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Arrhythmias and sudden death
Original research article
Systemic inflammation as a novel QT-prolonging risk factor in patients with torsades de pointes
  1. Pietro Enea Lazzerini1,
  2. Franco Laghi-Pasini1,
  3. Iacopo Bertolozzi2,
  4. Gabriella Morozzi1,
  5. Sauro Lorenzini1,
  6. Antonella Simpatico1,
  7. Enrico Selvi1,
  8. Maria Romana Bacarelli1,
  9. Francesco Finizola1,
  10. Francesca Vanni1,
  11. Deana Lazaro3,
  12. Ademuyiwa Aromolaran3,
  13. Nabil El Sherif3,
  14. Mohamed Boutjdir3,4,
  15. Pier Leopoldo Capecchi1
  1. 1 Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
  2. 2 Cardiology Intensive Therapy Unit, Department of Internal Medicine, Hospital of Carrara, Carrara, Italy
  3. 3 VA New York Harbor Healthcare System, SUNY Downstate Medical Center, Brooklyn, New York, USA
  4. 4 NYU School of Medicine, New York, New York, USA
  1. Correspondence to Pietro Enea Lazzerini, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy; lazzerini7{at}unisi.it

Abstract

Objective Increasing evidence indicates systemic inflammation as a new potential cause of acquired long QT syndrome (LQTS), via cytokine-mediated changes in cardiomyocyte ion channels. Torsade de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia occurring in patients with LQTS, usually when multiple QT-prolonging factors are simultaneously present. Since classical risk factors cannot fully explain TdP events in a number of patients, we hypothesised that systemic inflammation may represent a currently overlooked risk factor contributing to TdP development in the general population.

Methods Forty consecutive patients who experienced TdP (TdP cohort) were consecutively enrolled and circulating levels of C-reactive protein (CRP) and proinflammatory cytokines (interleukin-6 (IL-6), tumour necrosis factor alpha (TNFα), interleukin-1 (IL-1)) were compared with patients with active rheumatoid arthritis (RA), comorbidity or healthy controls. An additional 46 patients with different inflammatory conditions (acute infections, n=31; immune-mediated diseases, n=12; others, n=3) and elevated CRP (inflammatory cohort) were prospectively enrolled, and corrected QT (QTc) and cytokine levels were measured during active disease and after a CRP decrease of >75% subsequent to therapy.

Results In the TdP cohort, 80% of patients showed elevated CRP levels (median: ~3 mg/dL), with a definite inflammatory disease identifiable in 18/40 cases (acute infections, n=12; immune-mediated diseases, n=5; others, n=1). In these subjects, IL-6, but not TNFα and IL-1, was ~15–20 times higher than in controls, and comparable to RA patients. In the inflammatory cohort, where QTc prolongation was common (mean values: 456.6±30.9 ms), CRP reduction was associated with IL-6 level decrease and significant QTc shortening (−22.3 ms).

Conclusion The data are first to show that systemic inflammation via elevated IL-6 levels may represent a novel QT-prolonging risk factor contributing to TdP occurrence in the presence of other classical risk factors. If confirmed, this could open new avenues in antiarrhythmic therapy.

  • Torsades de pointes
  • sudden death
  • systemic inflammation
  • interleukin-6.

https://doi.org/10.1136/heartjnl-2016-311079

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    Introduction

    Torsade de pointes (TdP) is a polymorphic ventricular tachycardia occurring in patients with long QT syndrome (LQTS). It is life-threatening as it can degenerate into ventricular fibrillation (VF) and cause sudden cardiac death (SCD).1 TdP develops in patients with a markedly prolonged corrected QT (QTc; usually >500 ms), a condition in most cases requiring the simultaneous presence of multiple QTc-prolonging factors, congenital and/or acquired, synergistically operating in impairing ion channels responsible for the ventricular repolarisation process. In fact, normal cardiac repolarisation depends critically on the interplay of multiple ion currents, and these provide some redundancy (repolarisation reserve) to protect against excessive QTc prolongation in critical settings.1

    Clinically recognisable congenital LQTS, mainly resulting from mutations affecting genes encoding for potassium or sodium channels, is a well-established risk factor for TdP.1 Among acquired risk factors, concurrent use of more than one QT-prolonging drug, and electrolyte imbalances are those most frequently implicated in TdP development. Other currently known causes of acquired LQTS and TdP include structural heart diseases, bradyarrhythmias, endocrine disorders, liver diseases, nervous system injuries, HIV infection, starvation, hypothermia and toxins.1 However, since the above ‘classical’ risk factors cannot fully explain the development and recurrence of TdP events in a number of patients in which QTc remains prolonged despite elimination of classical triggers, identification of previously unrecognised risk factors represents a field of increasing interest. Indeed, in the recent years, both genetic (occult ‘latent’ congenital LQTS, genetic polymorphisms reducing repolarisation reserve)1 2 and acquired (autoimmune-mediated)3 4 conditions are emerging as novel and/or clinically silent risk factors significantly impacting the likelihood of TdP in the general population.

    In this scenario, mounting evidence indicates inflammatory activation as a new cause of acquired LQTS.5 In fact, both cardiac and systemic inflammation is associated with QTc prolongation and higher propensity to develop TdP, as demonstrated by accumulating data obtained in patients with myo/endocarditis,5 and systemic autoimmune diseases, particularly rheumatoid arthritis (RA)6 7 and connective tissue diseases,5 6 as well as in apparently healthy subjects.5 8 9 The putative underlying mechanisms are complex but essentially cytokine mediated including direct actions on cardiomyocyte ion channels expression and function.5 6 As such, it seems conceivable that systemic inflammation, regardless of its origin, may represent a currently overlooked risk factor for QTc prolongation and TdP in the general population. To test this hypothesis, we prospectively collected: (1) patients who experienced TdP associated with QTc prolongation to assess the incidence and the degree of systemic inflammation, as well as (2) patients with systemic inflammatory diseases of different origin to evaluate the relationship between inflammatory markers and QTc during active disease and remission.

    Patients and methods

    Study populations

    The local ethical committee approved the study, and patients from all groups gave their oral and written informed consent in accordance with the principles of the Declaration of Helsinki.

    We prospectively enrolled (2008–2016) 40 consecutive patients who presented with TdP, independent of ongoing therapies and concomitant diseases (TdP cohort). Demographic, clinical and laboratory characteristics of study patients, as well as ongoing treatment with QTc-prolonging medications are provided in table 1 and in the online supplementary table 1. Shortly after the first TdP episode (no later than 48 hours), patients underwent a venous withdrawal to determine circulating levels of C-reactive protein (CRP) and proinflammatory cytokines (interleukin-6 (IL-6), tumour necrosis factor alpha (TNFα), interleukin 1 (IL-1)). Since no established reference values for cytokine levels are currently available, three reference control groups were employed in order to correctly interpret cytokine findings in TdP patients: (1) a positive group, comparable to CRP levels of 10 patients with RA, a well-recognised immunomediated disease characterised by chronic high-grade systemic inflammation; all patients had active disease, in most cases (60%) of severe degree; patients who were under current treatment with anticytokine-targeted therapy with biological disease-modifying antirheumatic drugs were excluded; (2) a negative group of 10 patients comparable to the TdP cohort for age, sex and comorbidities, but without TdP or any clinically evident acute/chronic inflammatory disease (comorbidity controls, CC); (3) a negative group of 10 healthy subjects (healthy controls, HC) age and sex matched with patients with RA, without clinical signs of ongoing acute infections. More details on control groups are reported in online supplementary methods and supplementary table 2.

    Supplementary Material

    Supplementary methods

    Supplementary Material

    Supplementary Table 1

    Supplementary Material

    Supplementary Table 2
    View this table:
    Table 1

    Demographic, clinical and laboratory characteristics of patients with torsades de pointes

    Finally, to assess the clinical impact of systemic inflammation on ventricular repolarisation, we prospectively enrolled 46 patients with elevated CRP levels as the result of different inflammatory conditions, including acute inflammatory processes, septic or aseptic, or chronic immunomediated diseases during flares, comparable to those observed in the TdP cohort (table 2). In these patients (inflammatory cohort), whose demographic, clinical and laboratory characteristics are detailed in table 3, QTc and cytokine levels were measured during active disease and after different therapeutic interventions resulting in a CRP decrease of >75% compared with the baseline.

    View this table:
    Table 2

    Ongoing inflammatory diseases, and circulating levels of CRP and inflammatory cytokines in patients with torsades de pointes

    View this table:
    Table 3

    Demographic and clinical characteristics, and ongoing therapies of patients with inflammatory diseases

    ECG recordings

    Diagnosis of TdP was based on the presence of at least one episode of polymorphic ventricular arrhythmia and a rate ranging from 160 to 240 bpm, associated with QTc prolongation1 (online supplementary figure 1). The QTc measurement is detailed in online supplementary methods.

    Supplementary Material

    Supplementary Figure 1
    Figure 1
    Figure 1

    CRP levels in patients with TdP, patients with RA, CC and HC. Patients with TdP, n=40; patients with RA, n=10; CC, n=10; HC, n=10. Kruskal-Wallis test (p<0.01), with Dunn test, *p<0.05, **p<0.01. Horizontal dotted line indicates the upper limit of reference values, that is, 0.5 mg/dL. CC, comorbidity controls; CRP, C-reactive protein; HC, healthy controls; RA, rheumatoid arthritis; TdP, torsades de pointes. 

    Laboratory analysis

    CRP and cytokine measurement is detailed in online supplementary methods. CRP levels were measured in all subjects of the different groups under study (in total, n=116). Conversely, cytokine levels were evaluated in 90/116 subjects, including 30/40 patients with TdP (randomly selected), 10/10 patients with RA, 10/10 CC, 10/10 HC, and 30/46 patients of the inflammatory cohort (randomly selected).

    Statistical analysis

    The following parametric or non-parametric statistical analyses were respectively carried out: the Kruskal-Wallis test, and Dunn multiple comparison post hoc test to evaluate differences in quantitative variables among the four groups of TdP, RA, CC and HC subjects; the two-tailed Student’s paired ‘t’-test, or the two-tailed Wilcoxon matched-pairs test, or the two-tailed Mann-Whitney test to evaluate differences in quantitative variables between two groups of data/subjects (inflammatory cohort pre/post; TdP patient subgroups); the Spearman rank correlation test to verify possible statistical association between quantitative variables in TdP and inflammatory cohort patients. The two-sided Fisher’s exact test was performed to evaluate statistical correlation between categorical variables between two groups of data/subjects (inflammatory cohort pre/post; TdP patient subgroups). p Values <0.05 were considered significant (GraphPad-InStat, V.3.06 for Windows V.2000).

    Results

    Characteristics of patients with TdP

    As expected,1 most patients in TdP cohort were female (~70%) and older than 65 years (median age: ~80 years). Moreover, a high prevalence of recognised QTc-prolonging risk factors of acquired origin was present, the most recurrent condition being the presence of an underlying cardiac disease (82%; more frequently left ventricular hypertrophy, coronary artery disease and atrioventricular blocks, table 1), followed by electrolyte imbalances (70%) and QTc-prolonging medications (57%). Regarding specific risk factors, hypokalaemia was the most common (60%). Anti-Ro/SSA-52kD antibodies were detected in 52% of the cases, although in only two patients there was a history of autoimmune disease (one RA, one coeliac disease). Among drugs, amiodarone was the most frequently used (27%). Notably, in almost all cases more than one known QTc-prolonging factor was simultaneously identifiable; on average >4 (table 1; online supplementary table 1). In addition, a significant proportion of patients (22/40, 55%) experienced VF/cardiac arrest (CA) and/or underwent electric shock (TdP rapidly degenerated to VF/CA; out-of-hospital VF/CA followed by direct current shock, only later revealing a manifestation of TdP episodes; sustained TdP not responsive to medical therapy).

    Inflammatory markers in patients with TdP

    A definite inflammatory disease was present in 18/40 patients (45%), most frequently an acute infection (n=12), but also chronic immune-mediated diseases (n=5), or acute aseptic inflammatory processes (n=1)(table 2; online supplementary table 1). Notably, besides these subjects, the majority of patients with TdP (80%) showed elevated CRP levels (median value 2.92 mg/dL) over five times higher than the upper normal limit (table 2; online supplementary table 1; figure 1).

    Patients with TdP had elevated IL-6 levels, comparable to those observed in patients with active RA and ~15/20 times higher when compared with CC or HC, respectively (table 2; online supplementary table 2; figure 2A), which strongly correlated with CRP concentration (figure 2B). Conversely, TNFα and IL-1β levels in the TdP cohort were not different from HC. Specifically, TNFα levels were significantly higher in patients with RA than both TdP subjects and HC (table 2; online supplementary table 2; figure 2C,D).

    Figure 2
    Figure 2

    Serum cytokine levels in patients with TdP, patients with RA, CC and HC. Patients with TdP, n=40; patients with RA, n=10; CC, n=10; HC, n=10. (A) IL-6 levels. Kruskal-Wallis test (p<0.01), with Dunn test, *p<0.05, **p<0.01. (B) Relationship between CRP and IL-6 levels in patients with TdP. Spearman test. (C) TNFα levels. Kruskal-Wallis test (p=0.01), with Dunn test, *p<0.05. (D) IL-1 levels. Kruskal-Wallis test (p>0.05). CC, comorbidity controls; CRP, C-reactive protein; HC, healthy controls; IL-1, interleukin-1; IL-6, interleukin-6; RA, rheumatoid arthritis; TdP, torsades de pointes; TNFα, tumour necrosis factor alpha.

    No significant differences in CRP and cytokine levels were observed when patients with TdP who experienced VF/CA and/or underwent electric shock were compared with those who did not (online supplementary table 3).

    Supplementary Material

    Supplementary Table 3

    Relationship between inflammatory markers and QTc in patients with inflammatory diseases

    Patients with active inflammatory diseases (inflammatory cohort) displayed high prevalence of QTc prolongation (male >470 ms/female >480 ms: 26%; QTc >440 ms: 65%), with a mean QTc >450 ms. Conversely, mean QRS duration was normal (91.2 ms): only four patients (9%) showed a prolonged QRS (≥120 ms), without any appreciable impact on overall QTc values (table 4; online supplementary results). Therapeutic interventions, including antibiotics, anti-inflammatory drugs or protease inhibitors depending on the specific inflammatory disease present, were associated with a rapid (mean follow-up time 20.1±24.7 days) and significant reduction in both CRP levels (mean decrease 88.0%) and QTc duration (△QTc=−22.3 ms, from 456.6±30.9 to 434.3±25.1 ms) (table 4; figure 3A,B). Accordingly, the prevalence of QTc prolongation significantly decreased (from 26% to 4%, p=0.0072; table 4). Values of QTc significantly correlated with CRP levels (rho=0.32, p=0.0019) throughout the study time (figure 4A). Conversely, no significant changes were observed in other laboratory parameters, including electrolyte levels, or echocardiography findings (table 4).

    Supplementary Material

    Supplementary results
    Figure 3
    Figure 3

    Changes in the QTc interval duration in patients with active inflammatory diseases during active disease (pre) and after therapeutic interventions resulting in a CRP decrease of >75% when compared with the baseline (post). (A) Representative ECG strips of a patient with acute pancreatitis during active disease (pre; CRP 27.0 mg/dL) and after a 13-day treatment with gabexate mesilate (post; CRP 1.64 mg/dL). Vertical lines in lead V5 show QT interval. (B) QTc changes observed before (pre) and after (post) treatment in the entire study population. Patients, n=46. Two-tailed Student’s paired ‘t’-test, ***p<0.0001. CRP, C-reactive protein; QTc, corrected QT.

    Figure 4
    Figure 4

    Changes in inflammatory markers and their relationship with the QTc interval duration in patients with inflammatory diseases. (A) Relationship between QTc and CRP levels throughout the time. Patients, n=46. Spearman test. (B) IL-6 levels during active disease (pre) and after therapeutic interventions resulting in a CRP decrease of >75% when compared with the baseline (post); n=30. Two-tailed Wilcoxon matched-pairs test, ***p<0.0001. Horizontal dotted line indicates the upper limit of reference values in HC, that is, 1.25 pg/mL. (C) Relationship between QTc and IL-6 levels throughout the time; n=30. Spearman test. (D, E) TNFα and IL-1 levels during active disease (pre) and after therapeutic intervention (post); n=30. Two-tailed Wilcoxon matched-pairs test, p>0.05. Horizontal dotted lines indicate the upper limit of reference values in HC, that is, 3.24 pg/mL (TNFα) and 0.29 pg/mL (IL-1). CRP, C-reactive protein; HC, healthy controls; IL-1, interleukin-1; IL-6, interleukin-6; QTc, corrected QT; TNFα, tumour necrosis factor alpha.

    View this table:
    Table 4

    Changes in clinical, electrocardiographic, laboratory and echocardiography parameters in patients with inflammatory disorders (n=46) during active disease (pre) and after therapeutic interventions resulting in a CRP decrease of >75% when compared with the baseline (post)

    Notably, in our patients a concomitant and significant reduction in mean heart rate (HR) values (9.6 bpm, from 82.5±14.8 to 72.9±12.2 bpm; table 4) was observed, correlating with CRP levels (rho=0.36, p=0.0004; Spearman rank correlation test). Since the Bazett formula may overestimate or underestimate QTc at higher and lower HRs,10 respectively, we additionally evaluated QTc using alternative correction formulas, that is, Fridericia, Framingham and Hodges, the latter being recognised as the formula showing the least HR dependence.11 Although less marked, a significant QTc reduction was found in all cases (Fridericia: −12.9 ms, p<0.0001; Framingham: −10.5 ms, p=0.0014; Hodges: −13.0 ms, p<0.0001). Notably, QTc values obtained with Bazett formula strongly correlated with QTc values obtained with Fridericia, Framingham and Hodges formulae (online supplementary table 4).

    Supplementary Material

    Supplementary Table 4

    Determination of circulating inflammatory cytokines revealed high IL-6 levels during active disease, >20 times higher than HC, which almost normalised after therapeutic interventions (table 4; figure 4B). IL-6 levels throughout the study time significantly correlated with HR (rho=0.33, p=0.010, Spearman rank correlation test) and, more strongly, with QTc (rho=0.50, p<0.0001; figure 4C).

    Conversely, mean TNFα and IL-1 levels overlapped those detectable in HC and did not show any appreciable change after treatment (table 4; figure 4D,E).

    Discussion

    The main findings of the present study are the following: (1) in unselected patients with TdP (TdP cohort), elevated CRP levels were present in the large majority of cases (80%; median value: ~3 mg/dL), and a definite inflammatory disease identifiable in almost 50% of subjects; (2) in this cohort, IL-6 levels were elevated and comparable to those observed in patients with severe active RA, and ~15–20 times higher than in controls; (3) in patients with elevated CRP levels from different inflammatory conditions (inflammatory cohort), QTc prolongation was common; in these subjects, CRP reduction was associated with significant QTc shortening, which correlated with the decrease in IL-6 levels. Altogether, these data suggest that systemic inflammation, via elevation of IL-6 levels, may represent a novel risk factor for QTc prolongation contributing to the presence of other classical risk factors for TdP occurrence.

    Evidence indicates that systemic inflammation, as reflected by CRP and IL-6 levels, is associated with an increased risk of malignant ventricular arrhythmias and SCD, both in patients with overt cardiac diseases and in apparently healthy subjects.10 12–14 Moreover, in patients with chronic immune-mediated inflammatory diseases, the incidence of ventricular arrhythmias, CA and SCD, is increased, also correlating with disease activity.5 6 15 16 Although the most recognised underlying mechanism is the promotion of coronary atherosclerosis, accumulating evidence supports the hypothesis that systemic inflammation may also per se be arrhythmogenic by inducing cytokine-mediated electric myocardial remodelling.5 6 Indeed, many experimental studies demonstrated that inflammatory cytokines (IL-6, TNFα, IL-1) induce profound changes in potassium and calcium channels resulting in prolongation of cardiomyocyte action potential duration (APD) and increased susceptibility to re-entrant ventricular arrhythmias. In particular, evidence indicates that TNFα prolongs APD by reducing potassium currents (the transient outward, Ito, and the rapid, IKr, and slow, IKr, components of the delayed rectifier currents), while IL-1 and IL-6 by enhancing the L-type calcium current (ICaL).17–22 In accordance with these data, a significant relationship between QTc duration and systemic inflammatory activation, as assessed by CRP and cytokine levels, has been demonstrated in large populations of apparently healthy subjects,8 9 as well as in chronic inflammatory diseases, which frequently show QTc prolongation.23–25 In patients with RA, anticytokine therapy with tocilizumab, an anti-IL6 receptor antibody, was associated with a rapid QTc shortening which correlated with CRP decrease.24 Collectively, these data suggest that the link between inflammatory markers and SCD may be at least in part explained by a higher propensity to develop long QT-associated malignant arrhythmias, particularly TdP degenerating into VF.

    The results from the present study provide support to this point of view. In our cohort of unselected consecutive patients with TdP, systemic inflammatory activation as reflected by elevated CRP levels was a very common finding. CRP values were in many cases markedly increased (up to ~30 mg/dL; median: ~3 mg/dL) indicating the presence of high-grade systemic inflammation, more frequently as a result of acute infections, but also active chronic inflammatory diseases or acute aseptic inflammatory processes. The fact that in ~50% of cases a definite inflammatory disease was demonstrable, together with the evidence of comparable CRP and IL-6 levels in subjects who experienced VF/CA and/or underwent electric shock and who did not, strongly suggests that in these patients inflammatory activation is not the mere consequence of TdP-associated complications and/or critical care treatments. Nevertheless, in a significant proportion of patients (35%) no clearly defined inflammatory processes were diagnosed despite increases in CRP levels comparable to those observed in the entire cohort (median: 2.9 mg/dL, range: 0.67–11.6). Although this primarily points to occult inflammatory diseases, the fact that patients with TdP are rather old (median 80 years) and age-matched CC patients show slightly higher CRP and IL-6 levels versus HC, suggests that also ‘inflammaging’ (ie, low-grade chronic systemic inflammation due to the normal ageing process)26 may play a role. More intriguingly, according to recent data,27 inflammaging could contribute to explain why advanced age is a recognised TdP risk factor.1 In any case, these findings point to the concept that regardless of the specific aetiology, pathogenesis and targeted organs, systemic inflammation may per se represent the true risk factor for TdP development, via the action of common basic mediators involved in the different inflammatory processes. The results of the present study together with data from previously cited electrophysiological studies17-22strongly suggest that a key role is played by inflammatory cytokines, specifically IL-6.22 In fact, unlike TNFα and IL-1, in our TdP cohort circulating IL-6 was markedly elevated, ~20 times higher than HC and overlapping with those observed in a control group of patients with RA with severe active disease. Notably, consistent cytokine profiles were observed in large cohorts of patients with active RA,28 as well as in patients with septic processes29 representing the most common definite causes of inflammation in the TdP cohort. Particularly, several studies demonstrated that in sepsis, TNFα and IL-1 levels are not elevated or slightly increased.29 This is probably due to their role as early mediators, rapidly inducing downstream proinflammatory molecules, mainly IL-6, which then remain stably elevated, alongside inhibiting TNFα and IL-1 release.29 In this regard, the evidence that in TdP cohort IL-6 levels robustly correlated with CRP concentration, although expected,30 further supports the hypothesis that IL-6 is the mediator linking systemic inflammation and arrhythmic risk in these patients.

    From a pathophysiological point of view, the most likely mechanism by which systemic inflammation could increase TdP risk is a prolonging effect on the QT interval, possibly via IL-6-mediated electrophysiological changes in cardiomyocyte APD. Accordingly, in the second part of the study, we demonstrated that in patients with elevated CRP levels resulting from different inflammatory conditions (inflammatory cohort), QTc was frequently prolonged, but it was rapidly shortened as soon as inflammation was controlled. These patients showed elevated baseline IL-6 levels which almost normalised after treatment. Also QTc shortening correlated with the decrease in CRP and IL-6 levels. The fact that QTc changes occurred rapidly (~20 days) suggests electrophysiological effects independent of any structural heart modification. This hypothesis is consistent with in vitro experiments and supported by previous data from patients with RA treated with tocilizumab.24

    Besides exerting direct activities on the myocardium, IL-6 could also prolong QTc via indirect effects mediated by the autonomic nervous system. In fact, by targeting autonomic centres of the brain, inflammatory cytokines can increase the sympathetic outflow, in turn controlling cytokine production via inhibitory β2-adrenergic receptors on circulating lymphomonocytes (inflammatory reflex).5 Indeed, central sympathetic overactivity affects the whole body, including the heart where marked and complex changes in myocardial electrophysiology result in a net effect of APD prolongation.5 6 Accordingly, we found that suppression of inflammation was associated with a significant reduction in the sympathetic drive on the heart, as reflected by the decrease in the mean HR, which correlated with CRP and IL-6. Nevertheless, IL-6 levels more strongly correlated with QTc (rho=0.50, p<0.0001) than HR (rho=0.33, p=0.010), thus suggesting that direct myocardial effects probably play a predominant role in IL-6-mediated QTc prolongation.

    It is noteworthy that inflammation alone cannot explain marked QTc prolongation observed in the patients with TdP, and this is true for all recognised causes of LQTS when present alone.1 Rather, by reducing the ventricular repolarisation reserve, inflammation may represent a contributing factor synergistically operating with the other QT-prolonging factors concomitantly present. Indeed, as expected, in the TdP cohort the majority of patients exhibit more than one known risk factor (on average ~4). However, while most of these factors are well recognised and thus carefully taken in account for TdP treatment, the potential arrhythmogenic role of systemic inflammation in these patients is to date largely overlooked.

    Among the potential limitations of this study is the relative small sample size, which precluded any reliable adjusted analysis comparing TdP cases to controls. In this regard, it should also be noted that although no significant differences in inflammatory markers were found when patients with TdP who experience VF/CA and/or electric shock were compared with those who did not, we cannot exclude that the statistical power to detect such a difference among 40 subjects may be too low. Nevertheless, it should be underlined how TdP is an uncommon event, maybe also because underdiagnosed for the high propensity of this arrhythmia to induce SCD. Accordingly, in several of our patients, TdP rapidly degenerated to VF and CA, thus supporting the view that this arrhythmia may contribute more than expected to explain SCD occurring in subjects with elevated inflammatory markers.

    Further potential limitations include missing data on cytokine levels in a set of patients with TdP and inflammatory disease (~30%), as well as the lack of a genetic testing for concomitant LQTS-associated mutations. Although the genetic characterisation would have been useful for a more accurate definition of the total load of risk factors in the single patient (case series identified subclinical congenital LQTS in 5%–20% of cases of drug-induced TdP),1 we anticipate that the presence of systemic inflammation and genetic mutations along with other classical acquired risk factors will together predispose to TdP.

    In conclusion, our data, for the first time, provide evidence that systemic inflammation may represent a novel risk factor contributing to TdP development in the general population. The data also support the recommendation to translate into the clinical practice that in patients with a systemic inflammatory state, regardless of its origin, the potential impact of this condition on ventricular repolarisation should be carefully kept in mind, particularly when one or more QT-prolonging drugs are required. In addition, inflammatory mediators, such as IL-6, may represent an innovative target in patients with TdP, specifically in those showing high-grade systemic inflammation and not responding to conventional treatment. If confirmed by larger studies, this could open new avenues in antiarrhythmic therapy.

    Key messages

    What is already known on this subject?

    • Torsade de pointes (TdP) is a life-threatening ventricular arrhythmia occurring in patients with long QT syndrome.

    • Since ‘classical’ QT-prolonging risk factors cannot fully explain TdP development and recurrence in a number of subjects, identification of previously unrecognised risk factors represents a field of increasing interest.

    What might this study add?

    • Elevated C-reactive protein (CRP) and interleukin-6 (IL-6) levels were frequently observed in patients with TdP, where a definite inflammatory disease was identifiable in almost 50% of cases.

    • In patients with elevated CRP levels from different inflammatory conditions, QTc prolongation was common: in these subjects, CRP reduction was associated with significant QTc shortening, which correlated with IL-6 level decrease.

    How might this impact on clinical practice?

    • In patients with a systemic inflammatory state, regardless of its origin, the potential impact of this condition on ventricular repolarisation should be always carefully kept in mind by the clinician.

    • If our data are confirmed, inflammatory mediators, particularly IL-6, may represent an innovative target which could open new avenues in antiarrhythmic therapy.

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    Footnotes

    • Contributors All the authors have directly contributed to (1) conception and design or analysis and interpretation of data, or both; (2) drafting of the manuscript or revising it critically for important intellectual content; and (3) final approval of the manuscript submitted.

    • Funding This work has received funding from FAS-Salute ToRSADE project (FAS Salute 2014, Regione Toscana).

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Local ethical committee (Comitato Etico Regione Toscana Area Vasta Sud Est).

    • Provenance and peer review Not commissioned; externally peer reviewed.