Ivabradine induces cardiac protection by preventing cardiogenic shock-induced extracellular matrix degradation

Tesoro, Laura; Ramírez-Carracedo, Rafael; Hernández, Ignacio; Díez-Mata, Javier; Pascual, Marina; Saura, Marta; Sanmartín, Marcelo; Zamorano, José Luís; Zaragoza, Carlos

doi:10.1016/j.rec.2020.09.012

Cited by 4 publications

(6 citation statements)

References 32 publications

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“…Large animal models such as pigs play a pivotal role toward clinical translation since they better reflect human anatomy and (patho)physiology compared to rodents 90 . Thus far there are three porcine acute IR studies that support the benefits of ivabradine in terms of cardiac functional improvements and attenuation of cardiac remodeling 37–39 . As discussed in the previous section (“Effects of ivabradine in acute coronary syndrome: reports from clinical studies”; also see Table 4), several clinical trials also confirm some functional improvements in ivabradine‐treated MI patients.…”

Section: Perspective and Conclusionmentioning

confidence: 82%

“…Ivabradine also stabilized the EMMPRIN/HCN4/caveolin-3 complex, leading to the downregulation of matrix metalloproteinase 9 (MMP9), which may improve cardiac remodeling in the long term. 37 In other porcine IR models treated with inotropic agents or a cardiac assist device, co-treatment with ivabradine effectively reduced the infarct size, decreased myocardial oxygen consumption, and increased the stroke volume without altering blood pressure. 41,42 All of these findings suggested that ivabradine could be a promising pharmacological intervention for use in conjunction with a cardiac assist device or inotropes in MI patients.…”

Section: On Cardiac Ischemia-reperfusion Injury In Large Animal Modelsmentioning

confidence: 96%

“…Since CyPA is a ligand of the extracellular matrix metalloproteinase inducer (EMMPRIN), which can activate the inflammatory cascade, 40 the reduction of CyPA by ivabradine resulted in the reduction in inflammation caused by IR injury. Ivabradine also stabilized the EMMPRIN/HCN4/caveolin‐3 complex, leading to the downregulation of matrix metalloproteinase 9 (MMP9), which may improve cardiac remodeling in the long term 37 . In other porcine IR models treated with inotropic agents or a cardiac assist device, co‐treatment with ivabradine effectively reduced the infarct size, decreased myocardial oxygen consumption, and increased the stroke volume without altering blood pressure 41,42 .…”

Section: Effects Of Ivabradine On Cardiac Ischemia–reperfusion Injury...mentioning

confidence: 99%

“…When the heart was paced to preclude heart rate reduction, those beneficial effects of ivabradine were eradicated, suggesting that they are HR-dependent. 36 In addition to infarct size reduction, ivabradine (0.3 mg/kg, IV) administered 15 min after IR improved left ventricular (LV) function 37,38 through mechanisms that involve the reduction of cyclophilin A (CyPA) release from cardiac mitochondria. 39 Since CyPA is a ligand of the extracellular matrix metalloproteinase inducer (EMMPRIN), which can activate the inflammatory cascade, 40 the reduction of CyPA by ivabradine resulted in the reduction in inflammation caused by IR injury.…”

Section: On Cardiac Ischemia-reperfusion Injury In Large Animal Modelsmentioning

confidence: 99%

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Hyperpolarization‐activated cyclic nucleotide‐gated channel inhibitor in myocardial infarction: Potential benefits beyond heart rate modulation

Sripusanapan,

Yanpiset,

Sriwichaiin

et al. 2024

Acta Physiologica

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Myocardial infarction (MI) and its associated complications including ventricular arrhythmias and heart failure are responsible for a significant incidence of morbidity and mortality worldwide. The ensuing cardiomyocyte loss results in neurohormone‐driven cardiac remodeling, which leads to chronic heart failure in MI survivors. Ivabradine is a heart rate modulation agent currently used in treatment of chronic heart failure with reduced ejection fraction. The canonical target of ivabradine is the hyperpolarization‐activated cyclic nucleotide‐gated channels (HCN) in cardiac pacemaker cells. However, in post‐MI hearts, HCN can also be expressed ectopically in non‐pacemaker cardiomyocytes. There is an accumulation of intriguing evidence to suggest that ivabradine also possesses cardioprotective effects that are independent of heart rate reduction. This review aims to summarize and discuss the reported cardioprotective mechanisms of ivabradine beyond heart rate modulation in myocardial infarction through various molecular mechanisms including the prevention of reactive oxygen species‐induced mitochondrial damage, improvement of autophagy system, modulation of intracellular calcium cycling, modification of ventricular electrophysiology, and regulation of matrix metalloproteinases.

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Section: Perspective and Conclusionmentioning

confidence: 82%

Section: On Cardiac Ischemia-reperfusion Injury In Large Animal Modelsmentioning

confidence: 96%

Section: Effects Of Ivabradine On Cardiac Ischemia–reperfusion Injury...mentioning

confidence: 99%

Section: On Cardiac Ischemia-reperfusion Injury In Large Animal Modelsmentioning

confidence: 99%

See 2 more Smart Citations

Hyperpolarization‐activated cyclic nucleotide‐gated channel inhibitor in myocardial infarction: Potential benefits beyond heart rate modulation

Sripusanapan,

Yanpiset,

Sriwichaiin

et al. 2024

Acta Physiologica

View full text Add to dashboard Cite

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“…The complex CyPA/EMMPRIN worsens myocardial damage by contributing to leukocyte recruitment [ 4 , 25 ] and also by inducing extracellular matrix degradation through EMMPRIN-induced matrix metalloproteinase activation [ 26 ]. Recently, we found that Ivabradine induces cardiac protection by inhibiting EMMPRIN-mediated MMP activation [ 8 , 27 ], but the specific role of the complex CyPA/EMMPRIN has not been previously investigated.…”

Section: Discussionmentioning

confidence: 99%

Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion

Hernández

Tesoro

Ramírez-Carracedo

et al. 2021

IJMS

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In response to cardiac ischemia/reperfusion, proteolysis mediated by extracellular matrix metalloproteinase inducer (EMMPRIN) and its secreted ligand cyclophilin-A (CyPA) significantly contributes to cardiac injury and necrosis. Here, we aimed to investigate if, in addition to the effect on the funny current (I(f)), Ivabradine may also play a role against cardiac necrosis by reducing EMMPRIN/CyPA-mediated cardiac inflammation. In a porcine model of cardiac ischemia/reperfusion (IR), we found that administration of 0.3 mg/kg Ivabradine significantly improved cardiac function and reduced cardiac necrosis by day 7 after IR, detecting a significant increase in cardiac CyPA in the necrotic compared to the risk areas, which was inversely correlated with the levels of circulating CyPA detected in plasma samples from the same subjects. In testing whether Ivabradine may regulate the levels of CyPA, no changes in tissue CyPA were found in healthy pigs treated with 0.3 mg/kg Ivabradine, but interestingly, when analyzing the complex EMMPRIN/CyPA, rather high glycosylated EMMPRIN, which is required for EMMPRIN-mediated matrix metalloproteinase (MMP) activation and increased CyPA bonding to low-glycosylated forms of EMMPRIN were detected by day 7 after IR in pigs treated with Ivabradine. To study the mechanism by which Ivabradine may prevent secretion of CyPA, we first found that Ivabradine was time-dependent in inhibiting co-localization of CyPA with the granule exocytosis marker vesicle-associated membrane protein 1 (VAMP1). However, Ivabradine had no effect on mRNA expression nor in the proteasome and lysosome degradation of CyPA. In conclusion, our results point toward CyPA, its ligand EMMPRIN, and the complex CyPA/EMMPRIN as important targets of Ivabradine in cardiac protection against IR.

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Ivabradine in the Management of COVID-19-related Cardiovascular Complications: A Perspective

Baka

Repova

Luptak

et al. 2022

CPD

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Besides acute respiratory distress syndrome, acute cardiac injury is a major complication in severe coronavirus disease 2019 (COVID-19) and associates with a poor clinical outcome. Acute cardiac injury with COVID-19 can be of various etiologies, including myocardial ischemia or infarction and myocarditis, and may compromise cardiac function, resulting in acute heart failure or cardiogenic shock. Systemic inflammatory response increases heart rate (HR), which disrupts the myocardial oxygen supply/demand balance and worsens cardiac energy efficiency, thus further deteriorating the cardiac performance of the injured myocardium. In fact, the combination of elevated resting HR and markers of inflammation synergistically predicts adverse cardiovascular prognosis. Thus, targeted HR reduction may potentially be of benefit in cardiovascular pathologies associated with COVID-19. Ivabradine is a drug that selectively reduces HR via If current inhibition in the sinoatrial node without a negative effect on inotropy. Besides selective HR reduction, ivabradine was found to exert various beneficial pleiotropic effects, either HR-dependent or HR-independent, including anti-inflammatory, anti-atherosclerotic, anti-oxidant and antiproliferative actions and the attenuation of endothelial dysfunction and neurohumoral activation. Cardioprotection by ivabradine has already been indicated in cardiovascular pathologies that are prevalent with COVID-19, including myocarditis, acute coronary syndrome, cardiogenic shock or cardiac dysautonomia. Here, we suggest that ivabradine may be beneficial in the management of COVID-19-related cardiovascular complications.

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Ivabradine induces cardiac protection by preventing cardiogenic shock-induced extracellular matrix degradation

Cited by 4 publications

References 32 publications

Hyperpolarization‐activated cyclic nucleotide‐gated channel inhibitor in myocardial infarction: Potential benefits beyond heart rate modulation

Hyperpolarization‐activated cyclic nucleotide‐gated channel inhibitor in myocardial infarction: Potential benefits beyond heart rate modulation

Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion

Ivabradine in the Management of COVID-19-related Cardiovascular Complications: A Perspective

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