieved the best result in patients in the top blood pressure tercile, at 40%. In patients in the other two terciles, statin alone led to the best result, with a risk reduction of 30%.” In conclusion, Prof. Yusuf noted, “The strategy used in HOPE-3 – no dose titration, no regular follow-up – is incredibly simple, safe, and cost-effective, making it well suited for daily practice.”
Literature:
- Libby P, et al: Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells. Am J Pathol 1986; 124: 179-85.
- van Hout GP, et al: The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction. Eur Heart J. 2016 Jul 17. pii: ehw247. [Epub ahead of print]
- Technical information Ilaris® (Canakinumab). Status of the information: July 2014. www.swissmedicinfo.ch
- Ridker PM, et al: Effects of interleukin-1β inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation. 2012; 126: 2739-48.
- Ridker PM, et al: Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011; 162: 597-605.
- Lonn EM, et al: Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016; 374(21): 2009-20.
- Yusuf S, et al: Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016; 374: 2021-31.
- Yusuf S, et al: Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease. N Engl J Med. 2016; 374: 2032-43.
CARDIOVASC 2017; 16(2): 40-43
