A high resting heart rate increases the risk of adverse outcomes (morbidity and mortality) in patients with heart failure [6]. Thus, besides the reduction in excessive neurohumoral activation in patients with heart failure, slowing down the heart rate seems to be another therapeutic option [7,8]. This target is commonly achieved using β-blockers. However, clinically, uptitration of the drugs to the optimal dosage is complicated due to side effects [9]. Ivabradine (Figure 1), marketed as Procoralan^®, Ivabid^®, or Ivazine^®, is a pure heart rate reducer [7]. The drug was originally approved for the treatment of angina pectoris; however, since 2005, it has been used as an adjunct therapy in patients with stable symptomatic heart failure with reduced ejection fraction (HFrEF) with concomitant high resting heart rate (>70 beats per min), which is an independent predictor for cardiovascular disease [7,9].

Cardiac remodeling is a process that involves structural changes affecting the size and shape of the myocardium, characterized by cardiac hypertrophy. Cellular and molecular changes can lead to cardiac dysfunction [10]. Animal studies demonstrated that ivabradine therapy reduced these changes, evidenced by a reduction in growth factors, collagen, and matrix metalloproteinase (MMP) expression, the increase in which leads to myocardial fibrosis in animal models of heart failure [11,12]. It also ameliorated myocardial inflammation, apoptosis, and oxidative stress as well as improved myocardial biogenesis in the remodeled hearts [12,13,14,15], all factors potentially contributing to the antiremodeling effects.

Increased mortality due to cardiovascular events and frequent hospitalization are common in patients with heart failure. In addition, the progression of heart failure reduces the quality of life of these patients. Many clinical trials, such as the Systolic Heart Failure Treatment with the I_f Inhibitor Ivabradine Trial (SHIFT), Long-term Treatment with Ivabradine in Ambulatory Patients with Chronic Heart Failure (RELIf-CHF), Study Assessing the Morbidity-Mortality Benefits of the I_f Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY), and Morbidity-mortality Evaluation of the I_f Inhibitor Ivabradine in Patients with Coronary Disease and Left Ventricular Dysfunction (BEAUTIFUL), have been conducted to assess the outcomes. Heart failure patients taking ivabradine have a reduced risk, frequency, and length of hospitalization due to worsening heart failure, other cardiovascular disease, or other co-morbidities, compared with those who do not take ivabradine (Table 1) [16,17,18,19,20].

However, the effects of ivabradine on mortality rate in these patients were inconsistent. Most studies including principal trials (SHIFT, BEAUTIFUL, and SIGNIFY) reported that ivabradine therapy failed to decrease the rate of death due to cardiovascular disease or other causes despite the reduction in hospitalization [16,22,24,25,30,37]. Nevertheless, three studies reported positive outcomes on mortality due to cardiovascular events or heart failure following ivabradine treatment [19,21,28] in patients with a resting heart rate higher than 75 beats per minute; however, these outcomes were not observed in patients with a lower resting heart rate [21]. An elevated resting heart rate predisposes a patient to developing left ventricular systolic dysfunction [38]. Therefore, a reduction in heart rate by ivabradine would potentiate systolic function, leading to a reduction in the severity of the disease, evidenced by a lower New York Heart Association class [18,19,20,23,28,29,32,33,34,36]. Furthermore, this would decrease hospital readmissions due to the worsening of heart failure.

In terms of quality of life, ivabradine therapy improved global assessment, either by patient self-assessment or assessment by their physician (Table 1) [19]. This translated to increased health-related quality of life evidenced by a reduction in heart-failure-associated symptoms and improvements in physical, social, and emotional functioning, well-being, vitality, and general health. Furthermore, these improvements led to increased mental health scores [20,31,32,34]. A clinical trial was conducted on children (aged 6 months to 18 years old) with dilated cardiomyopathy. It was reported that ivabradine improved the quality of life in these children [36]. In summary, ivabradine therapy improves heart-failure-associated symptoms, resulting in a better quality of life for patients, but with limited success in reducing mortality in these patients.

As previously mentioned, one of the primary targets in patients with chronic heart failure is a reduction in excessive neurohumoral activation, particularly in terms of the attenuation of the sympathetic system and renin–angiotensin–aldosterone system activation. The use of β-blockers not only decreases the heart rate but also decreases cardiac contractility and blood pressure in these patients. In addition, high doses of β-blockers result in reduced patient tolerance for the drug’s side effects, which include fatigue and hypotension [9]. Ivabradine is used as a second-line treatment in addition to β-blockers and other drugs used for heart failure treatment [9,39]. The heart-rate-lowering property of ivabradine at doses of 5–7.5 mg twice daily has been observed in many clinical studies in both acute and chronic heart failure patients (Table 2) [18,28,40,41]. However, the effect was not apparent in heart failure patients with a resting heart rate lower than 75 beats per minute [21], suggesting that it has the potential to not cause bradycardia.

In contrast with β-blockers, ivabradine does not affect blood pressure [18,28,33,44] or myocardial contractility [9] in patients with heart failure. The reduction in heart rate observed in the patients taking ivabradine leads to a decrease in left ventricular end-diastolic volume (LVEDV) [19,46] and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/E′) (Table 2) [44]. However, other parameters of diastolic function, such as ratios of early-to-late diastolic mitral inflow velocity (E/A) and early diastolic mitral inflow velocity to early diastolic velocity of the septal mitral annulus (E/e′), were not significantly altered by ivabradine [27,44]. Following the improvement in diastolic function, ivabradine indirectly ameliorates systolic work in patients, manifested by increased left ventricular ejection fraction (LVEF), end-systolic elastance (Ees), and stroke volume and decreased end-systolic volume (LVESV) [18,19,23,35,40,41,46]. However, several studies demonstrated unaltered Ees [27,45] and LEVF [28,43,44] following ivabradine therapy.

Studies exploring the impact of ivabradine on right ventricular function in patients with heart failure are lacking. Only Gul et al. [47] reported that the drug therapy ameliorated right ventricular function based on the improvement of strain rate and global longitudinal strain parameters. However, it was a small non-randomized study involving only two centers. The improvement in the right ventricular function could arise from the improvement of the left ventricular performance, which decreases the right ventricular afterload.

Left ventricular dysfunction is closely related to prolonged atrial conduction time, with the latter increasing the risk of atrial fibrillation in patients with heart failure [48]. Only one study investigated the effects of ivabradine on atrial mechanical function. The delay in interatrial and right intra-atrial conduction was significantly reduced in patients with systolic heart failure after 3 months on ivabradine [44]. Furthermore, the drug improved atrial electromechanical function in these patients, indicated by decreased left atrial active emptying volume and fraction and decreased duration of onset of the P wave to the beginning of the late diastolic wave at the septal and lateral mitral annulus and right ventricular tricuspid annulus [44]. These observations suggest that ivabradine may exert beneficial effects on myocardial atrial performance, with the potential to reduce the risk of developing arrhythmia in patients with heart failure. However, a recent meta-analysis that included 13 clinical trials inferred that regardless of the dose, ivabradine increased the incidence of atrial fibrillation in patients. However, the drug is effective in preventing post-operative atrial fibrillation [49]. Nonetheless, more clinical studies should be conducted to confirm these findings. Collectively, the findings obtained to date suggest that ivabradine may restore left ventricular, right ventricular, and left atrial function in failing hearts.

The cardioprotective effects of ivabradine were also demonstrated in animal studies. Ivabradine administered at 10 mg/kg/day in drinking water for 2–12 weeks produced improvements in cardiac function in various animal models of cardiac remodeling (Table 3).

It enhanced systolic function by increasing stroke volume, LVEF, left ventricular fractional shortening (LVFS), systolic pressure (LVSP) and developed pressure (LVDP), maximal rate of fall (−dp/dt_max) and rise (+dp/dt_max) of left ventricular pressure, and LVESV in these animal models [11,12,13,51,53,57,59,60,62,67].

Left ventricular dysfunction, commonly seen in heart failure, is characterized by impaired left ventricular filling capacity [75]. Ivabradine potentiates diastolic work by increasing the diastolic filling time [52,64] and decreasing left ventricular diastolic wall stress [61] in chronic-hypertension-induced cardiac hypertrophy and myocardial-infarction-induced cardiac remodeling in animals. Reductions in left ventricular end-diastolic pressure (LVEDP), isovolumetric relaxation time (IVRT), Tau (early relaxation), LVEDV, and E/E′ were also noted (Table 3) [11,51,52,56,58,61,63,65,66,67].

The potential benefits of ivabradine were further investigated in right ventricular dysfunction. In a pulmonary-hypertension-induced heart failure rat model, oral administration of 10 mg/kg/day ivabradine for 3 weeks improved right ventricular systolic function evidenced by reduced maximum tricuspid systolic annular excursion (tTAPSE) and isovolumic contraction time (IVCT) and increased systolic tissue wave velocity (S’), stroke volume, and cardiac output (Table 3) [69,72]. Altered right ventricular +dp/dt_max and −dp/dt_max values were also reversed in the rats [72]. In addition, right ventricular diastolic function was preserved based on the improvement in IVRT, right ventricular end-diastolic pressure (RVEDP), and Tau [72]. Similar findings were noted in SU5416 (a tyrosine kinase inhibitor) plus hypoxia-induced cardiac remodeling and right-ventricular-pressure-overload-induced cardiac remodeling [72]. In primary right ventricular cardiomyocytes, ivabradine (0.01–1 μM) reduced beating frequency without affecting the beating amplitude [72], confirming its heart-rate-lowering effects with no direct impact on contractility.

Altered calcium uptake into the sarcoplasmic reticulum hinders contractile performance [76]. Sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) and phosphorylated phospholamban are two proteins that regulate calcium uptake into the sarcoplasmic reticulum [77,78]. Improved systolic work by ivabradine may partially be attributed to its influence on myocardial calcium regulation. The drug decreased the expression of SERCA2a and phosphorylated phospholamban in rats that were exposed to monocrotaline-induced pulmonary hypertension to induce cardiac remodeling [72]. The transporting function of SERCA was increased following ivabradine treatment without affecting the function of sodium–calcium exchanger (NCX) and sarcoplasmic reticulum calcium storage. The net effect was an increase in calcium transient amplitude in the heart [61]. NCX mediates the exchange of Na⁺ and Ca²⁺ when the extracellular Na⁺ is high due to the activity of Na⁺/K⁺-ATPase, which transports Na⁺ out of cells in favor of transporting K⁺ into cells [79]. Calcium is also required for ATP generation in the mitochondria. Increased mitochondrial calcium uptake enhances ATP production, leading to improvements in energy metabolism and supply to contractile proteins during systolic and diastolic actions [80]. However, studies investigating the role of ivabradine in mitochondrial calcium uptake and release are lacking.

Based on the reported findings, it can be stipulated that ivabradine confers protection against left and right ventricular dysfunction in animal studies, which confirms the clinical observations. These findings may partially be attributable to the effects of ivabradine on myocardial calcium homeostasis. Other factors that should be investigated are the influence of the drug on other calcium regulators, such Na⁺/K⁺-ATPase, ryanodine receptor 2, which facilitates Ca²⁺ release from the sarcoplasmic reticulum [77], and Ca²⁺/calmodulin-dependent protein kinase II (Ca²⁺/CaMKII), which is involved in Ca²⁺ signal transduction [81]. Its effects on mitochondrial voltage-dependent anion channel 1, calcium uniporter, and calcium uptake proteins—mitochondrial calcium regulatory proteins [80]—should also be studied.