Impaired Heart Rate Recovery and Chronotropic Incompetence in Patients With Heart Failure With Preserved Ejection FractionCLINICAL PERSPECTIVE
Background— This study assessed the chronotropic response to exercise and heart rate (HR) recovery after exercise in a carefully phenotyped group of patients with heart failure with preserved left ventricular ejection fraction (HfpEF) and a control group of similar age and gender distribution.
Methods and Results— We studied 41 patients with HfpEF, 41 healthy controls, and 16 hypertensive controls. None were taking HR-limiting medications. All study participants had clinical examination, 12-lead ECG, pulmonary function test, echocardiogram, and metabolic exercise test with HR monitoring throughout exercise. Chronotropic response was measured by the percentage of the HR reserve used during maximal exercise and the peak exercise HR as a percentage of predicted maximal HR. Patients with HfpEF were generally women (70%), overweight, aged 69±8 years. Controls were of similar gender (63%) and age (67±6 years). Patients with HfpEF had significantly reduced peak VO2 compared with controls (20±4 mL · kg−1 · min−1 versus 31±6 mL · kg−1 · min−1, P<0.001) and greater minute ventilation-carbon dioxide production relationship (Ve/Vco2 slope) (33±6 versus 29±4, P<0.001). Chronotropic incompetence was significantly more common in patients with HfpEF compared with matched healthy controls as measured by the percentage of the HR reserve used during maximal exercise (63% versus 2%, <0.001) and percentage of predicted maximal HR (34% versus 2%, <0.001). In addition, abnormal HR recovery 1-minute after exercise (defined as the reduction in the HR from peak exercise 1-minute after exercise) was also significantly more common in patients with HfpEF compared with controls (23% versus 2%, P=0.01). Hypertensive controls showed similar chronotropic response to peak exercise and HR recovery after exercise as healthy controls.
Conclusions— Patients with HfpEF have impaired chronotropic incompetence during maximal exercise and abnormal HR recovery after exercise.
- heart rate recovery
- chronotropic response
- heart failure with preserved ejection fraction
- metabolic exercise testing
Received May 5, 2009; accepted August 21, 2009.
Approximately 50% of patients with the clinical features of heart failure are found to have normal left ventricular ejection fraction (LVEF) and normal valvular function. The term heart failure with preserved LVEF (HfpEF) is applied to these patients.1 They are typically elderly women who frequently have associated hypertension, diabetes, and/or coronary artery disease.2 They have similar hospital length of stay, admission rates,3,4 and mortality rate to that of patients with systolic heart failure.3 The prevalence of HfpEF seems to be increasing, and in contrast to systolic heart failure the mortality rate of this disorder is not declining.4
Clinical Perspective on p 29
The pathophysiology of HfpEF has been a matter of considerable controversy. Impaired left ventricular relaxation, increased passive left ventricular stiffness, and contractile dysfunction (despite the presence of a normal LVEF), each seem to contribute to exercise limitation. However, one recent study in HfpEF reported an association between an impaired heart rate (HR) response to exercise and an exercise limitation.1 However, there are a number of important caveats. First, the patients were mainly African Americans with hypertension, and the relevance to HfpEF in a white population is unknown. Second, the patient numbers were relatively small. Third, many of the patients (and the hypertensive controls without breathlessness) were taking β-blockers. Although these were discontinued 24 hours before the study, the potential of either ongoing β-blockade (chronotropic incompetence5) or of rebound effects6 to have influenced the findings cannot be excluded. Thus, in this study, we aimed to assess HR response to exercise and during recovery in a larger group of patients with HfpEF who were not taking β-blockers using maximal symptom limited erect treadmill metabolic exercise testing.
Patients With HfpEF
We studied 41 patients with HfpEF prospectively and consecutively recruited from heart failure clinics. All study participants had clinical examination, 12-lead ECG, pulmonary function test, echocardiogram, and metabolic exercise test. All patients met the criteria of Yturralde and Gaasch7 for the diagnosis of diastolic heart failure. They had (1) signs and/or symptoms of heart failure; (2) objective evidence of exercise limitation on cardiopulmonary exercise testing (peak Vo <80% of predicted) with a pattern of gas exchange, indicating a cardiac cause for limitation exercise capacity; (3) normal LVEF and chamber size; and (4) LV hypertrophy and/or evidence of diastolic dysfunction on echocardiographic Doppler. Patients with severe pulmonary disease, significant valvular heart disease, atrial fibrillation, or evidence of hypertrophic cardiomyopathy were excluded similar to previous studies.1 Patients with HfpEF on β-blockers or nondihydropyridines calcium blockers (eg, verapamil and diltiazem) were also excluded to accurately assess chronotropic response and HR recovery. The investigations were performed at the University of Birmingham with the approval of the Research Ethics Committee. Informed consent was obtained from all subjects.
We studied 41 healthy controls with similar age and gender as our HfpEF population. They were volunteers recruited prospectively from the community with no cardiac history, hypertension, or diabetes mellitus. In addition, 16 newly diagnosed hypertensive controls from the community were studied to explore the possibility of hypertension per se as a cause of cardiac autonomic dysfunction. The majority of these hypertensive controls were studied before the commencement of any antihypertensive therapy. None was taking HR-lowering medication. All control subjects had a normal clinical cardiovascular examination, 12-lead ECG, echocardiogram, and metabolic exercise test.
Metabolic Exercise Testing
The metabolic exercise testing was performed on a Schiller CS-200 Ergo-Spiro exercise machine, which was calibrated before every study. Subjects underwent spirometry, and this was followed by symptom-limited erect treadmill exercise testing using incremental ramp protocol (speed and inclination was increased every minute) as described previously by our group8 with simultaneous respiratory gas analysis.9,10 Samplings of expired gases were performed continuously, and data were expressed as 30-second means. The minute ventilation-carbon dioxide production relationship (Ve/Vco2 slope), maximal oxygen consumption, carbon dioxide production, and respiratory exchange ratio was used to verify objective effort adequacy. Peak oxygen consumption (peak VO2) was defined as the average values of VO2 measured during the last 30 seconds of exercise. Blood pressure and ECG were monitored throughout. Subjects were encouraged to exercise to exhaustion with a minimal requirement of respiratory exchange ratio ≥1.
Chronotropic incompetence is defined as an inadequate HR response to exercise. Two methods were used to assess chronotropic response. The first was percentage of the HR reserve used during peak exercise, which was determined as the change in HR from rest to peak exercise as a percentage of HR reserve (the difference between the predicted maximal HR and the resting HR [%HHR]). A failure to use 80% of the HR reserve was considered to be evidence of chronotropic incompetence,11 which is an independent predictor of mortality.12 The second method was to calculate the peak exercise HR as a percentage of predicted maximal HR (%Max-PPHR). In this case, chronotropic incompetence was defined as a peak exercise HR <80% of the maximum age-predicted peak HR.13 HR recovery after exercise was defined as the reduction in the HR from the HR at peak exercise to the HR at 1 minute after the cessation of exercise. Abnormal HR recovery was defined as a reduction of ≤12 bpm in the first minute of exercise.14 Predicted maximal HR for an individual was calculated using the more recently determined formula of Tanaka et al15 (208−0.7×age in years).
Echocardiography was performed with participants in the left lateral decubitus position with a Vivid 7 echocardiographic machine and a 2.5-MHz transducer. Resting scans were acquired in standard apical 4-chamber and apical 2-chamber views. All echocardiographic measurements were averaged from 3 heart beats. LVEF was calculated from LV volumes (LV end-diastolic volume and LV end-systolic volume) by the modified biplane Simpson rule in accordance with the guidelines.16 From the LV-inflow pattern (measured at the tips of the mitral valve), peak early (E) and late (A) filling velocities, E/A ratio, and E-velocity deceleration time were measured.
Continuous variables are expressed as mean±SD. Variances of data sets were determined using Levene test. Comparisons were performed with 1-way ANOVA on all 3 groups. All presented continuous data in the Results section were normally distributed and meets the assumptions of ANOVA. Post hoc test were performed on ANOVA to examine individual mean differences (Tukey test). Categorical variables were compared using the χ2 test. Pearson correlation coefficient (r) was used to describe the relationship between variables. A 2-tailed P value of <0.05 was considered statistically significant. SPSS (version 15.0) was used to perform the statistical analyses.
Characteristics of Patients
Patients with HfpEF were generally women (70%), overweight, aged 69±8-years old with a history of hypertension. Healthy controls were of similar gender (63% women) and age (67±6 years; Table 1). Patients with HfpEF had significantly reduced peak VO2 compared with healthy controls (20±4 mL · kg−1 · min−1 versus 31±6 mL · kg−1 · min−1, P<0.001). The minute ventilation-carbon dioxide production relationship (Ve/Vco2 slope) was also higher in patients with HfpEF than healthy controls (33±6 versus 29±4, P<0.001; Table 2).
Chronotropic Response to Maximal Exercise Testing
Patients with HfpEF versus matched healthy controls had similar resting HR and predicted maximal HR, 78±14 versus 79±13 (P=0.99) and 160±6 versus 161±4 (P=0.53), respectively. Patients with HfpEF had lower peak HR response and lower change in HR (the difference between peak HR and resting HR) during peak exercise compared with matched healthy controls, 139±22 versus 171±18 (P<0.001) and 60±22 versus 93±21 (P<0.001), respectively (Figure 1). Chronotropic incompetence was significantly more common in patients with HfpEF compared with matched healthy controls as measured by the percentage of the HR reserve used during peak exercise and percentage of predicted maximal HR. In addition, abnormal HR recovery 1-minute after exercise was also significantly more common in patients with HfpEF compared with matched healthy controls (Table 3 and Figure 2). Peak oxygen consumption (peak VO2) correlated directly with peak exercise HR (r=0.57, P<0.001; Figure 3). Chronotropic incompetence and impaired heart recovery remained highly significant in patients with HfpEF when compared with hypertensive controls. There were no significant differences between hypertensive controls and healthy controls with respect to chronotropic response during peak exercise and HR recovery after exercise.
The principal findings of this study are (1) patients with HfpEF had similar resting and predicted maximal HR compared with matched healthy controls, but during peak dynamic exercise, patients with HfpEF displayed significant chronotropic incompetence. (2) Abnormal HR recovery 1-minute after exercise was more common in patients with HfpEF compared with matched healthy controls. (3) Hypertensive controls showed similar chronotropic response to peak exercise and HR recovery after exercise as healthy controls.
Chronic heart failure (CHF) is characterized by impaired exercise tolerance often because of breathlessness and fatigue. Metabolic exercise testing is an objective tool to measure exercise limitation in patients with CHF as indicated by reduced maximal oxygen consumption (peak VO2) and an increase in the ventilatory response to exercise (the relation of ventilation [Ve] to carbon dioxide production [Vco2] or Ve/Vco2 slope).17 In this study, we found that patients with HfpEF have reduced peak VO2 and higher Ve/Vco2 slope compared with older controls, which are supported by previous reports.18 Indeed, Ve/Vco2 slope has been shown to have prognostic value in patients with diastolic heart failure with respect to both mortality and hospitalization.19
In healthy subjects, the initial increase in HR during exercise results from a withdrawal of the physiological vagal tone present at rest and sympathetic tone is responsible for further increases in HR as exercise continues.20 After exercise sympathetic withdrawal contributes to early HR recovery and at a later stage parasympathetic reactivation plays a larger role in HR recovery.21
In CHF associated with LV systolic dysfunction, there is impaired autonomic function22 as a result of an impaired vagal tone23 and an overactivity of sympathetic function, which results in reduced responsiveness to β adrenergic stimulation because of both reduced adrenoreceptor number and reduced downstream signaling.24 The clinical sequalae of these autonomic changes include an impaired HR response to exercise (chronotropic incompetence), which may contribute to exercise limitation.25,26 Indeed, studies have shown that as the severity of systolic heart failure worsens the more common chronotropic incompetence during exercise becomes in patients with CHF.27 Nevertheless, even in asymptomatic patients with reduced LVEF and LV dilatation poor HR response has been reported.28 An impaired HR recovery after exercise is also common in patients with systolic heart failure29 and seems to be primarily due to low vagal tone.23 Impaired HR recovery after exercise also seems to be not only a powerful predictor of mortality in patients with systolic heart failure but also predicts cardiovascular mortality in apparently healthy subjects.14
In this study, we found patients with HfpEF had lower peak HR response during maximal exercise than controls, which is important because peak HR response is associated with coronary disease and cardiovascular mortality. Furthermore, we found that 34% of patients with HfpEF have chronotropic incompetence during maximal exercise when defined by percentage of predicted maximal HR and 63% when defined by the percentage of the HR reserve used during peak exercise. These proportions are quite similar to findings in patients with CHF due to systolic dysfunction.30 HR recovery was also found to be impaired in a significant proportion of patients with HfpEF, which suggest the presence of parasympathetic imbalance.
Borlaug et al1 showed in patients with hypertension (mainly African Americans) that chronotropic incompetence was a powerful predictor of the presence of symptoms of heart failure. However, this relationship between chronotropic incompetence and HfpEF may or may not be causal. Chronotropic incompetence in HfpEF may be an adaptation to improve diastolic filling, because increasing HR by atrial pacing has been shown to reduce supine resting stroke volume and cardiac output in patients with HfpEF.31 It will be important to undertake further studies to assess whether HR plays a causal role in exercise limitation in HfpEF, because if so, this may be amenable to rate responsive pacing.
The precise mechanism of impaired autonomic dysfunction in HfpEF is unclear, some have proposed a peripheral factor responsible rather than central.1 Studies in CHF have revealed a blunted baroreflex control could play an important role32 secondary to reduced arterial compliance,33 impaired central reflex integration, and a decrease in end-organ responsiveness.32 Increased sensitivity of muscle ergoreceptors and peripheral chemoreceptors has also been linked to autonomic impairment in CHF.25,34 A review on this topic has been discussed by our group elsewhere.22
Ideally, we would have liked to have recruited a control group of obese normotensive subjects for comparison with our HfpEF population; however, this in practice might be difficult given that these obese normotensive subjects would also have to have no cardiac history, hypertension, or diabetes mellitus. We have performed multiple statistical tests to examine individual mean differences; however, our findings are highly significant and are consistent with previous reports.
Patients with HfpEF have chronotropic incompetence during maximal exercise and abnormal HR recovery after exercise.
Sources of Funding
This work was supported by the British Heart Foundation.
Professor M. Frenneaux received Honoraria from Metronic, St Jude and Biotronik; is a Consultant/Advisory Board for Metronic, St Jude, Menarini and Biotronik; and is a Speaker on panel for Menarini.
- ↵Borlaug BA, Melenovsky V, Russell SD, Kessler K, Pacak K, Becker LC, Kass DA. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation. 2006; 114: 2138–2147.
- ↵Klapholz M, Maurer M, Lowe AM, Messineo F, Meisner JS, Mitchell J, Kalman J, Phillips RA, Steingart R, Brown EJ Jr, Berkowitz R, Moskowitz R, Soni A, Mancini D, Bijou R, Sehhat K, Varshneya N, Kukin M, Katz SD, Sleeper LA, Le Jemtel TH; New York Heart Failure Consortium. Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction: results of the New York heart failure registry. J Am Coll Cardiol. 2004; 43: 1432–1438.
- ↵Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Williams L, Ashrafian H, Horowitz J, Fraser AG, Clarke K, Frenneaux M. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation. 2005; 112: 3280–3288.
- ↵Katritsis D, Camm AJ. Chronotropic incompetence: a proposal for definition and diagnosis. Br Heart J. 1993; 70: 400.
- ↵Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005; 18: 1440–1463.
- ↵Witte KKA, Nikitin NP, Cleland JGF, Clark AL. Excessive breathlessness in patients with diastolic heart failure. Heart. 2006; 92: 1425–1429.
- ↵Janicki JS, Sheriff DD, Robotham JL, Wise RA. Cardiac output during exercise: contributions of the cardiac, circulatory, and respiratory systems. In: Handbook of Physiology Exercise: Regulation and Integration of Multiple Systems. Bethesda, MD: American Physiological Society; 1996: 649–704.
- ↵Savin WM, Davidson DM, Haskell WL. Autonomic contribution to heart rate recovery from exercise in humans. J Appl Physiol. 1982; 53: 1572–1575.
- ↵Frenneaux MP. Autonomic changes in patients with heart failure and in post-myocardial infarction patients. BMJ. 2004; 90: 1248–1255.
- ↵Ungerer M, Bohm M, Elce JS, Erdmann E, Lohse MJ. Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. Circulation. 1993; 87: 454–463.
- ↵Piepoli M, Clark AL, Volterrani M, Adamopoulos S, Sleight P, Coats AJS. Contribution of muscle afferents to the hemodynamic, autonomic, and ventilatory responses to exercise in patients with chronic heart failure effects of physical training. Circulation. 1996; 93: 940–952.
- ↵Colucci WS, Ribeiro JP, Rocco MB, Quigg RJ, Creager MA, Marsh JD, Gauthier DF, Hartley LH. Impaired chronotropic response to exercise in patients with congestive heart failure. Role of postsynaptic beta-adrenergic desensitization. Circulation. 1989; 80: 314–323.
- ↵Witte KKA, Cleland JGF, Clark AL. Chronic heart failure, chronotropic incompetence, and the effects of blockade. Heart. 2006; 92: 481–486.
- ↵Westermann D, Kasner M, Steendijk P, Spillmann F, Riad A, Weitmann K, Hoffmann W, Poller W, Pauschinger M, Schultheiss HP, Tschope C. Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation. 2008; 117: 2051–2060.
- ↵Kingwell BA, Cameron JD, Gillies KJ, Jennings GL, Dart AM. Arterial compliance may influence baroreflex function in athletes and hypertensives. Am J Physiol. 1995; 268: 411–418.
- ↵Ponikowski P, Chua TP, Piepoli M, Ondusova D, Webb-Peploe K, Harrington D, Anker SD, Volterrani M, Colombo R, Mazzuero G. Augmented peripheral chemosensitivity as a potential input to baroreflex impairment and autonomic imbalance in chronic heart failure. Circulation. 1997; 96: 2586–2594.
In this study, we have demonstrated that patients with heart failure with preserved left ventricular ejection fraction exhibit chronotropic incompetence during peak exercise and abnormal heart rate recovery after exercise. The latter indicates that these patients have impaired cardiac vagal tone. Chronotropic incompetence may be an overlooked cause of exercise intolerance in this group of patients. Furthermore, an abnormal heart rate recovery is an important prognostic marker. The potential clinical impact of our findings is that it raises the questions of whether the uses of rate-limiting therapy such as β-blockers, nondihydropyridines calcium blockers are appropriate in this group of patients. In addition, it raises the possibility of applying heart rate responsive pacing in this group of patients to improve exercise tolerance and quality of-life.