The role of Ivabradine in Diastolic Heart Failure with preserved Ejection Fraction. A Doppler-Echocardiographic study.

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.

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).[1] 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.[2] 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.[34] This hemodynamic state can be invasively evaluated by catheter-based technique.[5] However, echocardiographic examination represents an excellent, noninvasive tool to assess LV diastolic dysfunction.[6] 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.[7] However, it is known that the increase of HR is negatively correlated with CAD and cardiac mortality.[8] Several studies shown the benefits of the HR-reduction on cardiovascular mortality and morbidity in different populations with or without chronic HF.[8910] 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.[11121314] 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.[15]

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.[1] 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

Parameters	Values
n	25
Sex
Male	16
Female	9
Mean age	67±4
Body surface area	1.69±0.7
Fasting blood glucose (mmol/L)	6.1±0.6
Total cholesterol (mmol/L)	5.72±0.9
NYHA functional class (%)
Class II	16 patients (64)
Class III	9 patients (36)
Previous cardiovascular drugs (%)
Digitalis	8
β-blockers	84
ACE-inhibitors	60
ARBs	40
Loop diuretics	12
Thiazides	36
Aldosterone antagonists	28
ASA	81
Clopidogrel	19

NYHA=New York Heart Association, ACE=Angiotensin-converting-enzyme, ARBs=Angiotensin-receptor blockers, ASA=Acetylsalicilyc acid

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.[16] 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.[16] 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.

Statistical analysis

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

Parameters	Baseline	After ivabradine	P
Heart rate (beats/min)	81±2	74±3	P<0.05
Systolic blood pressure (mm Hg)	132±2.3	133±3.1	NS
Diastolic blood pressure (mm Hg)	83±3.3	82±3.2	NS
LVdV (ml)	84.2±2.5	85.8±3.4	NS
LVsV (ml)	67.3±2.2	65.7±1.8	NS
Stroke volume (ml)	33±0.9	41±1.2	P<0.05
Ejection fraction (%)	48±0.20	51±0.12	P<0.05

LVdV=Left ventricular diastolic volume, LVsV=Left ventricular systolic volume, NS=Not significant

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

Parameters	Baseline	Ivabradine	P
Diastolic mitral inflow
E wave velocity (cm/s)	65.3±2.1	70.2±2.0	NS
A wave velocity (cm/s)	75.2±1.3	68.2±1.2	NS
E/A ratio	0.86±0.11	1.0±0.8	P<0.05
DTE (ms)	186.2±3	235.3±2	P<0.01
Pulmonary vein flow pattern
S wave velocity (ms)	0.53±0.08	0.62±0.07	P<0.05
D wave velocity (ms)	0.49±0.09	0.44±0.05	NS
S/D waves ratio	1.1±0.4	1.41±0.5	P<0.05
Ar velocity (ms)	25.3±2	16.2±3	P<0.05
Ar duration (ms)	127.1±6	120.3±5	NS
Tissue Doppler imaging
E’ wave (cm/s)	4.2±2.2	5.4±2.0	P<0.05
A’ wave (cm/s)	9.7±1.9	10.2±1.8	NS
E/E’ ratio	14.6±2.1	12.5±1.8	NS

NS=Not significant, DTE=Deceleration time of the early diastolic flow mitral valve

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

Parameters	Baseline	Ivabradine	P
Diastolic mitral inflow
E wave velocity (cm/s)	55.3±1.3	58.3±2.6	NS
A wave velocity (cm/s)	43.1±2.1	55.2±1.7	P<0.05
E/A ratio	1.3±0.7	1.0±1.2	P<0.05
DTE (ms)	155.3±4	184.2±5	P<0.05
Pulmonary vein flow velocity pattern
S wave velocity (ms)	0.44±0.06	0.47±0.07	NS
D wave velocity (ms)	0.41±0.03	0.38±0.05	NS
S/D waves ratio	1.0±0.5	1.2±0.3	P<0.05
Ar velocity (ms)	40±5	38±4	NS
Ar duration (ms)	137±14	135±18	NS
Tissue Doppler imaging
E’ wave (cm/s)	3.9±1.5	5.1±1.9	P<0.05
A’ wave (cm/s)	6.1±1.7	7.9±1.7	P<0.05
E/E’ waves ratio	14.1±1.4	11.4±1.6	P<0.05

NS=Not significant, DTE=Deceleration time of the early diastolic flow mitral valve

DISCUSSION

HF is a clinical syndrome reported to an increased amount of extravascular fluid.[17] Epidemiologic studies suggest that about 50% HF has preserved EF% (HFpEF).[18] 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.[19]

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.[20]

Tissue Doppler imaging

The main advantages of the echocardiographic evaluation are its high feasibility, reproducibility, and easy application at bedside.[21] 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.[22] 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.[2324] 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.[21] 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.[2526] 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.[72728] 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).[7181920212223242526272829] 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.[30] A reduction in sympathetic overdrive, demonstrated by the reduction of plasma norepinephrine after IVA therapy must be underlined too.[31] Recently, Pal et al. confirmed the beneficial effects of selective HR slowing obtained with IVA.[32] Simantirakis et al. also underlined the effects of if channel inhibition both in diastolic function and exercise capacity in HFpEF.[33] 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.[34] 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.[35] 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.[36]

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.[37]

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

Nil.

Conflicts of interest

There are no conflicts of interest.