Bradycardia and the Role of β-Blockade in the Amelioration of Left Ventricular Dysfunction

Nagatsu, M; Spinale, Francis G.; Koide, Masaaki; Tagawa, Hirofumi; DeFreitas, Gilberto; Cooper, George; Carabello, Blasé A.

doi:10.1161/01.cir.101.6.653

Cited by 83 publications

(60 citation statements)

References 38 publications

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“…[3][4][5] Furthermore, pacing abolishes the increase of LV contractile function in a dog model of CHF after long-term ␤-blocker treatment. 6 Although these data support the hypothesis of an essential role of HRR in the effects observed after long-term ␤-blockade, other mechanisms, such as prevention of ␤-receptor downregulation or direct myocardial damage caused by catecholamines, 7 are potentially involved and cannot be excluded. Thus, whether long-term selective HRR per se exerts beneficial effects on cardiac function in CHF is still unclear.…”

mentioning

confidence: 81%

Long-Term Heart Rate Reduction Induced by the Selective I _f Current Inhibitor Ivabradine Improves Left Ventricular Function and Intrinsic Myocardial Structure in Congestive Heart Failure

et al. 2004

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Background-Heart rate reduction (HRR) improves left ventricular (LV) filling, increases myocardial O 2 supply, and reduces myocardial O 2 consumption, which are all beneficial in congestive heart failure (CHF). However, the long-term effects of HRR on cardiac function and remodeling are unknown. Methods and Results-We assessed, in rats with CHF, the effects of long-term HRR induced by the selective I f current inhibitor ivabradine (as food admix for 90 days starting 7 days after coronary artery ligation). To assess intrinsic modifications of LV tissue induced by long-term HRR, all parameters were reassessed 3 days after interruption of treatment. Ivabradine decreased heart rate over the 90-day treatment period (Ϫ18% versus untreated at 10 mg · kg Ϫ1 · d

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confidence: 81%

Long-Term Heart Rate Reduction Induced by the Selective I _f Current Inhibitor Ivabradine Improves Left Ventricular Function and Intrinsic Myocardial Structure in Congestive Heart Failure

et al. 2004

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“…The adverse outcome in trials of bantagonists with intrinsic sympathomimetic activity may be related to insufficient reduction in HR than that of drugs without such activity (Cleland et al, 1996). In an experimental heart failure model, preventing HR reduction by pacing largely abolished the beneficial effects of b-blockade (Nagatsu et al, 2000).…”

Section: X-j Du Et Almentioning

confidence: 99%

“…Thus, an elevated HR may impair ventricular diastolic filling, compromise coronary blood flow and increase myocardial oxygen demand. Indeed, there is evidence that the beneficial action of b-blockade in dogs or patients with heart failure is at least partly due to its HR-lowering effect (Packer et al, 1996;Nagatsu et al, 2000). Thus, HR reduction per se emerges as a potential therapeutic target for heart disease.…”

Section: Introductionmentioning

confidence: 99%

I_f channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities

Gao

et al. 2004

British J Pharmacology

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1 Ivabradine selectively reduces heart rate (HR) by inhibiting the cardiac pacemaker I f current, thus prolonging the duration of spontaneous depolarization in the sinus node. The activity of ivabradine under conditions of enhanced sympathoadrenergic activity has been addressed by investigating the effects of repeated oral administration in mice with sympathoadrenergic activation due to either stress, cardiac-restricted overexpression of b 2 -adrenergic receptors (b 2 AR), or b-agonist administration. HR and left ventricular fractional shortening (FS) were determined by echocardiography.2 Initial experiments showed that the conscious restrained state was associated with stress-mediated sympathetic activation, while sympathetic withdrawal occurred under anaesthetized conditions. In wild-type mice, ivabradine reduced HR under both conscious and anaesthetized states, with a similar degree in absolute reduction under both states. FS was unchanged by the treatment. 3 Ivabradine was similarly effective in reducing HR in the b 2 AR transgenic mice. Further, ivabradine at 10 mg kg À1 day À1 reduced the maximal HR increase in response to the b-agonist isoproterenol, without modifying the response of contractile parameters. 4 These data indicate that oral administration of ivabradine in mice reduces HR while ventricular performance is maintained. This specific HR-reducing action of ivabradine is well preserved under conditions that are associated with significant activation of the sympathoadrenergic system.

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“…Although the exact mechanisms by which ␤-blockers improve survival in patients with heart failure are not yet established, we found that ␤-blockers ameliorate LV contractile dysfunction in experimental chronic mitral regurgitation (MR) by restoring cellular contractile elements (27). However, this improvement did not occur when bradycardia was prevented by atrial pacing (17). These findings suggested that the LV dysfunction that develops in experimental chronic MR is at least in part heart rate dependent; this notion is supported by clinical heart failure trials in which patients with the fastest pretreatment heart rates had the most improvement when ␤-blockers were administered (14).…”

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confidence: 91%

PPAR-γ agonist rosiglitazone ameliorates ventricular dysfunction in experimental chronic mitral regurgitation

Nemoto¹,

Razeghi²,

Ishiyama³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Previously we reported that the beneficial effects of β-adrenergic blockade in chronic mitral regurgitation (MR) were in part due to induction of bradycardia, which obviously affects myocardial energy requirements. From this observation we hypothesized that part of the pathophysiology of MR may involve faulty energy substrate utilization, which in turn might lead to potentially harmful lipid accumulation as observed in other models of heart failure. To explore this hypothesis, we measured triglyceride accumulation in the myocardia of dogs with chronic MR and then attempted to enhance myocardial metabolism by chronic administration of the peroxisome proliferator-activated receptor (PPAR)-γ agonist rosiglitazone. Cardiac tissues were obtained from three groups of dogs that included control animals, dogs with MR for 3 mo without treatment, and dogs with MR for 6 mo that were treated with rosiglitazone (8 mg/day) for the last 3 mo of observation. Hemodynamics and contractile function (end-systolic stress-strain relationship, as measured by K index) were assessed at baseline, 3 mo of MR, and 6 mo of MR (3 mo of the treatment). Lipid accumulation in MR (as indicated by oil red O staining score and TLC analysis) was marked and showed an inverse correlation with the left ventricular (LV) contractility. LV contractility was significantly restored after PPAR therapy (K index: therapy, 3.01 ± 0.11*; 3 mo MR, 2.12 ± 0.34; baseline, 4.01 ± 0.29; ANOVA, P = 0.038; * P < 0.05 vs. 3 mo of MR). At the same time, therapy resulted in a marked reduction of intramyocyte lipid. We conclude that 1) chronic MR leads to intramyocyte myocardial lipid accumulation and contractile dysfunction, and 2) administration of the PPAR-γ agonist rosiglitazone ameliorates MR-induced LV dysfunction accompanied by a decline in lipid content.

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Bradycardia and the Role of β-Blockade in the Amelioration of Left Ventricular Dysfunction

Abstract: We conclude that institution of bradycardia is a major mechanism by which beta-blockers are effective for restoration of contractile function in a model of LV dysfunction.

Cited by 83 publications

References 38 publications

Long-Term Heart Rate Reduction Induced by the Selective I _f Current Inhibitor Ivabradine Improves Left Ventricular Function and Intrinsic Myocardial Structure in Congestive Heart Failure

Long-Term Heart Rate Reduction Induced by the Selective I _f Current Inhibitor Ivabradine Improves Left Ventricular Function and Intrinsic Myocardial Structure in Congestive Heart Failure

I_f channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities

PPAR-γ agonist rosiglitazone ameliorates ventricular dysfunction in experimental chronic mitral regurgitation

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Bradycardia and the Role of β-Blockade in the Amelioration of Left Ventricular Dysfunction

Abstract: We conclude that institution of bradycardia is a major mechanism by which beta-blockers are effective for restoration of contractile function in a model of LV dysfunction.

Cited by 83 publications

References 38 publications

Long-Term Heart Rate Reduction Induced by the Selective I f Current Inhibitor Ivabradine Improves Left Ventricular Function and Intrinsic Myocardial Structure in Congestive Heart Failure

Long-Term Heart Rate Reduction Induced by the Selective I f Current Inhibitor Ivabradine Improves Left Ventricular Function and Intrinsic Myocardial Structure in Congestive Heart Failure

If channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities

PPAR-γ agonist rosiglitazone ameliorates ventricular dysfunction in experimental chronic mitral regurgitation

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Long-Term Heart Rate Reduction Induced by the Selective I _f Current Inhibitor Ivabradine Improves Left Ventricular Function and Intrinsic Myocardial Structure in Congestive Heart Failure

Long-Term Heart Rate Reduction Induced by the Selective I _f Current Inhibitor Ivabradine Improves Left Ventricular Function and Intrinsic Myocardial Structure in Congestive Heart Failure

I_f channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities