Calcium Channel Blockers in Heart Failure

Elkayam, Uri

doi:10.1159/000047278

Cited by 56 publications

(15 citation statements)

References 47 publications

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“…Knockout of UCP3 increases the efficiency of ATP generation in skeletal muscle without affecting tricarboxylic acid cycle flux rate [37], and it is reasonable to assume that increased expression of UCP3 in the heart would predict reduction in the efficiency of ATP generation and have deleterious effects on cardiac function; however STC1 Tg mice display no overt cardiac phenotype. Moreover, while STC1 inhibits L-type calcium channels in cultured cardiomyocytes [1], an effect that may have a negative impact on myocardial contractility and blood pressure, particularly in the setting of heart failure [38], we observe normal blood pressure in STC1 Tg mice, and unpublished observations from our lab suggest that STC1 Tg mice outlive WT littermates.…”

Section: Discussionsupporting

confidence: 57%

Human Stanniocalcin-1 Suppresses Angiotensin II-Induced Superoxide Generation in Cardiomyocytes through UCP3-Mediated Anti-Oxidant Pathway

et al. 2012

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RationaleWe have previously shown increased cardiac stanniocalcin-1 (STC1) in patients with idiopathic dilated cardiomyopathy. STC1 localizes to the inner mitochondrial membrane and transgenic over-expression of STC1 is associated with increased energy utilization.ObjectiveWe examined the hypothesis that STC1 uncouples mitochondrial oxidative phosphorylation - to suppress superoxide generation and modulate neurohormonal effects on cardiomyocytes.Methods and ResultsCompared to WT mouse heart, STC1 Tg heart displays: 2-fold higher uncoupling protein 3 (UCP3) levels, but no effect on UCP2 protein; 40% lower ATP levels; but similar activities of respiratory chain complexes I-IV. In cultured adult rat and freshly-isolated mouse cardiomyocytes, rSTC1 induces UCP3, but not UCP2. Treatment of cardiomyocytes with STC1 decreases mitochondrial membrane potential and suppresses baseline and angiotensin II (Ang II)-induced superoxide generation. Furthermore, baseline superoxide generation is higher in freshly-isolated adult UCP3−/− mouse cardiomyocytes compared to WT, suggesting an important role for UCP3 in regulating cardiomyocyte ROS under physiologic conditions. Treatment of UCP3−/− cardiomyocytes with rSTC1 failed to suppress superoxide generation, suggesting that the effects of STC1 on superoxide generation in cardiomyocytes are UCP3-dependent.ConclusionSTC1 activates a novel anti-oxidant pathway in cardiac myocytes through induction of UCP3, and may play an important role in suppressing ROS in the heart under normal physiologic conditions and ameliorate the deleterious effects of Ang II-mediated cardiac injury. Importantly, our data point to a critical role for the mitochondria in regulating ROS generation in response to Ang II.

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Section: Discussionsupporting

confidence: 57%

Human Stanniocalcin-1 Suppresses Angiotensin II-Induced Superoxide Generation in Cardiomyocytes through UCP3-Mediated Anti-Oxidant Pathway

et al. 2012

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“…The decrease in bilirubin levels of the verapamil-treated patients may be related to the reduced hepatic congestion or improvement in hepatic perfusion or both. Additionally, the decrease in right ventricular diastolic dimension in our study and the serum uric acid levels in the verapamil-treated patients provide further evidence that the benefit of calcium antagonists may be mainly attributed to the direct peripheral vascular effects of the drugs associated with the diminishing of augmented peripheral vascular resistance and endothelial dysfunction [25,26,27]. …”

Section: Discussionmentioning

confidence: 56%

Therapeutic Window for Calcium-Channel Blockers in the Management of Dilated Cardiomyopathy: A Prospective, Two-Centre Study on Non-Advanced Disease

et al. 2010

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Objective: This study aimed to investigate the usefulness of the calcium-channel blocker verapamil in non-advanced dilated cardiomyopathy (DCM). Methods: This was a randomised trial of 70 DCM patients treated with carvedilol (36 patients) and verapamil (instead of β-blocker; 34 patients) for 12 months. The remaining heart failure (HF) therapy was constant in both groups. The primary outcomes were to determine selected echocardiography parameters and functional status of patients. The secondary outcome included death, heart transplantation and re-hospitalisation due to HF progression. Results: Of the primary outcomes, only the mean ratio of early to late transmitral flow velocities increased significantly in the verapamil-treated patients as compared with the carvedilol-based therapy (1.1 ± 0.3 vs. 0.7 ± 0.2; 95% CI –0.6 to –0.1; p = 0.015). Simultaneously, the Minnesota Quality of Life improved significantly in the verapamil group (95% CI 5.2–19.9; p = 0.002). It was accompanied by the favourable effect of verapamil therapy on exercise capacity in the 6-min walk test (95% CI 21.3–110.7; p = 0.005). Conclusion: The addition of verapamil to angiotensin-converting enzyme and aldosterone inhibitors in non-advanced DCM patients has been shown to have a neutral or even positive effect in a few patients.

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“…10,26,27 We hypothesized that pregabalin's action on the L-type calcium channels would increase the risk of heart failure analogous to other calcium channel blockers. 1,28 Our null findings may reflect our comparison drug, gabapentin. It is possible that the shared mechanism of action imparted similar cardiac risk despite gabapentin's decreased potency.…”

Section: Discussionmentioning

confidence: 81%