Ivabradine Improves Left Ventricular Function During Chronic Hypertension in Conscious Pigs

Rienzo, Mario; Mĕlka, J; Bizé, Alain; Sambin, Lucien; Jozwiak, Mathieu; Su, Jin Bo; Hittinger, Luc; Berdeaux, Alain; Ghaleh, Bijan

doi:10.1161/hypertensionaha.114.04323

Cited by 15 publications

(9 citation statements)

References 50 publications

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“…In Ang II-induced hypertension, ivabradine led to an improvement in the systolic and diastolic function, along with a reduction of cardiac hypertrophy and fibrosis [ 8 ]. Acute administration of ivabradine to chronic angiotensin II-induced hypertension improved both contraction and relaxation [ 24 ], and chronic ivabradine treatment prevented thyroid hormone-induced heart dysfunction without influencing LV hypertrophy or fibrosis [ 25 ]. On the other hand, ivabradine deteriorated the signs of HF and increased LVH and fibrosis in pressure overload-induced HF [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Ivabradine on a Hypertensive Heart and the Renin-Angiotensin-Aldosterone System in L-NAME-Induced Hypertension

Šimko

Baka

Poglitsch³

et al. 2018

IJMS

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Ivabradine, the selective inhibitor of the If current in the sinoatrial node, exerts cardiovascular protection by its bradycardic effect and potentially pleiotropic actions. However, there is a shortage of data regarding ivabradine’s interaction with the renin-angiotensin-aldosterone system (RAAS). This study investigated whether ivabradine is able to protect a hypertensive heart in the model of L-NAME-induced hypertension and to interfere with the RAAS. Four groups (n = 10/group) of adult male Wistar rats were treated as follows for four weeks: control, ivabradine (10 mg/kg/day), L-NAME (40 mg/kg/day), and L-NAME plus ivabradine. L-NAME administration increased systolic blood pressure (SBP) and left ventricular (LV) weight, enhanced hydroxyproline concentration in the LV, and deteriorated the systolic and diastolic LV function. Ivabradine reduced heart rate (HR) and SBP, and improved the LV function. The serum concentrations of angiotensin Ang 1–8 (Ang II), Ang 1–5, Ang 1–7, Ang 1–10, Ang 2–8, and Ang 3–8 were decreased in the L-NAME group and ivabradine did not modify them. The serum concentration of aldosterone and the aldosterone/Ang II ratio were enhanced by L-NAME and ivabradine reduced these changes. We conclude that ivabradine improved the LV function of the hypertensive heart in L-NAME-induced hypertension. The protective effect of ivabradine might have been associated with the reduction of the aldosterone level.

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Section: Discussionmentioning

confidence: 99%

Effect of Ivabradine on a Hypertensive Heart and the Renin-Angiotensin-Aldosterone System in L-NAME-Induced Hypertension

Šimko

Baka

Poglitsch³

et al. 2018

IJMS

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“…Ivabradine, the cardiac pacemaker “funny” [I( f )] inhibitor: Ivabradine is a heart-rate-lowering agent that acts by selectively and specifically inhibiting the I f , a mixed Na + -K + inward current that controls the spontaneous diastolic depolarization in the sinoatrial node and hence regulates the HR[ 200 , 201 ]. Ivabradine slows down HR and exerts cardioprotective effects[ 183 , 202 , 203 ].…”

Section: Treatment Of the Canmentioning

confidence: 99%

Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment

Serhiyenko¹,

Serhiyenko²

2018

WJD

185

135

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Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes mellitus (DM) that is strongly associated with approximately five-fold increased risk of cardiovascular mortality. CAN manifests in a spectrum of things, ranging from resting tachycardia and fixed heart rate (HR) to development of “silent” myocardial infarction. Clinical correlates or risk markers for CAN are age, DM duration, glycemic control, hypertension, and dyslipidemia (DLP), development of other microvascular complications. Established risk factors for CAN are poor glycemic control in type 1 DM and a combination of hypertension, DLP, obesity, and unsatisfactory glycemic control in type 2 DM. Symptomatic manifestations of CAN include sinus tachycardia, exercise intolerance, orthostatic hypotension (OH), abnormal blood pressure (BP) regulation, dizziness, presyncope and syncope, intraoperative cardiovascular instability, asymptomatic myocardial ischemia and infarction. Methods of CAN assessment in clinical practice include assessment of symptoms and signs, cardiovascular reflex tests based on HR and BP, short-term electrocardiography (ECG), QT interval prolongation, HR variability (24 h, classic 24 h Holter ECG), ambulatory BP monitoring, HR turbulence, baroreflex sensitivity, muscle sympathetic nerve activity, catecholamine assessment and cardiovascular sympathetic tests, heart sympathetic imaging. Although it is common complication, the significance of CAN has not been fully appreciated and there are no unified treatment algorithms for today. Treatment is based on early diagnosis, life style changes, optimization of glycemic control and management of cardiovascular risk factors. Pathogenetic treatment of CAN includes: Balanced diet and physical activity; optimization of glycemic control; treatment of DLP; antioxidants, first of all α-lipoic acid (ALA), aldose reductase inhibitors, acetyl-L-carnitine; vitamins, first of all fat-soluble vitamin B1; correction of vascular endothelial dysfunction; prevention and treatment of thrombosis; in severe cases-treatment of OH. The promising methods include prescription of prostacyclin analogues, thromboxane A2 blockers and drugs that contribute into strengthening and/or normalization of Na+, K+-ATPase (phosphodiesterase inhibitor), ALA, dihomo-γ-linolenic acid (DGLA), ω-3 polyunsaturated fatty acids (ω-3 PUFAs), and the simultaneous prescription of ALA, ω-3 PUFAs and DGLA, but the future investigations are needed. Development of OH is associated with severe or advanced CAN and prescription of nonpharmacological and pharmacological, in the foreground midodrine and fludrocortisone acetate, treatment methods are necessary.

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“…16,17 Recently, HR reduction with the use of IVA decreased the period of isovolumic contraction and relaxation both in resting and under dobutamine-stimulated conditions and contributed to favorable LV filling and preservation of ejection in conscious pigs with LVH induced by hypertension. 18 The histological findings in the improvement of LV fibrosis and myocyte hypertrophy and the restoration of decreased TH expression suggest that the improvement in diastolic properties may be associated with the amelioration of HF and survival benefit in this model.…”

Section: Discussionmentioning

confidence: 80%

Modulation of Sympathetic Activity and Innervation With Chronic Ivabradine and β-Blocker Therapies: Analysis of Hypertensive Rats With Heart Failure

Kakehi

Iwanaga

Watanabe

et al. 2019

J Cardiovasc Pharmacol Ther

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Background: Whether the reduction of heart rate with ivabradine (IVA) could affect sympathetic activation and cardiac innervation in heart failure (HF) remains unknown. Purpose: The present study assessed the chronic effects of IVA and b-blocker on the systemic and local sympathetic nervous systems of hypertensive animals with HF. Methods and Results: The Dahl saltsensitive rats received chronic IVA, bisoprolol (BIS), or placebo (CTL) therapy. The survival of the animal models with IVA and BIS significantly improved (median; 19.7 in IVA and 19.7 in BIS vs 17.0 weeks in CTL, P < .001). A similar decrease in 24-hour heart rate (mean; 305 in IVA and 329 in BIS vs 388 beats/min in CTL, P < .001) without effect on blood pressure, and an improvement in the left ventricular dysfunction (mean fractional shortening; 56.7% in IVA and 47.8% in BIS vs 39.0% in CTL, P < .001) were observed in the animals with IVA and BIS. However, a negative inotropic effect was only observed in the animals with BIS. Excessive urinary noradrenaline excretion in animals with CTL was only suppressed with the use of IVA (mean; 1.35 mg/d in IVA and 1.95 mg/d in BIS vs 2.27 mg/d in CTL, P ¼ .002). In contrast, atrial noradrenaline and acetylcholine depletion in the animals with CTL improved and the tyrosine hydroxylase expression in the both atria were restored with the use of both IVA and BIS. Conclusions: IVA therapy improved the survival of hypertensive animals with HF. Furthermore, it was associated with the amelioration of systemic sympathetic activation and cardiac sympathetic and parasympathetic nerve innervations. Chronic b-blocker therapy with negative inotropic effects had beneficial effects only on cardiac innervations.

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Ivabradine Improves Left Ventricular Function During Chronic Hypertension in Conscious Pigs

Cited by 15 publications

References 50 publications

Effect of Ivabradine on a Hypertensive Heart and the Renin-Angiotensin-Aldosterone System in L-NAME-Induced Hypertension

Effect of Ivabradine on a Hypertensive Heart and the Renin-Angiotensin-Aldosterone System in L-NAME-Induced Hypertension

Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment

Modulation of Sympathetic Activity and Innervation With Chronic Ivabradine and β-Blocker Therapies: Analysis of Hypertensive Rats With Heart Failure

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