Author + information
- Received March 26, 2013
- Revision received May 22, 2013
- Accepted June 13, 2013
- Published online October 8, 2013.
- Wojciech Kosmala, MD, PhD∗,
- David J. Holland, PhD†,
- Aleksandra Rojek, MD∗,
- Leah Wright, BS‡,
- Monika Przewlocka-Kosmala, MD, PhD∗ and
- Thomas H. Marwick, MD, PhD‡∗ ()
- ∗Wroclaw Medical University, Wroclaw, Poland
- †University of Queensland, Brisbane, Australia
- ‡Menzies Research Institute Tasmania, Hobart, Australia
- ↵∗Reprint requests and correspondence:
Dr. Thomas H. Marwick, Menzies Research Institute Tasmania, 17 Liverpool Street, Hobart, T7000, Australia.
Objectives The aim of this study was to test the effects of treatment with ivabradine on exercise capacity and left ventricular filling in patients with heart failure with preserved ejection fraction (HFpEF).
Background Because symptoms of HFpEF are typically exertional, optimization of diastolic filling time by controlling heart rate may delay the onset of symptoms.
Methods Sixty-one patients with HFpEF were randomly assigned to ivabradine 5 mg twice daily (n = 30) or placebo (n = 31) for 7 days in this double-blind trial. Cardiopulmonary exercise testing with echocardiographic assessment of myocardial function and left ventricular filling were undertaken at rest and after exercise.
Results The ivabradine group demonstrated significant improvement between baseline and follow-up exercise capacity (4.2 ± 1.8 METs vs. 5.7 ± 1.9 METs, p = 0.001) and peak oxygen uptake (14.0 ± 6.1 ml/min/kg vs. 17.0 ± 3.3 ml/min/kg, p = 0.001), with simultaneous reduction in exercise-induced increase in the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity (3.1 ± 2.7 vs. 1.3 ± 2.0, p = 0.004). Work load–corrected chronotropic response (the difference in heart rate at the same exercise time at the baseline and follow-up tests) showed a slower increase in heart rate during exercise than in the placebo-treated group. Therapy with ivabradine (β = 0.34, p = 0.04) and change with treatment in exertional increase in the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity (β = −0.30, p = 0.02) were independent correlates of increase in exercise capacity, and therapy with ivabradine (β = 0.32, p = 0.007) was independently correlated with increase in peak oxygen uptake.
Conclusions In patients with HFpEF, short-term treatment with ivabradine increased exercise capacity, with a contribution from improved left ventricular filling pressure response to exercise as reflected by the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity. Because this patient population is symptomatic on exertion, therapeutic treatments targeting abnormal exercise hemodynamic status may prove useful. (Use of Exercise and Medical Therapies to Improve Cardiac Function Among Patients With Exertional Shortness of Breath Due to Lung Congestion; ACTRN12610001087044)
Patients with heart failure with preserved ejection fraction (HFpEF) are characterized by symptoms of dyspnea and exercise intolerance, both of which contribute to reduced quality of life in this population. This is a major health care problem, accounting for almost one-half of all cases of chronic cardiac insufficiency in large-scale community studies (1,2). Current therapeutic recommendations are to effectively control the comorbidities associated with HFpEF, especially hypertension, diabetes, coronary artery disease, and obesity (3). However, there is a clear need for the development of new strategies beyond the management of underlying etiologies.
The latest heart failure guidelines have extended the treatment possibilities for heart failure with reduced left ventricular (LV) ejection fraction by incorporating ivabradine, a selective sinus node inward “funny” (If) channel inhibitor reducing heart rate, devoid of negative inotropic effect, which was shown to decrease mortality and morbidity in the Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial (4,5). In the early stages of HFpEF, while the primary problem relates to impaired LV relaxation (rather than impaired LV compliance or increased filling pressure at rest), high heart rates during exercise may be particularly detrimental by reducing time for diastolic filling and promoting increased LV filling pressure and exercise intolerance. Therapeutic measures prolonging the LV filling phase may optimize transmitral flow, thereby reducing increased filling pressures and the resultant dyspnea. Although beta-adrenoceptor blockade has been trialed in HFpEF, these agents' negative inotropic effect is disadvantageous. Thus, the use of ivabradine in this group of patients with heart failure might represent a novel opportunity to control exertion-associated tachycardia without a deleterious impact on myocardial contractility. This application of ivabradine is consistent with the results of previous experimental studies that have demonstrated improvements of myocardial diastolic properties by If blockade (6–10). Accordingly, the aim of this study was to investigate the effects of treatment with ivabradine on exercise capacity and LV function, particularly the LV filling pressure response to exercise, in patients with HFpEF.
The present study was designed as a prospective, blinded, parallel-group, placebo-controlled trial evaluating the potential of 7 days of therapy with ivabradine 5 mg twice daily to improve exercise tolerance and LV function, especially LV filling, with exercise in patients with HFpEF. This report follows the recommendations of the 2010 Consolidated Standards of Reporting Trials statement (11). The study adhered to the Declaration of Helsinki and was approved by the institutional ethics committees. Informed consent was obtained from all subjects before involvement in the study.
Current guidelines endorsed by the European Society of Cardiology were used to identify patients with true HFpEF from 2 large hospital-based echocardiography laboratories (University Hospital in Wroclaw, Poland, and Princess Alexandra Hospital in Brisbane, Australia) (12). In brief, patients presenting with signs or symptoms of heart failure (i.e., dyspnea, fatigue, and exercise intolerance) with normal systolic function as determined by LV ejection fraction ≥50% and evidence of diastolic dysfunction were deemed suitable for screening. The diagnosis of LV diastolic dysfunction was established according to the recommendations of the American Society of Echocardiography and the European Association of Echocardiography (13). To enhance the specificity of the association between diastolic abnormalities and impaired functional capacity (14,15), the key criteria essential for patient enrollment were exercise capacity <80% of age-predicted and sex-predicted normal ranges and a ratio of peak early diastolic mitral flow velocity (E) to peak early diastolic mitral annular velocity (e′) >13 after exercise, reflecting an increase in LV filling pressure during exertion, both evidenced from an exercise test.
From December 2011 to December 2012, of 114 patients meeting the criteria for diastolic dysfunction, we finally recruited 61 patients of Caucasian race who met the exercise capacity and E/e′ ratio criteria and were categorized in New York Heart Association functional class II or III (Fig. 1). Of the 50 patients who were not enrolled, 21 did not show significant reductions (<80% of normal ranges) in exercise capacity, and 38 did not show exertional E/e′ ratios >13.
Exclusion criteria were an absence of stable sinus rhythm; ischemic heart disease (excluded on the basis of the absence of significant atherosclerotic lesions on coronary angiography and no evidence of inducible ischemia during exercise testing); moderate and severe valvular heart disease; heart rate <60 beats/min; sick sinus syndrome; second-degree and third-degree atrioventricular block; severe obesity (body mass index >36 kg/m2); established or suspected pulmonary diseases (vital capacity <80% or forced expiratory volume in 1 second <80% of age-specific and sex-specific reference values); hemoglobin ≤11 g/dl; and treatment with nondihydropyridine calcium-channel blockers, class I antiarrhythmic agents, strong inhibitors of cytochrome P450 3A4, and QT interval–prolonging medications.
The baseline evaluation comprised physical examination, cardiopulmonary exercise testing, resting and immediate post-exercise echocardiography, and blood sampling for laboratory measurements, including brain natriuretic peptide (BNP).
The procedure of randomization to receive either ivabradine 5 mg or placebo twice daily was performed by computerized sequence generation. The hospital pharmacies were responsible for drug randomization and dispensing, and both the investigators and patients were blinded to the treatment option. To check for the presence of bradycardia, patients were seen on the second and fourth days after the initiation of treatment. In case of a resting heart rate <50 beats/min or the occurrence of signs or symptoms related to bradycardia, the dose of ivabradine was to be reduced to 2.5 mg twice daily, or if these persisted after dose reduction, the study medication was to be withdrawn.
After 7 days, the baseline investigations were repeated.
Echocardiographic imaging was performed using Vivid E9 and Vivid 7 equipment (GE Vingmed Ultrasound AS, Horten, Norway) with phased-array 2.5-MHz multifrequency transducers. All patients underwent screening echocardiography to determine their suitability for the trial by the evaluation of strict criteria for HFpEF. The same imaging protocol was used at each visit and performed by the same sonographer. Images were saved in digital format and stored on a secure server for offline analysis. The measurements of cardiac dimensions and wall thicknesses and left atrial volume (area-length method) were performed according to standard recommendations (16). LV ejection fraction was determined using a modified Simpson biplane method.
Peak E and late diastolic mitral flow velocity (A) and the deceleration time of the early diastolic flow wave were assessed from the apical 4-chamber view by pulsed-wave Doppler with the sample volume placed between the tips of the mitral leaflets. Similarly, pulsed-wave tissue Doppler was used to estimate peak early diastolic tissue velocities in the annular septum and lateral wall (septal and lateral e′, respectively). Gain settings were optimized to reduce spectral broadening. The E/e′ ratio, with e′ being an average value from the septal and lateral aspects of the mitral annulus, was calculated to approximate LV filling pressure, which was considered to be increased if E/e′ >13 (13,14). The values of the E/e′ ratio were averaged from 3 consecutive cardiac cycles.
Myocardial deformation was evaluated using a semiautomated 2-dimensional speckle-tracking technique (EchoPAC, GE Medical Systems, Milwaukee, Wisconsin) from the 3 apical views with typical temporal resolution of 60 frames/s. After initial tracing of the endocardial border and subsequent software processing, the operator confirmed adequate tissue tracking. Segments that could not be tracked were subjected to manual readjustments of the region of interest, and if this was unsuccessful, they were excluded from the analysis. The parameters (peak strain, defined as the greatest negative value on the strain curve, and peak systolic strain rate) were calculated from the entire myocardial region of interest.
Symptom-limited exercise testing was performed on a treadmill using a modified Bruce protocol and with standard cardiopulmonary stress equipment. Ventilation, oxygen uptake (Vo2), and carbon dioxide production were monitored continuously, and peak Vo2 was calculated as the average oxygen consumption during the last 30 s of exercise.
Echocardiographic evaluation of wall motion, myocardial deformation, and diastolic function with the assessment of E/e′ ratio was undertaken before initiation and immediately after termination of the test. Transmitral flow and tissue velocities were measured after the acquisition of 2-dimensional imaging loops. In the event of fusion of early and late diastolic Doppler signals (E and A and/or e′ and a′) at high heart rates, images were acquired at the earliest time point when separation of the E and A waves was discernible.
To assess the progression of increment in heart rate in the context of different exercise capacity during the post-treatment exercise test, we derived the work load–corrected chronotropic response (WCCR). This was calculated from the difference in heart rate between the baseline and follow-up tests at the same exercise time. This time was defined by test completion in the test with the lower exercise time. For example, in patients with increases in exercise duration at follow-up, we used the exercise time at the baseline test, so WCCR was the maximal heart rate on the baseline test minus the intermediate heart rate on a follow-up test at the comparable time point. In patients with decreases in exercise duration at follow-up, we used the exercise time on the follow-up test, so WCCR was an intermediate heart rate on a baseline test at the time point compatible with the exercise time on a follow-up test minus the maximal heart rate on the follow-up test.
Peripheral venous blood samples were drawn between 8 and 9 am after a 30-min rest in the supine position. Plasma samples were frozen at −70°C until assay. BNP level was quantified using a commercially available fluorescence immunoassay (Triage BNP Test, Biosite Diagnostics, Inc., San Diego, California).
The primary endpoints were changes in exercise capacity as assessed by peak Vo2 and post-exercise LV filling pressure (E/e′). Secondary endpoints included alterations in myocardial deformation (2-dimensional strain and strain rate) and peak e′, representing LV systolic and diastolic function, respectively, and changes in neurohormonal activation as measured by plasma BNP.
The initial sample size was calculated on the basis of assumption of a standard deviation of 30% of exercise capacity and a 20% effect size (assuming a similar improvement in exercise capacity as that obtained from nondihydropyridine calcium-channel blockers or beta-blockers in a recent meta-analysis of treatments for HFpEF ). Subsequent work showed that a 30% to 35% effect size for exercise capacity in heart failure could be achieved with ivabradine (mainly systolic heart failure) (17). On the basis of these assumptions, we planned a study of 31 patients per group to provide 80% power to show a difference in exercise tolerance at a 2-sided alpha level of 0.05.
Data are expressed as mean ± SD for normally distributed variables, as median (interquartile range) for skewed variables (BNP), and as counts and percents for categorical variables. Between-group comparisons were carried out using unpaired 2-sided Student t tests for continuous variables and chi-square tests for categorical variables. Homogeneity of variances was assessed using the Levene test. Longitudinal analyses were performed using paired 2-sided Student t tests. BNP, which was found not to fit a normal distribution, was analyzed using the Mann-Whitney U test for intergroup and the Wilcoxon test for within-group comparisons. Associations between variables were studied using Pearson or Spearman correlation coefficients and stepwise multiple regression analysis. Variables were put into the stepwise models in order of descending significance in the univariate analyses. Changes in particular parameters with intervention were calculated by subtracting the baseline value from the follow-up value and were expressed in the units of their measurements. The reproducibility of measurements of E/e′ ratio was evaluated in 20 randomly selected examinations and expressed using intraclass correlation and Bland-Altman (mean and 95% confidence interval [CI]) methods. All analyses were performed using standard statistical software (Statistica for Windows version 10, StatSoft Inc., Tulsa, Oklahoma). The level of statistical significance was set at a 2-sided p value <0.05, apart from assessment of the coprimary endpoints, for which Bonferroni correction was applied (p = 0.025).
Patient characteristics are displayed in Table 1. The study patients had a mean age of 67 ± 8 years, were overweight, and were mostly women. A history of hypertension and/or type 2 diabetes was common. At baseline, there were no differences in resting heart rate, blood pressure, BNP level, and cardiac morphology and function, nor in cardiac functional reserve and exercise capacity, between the treatment and placebo groups (Tables 2 and 3, Fig. 2). Delayed relaxation was diagnosed in 43 patients and increased filling pressure in 18 patients. There were no differences in clinical characteristics between groups allocated to ivabradine or placebo.
Effects of intervention
All enrollees completed the study. There were no reported adverse events or need to reduce the dose or stop the treatment with ivabradine in any participant.
Baseline exercise capacity (both estimated metabolic equivalents [METs] based on treadmill time and measured Vo2) was impaired. Figure 2 illustrates a significant increment of exercise capacity in the group treated with ivabradine, with no change in the control subjects. Consequently, the change in METs was greater in the treated patients than controls (1.5 ± 1.2 vs. 0.4 ± 1.2, p = 0.001), as was the change in peak Vo2 (3.0 ± 3.6 ml/kg/min vs. 0.4 ± 2.7 ml/kg/min, p = 0.003). This change was significant after correction for multiple comparisons. Likewise, changes indicating improvement in ventilation versus carbon dioxide production slope and peak oxygen pulse were seen in the ivabradine group (Table 2). All study subjects achieved peak respiratory exchange ratio values >1, satisfying the prerequisite for the validity of attained peak Vo2.
The treatment group showed an improvement in resting LV lusitropic function, as indicated by higher septal e′ (Table 2). There was no evidence that these changes occurred in response to increased pre-load, because there was no accompanying change in resting E/e′ or circulating BNP (Table 2). In post hoc analyses, this effect was shown only in patients with grade I diastolic dysfunction (E/A ratio 0.75 ± 0.12 at baseline vs. 0.94 ± 0.26 at follow-up, p = 0.01, and septal e′ 5.2 ± 1.1 cm/s at baseline vs. 6.0 ± 1.4 cm/s at follow-up, p = 0.004), but not in patients with grade ≥ II diastolic dysfunction (E/A ratio 1.42 ± 0.50 at baseline vs. 1.50 ± 0.43 at follow-up, p = 0.83, and septal e′ 6.0 ± 1.2 cm/s at baseline vs. 6.2 ± 1.0 cm/s at follow-up, p = 0.61). Although there was no change in resting E/e′ ratio, the treatment group demonstrated a reduction in exercise-induced increase in E/e′ ratio, suggesting an improvement in changes in LV filling pressure induced by exertion (Table 3).
There was a decrease in resting heart rate in the treatment group. The absence of change in the response of this parameter to exercise (Tables 2 and 3) may have reflected differences in exercise performance. WCCR (the difference in heart rate at the same exercise time on the baseline and follow-up tests) showed a slower increase in heart rate during exercise than in the placebo-treated group (Fig. 3).
Diastolic dysfunction and heart rate subanalyses
The effect of heart rate slowing may be different in patients with grade I and grade II diastolic dysfunction, on the basis of potential benefits of prolonging LV filling in the former and heart rate dependence of cardiac output in the latter. However, no differences between these subgroups of patients were found in baseline or follow-up BNP, METs, peak Vo2, and exercise increment of E/e′ ratio (Online Table 1). Similarly, subdivision according to resting heart rate subgroups of >70 and ≤70 beats/min, as well as with normal and reduced chronotropic response to exercise (a failure to achieve 80% of the maximum age-predicted peak heart rate) were similar (Online Tables 2 and 3). Likewise, there were no differences in exercise and hemodynamic responses to treatment or placebo in groups below and at or above the median stroke volume (Online Table 4).
Determinants of improvements in exercise capacity and response of E/e′ ratio to exercise
The independent correlates of changes in exercise capacity and diastolic physiology were assessed by modeling combinations of covariates. These included resting and maximal exercise heart rate and blood pressure, body mass index, LV mass index, baseline METs (for ΔMETs), background treatment with beta-blockers, and, for ΔMETs and Δ peak Vo2, change with treatment in exertional increases in LV ejection fraction and strain. Therapy with ivabradine was independently associated with improvement in exercise capacity, as indicated by increases in METs and peak Vo2 (Table 4). Other independent associations were WCCR, change with treatment in exertional increase in E/e′ ratio, age, and baseline peak Vo2 (for Δ peak Vo2). Improvement of LV filling pressure estimated by E/e′ ratio was independently associated with ivabradine treatment (β = −0.24), as well as the baseline value of exertional increase in E/e′ ratio (Table 4). The use of beta-blockers was not a significant correlate, either univariate or multivariate, of changes in exercise capacity and LV filling pressure.
The level of agreement in measurements of E/e′ ratio between both centers participating in this trial was high, as suggested by the intraclass correlation coefficients (ICCs) and mean differences: ICC = 0.93 (p < 0.001) and −0.4 (95% CI: −1.5 to 0.7) at rest and ICC = 0.92 (p < 0.001) and 0.2 (95% CI: 1.0 to 0.6) at exercise. Intraobserver and interobserver variability of E/e′ ratio were as follows: at the Polish center, ICC = 0.96 (p < 0.001) and 0.5 (95% CI: 0.0 to 1.0) and ICC = 0.96 (p < 0.001) and −0.2 (95% CI: −0.6 to 0.2) at rest and ICC = 0.94 (p < 0.001) and −0.3 (95% CI: −1.0 to 0.3) and ICC = 0.97 (p < 0.001) and 0.7 (95% CI: 0.2 to 1.2) during exercise; at the Australian center, ICC = 0.99 (p < 0.001) and 0.0 (95% CI: −0.3 to 0.3) and ICC = 0.93 (p < 0.001) and 0.3 (95% CI: −0.4 to 1.0) at rest and ICC = 0.97 (p < 0.001) and 0.0 (95% CI: −0.3 to 0.3) and ICC = 0.98 (p < 0.001) and −0.1 (95% CI: −0.7 to 0.4) during exercise.
This randomized, placebo-controlled study demonstrated that short-term treatment with ivabradine improves exercise capacity in patients with HFpEF. This coincided with a reduction of the exercise-induced increase in LV filling pressure (E/e′ ratio). These findings in carefully selected patients with reduced exercise capacity, exercise-induced diastolic dysfunction, and low resting BNP levels support further investigations of ivabradine in larger and longer duration clinical trials in patients with HFpEF.
Exertional dyspnea is a nonspecific symptom, and concern is often expressed over the frequency of diastolic dysfunction leading to the overdiagnosis of HFpEF. The present study was performed in a carefully selected group of symptomatic, functionally impaired patients with HFpEF after the exclusion of other plausible causes of shortness of breath, such as lung disease or anemia. The lack of specificity of diastolic abnormalities as the reason for exercise intolerance is a limitation of previous investigations in HFpEF. We sought to avoid this in this study by performing the evaluation during exercise, which allowed us to relate symptomatic status to exercise changes in hemodynamic status.
Delayed relaxation represents the early process associated with diastolic dysfunction, which is followed by LV stiffening, both exerting deleterious effects on diastolic filling (18,19). Importantly, significant slowing of LV relaxation may result in elevation of both early and, to a lesser extent, late diastolic pressure, regardless of coexisting abnormalities of myocardial compliance (19). Despite near normal LV filling pressure values at rest in some patients, elevation of LV filling pressure on exertion is associated with exertional dyspnea (20–22). Patients with increments of E/e′ ratio with exercise were selected to make the group more specific for cardiac dyspnea (15,23–25).
A number of mechanisms may explain the favorable effect of ivabradine in HFpEF. In patients with delayed relaxation, lengthening of diastolic filling time may permit more complete LV filling. Patients with HFpEF have inappropriate tachycardia during exercise, with higher heart rates at constant work loads than in subjects with normal LV filling (20,26), on the basis of impaired stroke volume reserve and reliance on increasing heart rate to augment cardiac output. Interestingly, patients with increased LV filling pressure or the absence of resting tachycardia were no less likely to respond to ivabradine (Online Tables 1 and 2).
As demonstrated in animal models, the mechanisms behind the favorable effect of ivabradine on LV diastolic function are not confined to a simple lengthening of diastolic filling time. Other benefits include acceleration of myocardial relaxation by enhancing the phosphorylation of phospholamban and subsequent stimulation of sarcoplasmic reticulum Ca2+ adenosine triphosphatase, increase in myocardial compliance by reducing the expression of the titin N2B isoform and myocardial collagen content, and improvement of arterial stiffness and endothelial function (6,8,27). Clearly, some of these mechanisms require a longer treatment duration to be effective.
As evidenced in our analysis, the improvement of exercise capacity with ivabradine was associated with a slower increase in heart rate during exercise (as expressed by WCCR). This may have been paralleled by a slower exertional increase in LV filling pressure with delayed onset of dyspnea and exercise termination. Indeed, some patients might have developed similar levels of LV filling pressures as in the pre-treatment period but at a later stage of exercise. Unfortunately, noninvasive estimation of LV filling pressure during exercise (in contrast to post-exercise measurements in our protocol) using the E/e′ ratio is difficult because of the fusion of the E and A waves of the mitral inflow and annular e′ and a′ waves at high heart rates. These considerations may explain the lack of post-treatment reduction in exercise-induced increase in E/e′ ratio between treatment and control.
We did not demonstrate significant differences in beneficial effect of ivabradine on exercise tolerance between patients with grade I and grade ≥II diastolic dysfunction, but this finding needs to be verified in larger patient populations.
Heart rate control and heart failure
Although the heart failure guidelines mention a possible use of heart rate–slowing drugs (especially beta-blockers) for alleviating heart failure symptoms in patients with HFpEF (3,4), the role of therapeutic bradycardia in this population is controversial. Previous studies showed inconsistent results concerning effects of beta-blockade on LV diastolic function and exercise tolerance in patients with HFpEF (28–33). Notably, heart rate control attained with beta-receptor antagonists is accompanied by the negative inotropic and lusitropic effects of this class of drugs. Apart from this, beta-blockade may directly increase cardiomyocytes stiffness (34). Compared with atenolol, ivabradine lacks a negative lusitropic effect at similar levels of heart rate reduction (10) and provides similar decreases in myocardial oxygen demand without detrimentally affecting LV contractility (35,36). Finally, traditional beta-blockade may contribute to increased central systolic loading, despite lowering brachial blood pressure (37). This effect may be detrimental to central hemodynamic status in HFpEF, especially on exertion, and substitution of this drug class with ivabradine may be particularly useful. Indeed, apart from the beneficial changes during exercise, ivabradine therapy was associated with a positive lusitropic effect at rest in patients with HFpEF with grade I diastolic dysfunction, as indicated by higher septal e′ and mitral E/A ratio. This finding is in line with prior experimental studies (6,7,9,10).
First, BNP was ineffective in tracking clinical and hemodynamic improvements in this study. This reflects challenges in applying BNP in this population, especially in the context of their mean body mass index of 30 kg/m2 (38). Additionally, we measured this marker only at rest, not during exercise, when the favorable effect of ivabradine on LV filling pressure was observed.
Second, the improvement in exercise capacity after a short duration of treatment represents the acute effect of therapy on hemodynamic status. Long-term treatment may permit patients with HFpEF to engage in greater levels of physical activity, further improving functional capacity.
Third, we studied the effects of ivabradine on maximal exercise performance and cannot extrapolate our data to the effects of the drug on submaximal exercise hemodynamic status.
Fourth, we did not evaluate the effect of ivabradine on arterial function, especially in the context of its potential impact on exercise tolerance.
Fifth, there is a dose-response effect of ivabradine on heart rate reduction (39). In this study, we examined the effects of a fixed dose of ivabradine (5 mg), which is effective for rate reduction, but we did not titrate the drug to reach specific heart rate thresholds.
Finally, the limited sample size precluded testing interactions with treatment groups in the multivariate regression model.
Ivabradine therapy is an effective therapy to increase exercise tolerance in patients with HFpEF. This beneficial effect is potentially mediated by the improved LV filling pressure response to exercise. Because patients with HFpEF are often symptomatic only on exertion, treatments targeting abnormal exercise hemodynamic status may prove useful.
For supplementary tables, please see the online version of this article.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- late diastolic mitral flow velocity
- brain natriuretic peptide
- confidence interval
- peak early diastolic mitral flow velocity
- peak early diastolic mitral annular velocity
- heart failure with preserved ejection fraction
- intraclass correlation coefficient
- inward “funny”
- left ventricular
- metabolic equivalent
- work load–corrected chronotropic response
- oxygen uptake
- Received March 26, 2013.
- Revision received May 22, 2013.
- Accepted June 13, 2013.
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