Heart Rate Turbulence

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Heart Rate Turbulence Iwona Cygankiewicz⁎ Department of Electrocardiology, Medical University of Lodz, Sterling Regional Center for Heart Diseases, 91–425 Lodz, Poland

A R T I C LE I N FO

AB S T R A C T

Keywords:

Heart rate turbulence (HRT) is a baroreflex-mediated biphasic reaction of heart rate in

Heart rate turbulence

response to premature ventricular beats. Heart rate turbulence is quantified by: turbulence

Heart rate variability

onset (TO) reflecting the initial acceleration of heart rate following premature beat and

Risk stratification

turbulence slope (TS) describing subsequent deceleration of heart rate. Abnormal HRT

Sudden death

identifies patients with autonomic dysfunction or impaired baroreflex sensitivity due

Heart failure

to variety of disorders, but also may reflect changes in autonomic nervous system induced by different therapeutic modalities such as drugs, revascularization, or cardiac resynchronization therapy. More importantly, impaired HRT has been shown to identify patients at high risk of all-cause mortality and sudden death, particularly in postinfarction and congestive heart failure patients. It should be emphasized that abnormal HRT has a well-established role in stratification of postinfarction and heart failure patients with relatively preserved left ventricular ejection fraction. The ongoing clinical trials will document whether HRT can be used to guide implantation of cardioverter-defibrillators in this subset of patients, not covered yet by ICD guidelines. This review focuses on the current state-of-the-art knowledge regarding clinical significance of HRT in detection of autonomic dysfunction and regarding the prognostic significance of this parameter in predicting allcause mortality and sudden death. © 2013 Elsevier Inc. All rights reserved.

Heart rate variability (HRV), based on RR-intervals assessment, is one of the oldest Holter-derived risk stratification parameters. A shift toward sympathetic overdrive and a withdrawal of vagal tone reflected as decreased HRV are believed to be a mechanism contributing to an increased risk of developing life threatening arrhythmias.1 In 1999, Schmidt and coworkers described a phenomenon of heart rate turbulence (HRT) which is manifested by short-time heart rate changes induced by a premature ventricular beat.2 In healthy subjects a ventricular premature ectopic beat provokes a biphasic reaction of an early acceleration, and late deceleration of heart rate, while in high risk subjects such a

reaction is diminished or even completely non-existent. Several large-population studies have shown that the decreased (or abnormal) HRT identifies patients at high risk of mortality, including sudden death.3

HRT calculation Heart rate turbulence is represented by two numeric descriptors: turbulence onset (TO) reflecting the initial acceleration of heart rate after a ventricular premature beat (VPB) and turbulence slope (TS) describing subsequent deceleration

Statement of Conflict of Interest: see page 168. ⁎ Address reprint requests to Iwona Cygankiewicz MD, PhD, Department of Electrocardiology, Medical University of Lodz, Sterling Regional Center for Heart Diseases, Ul.Stelinga 1/3, 91–425 Lodz, Poland. E-mail address: [email protected]. 0033-0620/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pcad.2013.08.002

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Abbreviations and Acronyms BRS = baroreflex sensitivity CHF = chronic heart failure CI = confidence interval CRT = cardiac resynchronization therapy HR = hazard ratio HRT = heart rate turbulence HRV = heart rate variability ICD = implantable cardioverter defibrillator LVEF = left ventricular ejection fraction SDNN = standard deviation of normal-to-normal RR intervals TO = turbulence onset TS = turbulence slope TWA = T wave alternans VPB = ventricular premature beat VT = ventricular tachycardia ATRAMI = The Autonomic Tone and Reflexes after Myocardial Infarction CARISMA = Cardiac Arrhythmias and Risk Stratification after Acute Myocardial Infarction EMIAT = European Myocardial Infarction Amiodarone Trial EPHESUS = Eplerenone Post-AMI Heart Failure Efficacy and Survival FINGER = FINland and GERmany Post-infarction GISSI-HF = The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico Heart Failure ISAR-HRT = Innovative Stratification of Arrhythmic Risk MPIP = Multicenter Postinfarction Program MUSIC = Muerte Subita en Insufficiencia Cardiaca REFINE = The Risk Estimation Following Infarction Noninvasive Evaluation

of heart rate following a ventricular premature beat. TO is defined as a percentage of relative change of the mean of 2 RR intervals before and 2 RR intervals after a VPB. TS is the slope of the steepest regression line computed over the sequence of every 5 consecutive RR intervals following a VPB within the 15 RR intervals after the VPB and it is expressed in ms/RR (Fig 1). HRT was primarily invented and calculated from long-term Holter recordings. Specialized computer software is required to quantify small beatto-beat variations in heart rate (RR intervals). Final TO value reported for given recording is expressed as a mean of all TO values computed for all eligible VPBs. For TS calculation, a graphical representation of RR interval variations is aligned and averaged from RR sequences following all VPBs in given recording (Fig 2). Only ECG strips including an eligible VPB, a single VPB with the neighboring 20 RR intervals free of artifacts including additional premature beats, are considered for analysis. Furthermore, additional filtering algorithms limit HRT calculation to premature VPBs with adequate coupling intervals and compensatory pauses to ensure reliable calculation of HRT by excluding interpolated beats. According to guidelines on HRT measurements only recordings

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with at least 5 VPBs should be considered as valid for HRT analysis. Detailed methodology of HRT calculation is available at www.h-r-t.org and summarized in the consensus document written under the auspices of the International Society for Holter and Noninvasive Electrocardiology.3 HRT-based risk assessment has some limitations related to its calculation. This method can be applied only to patients with sinus rhythm presenting with eligible VPBs (as described above). Even with a less strict approach toward the minimum ectopic beats required for calculation (allowing for inclusion Holters with ≥ 1 VPB) there is a substantial percentage of patients in whom HRT cannot be calculated, but usually patients without VPBs are at low risk of cardiac events. Manzano-Fernandez et al.4 demonstrated that longer-term Holter recording substantially increased (from 69% to 94%) the possibility of HRT calculation with no additional value when the recordings were extended beyond the 3rd day.

Physiological background Based on data from experimental and clinical studies, HRT is most likely mediated via the baroreceptor reflex; however, other mechanisms such as postextrasystolic potentiation have been proposed.5–11 A premature ventricular ectopic beat results in a transient drop in blood pressure which triggers activation of baroreceptors, and leads to an immediate vagal inhibition, and increase in heart rate. Augmented myocardial contractility following a VPB and the subsequent increase in blood pressure lead to an opposite reaction with subsequent decrease in sinus node activity, and thus the biphasic HRT curve of acceleration and deceleration is created. La Rovere et al.9 studied the relationship between HRT and baroreflex sensitivity (BRS) in a cohort of 157 heart failure patients in whom Holter-derived HRT and phenylephrine induced BRS were evaluated. Both TO and TS significantly correlated with phenylephrine-derived slope of blood pressure and RR interval, with a stronger correlation observed for TS (r = 0.66, p < 0.0001). These findings strongly support the theory that HRT is mediated by baroreflex response and suggest that HRT could be considered as an indirect measure and surrogate of baroreflex sensitivity for clinical purposes.

Clinical and ECG covariates Over the years numerous papers have demonstrated abnormal HRT parameters in various subsets of patients, likely reflecting impairment of the autonomic nervous system and baroreflex response. Substantial numbers of subjects with impaired HRT were observed in patients after myocardial infarction, in heart failure patients and in patients with other cardiac diseases.12–15 Abnormal TO and TS were also observed in diabetes, obstructive sleep apnea, connective tissue diseases, hypo-and hyperthyroidism, myotonic dystrophy type 1, chronic obstructive pulmonary disease, and renal insufficiency requiring hemodialysis.16–22 Abnormalities in HRT, potentially reflecting autonomic dysfunction or impaired

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rate or a number of VPBs is a matter of debate. Both HRT parameters, but especially TS, were found to correlate with mean heart rate and the number of ventricular premature beats.25,26 Steeper TS values are observed in patients with slower heart rate and low number of premature ventricular beats, but to date no widely accepted formula for correction has been developed. Not surprisingly, HRT was also found to significantly correlate with HRV parameters both in time and frequency domain.25 HRT dependence on heart rate, number of VBPs and strong correlations with baroreflex sensitivity and heart rate variability should not be surprising as HRT combines all these factors.

Fig 1 – Heart rate turbulence calculation. Turbulence onset is the relative change of R-R intervals (red lines) from before to after the VPC. Turbulence slope is the slope of the steepest regression line fitted over the sequences of 5 consecutive sinus rhythm R-R intervals within the 15 R-R intervals after the VPC. The light blue lines are the 11 possible regression lines. The dark blue line is the steepest one used for TS calculation. Reprinted from Bauer et al.3 with permission from Elsevier.

baroreflex sensitivity were also observed in apparently healthy subjects.23 A variety of clinical covariates such as age, LVEF, diabetes, NYHA classes are known to correlate with HRT measures.13,16,24 In chronic heart failure (CHF) patients, HRT is correlated not only with LVEF but also with parameters reflecting heart failure advancement such as NT-proBNP levels, considered as a reliable measure of heart failure progression.13 Whether HRT should be corrected for heart

Clinical applications of heart rate turbulence High-risk patients are characterized by depressed HRT, expressed as the lack of an immediate acceleration, or even deceleration of a sinus rhythm (positive values of TO), and blunted rate of subsequent deceleration with lower TS values (flattened slope) (Fig 2). Following the original paper by Schmidt et al.,2 TO ≥0% and TS ≤2.5 ms/RR values are considered as abnormal. Patients are categorized into 3 groups: HRT0 – both HRT parameters (TO and TS) normal, HRT1 – one of the parameters abnormal, and HRT2 – both parameters abnormal. Patients in whom HRT analysis cannot be performed due to lack of VPBs or rejection of VPBs by filtering algorithms are categorized as no HRT measured Ø category, and for the risk stratification purposes usually merged with the low risk HRT0 group. Since 1999 several large and numerous smaller clinical studies have demonstrated the prognostic value of abnormal HRT in predicting unfavorable outcome in different populations, especially in postinfarction and CHF patients27–59 (Tables 1 and 2). The clinical value of HRT in predicting

Fig 2 – Normal and abnormal heart rate turbulence. Ventricular premature complex (VPC) tachograms showing normal (left) and abnormal (right) heart rate turbulence (HRT). In healthy subjects a biphasic reaction of acceleration and deceleration is observed (left side) while in high-risk patients HRT reaction is decreased or even non-existant. HRT is composed of the transient acceleration phase of heart rate (R-R interval shortening) immediately after the compensatory pause followed by a subsequent and gradual deceleration phase (R-R interval prolongation). Orange curves show single VPC tachograms. Bold brown curves show the averaged VPC tachogram over 24 h. Reprinted from Bauer et al.3 with permission from Elsevier.

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Table 1 – Prognostic value of heart rate turbulence in patients with coronary artery disease. # of patients

Studied population

Schmidt et al.2 1999 Schmidt et al.2 1999

577

Ghuran et al.7 2002

1212

Barthel et al.27 2003

1455

Cygankiewicz et al.24 2003

146

Jokinen et al.26 2003

600

Berkowitsch et al.25 2004 Makikallio et al.28 2007

884

Exner et al.29 2007

322

REFINE Myocardial infarction and LVEF <50%

Perkiomaki et al.30 2008 Stein and Deedwania40 2009 Maeda et al.38 2009

675

Acute MI

481

Post-AMI with CHF and/ or diabetes and LVEF dysfunction Postinfarction group with and without VT

Huikuri et al.31 2009

312

CARISMA postinfarction

Huikuri et al.32 2010

634

REFINE, and CARISMA

Perkiomaiki et al.41 2010 Perkiomaki et al.35 2011 Szydlo et al.37 2011

569

Postinfarction

292

Miwa et al.39 2011

531

CARISMA Postinfarction, EF <40% Postinfarction patients with (94) or without (54) a history of VT/VF Postinfarction patients with (231) or without DM

Cebula et al.34 2012

500

614

2130

63

158

MPIP Postinfarction EMIAT Postinfarction LVEF < =40% (av.30%) ATRAMI Postinfarction Av. LVEF = 49% ISAR-HRT Postinfarction 90% PCI Coronary patients undergoing CABG, 30% postinfarction, av.EF52% MRFAT postinfarction

MADIT II Postinfarction, LVEF < =30% FINGER Postinfarction, mean LVEF 51%

Acute MI treated invasively

Follow up 22 months 21 months

21 months

22 months

Results HRT2, and abnormal TS predictive for all-cause mortality with multivariate HR = 3.2,and 2.5, respectively Abnormal TO, and abnormal TS predictive for all-cause mortality. The highest HR observed for HRT2 (HR = 3.2) For a combined endpoint of fatal, and non-fatal cardiac arrhythmias HR = 2.47 for TS; HR = 4.07 for HRT2 HR = 5.9 for HRT2 in predicting total mortality

12 months

Cardiac mortality predicted by TS (HR 1.25 per 1 mm/RR decrease, and HR 9.83 for TS < =4.25 (Q1))

40 months

Dynamic changes in HRT (increase in TO, stable TS 12 months after MI) Baseline TO, and TS predictive for all cause mortality and cardiac deaths. Late after MI only TS predictive for endpoints HRT assessed from 10 minute recording not predictive

22 months 33 months

HR = 2.9 for abnormal TS in predicting sudden death, and HR = 3.2 in predicting non-sudden death Abnormal TS predictive for sudden death in patients with LVEF >35% (HR = 4.7) 47 months HRT assessed 10–14 weeks after MI predictive for cardiac death or resuscitated cardiac arrest (HR = 2.91 for HRT1) Not predictive if evaluated 2–4 weeks after MI. Combination of HRT and abnormal TWA HR = 3.58 (for exercise TWA) and 4.18 for Holter TWA Combination of abnormal HRT with abnormal TWA and low LVEF possessed the highest predictive value 30 months TS predictive for acute coronary events only in univariate analysis 12 months Different optimal cut offs: TS < =3 mm/RR HRT2 and LVEF < =30% independently associated with cardiovascular death (HR = 3.64, and 1.97 respectively) 72 months HRT and TWA MMA evaluated. Patients with a history of VT had more frequently abnormal HRT. Only TWA predictive for arrhythmias 2 years TS evaluated 6 weeks after MI predictive for a primary endpoint of ECG-documented VT/VF HR = 2.8 for abnormal TS. TO not predictive No prognostic value for HRT evaluated 1 week after MI Dynamic changes in HRT parameters after MI Attenuated recovery of HRT (delta TS <2.0) predictive for SVT/VF in CARISMA (HR = 9.4), and for fatal or non-fatal events in REFINE (HR =7.0) 8 years BNP, HRV, and HRT predictive for heart failure hospitalization in postinfarction patients with no previous history of CFH TS < =1.75 mm/RR predictive for perpetuating, but not for self-terminating ventricular tachycardia (HR = 4.57) retrospective VT/VF group characterized by higher TO (−0.22 vs −0.8) and lower TS (2.6 vs 4.1) values 29 months

15 months

In diabetic patients renal dysfunction and abnormal HRT predictive for cardiac mortality (HR = 4.7 and 3.5 respectively). In non-DM patients only abnormal HRT predictive for endpoints Abnormal TO, TS, and TT predictive for MACE Combination of HRT with HRV index increased PPV (continued on next page)

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Table 1 (continued) # of patients Hoshida et al.33 2013

313

Studied population Postinfarction patients

Follow up 39 months

Results Abnormal HRT the most powerful predictor of a combined endpoint of cardiac mortality and fatal arrhythmic events (HR5.7). TWA MMA, but not HRT-specific for arrhythmic events

HRT = heart rate turbulence, TO = turbulence onset; TS = turbulence slope; TT = turbulence timing; TWA MMA-T wave alternans, modified moving average method; HRV = heart rate variability; PPV = positive predictive value; MI = myocardial infarction; DM = diabetes; VT/VF = ventricular tachycardia/fibrillation; HR = hazard ratio; BNP = brain natriuretic peptide; LVEF = left ventricular ejection fraction.

outcome in patients with no apparent heart diseases has not been fully elucidated yet. However, the Cardiovascular Health Study, a population-based study of risk factors for coronary artery disease and stroke in apparently

healthy subjects over 65 years showed that as compared to controls those who experienced sudden death during a follow up were characterized by abnormal values of TS. 27

Table 2 – Prognostic value of heart rate turbulence in cardiomyopathies and/or heart failure. Cardiomyopathies and heart failure 50 Koyama et al.49 2002 Grimm et al.44 242 2003

Moore et al.50 2006

358

Klingenheben 114 et al.45 2008 Cygankiewicz 607 et al.51 2008

Cygankiewicz 294 et al.53 2009

CHF, mean EF 39%, 32% ischemic etiology Marburg Study Dilated idiopathic cardiomyopathy, mean LVEF = 30% UK Heart Study CHF (I-III NYHA class; mean. LVEF41%) Frankfurt Dilated Cardiomyopathy database, mean LVEF = 28% MUSIC study CHF in NYHA class II-III, mean LVEF = 37%, 50% ischemic etiology MUSIC study CHF NYHA II-III, subgroup with LVEF >35%

Miwa et al.55 2009

375 Ischemic (241), and non-ischemic (134) cardiomyopathy

Sredniawa et al.54 2010

110 CHF NYHA II-IV, mean EF30%

Ikeda et al.46 2011 Kawasaki et al.48 2012 Miwa et al.39 2012

134 Nonischemic dilated cardiomyopathy 104 Hypertrophic cardiomyopathy

La Rovere et al.52 2012

299 Ischemic and nonischemic cardiomyopathy with LVEF < = 40% 388 GISSI-HF CHFNYHA II-III class

26 months Abnormal TS (<=3 ms/RR) predictive for death and hospitalizations for heart failure (HR = 10.2, CI = 3.2–37.5) 41 months Turbulence onset as predictor of transplant free survival. TO and TS –only univariate predictor of major arrhythmic events

5 years

Abnormal TS (<=2.5 ms/RR) predicts heart failure decompensation

22 months HRT not predictive for arrhythmic events

44 months Abnormal TS (<=2.5 ms/RR) and HRT2 predictive for all-cause mortality, sudden death and heart failure death (for HRT2 HR = 2.52; 2.25 and 4.11, respectively for modes of death) 44 months Abnormal HRT predictive for all cause mortality. Abnormal TS predictive for sudden death Risk score based on abnormal SDNN, QT/RR and TS as optimal prediction for all cause mortality and sudden death 15 months Abnormal HRT predictive for cardiac mortality and a combined endpoint of cardiac death and/or stable sustained VT (HR = 6.4 and 5.1, respectively). Prognostic value observed in both ischemic and non-ischemic cardiomyopathy (for cardiac mortality HR = 4.9, and 12.5 respectively) 5.8 years SDNN, LVEF < =35%, TT >10, and abnormal TO predictive for a combined endpoint of end stage CHF requiring hospitalization, and all-cause mortality 15 months Abnormal HRT predictive for a combined endpoint of cardiac mortality and sustained VT (HR =4.5) 27 months HRT failed to predict death and arrhythmic events 32 months Abnormal HRT (HRT2), nsVT, and DM predictive for a combined endpoint of sudden cardiac death and sustained VT 33 months Abnormal TS predictive for cardiac mortality and a combined endpoint of sudden death or ICD discharge. Abnormal TS predictive for endpoints in CHF subgroup of patients with LVEF >30%

HRT = heart rate turbulence, TO = turbulence onset; TS = turbulence slope; TT = turbulence timing; HRV = heart rate variability; MI = myocardial infarction; DM = diabetes; nsVT = nonsustained ventricular tachycardia; HR = hazard ratio; BNP = brain natriuretic peptide; LVEF = left ventricular ejection fraction; CHF = chronic heart failure; NYHA = New York Heart Association; ICD = implantable cardioverter defibrillator.

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Risk stratification in postinfarction patients The prognostic value of abnormal HRT for predicting mortality was first confirmed in large cohorts of postinfarction patients from the MPIP (Multicenter Postinfarction Program) and EMIAT (European Myocardial Infarction Amiodarone Trial) studies.2 In these populations patients with blunted HRT had a higher risk of all-cause mortality than could be explained by left ventricular ejection fraction (LVEF), with a two-year mortality over 30% in the HRT2 group. Retrospective analysis of HRT in the ATRAMI (The Autonomic Tone and Reflexes after Myocardial Infarction) trial showed that abnormal HRT was related not only to increased all-cause mortality but more importantly identified postinfarction patients at risk of arrhythmic events defined as fatal or nonfatal cardiac arrest..8 The highest risk group, defined as HRT2, showed a four-fold higher risk of cardiac arrhythmic death during a follow up than the HRT0 group. Prospective and retrospective analyses based on newer populations treated by percutaneous coronary angioplasty and guidelines-based pharmacotherapy including high beta blockers and ACE inhibitors confirmed an independent value of HRT in predicting outcome of postinfarction patients.30–43 The ISAR- HRT (Innovative Stratification of Arrhythmic Risk) study found HRT2 to be an independent predictor of 2-year mortality, providing the highest hazard ratio (5.9) followed by decreased LVEF, age, diabetes and HRT1.30 Three large studies: FINGER, REFINE, and CARISMA, have focused on evaluation and comparison of the prognostic value of various invasive and non-invasive ECG-based parameters in predicting outcome in modern postinfarction patients.31,32,34 Data from FINGER (FINland and GERmany Post-infarction) study showed that among several Holter predictors only decreased TS and nonsustained ventricular tachycardia were associated with sudden death when adjusted for clinical covariates. Abnormal TS carried a nearly 3-fold higher risk (HR = 2.9, CI = 1.6–5.5, p = 0.0008) of sudden death during a 33-month follow-up in over 2000 patients assessed in the early postinfarction period.31 The REFINE (The Risk Estimation Following Infarction Noninvasive Evaluation) trial, which enrolled 322 postinfarction patients with LVEF <50%, combined evaluation of autonomic nervous tone and electrical instability in predicting a primary endpoint of cardiac death or resuscitated cardiac arrest.32 Abnormal HRT in this study was defined as having either TO or TS abnormal versus both parameters being normal. The noninvasive parameters were analyzed twice: in an early (2–4 weeks after MI) and late (10–14 weeks) period after an event. Low LVEF was the strongest risk predictor of arrhythmic events in the early and late phase. None of noninvasive ECG markers assessed in an early postinfarction phase predicted outcome, while increased T wave alternans (TWA), abnormal HRT and decreased BRS analyzed between 10 and 14 weeks postinfarction were predictive of the primary endpoint. Similar findings were provided by the CARISMA (Cardiac Arrhythmias and Risk Stratification after Acute Myocardial Infarction) study in which for the first time the arrhythmic endpoints were documented by means of implantable loop recorder.34 A variety of noninvasive ECG risk markers were

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assessed at the early phase and late phase (6 weeks) after an acute myocardial infarction in patients with LVEF ≤ 40% followed for up to 24 months. TS, evaluated both as a continuous as well as a dichotomized value (≤2.5 ms/RR) 6 weeks after myocardial infarction was predictive for a primary endpoint defined as ECG-documented ventricular fibrillation or symptomatic ventricular tachycardia. Abnormal TS had a relative risk of 2.8 for an arrhythmic event when adjusted for other significant covariates. Similar to REFINE results no prognostic value was observed for HRT assessed in an early postinfarction phase. Furthermore, similar to what was observed in other studies, TO alone did not have prognostic information. One of subsequent subanalyses of CARISMA study35 focused on predicting different types of ventricular tachycardia (VT) episodes. The question was posed, whether or not it is possible to differentiate predictors of perpetuating versus self-terminating ventricular tachyarrhythmias. During a follow up of 24 months, 9% of patients had an episode of self-terminating VT while 7% experienced perpetuating VT which in 9 cases ended by ventricular fibrillation resulting in fatal or non-fatal cardiac arrest. Low TS (≤ 1.75 ms/RR) was found as a significant predictor of perpetuating VT, but not self-terminating VT.

Dynamic changes of HRT and its prognostic role Positive or unfavorable structural remodeling following myocardial infarction significantly influences prognosis of postinfarction patients. Similarly, dynamic changes in autonomic nervous tone can be observed. Jokinen et al.36 for the first time described dynamic changes in both HRT and HRV parameters over time following an acute myocardial infarction. All time domain and spectral HRV indices and TO significantly improved while TS remained stable during the first 12 months (TO decreased from 0.27 to − 0.92). Data from a combined REFINE and CARISMA analysis indicated a similar pattern with HRV and HRT parameters improving over time.37 In both cohorts TO decreased, and TS increased (favorable changes) in late postinfarction period, nevertheless, statistical significance was observed only for TS (av.6.6 vs. 8.0, p < 0.01, and 7.7 vs. 9.1 ms/RR p < 0.001 for CARISMA and REFINE, respectively). This favorable recovery of parameters reflecting autonomic tone was parallel to positive structural remodeling expressed as an increase in LVEF (31% vs. 35% in CARISMA, and 39% vs. 47% in REFINE). Noteworthy, lack of recovery in HRT defined as delta TS < 2.0 ms/RR was associated with nearly 10-fold higher risk of life threatening arrhythmias in CARISMA and a 7-fold higher risk of reaching primary endpoint in REFINE study. More importantly, these changes were related to arrhythmic but not non-arrhythmic mode of death. However, similar to what has been observed in a majority of risk stratification papers; this stratification model was characterized by a very high negative but low positive predictive value.37

Nonischemic cardiomyopathies Contrary to postinfarction populations, data on the predictive value of HRT in patients with nonischemic cardiomyopathies

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remains limited and controversial.44–48 In the Marburg Study TO was found to be a significant predictor of transplant free survivals in 242 patients with idiopathic cardiomyopathy.44 None of HRT descriptors remained a significant risk marker for arrhythmic events in multivariate analysis. Analysis of the Frankfurt DCM database, published 5 years later, showed that among autonomic markers (HRV, HRT, and BRS) only blunted BRS was associated with arrhythmic events.45 On the other hand, Ikeda et al.46 in a cohort of 134 patients nonischemic cardiomyopathy with LVEF ≤ 40% and NYHA class II-III abnormal HRT (HRT2) predicted primary endpoint defined as cardiac mortality or sustained VT during a follow up and was associated with 4.5-fold higher risk. In patients with hypertrophic cardiomyopathy HRT parameters were not different from those in the control group of healthy subjects and were not predictive for clinical prognosis.47,48

Chronic heart failure Early neurohormonal activation with sympathovagal shift toward adrenergic stimulation constitutes the main feature of CHF, independent of its etiology, and plays an important role in initiation and progression of hemodynamic changes observed in this disease. Therefore, it has been suggested that HRT, being a vagally-dependent effective measure of baroreflex sensitivity related to the advancement of heart failure, might be used as a marker of congestive heart failure progression.13 Indeed, in patients with heart failure regardless of etiology, HRT consistently predicted heart failure progression and all-cause mortality49–55 (Table 2). In the UK Heart Study in 358 CHF patients with mild to moderate heart failure (NYHA class II-III), abnormal TS was found to be an independent risk predictor of death due to decompensated heart failure at 5-years follow up.50 The MUSIC (Muerte Subita en Insufficiencia Cardiaca) study enrolled 607 CHF patients in NYHA class II-III of both ischemic and non-ischemic etiology regardless of LVEF and confirmed that HRT predicts all-cause mortality and heart failure progression, and for the first time documented that abnormal HRT, especially TS, also predicts sudden death.51 However, consistent with postulated mechanisms of HRT related to abnormal baroreflex sensitivity and autonomic imbalance, abnormal HRT showed a trend toward a stronger association with heart failure death (HR = 4.11, CI = 1.84–9.19, p < 0.001) than with sudden death (HR = 2.25, CI = 1.13–4.46, p = 0.021). Similar to previous reports, TS was a significant risk stratifier for all modes of death, while TO was predictive only for total mortality and heart failure death. Most papers on risk stratification in postinfarction patients applied classical HRT cut offs; however, data from the EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival) trial indicated that in postinfarction patients with heart failure other cut offs performed better.52 Retrospective analysis of Holter data from this trial showed that TS ≤3.0 ms/ RR (instead of 2.5 ms) yielded optimal results for risk stratification in ischemic heart failure patients. In this cohort of 481 postinfarction patients with heart failure and left ventricular dysfunction, of whom 55 died mostly from cardiovascular causes, abnormal HRT was found as an independent predictor of cardiovascular death with HRT2

indicating 3.64 higher risk. Similar to previous studies when the two HRT descriptors were analyzed only abnormal TS was related to unfavorable outcome. The role of autonomic markers in predicting mortality of heart failure patients was recently confirmed by the Italian group investigating the usefulness of autonomic nervous tone markers in a similar contemporary cohort of CHF patients from the GISSI-HF trial (The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico Heart Failure).53 Data from the GISSI-HF Holter substudy based on recordings performed at enrollment in 390 sinus rhythm patients with CHF of any cause and any LVEF (50% ischemic patients, mean LVEF33%, NYHA class II–IV) was used to calculate several HRV parameters both traditional as well as nonlinear, HRT and deceleration capacity. Multivariate analysis showed that the standard deviation of the normal-to-normal RR intervals (SDNN), spectral and nonlinear HRV parameters, and TS were independent risk predictors for cardiovascular death, while only very low and low frequency power HRV indices and TS were associated with arrhythmic events defined as sudden death or appropriate discharge by an implantable cardioverter defibrillator (ICD). It is worth mentioning, that in postinfarction patients abnormal HRT could be considered as an early marker of heart failure risk and used to identify patients with no previous history of heart failure who are prone to develop heart failure during a follow up. Perkiomaki et al.56 showed in a large cohort of 569 patients that the presence of abnormal autonomic tone, expressed as decreased HRV, BRS, abnormal HRT, and elevated BNP levels, was significantly associated with subsequent hospitalizations due to heart failure during an 8 years follow up. The prognostic value remained significant after adjustment for significant clinical covariates such as LVEF, medications use, and diabetes.

Risk stratification in patients with LVEF > 30% HRT seems to be particularly useful in identifying high-risk patients with preserved left ventricular function, the group not covered by current indications for implantable cardioverter defibrillators. ISAR-HRT was the first study that showed independent role of HRT in predicting mortality not only in patients with significantly decreased LVEF but especially in those with LVEF above 30%.30 FINGER study showed that TS ≤2.5 ms/RR was of special value in a subgroup of patients with relatively preserved LVEF (>35%) associated with nearly 5-fold higher risk for sudden death.31 The risk of sudden cardiac death in patients with LVEF >35% and abnormal TS was higher that of patients with low LVEF. The ISAR-Risk study demonstrated that the presence of severe autonomic failure, composed of HRT2 and abnormal deceleration capacity, was able to identify a subset of postinfarction patients with LVEF > 30% with a mortality risk comparable to a high risk group of patients with significantly depressed LVEF.57 The 5 year mortality rate in patients with severe autonomic failure was 38.6% as compared to 6.1% in those without autonomic dysfunction (p < 0.001) with similar patterns observed for cardiac and sudden deaths.57 These findings were further confirmed by a retrospective analysis of

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4 trials (ISAR-Risk, St George Hospital Medical School Postinfarction Survey, placebo arm of EMIAT trial, and MRFAT).58 Similar patterns are observed in CHF patients. In GISSI-HF patients with LVEF > 30%, abnormal TS (≤2.5 ms/RR) was associated with nearly 4-fold higher risk of arrhythmic events.53 In the MUSIC study abnormal TS was the strongest risk predictor of all-cause mortality followed by abnormal QT dynamicity and decreased SDNN in a subgroup of CHF patients with LVEF > 35%. Similar to other studies patients with relatively preserved LVEF but abnormal TS had mortality rate similar to those with LVEF <35% (Fig 3).59

Heart rate turbulence as a part of risk scores Whether combined use of HRT with other parameters could enhance its positive predictive value was tested in several studies. Early papers showed that HRT has independent prognostic value, but its significance can be enhanced by combination with a structural parameter (LVEF). In the ISAR Risk study the combination of HRT2 with LVEF increased the positive predictive value up to 40%.30 ATRAMI data indicated that a composite index of abnormal TO, TS, SDNN, and BRS identified patients nearly 9 times more likely (HR = 8.67) to have a cardiac arrest than those with all autonomic markers normal.8 A combined approach of abnormal autonomic tone reflected as decreased deceleration capacity and abnormal autonomic reflexes defined as HRT2 led to construction of a new risk score named severe autonomic failure.57,58 Based on a classical Coumel risk triangle it is plausible that optimal risk stratification could be obtained by combining HRT with measures of abnormal repolarization reflected as increased TWA. This approach was tested in REFINE study as well as in other postinfarction cohorts.32,38,42 Exner et al.32 showed that patients with both abnormal HRT and TWA had a 4-fold higher risk of reaching a primary endpoint which was higher than based on HRT or TWA alone. Further combination of noninvasive ECG parameters with low LVEF provided the highest accuracy in detecting a high risk group. The combined use of HRT and nonsustained VT also increased prognostic

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value of HRT in predicting sudden death or sustained ventricular arrhythmias in patients with left ventricular dysfunction.43 In patients with relatively preserved LVEF from the MUSIC study, a combination of abnormal HRT, decreased HRV and impaired repolarization dynamics provided the highest accuracy in identifying high risk group for all-cause mortality and sudden death among patients with heart failure and LVEF > 35%. 59 A similar pattern was found in CHF patients. In GISSI-HF study optimal risk stratification was achieved when abnormal TS was combined with abnormal creatinine values. 53 Low risk patients with creatinine levels ≤ 1.2 m and preserved TS had 3% rate of arrhythmic events as compared to 17% in patients with higher creatinine levels and abnormal TS. This observation is in line with several previous studies that underscored the role of renal insufficiency in unfavorable outcomes and that found autonomic markers to be of special use in patients with relatively preserved LVEF. 31,59,60

Modification of HRT by therapeutic strategies HRT parameters are known to be modified by several noninvasive and invasive therapeutic strategies61–68 (Table 3). Therefore, monitoring of HRT parameters may reflect changes in autonomic nervous tone induced by pharmacotherapy, revascularization, or cardiac resynchronization therapy (CRT). Revascularization procedures and pharmacotherapy were documented to modify HRT reaction in coronary patients.62–64 Percutaneous coronary intervention during an acute myocardial infarction resulted in restoration of HRT parameters assessed within 12 hours after the procedure compared with pre-procedure values, but only in TIMI 3 and not in TIMI 2 flow patients suggesting that attenuated microcirculation might be responsible for this finding.62 Significant changes in HRT parameters have been observed following myocardial infarction and are attributed to positive mechanical and autonomic remodeling,.36,37 On the other hand, HRT is unlikely to provide reliable information on risk stratification while assessed within the first 12 months after coronary bypass surgery. Impairment of autonomic nervous fibers in the course of aorta clamping in patients undergoing coronary by-pass surgery is the most probable cause of postoperative deterioration of HRT parameters despite successful revascularization.63

Table 3 – Interventions known to modify heart rate turbulence.

Fig 3 – Prognostic significance of turbulence slope in heart failure patients with EF > 35% enrolled in MUSIC study. Reprinted from Cygankiewicz et al.59 with permission from Elsevier.

Drugs Atropine56 Beta blockers59 ACE inhibitors60 Angiotensin receptor blockers61 Percutaneous coronary intervention57 Coronary artery bypass grafting58 Cardiac resynchronization therapy62 Baroreceptor stimulation in patients with hypertension63

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Both pharmacotherapy as well as CRT are known to modify HRT parameters in CHF patients.64–67 In a small clinical study abnormal HRT parameters were restored following 3 months of beta-blocker therapy. The evolution of TS was accompanied by parallel changes in HRV parameters reflecting parasympathetic tone.65 CRT has become the gold standard method of invasive treatment in CHF patients on optimal pharmacotherapy, and currently it is indicated not only in severe CHF but also in earlier stages as a method of prevention of unfavorable remodeling. Sredniawa and coworkers67 documented that in a group of 58 CHF patients who underwent CRT implantation, TO decreased and TS increased after 6 months of therapy (TS from 2.0 to 3.9, p < 0.05) which resulted in significantly lower percentage of patients with abnormal HRT. Furthermore such increase was observed in responders, while no changes were observed in patients who failed to respond to CRT. In patients with drug-resistant hypertension enrolled in the Device Based Therapy in Hypertension trial (DEBuT-HT Trial) chronic electric stimulation of carotic baroreceptors was found to modulate autonomic tone as expressed by changes in HRV and HRT. Apart from device-related decrease in blood pressure, parallel decrease in mean heart rate and changes in HRV and HRT were observed. Three months treatment with chronic baroreceptors stimulation resulted in significant improvement of HRV/HRT parameters which were consistent with a decrease in sympathetic and increase in vagal tone activity.68

Heart rate turbulence as a risk marker for atrial fibrillation Another intriguing application of HRT, apart from the risk stratification for ventricular life-threatening arrhythmias, emerged from the CARISMA study. This study showed, that abnormal TS was associated with an increased risk of newonset atrial fibrillation as documented by implantable loop recorders.69 Similarly to mortality risk stratification, the approach based on a combined assessment yielded the best results. The combination of age > 60 years old, low values of low frequency power, TS, and detrended fluctuation index were included in a risk score. Patients with the highest values of this score (3–4 points) had 7-fold higher risk of new onset occurrence during a 2-year follow up. The prognostic value of Holter-derived parameters was independent of wellestablished clinical covariates such as age, left atrial diameter, or pulmonary disease. Similar data were presented by Rademacher et al.70 who confirmed in a group of 45 patients that an early occurrence of atrial fibrillation after cardioversion can be predicted by a multivariate model composed of TO, deceleration capacity, spectral and nonlinear HRV indices reflecting autonomic nervous tone.

Future directions Despite large amount of data on HRT as a risk marker of sudden death, current guidelines indicate HRT as class II b in

risk stratification.71 The major limitation is the lack of prospective randomized studies showing a significant role for HRT in categorizing patients for ICD implantation.72 In the light of the current guidelines it is unlikely that testing such an approach in patients with severely depressed LVEF will take place. Therefore, attempts are being made to expand the role of HRT as a risk stratifier in patients with preserved LVEF. Based on the results from previously published clinical studies it appears that HRT might have greater value as a risk marker of sudden cardiac death in patients with ejection fraction above 35%.31,53,59 Therefore, we are looking forward to the results of the ongoing clinical trials that are to test this hypothesis. The REFINE ICD (Risk Estimation Following Infarction Noninvasive Evaluation – ICD Efficacy) is designed to assess whether prophylactic ICD therapy, guided by noninvasive risk assessment tools, reduces mortality in MI survivors with better-preserved LV function (http:// clinicaltrials.gov/ct2/show/NCT00673842). The other trial, EUTrigTreat, will explore the role of noninvasive risk markers and genetics in delineating the mechanisms of sudden cardiac death. This study is designed as a prospective multicenter observational study conducted in patients with ICD indications who will undergo not only noninvasive ECG stratification including plethora of Holter-derived markers as TWA, T wave morphology, arrhythmias, HRV and HRT.73 In summary, abnormal HRT as a risk stratifier combines three parameters contributing to an increased risk of sudden death: ventricular ectopy, impaired baroreflex sensitivity, and decreased short-term heart rate dynamics. Further combination of risk predictors reflecting different mechanisms participating in the chain of events leading to sudden death may increase the positive predictive value and lead to more accurate identification of high-risk patients. It seems that in order to enhance its predictive value HRT should be evaluated in combination with other markers. Most likely, such multiparameter stratification should be based on a combined assessment including HRT with preferably one structural markers, and other stratifiers reflecting electrical instability such as repolarization markers or the presence of arrhythmia.

Statement of Conflict of Interest The author declares that there are no conflicts of interest.

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