Sudden death can be prevented by prophylactic implantation of cardioverter-defibrillators (ICDs) in high-risk patients1 and/or by optimal pharmacotherapy of heart failure (HF), including beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and aldosterone antagonists.2,3 Heart rate turbulence (HRT)4 is an electrocardiogram-based autonomic marker that might help 1) to select high-risk patients after myocardial infarction (MI) who might benefit from prophylactic ICD implantation; and (2) to guide pharmacotherapy of HF. The present article reviews the physiological background of HRT, reports on pharmacologic effects on HRT, describes the clinical evidence of HRT as a risk predictor after MI, discusses the rationale and evidence for using HRT as a treatment target in patients with HF, mentions the limitations of the method, and provides an overview of ongoing and planned HRT studies.
Phenomenon of Heart Rate Turbulence: Methodology, Physiological Mechanisms, and Pharmacologic Effects
The term HRT describes the physiological short-term oscillation of beat-to-beat (RR) intervals after spontaneous ventricular premature complexes (VPCs).4 In normal subjects, the response to a VPC is biphasic, namely, an initial heart rate acceleration (RR shortening) followed by a gradual heart rate deceleration (RR prolongation) before returning to baseline (Fig. 1). Because postextrasystolic patterns of RR intervals are in the range of milliseconds and are overlaid by heart rate variability of other origin, HRT is typically assessed as the average response of RR intervals to VPCs recorded over longer periods (for example, 24 hours).5 The so-called “local averaged VPC tachogram” is constructed by aligning and averaging RR interval sequences surrounding isolated VPCs (Fig. 1). These sequences include at least two sinus RR intervals preceding the VPC coupling interval and 15 sinus RR intervals after the compensatory pause. Only VPCs fulfilling certain criteria with respect to prematurity and compensatory pause are included for HRT calculation.5
The two phases of HRT are quantified by two numeric descriptors, turbulence onset (TO) and slope (TS).
TO is calculated as:
where RR−2 and RR−1 are the two RR intervals immediately preceding the VPC coupling interval, and RR1 and RR2 are two RR intervals immediately after the compensatory pause (Fig. 1). TS is defined as the maximum positive regression slope assessed over any five consecutive sinus rhythm RR intervals within the first 15 sinus rhythm RR intervals after the VPC (Fig. 1). Hence, in normal subjects, the initial brief acceleration of sinus rate after the VPC is characterized by negative TO, whereas the subsequent rate deceleration is characterized by positive TS.
For risk stratification, HRT values are usually classified into three categories: HRT Category 0: both TO and TS are normal (TO <0% and TS >2.5 ms/RR interval); HRT Category 1: either TO or TS is abnormal; and HRT Category 2: both TO and TS are abnormal. If HRT cannot be calculated because no or too few suitable VPC tachograms are found in the recording, HRT is classified as Category 0.6
Physiological mechanisms of HRT have been extensively reviewed.5 The VPC leads to a transient fall in systolic and diastolic arterial blood pressure, which is caused by several factors, including incomplete electrical restitution, short period of diastolic filling, missing atrial kick, reduced contractility, higher afterload at the time of VPC, and less synchronized ventricular contraction.7 The fall in systolic arterial blood pressure activates the baroreceptors of the carotid arteries and the aortic arch to trigger both vagal withdrawal and sympathetic nerve activation.
Vagal withdrawal directly effects sinus node depolarization frequency. As a result of the short latency of vagus nerve activity, heart rate acceleration (as measured by TO) occurs very early. In normal subjects, the first sinus RR interval after the compensatory pause is shortened.
Postextrasystolic sympathetic nerve activation occurs not earlier than at the time of the first postextrasystolic beat.8-12 Because the latency of hemodynamic response to sympathetic nerve stimulation is approximately 5 seconds,13 sympathetic chronotropic effects on heart rate acceleration are very unlikely. However, postextrasystolic sympathetic activation provokes noradrenaline release in perivascular sympathetic nerve endings, leading to a gradual increase in peripheral vascular resistance. With increasing systolic arterial blood pressure, vagus nerve activity recovers and heart rate gradually decelerates as measured by TS. Under physiological conditions, even a significant overshoot of systolic arterial blood pressure and RR prolongation over the baseline values can be observed.14,15
The biphasic HRT pattern is fully compatible with baroreflex physiology.7,16-20 However, it is important to note that the normal HRT pattern requires an intact interplay of both vagus and sympathetic nerve activity (Fig. 2).
In patients with structural heart disease or reduced left ventricular performance, additional, nonautonomic mechanisms contribute to attenuated HRT. In a significant number of patients with poor left ventricular performance, prominent postextrasystolic potentiation and mechanical alternans can be observed,16,21 which may indirectly contribute to blunted HRT. Moreover, in patients with elevated baseline sympathetic nerve activity, the surge in sympathetic nerve activity resulting from the VPC might be relatively minor and therefore might not elicit comparable increases in vascular resistance.
Other putative, nonautonomic mechanisms of HRT, including mechanical stretch of sinus nodal tissue22,23 or perfusion pressure reduction of the sinus nodal artery,24 have been suggested but probably play a minor role.
Pharmacologic effects on HRT are closely related to its physiology. However, in this context, it is important to differentiate between acute and chronic effects as well as between effects in health and disease.
Marine et al were the first to show that both phases of HRT can be completely abolished by intravenous administration of 1 mg atropine.25 In this study, HRT was induced through paced VPCs from the right ventricular apex in 12 patients undergoing electrophysiological testing. Later, these findings have been confirmed by two other studies analyzing spontaneous HRT.17,26 Correspondingly, augmentation of vagal tone by pirenzepine has positive effects on HRT.26 In contrast to acute blockade or stimulation of the vagal system, acute beta-adrenergic blockade by intravenous application of esmolol has no significant effects on HRT.17
Bonnemeier et al assessed the additional effects of alpha-1 adrenoreceptor blockade to beta-adrenergic blockade on HRT in the setting of acute MI.27 In this randomized study, patients receiving metroprolol had higher TS values compared with patients receiving carvedilol. This finding might be explained by attenuation of the postextrasystolic increase of arterial blood pressure by alpha-blockade.
Studies investigating chronic drug effects on HRT are limited to patients with cardiac diseases. Lin et al reported restoration of initially abnormal HRT by titrated addition of atenolol in 10 patients with chronic HF over a time course of 3 months.28 Similar observations have been made for ACE inhibitors29 and angiotensin receptor blockers.29,30 Chronic effects of HF drugs are believed to reflect better clinical status, which in turn leads to improvement of cardiac autonomic function. Potential use of HRT as a treatment guide for HF is discussed subsequently.
Knowledge about other drug effects on HRT is limited. In a small observational nonrandomized study by Cygankiewicz et al including 122 patients with coronary artery disease, statins and nitrates were associated with higher TS. In contrast, calcium antagonists were associated with lower TS.31 Effects of antiarrhythmic drugs on HRT are unknown and need further investigation.
Heart Rate Turbulence as a Risk Predictor After Myocardial Infarction
Abnormal HRT is associated with increased risk of mortality in patients with various cardiac diseases.5 The strongest evidence of predictivity is among postinfarction patients. Retrospective analyses of six large-scale studies4,32-34 and four prospective studies6,35-37 have confirmed the strong and independent prognostic value of HRT in prediction of mortality in survivors of acute MI. The retrospective analyses included the Multicenter Post-Infarction Program (MPIP) trial,4,38 the placebo arm of the European Myocardial Infarction Amiodarone Trial (EMIAT),4,39 the Autonomic Tone and Reflexes after Acute Myocardial Infarction (ATRAMI) trial,32,40 the Cardiac Arrhythmia Suppression Trials (CAST) I and II,33,41,42 and the FINland and GERmany Post-Infarction Trial (FINGER).6,34 The prospective studies include the Innovative Stratification of Arrhythmic Risk (ISAR)-HRT study,6 the Risk Estimation Following Infarction Noninvasive Evaluation (REFINE) study,35 the ISAR-Risk study,36 and the Cardiac Arrhythmias and Risk Stratification after Acute Myocardial Infarction (CARISMA) study.37 Details of HRT postinfarction studies are shown in Table 1 and are also summarized in a recently published consensus article on HRT.5 In cumulative univariate analysis, patients with HRT Category 2 (abnormal TO and abnormal TS) had a 4.4-fold to 11.3-fold risk of subsequent death compared with patients with normal HRT. In cumulative multivariate analysis, HRT 2 was an independent predictor of mortality in all studies, yielding relative risks of 2.8 to 5.9, comparable to the risk of patients with left ventricular dysfunction.
The power of risk prediction can be significantly increased when HRT is combined with left ventricular ejection fraction (LVEF) and/or other risk predictors. The REFINE study analyzed the usefulness of a combined assessment of autonomic function and repolarization alternans to predict the outcome after MI.35 In this study, the combination of HRT Category 1 and abnormal T-wave alternans assessed at 10 to 14 weeks after MI was a strong predictor of cardiac death or resuscitated cardiac arrest, death from any cause, and fatal or nonfatal cardiac arrest. The recent ISAR-RISK study specifically focused on postinfarction patients with preserved left ventricular function (LVEF greater than 30%), a patient group that is not covered by current ICD guidelines.36 This prospective cohort study included 2343 consecutive survivors of acute MI aged 75 years or younger and tested the usefulness of the combination of HRT with another autonomic marker, deceleration capacity (DC). The rationale for combining HRT and DC was twofold; in contrast to HRT, which is related to specific autonomic reflexes, DC is an integral measure of all deceleration-related regulatory processes observed over 24 hours, thus expressing the overall status of the autonomic, predominantly vagal, balance. Previous studies had suggested that DC might be more useful in identification of low-risk patients,43 whereas the strength of HRT is the selection of high-risk patients.6 For the combined finding of HRT Category 2 and abnormal DC (4.5 ms or less), the term “severe autonomic failure” was introduced. Among 2223 ISAR-RISK patients with LVEF greater than 30% (94.9% of the total population), severe autonomic failure identified a high-risk group of 117 patients (5.0% of the total population; 5.2% of patients with LVEF greater than 30%) with a 5-year mortality rate of 38.6% (Fig. 3). The mortality rate of patients with severe autonomic failure and LVEF greater than 30% was practically comparable to that of patients with LVEF 30% or less (37.9%). Results were similar for secondary end points of cardiac mortality and sudden death.
Available data do not allow specifying the optimum time after acute MI for HRT assessment. In most studies, Holter recordings had been performed during the second week after the index infarction.4,6,32-34 In the REFINE study, however, HRT-based risk assessment at 10 to 14 weeks after MI was more effective than risk assessment early after MI.35 Also in the CARISMA study, risk assessment at 6 weeks after MI was superior to risk assessment at 1 week after MI.37 Studies assessing HRT during the chronic phase of MI (greater than 4 weeks) are needed.
The value of HRT-based risk prediction is not affected by beta-blocker therapy, regardless of whether beta-blocker medication was used infrequently (less than 20%, ATRAMI40; 32%, MPIP38), moderately (45%, EMIAT4), or frequently (greater than 90%, ISAR-HRT,6 ISAR-RISK,36 and CARISMA37) and was independent of the frequency of reperfusion therapy and of left ventricular function. This finding contrasts with most other mortality predictors after MI such as the presence of ventricular late potentials, which lost prognostic value among postinfarction patients treated according to contemporary standards of care.44
Most postinfarction HRT studies (MPIP, EMIAT, CAST, ISAR-HRT, and ISAR-RISK) used total mortality as the primary end point.4,6,33,36 ATRAMI used the composite of fatal and nonfatal cardiac arrest.32 The FINGER study was designed to assess the value of HRT in sudden cardiac death prediction.34 In CARISMA, the primary end point was ventricular fibrillation or symptomatic sustained ventricular tachycardia documented by implantable electrocardiographic loop recorders.37 Because HRT was found to be a strong end point predictor in all of these studies, its prognostic value does not seem to be exclusively associated with any specific mechanism of death, consistent with the predictive value of other autonomic markers.
Heart Rate Turbulence to Guide Treatment for Heart Failure
Evidence-based pharmacotherapy of HF includes ACE inhibitors, angiotensin receptor blockers, beta-blockers, aldosterone antagonists, and diuretics as recommended by current national and international guidelines.2,3 All of these drugs have been shown to reduce mortality and/or morbidity in patients with HF significantly. Because sudden death accounts for up to 50% of cardiac deaths in patients with HF, strategies aiming to reduce mortality in patients with HF also aim to reduce sudden death.
Implementation of trial-based pharmacotherapy in clinical practice remains unsatisfactory.4 Drugs are often underused, and high-risk patients who might benefit most are least likely to receive evidence-based therapy.45 One reason might be that titration of HF drugs is not directed by objective treatment targets. Rather, it is based on physician experience and patient symptoms and is influenced by fear of adverse reactions such as arterial hypotension or renal impairment.
A promising approach to guiding HF therapy might be to adjust therapy according to status of cardiac autonomic function. Alterations in autonomic nervous system activity, including sympathetic nerve excitation and loss of vagal reflexes, occur early and are well-known characteristics in patients with HF.46
Among available autonomic markers, HRT might play an important role in patients with HF. First, HRT has been shown to correlate with severity of disease as reflected by clinical, biochemical, and echocardiographic changes. Thus, in patients with HF, HRT is correlated not only with clinical markers including the presence of third heart sound, peripheral edemas, jugular distension, and pulmonary congestion, but also with LVEF and levels of brain natriuretic peptides.47 Second, HRT is a strong and independent predictor of outcome in patients with HF. The UK-Heart study was the first to show that abnormal HRT independently predicted heart failure decompensations.48 The Muerte Subita e Insuficiencia Cardiaca (MUSIC) study included 607 patients with New York Heart Association Class II-III, of whom 129 patients died during a follow up of 44 months. After adjustment for LVEF and other clinical covariates, HRT Category 2 indicated a 2.5-fold, 2.3-fold, and 4.1-fold risk for death, sudden death, and death, respectively, resulting from HF decompensation.49 Miwa and colleagues recently investigated the prognostic power of HRT in 375 patients with dilated cardiomyopathy. Independent from etiology of cardiomyopathy (ischemic or nonischemic), HRT Category 2 indicated a 6.4-fold risk for cardiac death.50 However, HRT is not only predictive in the chronic phase of HF, but also in HF after acute MI as shown in the Holter substudies of the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT)51 and the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).51 Finally, HRT is responsive to both pharmacologic and device-based HF therapy, that is, HRT normalizes with improvement of HF status. Lin and colleagues demonstrated that titrated beta-blocker therapy led to a significant improvement of TS.28 Similarly, HRT tracks efficacy of ACE inhibitor and angiotensin receptor blocker use.29,30 Recently, the effect of resynchronization therapy on HRT was investigated in 58 patients with HF in New York Heart Association Class III-IV.52 After 6 months of follow up, TS increased significantly in 42 responders, whereas it was unchanged in nonresponders. HRT might therefore fulfill the requirements of an endogenous feedback system suitable to guide pharmacotherapy of HF. Moreover, HRT might also be useful to monitor asymptomatic cardiac patients (eg, postinfarction patients) in the absence of clinical HF in whom HRT is of prognostic value.
In the future, HRT might also be assessed from implanted devices either by analyzing HRT after spontaneous VPCs (DECIDE-HF study, ClinicalTrials.gov number NCT00949676) or after device stimuli.53 However, further studies are needed to determine whether pharmacotherapy of HF guided by HRT will result in reduced mortality rates and/or reduced rates of HF-related hospitalizations.
Limitations of Heart Rate Turbulence
One of the most important limitations of the HRT is that the method requires the presence of sinus rhythm. Prevalence of atrial fibrillation after acute MI can be as high as 19%54 and in patients with HF much higher.55 Postinfarction patients presenting with atrial fibrillation are at increased risk for sudden and nonsudden cardiac death.54 Also in patients with HF, prevalence of atrial fibrillation is correlated with severity of disease.54
Furthermore, in most prognostic HRT studies, elderly patients (age older than 75 years) were excluded (Table 1). Therefore, conclusions drawn from these studies cannot be extrapolated to older patients. It is well known from the ATRAMI study that baroreflex sensitivity not only declines with increasing age, but also loses its predictive value.40 Similar observations were made for HRT in the ISAR-HRT study.56
HRT cannot be measured without VPCs in Holter recording. In most studies, patients without VPCs have therefore been excluded from the analysis. As shown in the ISAR-HRT study, the prognosis of postinfarction patients without VPCs is equivalent to that of patients with normal HRT.6 However, these findings should not be extrapolated to other patient groups such as patients with HF.
All studies that reported high predictive values of HRT used 24-hour recordings. Whether HRT derived from shorter recordings provides similar predictive value needs further investigation. However, a retrospective analysis of HRT in the Multicenter Automatic Defibrillator Implantation Trial 2 that used only 10-minute recordings showed the inappropriateness of very short recordings.57
Ongoing and Planned Heart Rate Turbulence Studies
Currently, there is one ongoing and three planned clinical trials investigating HRT as a predictor of HF-related decompensations, as a selection criterion for prophylactic ICD implantation, or as a treatment target for patients with HF.
The ongoing multicenter Deceleration Capacity and Heart Rate Turbulence In Decompensated Heart Failure Patients study (DECIDE-HF, ClinicalTrials.gov number NCT00949676) investigates whether DC43 and HRT predict decompensation in patients with HF. To allow for continuous autonomic monitoring, DC and HRT are calculated in 8-hour intervals from implanted devices using dedicated software algorithms. Patients are included if they are aged older than 18 years, present with sinus rhythm, are in New York Heart Association Class II or III, and have a history of previous HF-related hospitalization within the last 12 months.
The aim of the Risk Estimation Following Infarction, Noninvasive Evaluation-ICD efficacy (REFINE-ICD, ClinicalTrials.gov number NCT00673842) trial is to test whether high-risk patients greater than 8 weeks after MI identified by abnormal repolarization alternans plus impaired HRT benefit from prophylactic ICD implantation. The main inclusion criteria are recent MI (8-26 weeks), age 18 to 80 years, presence of sinus rhythm, and LVEF of 36% to 49%. In this multicenter trial, 1200 patients will be randomized. Enrollment will start within the next months.
The planned multicenter randomized Innovative Stratification of Arrhythmic Risk-ICD (ISAR-ICD) trial will test whether high-risk patients after MI with preserved left ventricular function benefit from prophylactic ICD implantation. Based on the results of the ISAR-RISK study,36 patients are identified as at high risk if they have abnormal HRT and abnormal DC (“severe autonomic failure”). Main inclusion criteria are age 80 years or younger, presence of sinus rhythm, and LVEF greater than 30%.
The planned, multicenter, randomized controlled Cardiac Autonomic Function to guide Heart Failure Therapy trial (CAF-HEFT) will test the hypothesis whether pharmacotherapy of HF guided by cardiac autonomic function is superior to symptom-guided trial-based therapy according to current guidelines. Treatment targets in the interventional group are normal TS and normal DC. If these targets are not achieved, drug therapy is intensified according to a predefined stepwise protocol in line with current American Heart Association/American College of Cardiology guidelines. In the control group, treatment is adjusted using an objective scoring system to assess clinical status. In both arms, status is assessed at baseline and every 3 months. If adjustment of therapy is indicated, status is reassessed 3 weeks thereafter. Last visit is at 18 months after enrollment. Main inclusion criteria are sinus rhythm, age 75 years or younger, LVEF 45% or less, New York Heart Association Class II or greater, and history of HF-related hospitalization within the last year.
HRT is an electrocardiographic phenomenon that allows for noninvasive evaluation of baroreflex function. Physiological mechanisms of HRT are complex and involve both sympathetic and parasympathetic nervous systems. The strong and independent prognostic value of HRT as a predictor of mortality after acute MI has been validated in several retrospective and prospective large-scale studies. For selection of high-risk individuals after MI who might benefit from prophylactic ICD implantation, HRT should be combined with other noninvasive markers, including DC or T-wave alternans. However, HRT might also be of clinical value in guiding pharmacotherapy of patients with HF. It is correlated with clinical status, predicts outcome and, importantly, reflects efficacy of therapy. Limitations of HRT as mentioned should be recognized. Finally, only future interventional studies will show whether HRT-based risk prediction translates into HRT-based risk reduction.
We thank S. S. Verrier for editorial assistance.
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