Ivabradine and Blood Pressure Reduction: Underlying Pleiotropic Mechanisms and Clinical Implications

Šimko, Fedor; Baka, Tomáš

doi:10.3389/fcvm.2021.607998

Cited by 15 publications

(12 citation statements)

References 74 publications

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“…Elevated HR is a risk factor in healthy individuals and various cardiovascular pathologies [ 44 ]. Ivabradine selectively inhibits the I f current of the pacemaker cells in the sinoatrial node, thus reducing HR without negative inotropy [ 45 ]. Although HR reduction coming with an improvement in myocardial energy balance seems to be the principal factor underlying the protection offered by ivabradine in HF patients, a number of pleiotropic effects, including antioxidative, anti-inflammatory, and neurohumoral action modulation, may contribute to heart protection [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Sacubitril/Valsartan and Ivabradine Attenuate Left Ventricular Remodelling and Dysfunction in Spontaneously Hypertensive Rats: Different Interactions with the Renin–Angiotensin–Aldosterone System

et al. 2022

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This study investigated whether sacubitril/valsartan and ivabradine are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in a rat experimental model of spontaneous hypertension (spontaneously hypertensive rats, SHRs) and whether this potential protection is associated with RAAS alterations. Five groups of three-month-old male Wistar rats and SHRs were treated for six weeks as follows: untreated Wistar controls, Wistar plus sacubitril/valsartan, SHR, SHR plus sacubitril/valsartan, and SHR plus ivabradine. The SHRs developed a systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, and LV systolic and diastolic dysfunction. However, no changes in serum RAAS were observed in SHRs compared with the controls. Elevated SBP in SHRs was decreased by sacubitril/valsartan but not by ivabradine, and only sacubitril/valsartan attenuated LV hypertrophy. Both sacubitril/valsartan and ivabradine reduced LV collagen content and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7, and aldosterone, while ivabradine did not affect the RAAS. We conclude that the SHR is a normal-to-low serum RAAS model of experimental hypertension. While the protection of the hypertensive heart in SHRs by sacubitril/valsartan may be related to an Ang II blockade and the protective Ang 1-7, the benefits of ivabradine were not associated with RAAS modulation.

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Section: Discussionmentioning

confidence: 99%

Sacubitril/Valsartan and Ivabradine Attenuate Left Ventricular Remodelling and Dysfunction in Spontaneously Hypertensive Rats: Different Interactions with the Renin–Angiotensin–Aldosterone System

et al. 2022

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“…Furthermore, ivabradine upregulated the expression of miR-133a under Ang II exposure and inhibited Ang II-induced PVF activation, suggesting that ivabradine inhibits cardiac fibroblast activation and ameliorates myocardial fibrosis by upregulating miR-133a expression. Besides heart rate reduction, ivabradine was also shown to exert effects within the vasculature in terms of inflammation and oxidative stress reduction [ 48 , 49 ]. For example, ivabradine could diminish ROS generation in endothelial cells by provoking mTORC2/Akt phosphorylation [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Ivabradine Ameliorates Cardiac Function in Heart Failure with Preserved and Reduced Ejection Fraction via Upregulation of miR‐133a

Shao

Zhang

Gong

et al. 2021

Oxidative Medicine and Cellular Longevity

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Heart failure (HF) is a clinical syndrome caused by impairment of ventricular filling, ejection of blood, or both and is categorized as HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF) based on left ventricular function. Cardiac fibrosis contributes to left ventricular dysfunction and leads to the development of HF. Ivabradine, an If current selective specific inhibitor, has been shown to improve the prognosis of patients with HF. However, the effects of ivabradine on cardiac function and fibrosis in HFpEF and HFrEF and the underlying mechanism remain unclear. In the present study, we utilized mouse models to mimic HFpEF and HFrEF and evaluated the therapeutic effects of ivabradine. By treating mice with different doses (10 mg/kg/d and 20 mg/kg/d) of ivabradine for 4 or 8 weeks, we found that a high dose of ivabradine improved cardiac diastolic function in HFpEF mice and ameliorated cardiac diastolic and systolic function and ventricular tachycardia incidence in HFrEF mice. Moreover, ivabradine significantly reduced the activation of cardiac fibroblasts and myocardial fibrosis in mice. Mechanistically, microRNA-133a, which was upregulated by ivabradine, targeted connective tissue growth factor and collagen 1 in cardiac fibroblasts and might contribute to the protective role of ivabradine. Together, our work utilized mouse models to study HFpEF and HFrEF, demonstrated the protective role of ivabradine in HFpEF and HFrEF, and elucidated the potential underlying mechanism, which provides an effective strategy for related diseases.

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“…276 In the SHIFT (Systolic Heart failure treatment with the I f inhibitor ivabradine Trial), ivabradine decreased the composite end-point of mortality and hospitalizations for HF. 277 Moreover, a number of ivabradine pleiotropic effects have been described, including anti-inflammatory, antiapoptotic, antiremodeling, oxidative stress-reducing, and hypotensive actions, [278][279][280][281][282][283] that may be potentially beneficial in several off-labeled indications. 284 The potential effects of ivabradine on mood, cognition, and behavior in experimental animals and humans remain elusive.…”

Section: Ivabradinementioning

confidence: 99%

Cardiovascular therapeutics: A new potential for anxiety treatment?

Repova

Aziriova

Krajcirovicova

et al. 2022

Medicinal Research Reviews

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Besides the well-recognized risk factors, novel conditions increasing cardiovascular morbidity and mortality are emerging.Undesirable emotions and behavior such as anxiety and depression, appear to participate in worsening cardiovascular pathologies. On the other hand, deteriorating conditions of the heart and vasculature result in disturbed mental and emotional health. The pathophysiological background of this bidirectional

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Ivabradine and Blood Pressure Reduction: Underlying Pleiotropic Mechanisms and Clinical Implications

Cited by 15 publications

References 74 publications

Sacubitril/Valsartan and Ivabradine Attenuate Left Ventricular Remodelling and Dysfunction in Spontaneously Hypertensive Rats: Different Interactions with the Renin–Angiotensin–Aldosterone System

Sacubitril/Valsartan and Ivabradine Attenuate Left Ventricular Remodelling and Dysfunction in Spontaneously Hypertensive Rats: Different Interactions with the Renin–Angiotensin–Aldosterone System

Ivabradine Ameliorates Cardiac Function in Heart Failure with Preserved and Reduced Ejection Fraction via Upregulation of miR‐133a

Cardiovascular therapeutics: A new potential for anxiety treatment?

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