|Year : 2017 | Volume
| Issue : 4 | Page : 126-131
The role of ivabradine in diastolic heart failure with preserved ejection fraction. A doppler-echocardiographic study
Federico Cacciapuoti, Valerio Massimo Magro, Michele Caturano, Diana Lama, Fulvio Cacciapuoti
Department of Internal Medicine, Ambulatory of Echocardiography, “Luigi Vanvitelli” University, Naples, Italy
|Date of Web Publication||12-Oct-2017|
Department of Internal Medicine, Ambulatory of Echocardiography, Second University of Naples, Piazza L. Miraglia, 280138, Naples
Source of Support: None, Conflict of Interest: None
Background: Ivabradine (IVA) is effective in patients with coronary artery disease (CAD) or systolic heart failure in sinus rhythm. Its action consists in reducing heart rate (HR) and improving the time of left ventricular (LV) diastolic filling. The aim of this study was to evaluate the effects of IVA added to conventional therapy on patients with diastolic heart failure (DHF) and preserved ejection fraction (HFpEF). Methods: We evaluated 25 patients with DHF in the New York Heart Association (NYHA) Class II-III and sinus rhythm. In these, IVA per os (5 mg/twice a day) was added to the conventional medical therapy and given for 12 weeks. Immediately before the beginning of IVA therapy and 3 months later, patients underwent echocardiographic evaluation by two-dimensional (2D) ultrasound and tissue Doppler imaging (TDI). The patterns of diastolic mitral inflow and pulmonary venous flow were recorded using 2D echocardiography, while the diastolic phase of mitral flow was recorded by TDI, from the lateral mitral annulus. Results: Three months after the addition of IVA to conventional treatment, HR significantly decreased in comparison to the baseline values. On the contrary, the echocardiographic indexes of LV diastolic dysfunction improved. Conclusions: These results testify that the addition of IVA to conventional therapy in patients with HFpEF can improve LV diastolic function evaluated by 2D and tissue Doppler-echocardiographic patterns. These Doppler-echocardiographic results match with the clinical improvement of patients evaluated.
Keywords: Diastolic heart failure with preserved ejection fraction, Doppler-echocardiographic parameters, ivabradine, left ventricular diastolic function
|How to cite this article:|
Cacciapuoti F, Magro VM, Caturano M, Lama D, Cacciapuoti F. The role of ivabradine in diastolic heart failure with preserved ejection fraction. A doppler-echocardiographic study. J Cardiovasc Echography 2017;27:126-31
|How to cite this URL:|
Cacciapuoti F, Magro VM, Caturano M, Lama D, Cacciapuoti F. The role of ivabradine in diastolic heart failure with preserved ejection fraction. A doppler-echocardiographic study. J Cardiovasc Echography [serial online] 2017 [cited 2018 May 23];27:126-31. Available from: http://www.jcecho.org/text.asp?2017/27/4/126/216680
| Introduction|| |
Diastolic heart failure (DHF) is a clinical syndrome characterized by symptoms of the left ventricular heart failure (HF) as fatigue, dyspnea at moderate effort, exercise intolerance, and normal left ventricular (LV) systolic function. This condition was also defined as “Heart Failure with preserved Ejection Fraction” (HFpEF). HFpEF occurs when LV chamber can accept an adequate volume of blood during diastole, to maintain an appropriate stroke volume, and it is characterized by a normal or slightly reduced left ventricular ejection fraction (between 40% and 50%), even compensated by an increased filling pressures. These conditions usually realize oneself for an increased myocardial stiffness, characterized by an impaired diastolic relaxation. This hemodynamic condition results in the left atrial pressure higher than that found in healthy subjects. In turn, high LA pressures, leads to pulmonary venous congestion, inducing dyspnea (especially on exertion). Pathologic processes, such as cardiac fibrosis, LV hypertrophy, diabetes mellitus, coronary artery disease (CAD), and “aging heart” are the most frequent causes responsible for an increased LV myocardial stiffness., This hemodynamic state can be invasively evaluated by catheter-based technique. However, echocardiographic examination represents an excellent, noninvasive tool to assess LV diastolic dysfunction. The main echocardiographic methods for define LV diastolic function are transmitral diastolic velocity flow pattern, pulmonary venous flow pattern, and diastolic phase of mitral flow recorded by tissue Doppler imaging (TDI) from the mitral annulus.
It is known that heart rate (HR) increases in both systolic and diastolic chronic heart failure (CHF) to maintain cardiac output. However, it is known that the increase of HR is negatively correlated with CAD and cardiac mortality. Several studies shown the benefits of the HR-reduction on cardiovascular mortality and morbidity in different populations with or without chronic HF.,, Ivabradine (IVA) is a specific HR decreasing agent, whose chemical structure is similar to that of verapamil. It acts on sinoatrial node by selectively inhibiting the pacemaker if current. That reduces HR both at rest as well as during exercise, with minimal effect on myocardial contractility, blood pressure, and intracardiac conduction. The drug has a negative chronotrope effect that is not a negative inotrope effect and a beneficial influence on myocardial relaxation.,,, In addition, Busseuil et al. demonstrated that IVA reduces both atrial and ventricular fibrosis and ventricular collagen Type I, increasing the improvement in diastolic function.
The aim of this study was to test the echocardiographic effects of IVA on LV diastolic dysfunction in patients with HFpEF.
| Methods|| |
From October 2014 to February 2016, twenty-six patients (17 males and 9 females) were enrolled, chosen among those admitted to the Department of Internal Medicine and Geriatrics or Ambulatory of Echocardiography for fatigue, dyspnea on exertion, and exercise intolerance. All aged from 67 to 75 years (mean age = 71 ± 4 years) and were in sinus rhythm, with a mean HR >75 bpm (mean value = 81 ± 2). All these were affected by HFpEF, in accordance to the clinical and echocardiographic criteria previously referred. Exclusion criteria were evidence of moderate and/or severe heart valvular disease, absence of sinus rhythm and presence of conduction disturbance, pulmonary disease, and severe obesity. According to with their cardiorespiratory symptoms, the patients were divided in II and III NYHA class. Specifically, those with slight limitations of ordinary physical activity were included in II NYHA class. On the contrary, the patients with marked limitations of ordinary physical activity were included in III NYHA class. At recruitment, the participants to the study were treated with the following cardiovascular drugs: digitalis (2 participants); β-blockers (21 participants); angiotensin-converting-enzyme -inhibitors (15 participants); angiotensin-receptor blockers (10 participants); loop diuretics (3 participants); thiazides (9 patients); and Aldactone antagonists (7 participants).
The baseline evaluation comprised physical examination, 12-leads transthoracic electrocardiography, transthoracic mono- two-dimensional (2D) and Doppler echocardiography and TDI. Echocardiographic images were recorded in digital format. One patient ruled out from the study for further cardiac complications. Demographic, metabolic, clinical, and pharmacologic characteristics of the remaining 25 patients are reported in [Table 1]. After enrollment, IVA 5 mg/os twice was added to remaining the therapy and was carried out for 12 weeks.
|Table 1: Main demographic, metabolic, clinical, and pharmacologic characteristics of patients|
Click here to view
M- and two-mode transthoracic echocardiography
Mono and 2D echocardiographic examinations were performed using a PHILIPS iE33 (Eindhoven NL) echocardiograph. All measurements were obtained in accordance with the American Society of Echocardiography and the European Association of Echocardiography. LV ejection fraction percentage was calculated by modified Simpson biplane method. The peak of early (E) and late (A) waves of diastolic mitral inflow were measured in cm/sec, and subsequently, the E/A wave ratio was defined. Deceleration time of the early diastolic flow mitral valve (DTE) was also assessed in ms according to the recommendations previous referred. All these evaluations were performed in longitudinal approach, from apical 4 and 2 chambers views, placing the sample volume between the tips of the mitral leaflets. Pulmonary venous flow was recorded placing the sample volume 0.5 to 1 cm into the upper right pulmonary vein and was used to measure the systolic flow (S), diastolic flow (D), S/D waves ratio, and reversed atrial flow (Ar) in ms.
Pulsed Doppler tissue imaging
Values of peak early (E') and late (A') diastolic annular velocities were recorded in cm/sec. Measurements were performed during end-expiration to eliminate the respiratory variations and an average of three consecutive beats measured. Subsequently, the E/E' ratio was calculated.
The previously described standard echocardiographic and DTI examinations were repeated at the end of 12 weeks of IVA treatment.
All echocardiographic parameters obtained before and after 12 weeks of IVA in two groups-patients divided on the basis of NYHA class were reported as mean + standard deviation (SD). Differences were calculated using student's t-test for paired data. Values P < 0.05 were considered statistically significant. All analyses were performed using standard statistical software (Matlab - Mathworks).
| Results|| |
All IVA-treated patients showed a significant decrease of HR in comparison to its mean basal value (P < 0.05). On the contrary, both systolic and diastolic blood pressure did not significantly change. In addition, while left ventricular diastolic volume slightly increased, left ventricular systolic volume not significantly reduced. After the addition of IVA to previous treatments, these changes of LV volumes caused significant increase (P < 0.05) of stroke volume and EF% [Table 2].
|Table 2: Values of some cardiovascular and echocardiographic parameters at baseline and after ivabradine|
Click here to view
In 16 among 25 patients included in II NYHA functional class, the E/A waves ratio increased from 0.86 ± 0.11 to 1.0 ± 0.8 (P < 0.05). This result was obtained for a moderate increase of E wave velocity and a decrease of A wave velocity. The mean value of DTE recorded at baseline was 186.2 ± 3 msec and increased to 253.3 ± 2 ms after IVA treatment (P < 0.01). Pulmonary venous flow pattern showed an S/D waves ratio of 1.1 ± 0.4 at baseline, that risen to 1.41 ± 0.5 (P < 0.05) after IVA addition. The result, deriving from an S wave velocity (0.53 ± 0.08 ms) and a D wave velocity (0.49 ± 0.09 ms), was significantly (P < 0.05) increased after IVA administration. That happened for slightly increased of S wave velocity (0.62 ± 0.07 ms) and decreased for D wave velocity (0.44 ± 0.05 ms). The peak velocity of reversal A wave (Ar) was 25.3 ± 2 ms in basal conditions, and decreased to 18.2 ± 3 msec after IVA (P < 0.05). Analogously, Ar duration lightly decreased from 127.1 ± 6 to 120.3 ± 5 ms. Finally, TDI recorded at baseline shown a mean of 4.2 ± 2.2 cm/sec for E' wave, and 9.7 ± 1.9 cm/sec. for A' wave. The first-wave velocity (E') significantly (P < 0.05) increased (5.4 ± 2 cm/sec.) after IVA treatment, whereas A' wave velocity little increased (10.2 ± 1.8 cm/sec.). The E/E' ratio resulted in nonsignificant decrease (from 14.6 ± 2.1 to 12.0 + 1.8) [Table 3].
|Table 3: Echocardiographic parameters of left ventricular diastolic function of 16 patients in II New York Heart Association class|
Click here to view
In the remaining nine patients included in III NYHA class, the basal value of E/A ratio was equal to 1.3 ± 0.7. This decreased to 1.0 ± 1.2 after IVA (N.S.). The reduction derives from a nonsignificant increase of E wave velocity (55.3 ± 1.3 cm/sec. to 58.3 ± 2.6. cm/sec), and a more clean raising (P < 0.05) of A wave velocity. In agreement, DTE increased from 155.3 ± 4 ms to 184.2 ± 5 ms (P < 0.05). Pulmonary venous flow showed a little increase of S wave (from 0.44 ± 0.06 ms to 0.47 ± 0.07 ms) and a decrease of D wave velocities (from 0.41 ± 0.03 ms to 0.38 ± 0.05 ms) while S/D ratio significantly (P < 0.05) increased (from 1.0 ± 0.5 to 1.2 ± 0.3). Contrarily, Ar velocity and duration lightly decreased (N.S.). Finally, at TDI evaluation, E' wave velocity increased from baseline (3.9 ± 1.5 cm/sec.) to the end of IVA therapy (5.1 ± 1.9 cm/sec) (P < 0.05). A' wave's velocity also increased (from 6.1 ± 1.7 cm/sec to 7.9 ± 1.7 cm/sec) (P < 0.05). Finally, E/E' ratio significantly (P < 0.05) changed (from 14.1 ± 1.4 to 11.4 ± 1.6) [Table 4].
|Table 4: Echocardiographic parameters of left ventricular diastolic function of 9 patients in III class|
Click here to view
| Discussion|| |
HF is a clinical syndrome reported to an increased amount of extravascular fluid. Epidemiologic studies suggest that about 50% HF has preserved EF% (HFpEF). Hemodynamic impairment in this syndrome involves LV diastolic function alone while systolic function is preserved (at beginning at least). This condition can be recognized through the assessment of myocardial relaxation, filling pressures, and LV compliance. The Doppler-echocardiography is an useful tool to noninvasively evaluate LV diastolic function, mainly using the described technique. In this study, we first evaluated left ventricular diastolic function and changes IVA-dependent by the Doppler-echocardiographic technique alone.
Diastolic mitral inflow
Patients in II NYHA class, the basal diastolic mitral Doppler flow was indicative of an impairment of LV diastolic function (E/A ratio <1). However, an increase of E velocity and a decrease of A wave velocity (with reduction of E/A waves ratio) were recorded after 12 weeks of IVA. On the contrary, in patients in III NYHA class, the initial condition of “pseudo-normalization” of transmitral D (E/A ratio >1) reduced. In accordance, DTE lengthened respect to the basal value both in II and in III NYHA class.
Pulmonary venous flow
The reduction of S/D waves ratio recorded in basal conditions in both NYHA classes is due to the progressive increase of D wave velocity, as an expression of increased filling pressure. As a consequence of IVA treatment, S/D ratio increased for the reduction of D wave velocity. In addition, the increased resistance to atrial forward flow, as the result of increased ventricular stiffness, induces a growth of Ar velocity and duration at baseline, and their reduction after IVA therapy.
Tissue Doppler imaging
The main advantages of the echocardiographic evaluation are its high feasibility, reproducibility, and easy application at bedside. The diastolic phase of mitral flow is composed by an early (E') and late (A') wave. Normally, the E' velocity is equal to or higher than A'. However, to evaluate LV diastolic dysfunction E' wave velocity alone must be measured. In our patients, E' wave velocity decreased, both in II and in III NYHA class in comparison to the normal values, in accordance with the advancing stages of diastolic dysfunction. Concerning this, must be also added that, since E' is less dependent on volume and loading conditions than transmitral E wave, the E/E' ratio has been proposed as a reliable estimate LV filling pressures., Regarding to this issue, Nagueh et al. previously demonstrated that E/E' ratio >10 predicts pulmonary capillary wedge pressure >12 mmHg while a value of E/E' ratio <8 mmHg is indicative for normal LV filling pressure. In our patients, the E/E' ratio constantly exceeded the value of 10, both in patients in II and III NYHA class, before and after IVA treatment.
As previously affirmed, increased HR in chronic HF as a consequence of cardiac dysfunction is positively correlated with mortality. Therefore, the reduction of HR represents a specific therapeutic target in HF., IVA is a HR decreasing agent which acts on the sino-atrial node by inhibiting the pacemaker if current. The HR reduction obtained by IVA administration in chronic HF can increase LV contraction, lower myocardial oxygen consumption, and prolong LV diastolic filling.,, However, the mechanism behind the beneficial effects of IVA on LV diastolic dysfunction cannot be related to a simple lengthening of diastolic filling time, but it must be also reported to a reduction in oxidative stress, circulating angiotensin II-aldosterone levels, and in cardiac structural remodeling (cardiac fibrosis).,,,,,,,,,,,, In addition, IVA treatment is associated with normalization of pro-inflammatory cytokines, evidenced by decreased plasma levels of tumor necrosis factor-α and IL-6. A reduction in sympathetic overdrive, demonstrated by the reduction of plasma norepinephrine after IVA therapy must be underlined too. Recently, Pal et al. confirmed the beneficial effects of selective HR slowing obtained with IVA. Simantirakis et al. also underlined the effects of if channel inhibition both in diastolic function and exercise capacity in HFpEF. Usually, IVA was used in association or in substitution to β-blockers. Contrarily, IVA lowers HR through selective inhibition of the mixed sodium/potassium current in sinoatrial pacemaker nodal cells. Another important difference between β-blockers and IVA is that HR reduction attained with β-receptor antagonists is accompanied by negative inotropic and lusitropic effects. On the contrary, IVA lacks of the negative lusitropic effect at similar levels of HR reduction but provides similar decreases in myocardial oxygen demand without the detrimental action of LV contractility. Nevertheless, with regard to IVA, the beneficial effects on HF cannot be ascribed to slowing of heart-beats, with lengthening of diastolic time alone, but also to its “pleiotropic” effects, as improvement of ventricular relaxation by enhancing the reuptake of calcium by the sarcoplasmic reticulum, increase in myocardial compliance, LV remodeling, no changes in blood pressure, or reduction of infarct size (in CAD) and improvement of endothelial function.
| Conclusions|| |
On account of these characteristics, IVA can be considered a drug acting with an innovative mechanism both against CAD and CHF in sinus rhythm. Particularly, in HFpEF patients IVA can be usefully used alone, in association or alternatively to β-blockers (when not tolerated), to improve the hemodynamic and clinical signs of this syndrome. However, concerning this therapeutic association, the CARVIVA-HF (CARvedilol, IVA or their combination on exercise capacity in patients with Heart Failure) trial demonstrated that IVA alone or in combination with carvedilol was more effective than Carvedilol alone in improving exercise capacity and quality of life in patients with HF.
| Study's Limitations|| |
Although the study clearly demonstrated that IVA can bring important Doppler-echocardiographic and clinical advantages to diastolic HFpEF patients, it suffers from some limitations due to the little number of participants that could influence the results obtained and their statistical significance. Another limitation is that the Doppler-echocardiographic finding was not recorded before and after IVA. Finally, the variability of etiology in the evaluated patients could differently influence HFpEF, conditioning that in many ways. Despite these limitations, results obtained demonstrate that:
- IVA added to conventional therapy, can improve the main hemodynamics in HFpEF-patients
- Doppler echocardiography is a useful and extremely sensitive tool to evaluate the usefulness of IVA in inducing this hemodynamic improvement.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, et al.
How to diagnose diastolic heart failure: A consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28:2539-50.
Brutsaert DL, Sys SU, Gillebert TC. Diastolic failure: Pathophysiology and therapeutic implications. J Am Coll Cardiol 1993;22:318-25.
Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features and prognosis of diastolic heart failure: An epidemiologic perspective. J Am Coll Cardiol 1995;26:1565-74.
Prioli A, Marino P, Lanzoni L, Zardini P. Increasing degrees of left ventricular filling impairment modulate left atrial function in humans. Am J Cardiol 1998;82:756-61.
Kass DA. Assessment of diastolic dysfunction. Invasive modalities. Cardiol Clin 2000;18:571-86.
Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al.
Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009;22:107-33.
Cohn JN. Abnormalities of peripheral sympathetic nervous system control in congestive heart failure. Circulation 1990;82:I59-67.
Kannel WB, Kannel C, Paffenbarger RS Jr., Cupples LA. Heart rate and cardiovascular mortality: The Framingham Study. Am Heart J 1987;113:1489-94.
Gillman MW, Kannel WB, Belanger A, D'Agostino RB. Influence of heart rate on mortality among persons with hypertension: The Framingham Study. Am Heart J 1993;125:1148-54.
Pocock SJ, Wang D, Pfeffer MA, Yusuf S, McMurray JJ, Swedberg KB, et al.
Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J 2006;27:65-75.
Riccioni G. Ivabradine: From molecular basis to clinical effectiveness. Adv Ther 2010;27:160-7.
Tardif JC. Clinical results of I(f) current inhibition by ivabradine. Drugs 2007;67 Suppl 2:35-41.
Thollon C, Cambarrat C, Vian J, Prost JF, Peglion JL, Vilaine JP, et al.
Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: Comparison with UL-FS 49. Br J Pharmacol 1994;112:37-42.
Kosmala W, Holland DJ, Rojek A, Wright L, Przewlocka-Kosmala M, Marwick TH, et al.
Effect of if-channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: A randomized trial. J Am Coll Cardiol 2013;62:1330-8.
Busseuil D, Shi Y, Mecteau M, Brand G, Gillis MA, Thorin E, et al.
Heart rate reduction by ivabradine reduces diastolic dysfunction and cardiac fibrosis. Cardiology 2010;117:234-42.
Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al.
Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28: 1-39.e14.
Jessup M, Brozena S. Heart failure. N Engl J Med 2003;348:2007-18.
Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol 2004;43:317-27.
Appleton CP, Hatle LK, Popp RL. Relation of transmitral flow velocity patterns to left ventricular diastolic function: New insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol 1988;12:426-40.
Smiseth OA, Thompson CR, Lohavanichbutr K, Ling H, Abel JG, Miyagishima RT, et al.
The pulmonary venous systolic flow pulse – Its origin and relationship to left atrial pressure. J Am Coll Cardiol 1999;34:802-9.
Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd
, Dokainish H, Edvardsen T, et al.
Recommendations for the evaluation of left ventricular diastolic function by echocardiography: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2016;29:277-314.
Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, et al.
Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study. Circulation 2000;102:1788-94.
Hasegawa H, Little WC, Ohno M, Brucks S, Morimoto A, Cheng HJ, et al.
Diastolic mitral annular velocity during the development of heart failure. J Am Coll Cardiol 2003;41:1590-7.
Oki T, Tabata T, Yamada H, Wakatsuki T, Shinohara H, Nishikado A, et al.
Clinical application of pulsed Doppler tissue imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 1997;79:921-8.
Lei L, Zhou R, Zheng W, Christensen LP, Weiss RM, Tomanek RJ, et al.
Bradycardia induces angiogenesis, increases coronary reserve, and preserves function of the postinfarcted heart. Circulation 2004;110:796-802.
Leite-Moreira AF, Correia-Pinto J, Gillebert TC. Afterload induced changes in myocardial relaxation: A mechanism for diastolic dysfunction. Cardiovasc Res 1999;43:344-53.
Custodis F, Baumhäkel M, Schlimmer N, List F, Gensch C, Böhm M, et al.
Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation 2008;117:2377-87.
Yue-Chun L, Teng Z, Na-Dan Z, Li-Sha G, Qin L, Xue-Qiang G, et al.
Comparison of effects of ivabradine versus carvedilol in murine model with the Coxsackievirus B3-induced viral myocarditis. PLoS One 2012;7:e39394.
Sabbah HN, Gupta RC, Kohli S, Wang M, Zhang K, Rastogi S, et al.
Heart rate reduction with ivabradine improves left ventricular function and reverses multiple pathological maladaptations in dogs with chronic heart failure. ESC Heart Fail 2014;1:94-102.
Heusch G. Pleiotropic action(s) of the bradycardic agent ivabradine: Cardiovascular protection beyond heart rate reduction. Br J Pharmacol 2008;155:970-1.
Colin P, Ghaleh B, Hittinger L, Monnet X, Slama M, Giudicelli JF, et al.
Differential effects of heart rate reduction and beta-blockade on left ventricular relaxation during exercise. Am J Physiol Heart Circ Physiol 2002;282:H672-9.
Pal N, Sivaswamy N, Mahmod M, Yavari A, Rudd A, Singh S, et al.
Effect of selective heart rate slowing in heart failure with preserved ejection fraction. Circulation 2015;132:1719-25.
Simantirakis EN, Nakou ES, Kallergis EM, Arkolaki EG, Patrianakos AP, Papakonstantinou PE, et al.
Long-term effect of if-channel inhibition on diastolic function and exercise capacity in heart failure patients with preserved ejection fraction. Int J Cardiol 2015;187:9-11.
Tardif JC. Ivabradine: I(f) inhibition in the management of stable angina pectoris and other cardiovascular diseases. Drugs Today (Barc) 2008;44:171-81.
Joannides R, Moore N, Iacob M, Compagnon P, Lerebours G, Menard JF, et al.
Comparative effects of ivabradine, a selective heart rate-lowering agent, and propranolol on systemic and cardiac haemodynamics at rest and during exercise. Br J Clin Pharmacol 2006;61:127-37.
Colin P, Ghaleh B, Monnet X, Su J, Hittinger L, Giudicelli JF, et al.
Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol 2003;284:H676-82.
Volterrani M, Cice G, Caminiti G, Vitale C, D'Isa S, Perrone Filardi P, et al.
Effect of carvedilol, ivabradine or their combination on exercise capacity in patients with heart failure (the CARVIVA HF trial). Int J Cardiol 2011;151:218-24.
[Table 1], [Table 2], [Table 3], [Table 4]