Novel risk factors for atrial fibrillation, conduction disturbances, sudden coronary death, and device infection

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on arrhythmias contains the Fast Track Clinical Research article ‘Device-related complications in subcutaneous versus transvenous ICD: a secondary analysis of the PRAETORIAN trial’ by Reinoud Knops from the University of Amsterdam in the Netherlands, and colleagues.1 The authors note that the subcutaneous implantable cardioverter-defibrillator (S-ICD) is developed to overcome lead-related complications and systemic infections, inherent to transvenous ICD (TV-ICD) therapy. The PRAETORIAN trial demonstrated that the S-ICD is non-inferior to the TV-ICD with regard to the combined primary endpoint of inappropriate shocks and major complications. This pre-specified secondary analysis evaluates all complications in the PRAETORIAN trial. The PRAETORIAN trial is an international, multicentre, randomized trial in which 849 patients with an indication for ICD therapy were randomized to receive an S-ICD (n = 426) or a TV-ICD (n = 423) and followed for a median of 49 months. Endpoints were device-related complications, lead-related complications, systemic infections, and the need for invasive interventions. Thirty-six device-related complications occurred in 31 patients in the S-ICD group, of which bleedings were the most frequent. In the TV-ICD group, 49 complications occurred in 44 patients, of which lead dysfunction was most frequent [hazard ratio (HR): 0.69; P = 0.11]. In both groups, half of all complications were within 30 days after implantation. Lead-related complications and systemic infections occurred significantly less in the S-ICD group compared with the TV-ICD group (P < 0.001 and P = 0.03, respectively). Significantly more complications required invasive interventions in the TV-ICD group compared with the S-ICD group (8.3% vs. 4.3%, HR 0.59; P = 0.047) (Figure 1). Shown is the summary of the main endpoints of the manuscript: device-related complications in the subcutaneous and transvenous ICD: a secondary analysis of the PRAETORIAN trial. ICD, implantable cardioverter-defibrillator.1 Knops et al. conclude that their secondary analysis shows that lead-related complications and systemic infections are more prevalent in the TV-ICD group compared with the S-ICD group. In addition, complications in the TV-ICD group are more severe as they require significantly more invasive interventions. These data contribute to shared decision-making in clinical practice. The contribution is accompanied by an Editorial by Ilan Goldenberg and David Huang from the University of Rochester Medical Center in Rochester, NY, USA.2 The authors note that these important data, showing that S-ICD is associated with a significant reduction in the risk of major device-related complications, raise the question of why the S-ICD is still considered currently in clinical practice only as an alternative resort, mainly among younger patients or those who are more prone to infection. Reasons for this may be multiple and include: (i) a more conservative approach to ICD programming and widespread implementation of antitachycardic pacing (ATP) programming, despite the fact that lower rate therapies (<200 bpm) were shown to be associated with an increased risk of inappropriate ICD therapy and death; (ii) relatively less familiarity of the local anatomy and the surgical handling of the subcutaneous vasculature and neurovascular bundles with an S-ICD implant, which may result in a higher incidence of bleeding; (iii) larger incision and larger pocket necessary for S-ICD implantation due to the larger generator size, thereby increasing the risk of local complications; (iv) a more conservative approach to pacing requirements, in which dual-chamber devices may be preferred due to concerns of need for pacing in the future rather than a current indication; (v) residual concerns regarding over-/under-sensing associated with the device (despite recent improvement) and consequent need for ECG pre-screening to assess S-ICD eligibility; and (vi) perceived longer implant procedure times, which, however, were not significantly different between S-ICD and TV-ICD in PRAETORIAN. Sudden cardiac arrest remains a major health problem and is frequently related to ventricular fibrillation (VF).3–10 In a Clinical Research article entitled ‘Ventricular fibrillation in acute myocardial infarction: 20-year trends in the FAST-MI study’, Rodrigue Garcia from the Université Paris Cité in France, and colleagues evaluated the incidence and impact of VF among patients hospitalized for acute myocardial infarction (AMI).11 Data from the FAST-MI programme consisting of five French nationwide prospective cohort studies between 1995 and 2015 were analysed, in total including 14 423 patients with AMI (66 years, 72% males, 59% ST-elevation myocardial infarction). Overall, the proportion of patients presenting in-hospital VF decreased from 3.9% in 1995 to 1.8% in 2015 (P < 0.001). One-year mortality decreased from 60.7% to 24.6% (P < 0.001). However, compared with patients who did not develop VF, the over-risk of 1-year mortality associated with VF was stable over time [hazard ratio (HR) 6.78 in 1995 and HR 6.64 in 2015, P = 0.52]. This increased mortality in the VF group was mainly related to fatal events occurring prior to hospital discharge, representing 86.2% of 1-year mortality, despite the very low rate of ICDs in the VF group (2.6%). The authors conclude that their study demonstrates that in-hospital VF incidence and mortality in the setting of AMI have significantly decreased over the past 20 years. Nevertheless, VF remains steadily associated with an ∼10-fold increased relative risk of in-hospital mortality, without an impact on post-discharge mortality. Beyond long-term cardiac defibrillation strategy, these results emphasize the need to identify in-hospital interventions to further reduce mortality in VF patients. The contribution is accompanied by an Editorial by Lauri Holmstrom and Sumeet Chugh from the Cedars-Sinai Health System in Los Angeles, CA, USA.12 Holmstrom and Chugh conclude that while the present study provides important information on the incidence and impact of in-hospital AMI-VF, future studies should also focus on pulseless electrical activity (PEA), which is a less recognized manifestation of cardiac arrest in AMI. PEA as a proportion of cardiac arrest continues to rise in all settings, prognosis is dismal, and recent evidence points to AMI as a trigger in a substantial proportion of patients. In the meantime, efforts directed at primary prevention of VF associated with AMI are likely to have the most impact on AMI-associated mortality. Risk of adverse outcomes according to new bleeding events. Shown are adjusted hazard ratios with 95% confidence intervals for adverse outcomes according to new bleeding events. CRNMB = clinically relevant non-major bleeding; composite = composite outcome of stroke, MI, and death; MI = myocardial infarction.21 Stroke is a major complication of atrial fibrillation (AF), and oral anticoagulation (OAC) is a key preventive treatment although associated with a higher bleeding risk.11,13–20 In a Clinical Research article entitled ‘Bleeding and ischaemic events after first bleed in anticoagulated atrial fibrillation patients: risk and timing’, Pascal Meyre from the University Hospital Basel in Switzerland, and colleagues determined the risk of subsequent adverse clinical outcomes in anticoagulated patients with AF who experienced a bleeding event.21 The primary outcome was a composite of stroke, MI, or all-cause death. Median follow-up was 4 years. Of the 3277 patients included (mean age 72 years, 28% women), 217 (9.1%) developed a major bleeding. Recurrent bleeding occurred in 126 patients with or without a major bleeding, the incidence of the primary outcome was 11 and 4.06 per 100 patient-years, respectively (adjusted HR 2.04; P < 0.001); median time to a primary outcome was 142 days. Patients who had their OAC discontinued after their first bleeding episode had a higher incidence of the primary composite than those who continued OAC (adjusted HR 4.46; P < 0.001) (Figure 2). Meyre and colleagues conclude that in anticoagulated AF patients, a major bleeding is associated with a high risk of adverse outcomes, part of which may be explained by OAC discontinuation. Most events occur late after the bleeding episode, emphasizing the importance of long-term follow-up in these patients. This manuscript is accompanied by an Editorial by Josephine Harrington and Christopher Granger from the Duke University Medical Center, Durham, NC, USA.22 Harrington and Granger conclude that the study by Meyre et al. provides important information on bleeding and its consequences in patients with AF on anticoagulation. These findings call for further investigation into strategies to reduce bleeding risk in these patients and to better understand how and when to resume anticoagulation after bleeding events. Anti-Ro/La autoantibodies are especially prevalent in autoimmune diseases but are also relatively frequent in healthy adults. Their arrhythmogenic effect on the immature cardiac conductive system is well established, with substantial evidence demonstrating an increased risk for congenital atrioventricular block in neonates of seropositive mothers. In a Clinical Research article entitled ‘Association of anti-Ro seropositivity with cardiac rhythm and conduction disturbances’, Aviram Akuka from Tel-Aviv University in Israel, and colleagues note that despite their wide distribution and their arrhythmogenic potential effect, there are no large population studies conducted in seropositive adults.23 Thus, this is the first large population-based study to examine the association of anti-Ro/La seropositivity with cardiac rhythm and conduction disturbances. This cross-sectional designed study involved the electronic health records of the largest health maintenance organization in Israel. All subjects who tested positive for anti-Ro/anti-La antibodies between the years 2002 and 2019 were included and were matched with controls by age, gender, and place of residence. Rates of different cardiac rhythm and conduction disturbances were compared between groups. Sensitivity analyses were performed using propensity score matching. The study population included 17 231 anti-Ro/La seropositive subjects and 84 368 controls. Anti-Ro seropositive patients had higher rates of conduction disturbances (3.0% vs. 1.7%, P < 0.001) and rhythm disturbances (10.5% vs. 7.0%, P < 0.001). Patients who tested positive for anti-La alone did not demonstrate a significant association with arrhythmias. Multivariate logistic regression analysis, controlling for possible confounders, showed an increased risk for cardiac conduction disturbances [odds ratio (OR) 1.44, P < 0.001], as well as for cardiac rhythm disturbances (OR 1.21, P < 0.001) among anti-Ro seropositive patients. The authors conclude that anti-Ro seropositivity is positively associated with adult cardiac conduction disturbances and, to a lesser extent, cardiac rhythm disturbances, regardless of the presence of concurrent autoimmune disease. The contribution is accompanied by an Editorial by Pietro Enea Lazzerini and Pier Leopoldo Capecchi from the University of Siena in Italy, and Mohamed Boutjdir from SUNY Downstate Health Sciences University in New York, NY, USA.24 The authors conclude that identifying circulating anti-Ro antibodies in patients with ‘idiopathic’ rhythm disturbances (or even with structural heart disease or inherited channelopathies not responding to conventional therapeutic approaches) could lead to innovative treatment and prophylactic opportunities (including immunomodulatory interventions, and decoy peptide- and peptide/antibody-based antiarrhythmic therapies) with unanticipated epidemiological implications. Large prospective studies and interventional trials are warranted to further confirm the actual clinical impact of anti-Ro antibodies on arrhythmic events in the general population. At least 50% of deaths due to coronary artery disease (CAD) are sudden cardiac deaths (SCDs), but the role of acute plaque complications25–28 in the incidence of sudden death in CAD is somewhat unclear. In a Clinical Research article entitled ‘Plaque histology and myocardial disease in sudden coronary death: the Fingesture study’ Lauri Holmström from the University of Oulu and Oulu University Hospital in Finland, and colleagues aimed to investigate plaque histology and concomitant myocardial disease in SCD.29 The study population is derived from the Fingesture study, which has collected data from 5869 consecutive autopsy-verified SCD victims in Northern Finland (population ∼600 000) between 1998 and 2017. In this substudy, histological examination of culprit lesions was performed in 600 SCD victims whose death was due to CAD. Determination of the cause of death was based on the combination of medical records, police reports, and autopsy data. Plaque histology was classified as either (i) plaque rupture or erosion; (ii) intraplaque haemorrhage; or (iii) stable plaque. The mean age of the study subjects was 64.9 ± 11.2 years, and 82% were male. Twenty-four per cent had plaque rupture or plaque erosion, 24% had an intraplaque haemorrhage, and 52% had a stable plaque. Myocardial hypertrophy was present in 78% and myocardial fibrosis in 93% of victims. The presence of myocardial hypertrophy or fibrosis was not associated with specific plaque histology. The authors conclude that less than half of sudden deaths due to CAD had evidence of acute plaque complication, an observation which is contrary to historical perceptions. The prevalence of concomitant myocardial disease is high and independent of associated plaque morphology. The manuscript is accompanied by an Editorial by Gaetano Thiene from the University of Padua in Italy.30 Thiene points out that a potential cause of acute ischaemia responsible for SCD in the absence of plaque disruption is coronary artery spasm. Lack of information on symptoms (angina) and electrocardiography recording does not allow determination of how many patients without plaque disruption had an acute ischaemic episode before sudden death. In the Registry of the Veneto Region (Italy), Thiene had the chance to record transient myocardial ischaemia with Holter monitoring on the eve of the arrhythmic cardiac arrest, suggesting coronary artery vasospasm as the fatal mechanism. AF is now regarded as a preventable disease, requiring a search for modifiable risk factors. In a Clinical Research contribution entitled ‘Cannabis, cocaine, methamphetamine, and opiates increase the risk of incident atrial fibrillation’, Anthony L. Lin from the University of California in San Francisco, CA, USA and colleagues point out that with legalization of cannabis and more lenient laws regarding the use of other illicit substances, investigation into the potential effects of methamphetamine, cocaine, opiate, and cannabis exposure on incident AF is needed.31 Using Office of Statewide Health Planning and Development databases, a longitudinal analysis was performed of adult Californians ≥18 years of age who received care in an emergency department, outpatient surgery facility, or hospital from 1 January 2005 to 31 December 2015. Among 23 561 884 patients, ∼98 000 used methamphetamine, 49 000 used cocaine, 10 000 used opiates, and 13 000 used cannabis. Of the total population, 4.2% developed incident AF during the study period. After adjusting for potential confounders and mediators, use of methamphetamines, cocaine, opiates, and cannabis were each significantly associated with increased incidence of AF: HRs 1.86, 1.61, 1.74, and 1.35, respectively. The authors conclude that methamphetamine, cocaine, opiate, and cannabis use are each associated with increased risk of developing incident AF. Efforts to mitigate the use of these substances may represent a novel approach to AF prevention. The contribution is accompanied by an Editorial by Monika Gawałko from the Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht in the Netherlands and Prashanthan Sanders from the University of Adelaide in Australia.32 The authors note that collectively, this research strengthens medical and community efforts aimed at reducing drug abuse by presenting arrhythmogenic effects of analysed drugs. The arrhythmogenic risks of methamphetamines cocaine, opiates, and cannabis warrant continued discussion in the medical and scientific communities. The lack of guidelines raises the questions, as yet unanswered, about antiarrhythmic and antithrombotic therapy for prophylaxis, type and length of follow-up, as well as manner of the treatment of AF episodes in patients with substance use. It is important for future research to examine and understand the impact of drugs on AF, particularly in the light of drug policy reform and legalisation. Cardiac implantable electronic device (CIED) infection is a severe complication to modern management of cardiac arrhythmias. In a Clinical Research article entitled ‘Risk factors for cardiac implantable electronic device infections: a nationwide Danish study’, Thomas Olsen from the Odense University Hospital in Denmark aimed to identify lifelong patient-related risk factors for CIED infections.33 Consecutive Danish patients undergoing a CIED implantation or reoperation between January 1996 and April 2018 were included. The cohort consisted of >84 000 patients undergoing >108 000 CIED surgeries with a combined follow-up of 458 257 CIED-years. A total of 1556 CIED explantations were classified as either pocket or systemic CIED infection. Using multiple-record and multiple-event per subject proportional hazard analysis, specific patient-related risk factors were identified. CIED reoperations were significantly associated with the highest risk of pocket CIED infection (HR 1.62), but also CIED type, younger age, and prior valvular surgery. Severe renal insufficiency/dialysis (HR 2.40), dermatitis (HR 2.80), and prior valvular surgery (HR 2.09) were associated with the highest risk of systemic CIED infections. Congestive heart failure, ischaemic heart disease, malignancy, chronic obstructive pulmonary disease, and temporary pacing were not significant at multivariate analysis. The authors conclude that specific comorbidities and surgical procedures were associated with a higher risk of CIED infections but with variations amongst pocket and systemic CIED infection. Pocket CIED infections were associated with CIED reoperations, young age, and more complex type of CIED, whereas systemic CIED infections were associated with risk factors predisposing to bacteraemia. The contribution is accompanied by an Editorial by Haran Burri from the University Hospital of Geneva in Switzerland.34 Burri concludes that the present study is a good example of how research can be generated by cross-linking of databases, which is made possible using a unique national patient identifier. The CIED registry provides procedural data captured by the implanting physician, hospital coders capture comorbidities and complications (initially intended for insurance claims), centralized outpatient drug prescriptions provide data on pharmacological treatment, and the civil registry provides data on survival. Further cross-linking with remote monitoring databases, ideally from middleware companies which centralize transmissions from all manufacturers, would provide additional granularity on device programming and diagnostic parameters. Such data mining of different sources allows efficient conduct of large, pragmatic studies at an affordable cost, and offers new perspectives for clinical research. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Sudden cardiac death risk in arrhythmogenic ventricular the of complex and its impact in clinical from the University of in Italy, and colleagues on the recent risk in arrhythmogenic ventricular of the arrhythmogenic ventricular risk by from the Université in and et al. in a from other from the The that this issue of the be of to its to and for with of this