PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 6 ( 2 0 13 ) 16 0–1 71
Available online at www.sciencedirect.com
ScienceDirect www.onlinepcd.com
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
PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S 5 6 (2 0 1 3) 16 0–1 7 1
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
161
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
162
PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 6 ( 2 0 13 ) 16 0–1 71
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.
163
PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S 5 6 (2 0 1 3) 16 0–1 7 1
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
Available online at www.sciencedirect.com
ScienceDirect www.onlinepcd.com
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
PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S 5 6 (2 0 1 3) 16 0–1 7 1
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
161
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
162
PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 6 ( 2 0 13 ) 16 0–1 71
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.
163
PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S 5 6 (2 0 1 3) 16 0–1 7 1
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
