PracticeUpdate: Cardiology | Vol1 - No.2 - 2016

MYOCARDIAL DISEASE

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EXPERT OPINION The pivotal position of IL-6 in the pathogenesis of ischaemic heart disease, and a lot of new questions By Petter Libby, MD The cytokine interleukin (IL)-6 occupies a pivotal position in the innate immune inflammatory cascade. The better-known proinflammatory cytokines IL-1 and tumour necrosis factor (TNF) strongly induce IL-6. IL-6 in turn regulates the acute-phase response in the hepatocyte, boosting the production of fibrinogen and the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), proteins implicated in the formation and stability of thrombi. Thus, IL-6, sandwiched between “primary” proinflammatory cytokines and the acute-phase response, occupies a central pivot point putatively involved in the pathogenesis of ischaemic heart disease. R ecent large, well-conducted, and concordant studies using Mendelian randomisation

responses to PCI-related myocardial injury. The patients in the tocilizum- ab-treated group had an increase in IL-6. The authors hypothesise that the monoclonal antibody inhibits the clearance of this cytokine that has a short dwell time in the blood compartment under usual circum- stances. Nonetheless, one must always remain vigilant regarding counter-regulatory responses when perturbing innate immunity. Although one proximal inducer of IL-6, IL-1b, was similar in the two groups, unmeasured proximal proinflammatory cytokines such as TNF or IL-1a might have increased. In the MRC-ILA-HEART study, individuals with non-ST-segment el- evation ACS allocated to treatment with the IL-1 receptor antagonist showed a “rebound” in hs-CRP, and a disquieting excess of recurrent ma- jor adverse cardiovascular events in the IL-1Ra group. 5 The tocilizumab study also documented a decrease in granulocyte count. As we have increasing apprecia- tion of the roles of leukocytes of vari- ous functional classes in the healing of myocardial ischaemic injury, this observation begs the question of the effects of tocilizumab on monocyte subpopulations in peripheral blood, and more importantly the identity and sequencing of leukocytes in- volved in myocardial repair following

curve (AUC) for high-sensitivity C- reactive protein (hs-CRP) between days 1 and 3. They also studied the AUC for high-sensitivity troponin T (hsTnT) during this time window. This study used a daring design, as acute coronary syndromes (ACS) in- crease inflammation remarkably, ren- dering it difficult to show a change. The standard of care for ACS pa- tients decreases CRP, and of course troponin also rises and declines with- out intervention post-ACS. In a substudy of the Myocardial Ischemia Reduction withAcute Cho- lesterol Lowering (MIRACL) trial, the CRP fell from 11 to 2.9 mg/L 16 weeks after ACS in a placebo-treated group and fell from 11.5 to 1.9 in a group treated with atorvastatin at 80 mg per day. 4 The MIRACL study

ACS. 6 While the authors noted no excess adverse events in 6 months of follow-up, the study was insuf- ficiently powered to exclude either benefit or harm in terms of cardiac function or outcomes. This study has great importance for the inflammation hypothesis of is- chaemic heart disease. It shows that a biological approach to interfering with the action of a proinflammatory cy- tokine can limit biomarkers associated with adverse outcomes. Yet, like most good studies, this one raisesmany new questions, as touched upon above. References 1. Hingorani AD and Casas JP. Lancet 2012;379:1214-1224. 2. Sarwar N, Butterworth AS, Freitag DF, et al. Lancet 2012;379:1205-1213. 3. Kleveland O, Kunszt G, Bratlie M, et al. Eur Heart J 2016;37:2406-2413. 4. Kinlay S, Schwartz GG, Olsson AG, et al. Circulation 2003;108:1560-1566. 5. Morton AC, Rothman AM, Greenwood JP, et al. Eur Heart J 2015;36:377-384. 6. Libby P, Nahrendorf M, Swirski FK. J Am Coll Cardiol 2016;67:1091-1103. Dr Libby is Chief of Cardiovascular Medicine, Brigham and Women’s Hospital in Boston, and Mallinckrodt Professor of Medicine,

was conducted before high-dose statin therapy became the standard of care for ACS patients. Thus, there was 34% statistically significant lower CRP after 4 months (P < 0.001), but the magnitude of the absolute change in hs-CRP was modest compared with the fall in the placebo group just with “tincture of time.” As 90+% of the patients in the Kleveland study were treated with statins, it raises the bar even higher for distinguish- ing a difference in the inflammatory biomarker due to the tocilizumab therapy. Yet, this new study handily met its primary endpoint of theAUC of hs-CRP from days 1 to 3, which was 4.2 in the placebo group and 2.0  mg/L/h in the tocilizumab-treat- ed patients (P < 0.001). The AUC of hs-TnT follows a similar pattern (234 vs 159 ng/L/h; P = 0.007). Actually, one could view this study as an investigation of the effects of tocilizumab on patients undergoing PCI in the context of NSTEMI rather than NSTEMI itself, as the benefit occurred in the PCI group and treatment followed the hyper- acute phase of the ACS – a 2-day lag. The authors hypothesise that tocilizumab attenuates secondary ischaemia reperfusion injury as a mechanism of its reduction in the biomarkers studied. Another plausible interpretation would be that tocilizumab blunts the

provide strong evidence for a causal role for IL-6 in coronary events. 1,2 Thus, IL-6 could represent an at- tractive target for reducing inflam- mation in cardiovascular conditions. Kleveland et al conducted a two-centre, double-blind placebo- controlled trial that enrolled 117 patients with non-ST-segment elevation myocardial infarction (NSTEMI) 2 days after onset of symptoms. 3 They randomised this cohort of patients to placebo or the anti-IL-6 monoclonal antibody tocilizumab one-to-one. The biologi- cal agent was given before coronary arteriography. The study’s primary endpoint was the area under the

Harvard Medical School, Boston, Massachusetts.

MY APPROACH My approach to the patient with arrhythmogenic right ventricular cardiomyopathy By Angeliki Asimaki, MD C linical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is challenging owing to the broad range of or sudden cardiac death (SCD), ECG, sig- nal-averaged ECG, Holter monitoring, and noninvasive imaging tests, typically echocar- diography. Following the recent identification of left-dominant and biventricular forms of ARVC, comprehensive imaging of the LV is also indicated.

disease) and in selected cases with intractable, incessant ventricular arrhythmias. Particular caution should be addressed to avoid competitive sport activities, which in- crease disease progression and arrhythmic risk. ARVC is familial in over 50% of cases. Screen- ing of family members is therefore of pivotal importance. Clinical evaluation of relatives should be guided by the observation that SCD inARVC is extremely rare in children under 10 years of age. Family members who meet TFC should be closely monitored. However, since electrical abnormalities precede structural changes in ARVC, evaluation in family mem- bers not meeting TFC should initially focus on the electrical aspects of the disease by ECG and Holter monitoring. Alternatively, genetic testing can be performed, and, if a pathogenic mutation is identified in the proband, family members can be tested as well to determine whether they are at risk of disease manifesta- tion in the future.

sustained VT are considered high-risk and should get an ICD. Syncope, non-sustained VT, family history of SCD, severe RV dysfunc- tion, LV involvement, and QRS dispersion are considered intermediate risk factors, but their individual or combined prognostic value has not been prospectively assessed. Accordingly, ICD implantation should be decided on a case-by-case basis. Radiofrequency ablation should be considered in those patients who are not candidates for an ICD or who have an ICD but get multiple shocks despite pharmacologi- cal treatment. Anti-arrhythmic medications may be used to control symptoms in ARVC. The combination of beta blockers (sotalol) and amiodarone has proven beneficial in reducing sustained VT and preventing syncope. Beta blockers and ACE inhibitors can also be used in ARVC patients, particularly those with biventricular dysfunction or heart failure. Cardiac trans- plantation is indicated in patients with severe heart failure (typically characterising endstage

phenotypic manifestations, reduced genetic penetrance, and age-related progression char- acterising the disease. There is no single “gold-standard” test for ARVC, and diagnosis relies on a scoring sys- tem of “major” and “minor” criteria based on the demonstration of a combination of defects in ventricular morphology and function, de- polarisation/repolarisation ECG abnormali- ties, myocardial tissue histological changes, arrhythmias, and family history. Definitive diagnosis, based on the Revised 2010 Task Force Criteria (TFC), requires two major, one major and two minor, or four minor criteria from different categories. Therefore, the initial evaluation of all patients suspected of having ARVC should include physical examination, clinical history, family history of arrhythmias

More recently, cardiac magnetic resonance (CMR) has been introduced in the clinical practice when evaluating a patient with pos- sible ARVC as it can quantitatively assess ven- tricular volumes and ejection fractions, wall motion abnormalities, and give information on tissue characterisation (fatty infiltration and myocardial fibrosis through late gadolinium enhancement). If a noninvasive workup is suggestive but not diagnostic, further testing should be considered including angiography, electroanatomic mapping, and, rarely, endo- myocardial biopsy. The most important task when managing a patient with ARVC is prevention of SCD. Patients with a history of aborted SCD or

Dr Asimaki is Research Associate, Beth Israel

Deaconess Medical Center, Faculty member (Instructor), Harvard Medical School, Boston, Massachusetts.

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