Heart rate reduction with ivabradine increases ischaemia-induced ventricular fibrillation threshold: role of myocyte structure and myocardial perfusion

Aims

We showed previously that ivabradine (IVA), a selective inhibitor of the cardiac pacemaker I_f current, achieved protection against ischaemia-induced ventricular fibrillation (VF) in pigs by increasing the VF threshold (VFT). This was correlated to the heart rate reduction (HRR), the limitation of monophasic action potential shortening and the reduction of the hypoxic area. This study investigated myocyte ultrastructure and regional myocardial blood flow (RMBF), potentially involved in these cardioprotective effects of IVA.

Methods and results

Myocardial ischaemia was induced in pigs by total 1-min occlusion of the left anterior descending coronary artery following i.v. administration of saline (n = 6) or IVA (0.25 mg/kg, n = 6). Electrophysiological and haemodynamic parameters, the hypoxic area and the presence of myocyte ultrastructural lesions were evaluated. The RMBF was assessed using positron emission tomography following ischaemia/reperfusion in IVA (0.25 mg/kg, i.v., n = 6) or vagal stimulation (n = 4) groups. Compared with saline, IVA induced a 32% HRR (p < 0.01), a 2.9-fold increase in the VFT (p < 0.001) and a reduction of the hypoxic area without any change in left ventricular dP/dt_max. IVA preserved cardiomyocyte morphology, particularly mitochondrial ultrastructure. Compared with baseline, RMBF during reperfusion was increased in the hypoxic area following IVA administration (+218% vs. +97%, p < 0.05) or vagal stimulation (+195% vs. +127%, p < 0.05). This increase was sharply reduced by atrial pacing in IVA-group.

Conclusion

IVA exerts a cardioprotection from ischaemia-induced VF by increasing RMBF and preserving cardiomyocyte and mitochondrial ultrastructure, which opens new perspectives regarding potential targets that would be involved in the anti-ischaemic effects of IVA.     

Does terfenadine-induced ventricular tachycardia/fibrillation directly relate to its QT prolongation and Torsades de Pointes?

BACKGROUND AND PURPOSE

Terfenadine has been reported to cause cardiac death. Hence, we investigated its pro-arrhythmic potential in various in vitro models.

EXPERIMENTAL APPROACH

Pro-arrhythmic effects of terfenadine were investigated in rabbit isolated hearts and left ventricular wedge preparations. Also, using whole-cell patch-clamp recording, we examined its effect on the human ether-à-go-go-related gene (hERG) current in HEK293 cells transfected with hERG and on the I_Na current in rabbit ventricular cells and human atrial myocytes.

KEY RESULTS

Terfenadine concentration- and use-dependently inhibited I_Na in rabbit myocytes and in human atrial myocytes and also inhibited the hERG. In both the rabbit left ventricular wedge and heart preparations, terfenadine at 1 µM only slightly prolonged the QT- and JT-intervals but at 10 µM, it caused a marked widening of the QRS complex, cardiac wavelength shortening, incidences of in-excitability and non-TdP-like ventricular tachycardia/fibrillation (VT/VF) without prolongation of the QT/JT-interval. At 10 µM terfenadine elicited a lower incidence of early afterdepolarizations versus non- Torsades de Pointes (TdP)-like VT/VF (100% incidence), and did not induce TdPs. Although the concentration of terfenadine in the tissue-bath was low, it accumulated within the heart tissue.

CONCLUSION AND IMPLICATIONS

Our data suggest that: (i) the induction of non-TdP-like VT/VF, which is caused by slowing of conduction via blockade of I_Na (like Class Ic flecainide), may constitute a more important risk for terfenadine-induced cardiac death; (ii) although terfenadine is a potent hERG blocker, the risk for non-TdP-like VT/VF exceeds the risk for TdPs; and (iii) cardiac wavelength (λ) could serve as a biomarker to predict terfenadine-induced VT/VF.     

The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

Ambient particulate matter (PM) can increase the incidence of arrhythmia. However, the arrhythmogenic mechanism of PM is poorly understood. This study investigated the arrhythmogenic mechanism of PM. In Sprague-Dawley rats, QT interval was increased from 115.0 ± 14.0 to 142.1 ± 18.4 ms (p = 0.02) after endotracheal exposure of DEP (200 μg/ml for 30 min, n = 5). Ventricular premature contractions were more frequently observed after DEP exposure (100%) than baseline (20%, p = 0.04). These effects were prevented by pretreatment of N-acetylcysteine (NAC, 5 mmol/L, n = 3). In 12 Langendorff-perfused rat hearts, DEP infusion of 12.5 μg/ml for 20 min prolonged action potential duration (APD) at only left ventricular base increasing apicobasal repolarization gradients. Spontaneous early afterdepolarization (EAD) and ventricular tachycardia (VT) were observed in 8 (67%) and 6 (50%) hearts, respectively, versus no spontaneous triggered activity or VT in any hearts before DEP infusion. DEP-induced APD prolongation, EAD and VT were successfully prevented with NAC (5 mmol/L, n = 5), nifedipine (10 μmol/L, n = 5), and active Ca^2 +/calmodulin-dependent protein kinase II (CaMKII) blockade, KN 93 (1 μmol/L, n = 5), but not by thapsigargin (200 nmol/L) plus ryanodine (10 μmol/L, n = 5) and inactive CaMKII blockade, KN 92 (1 μmol/L, n = 5). In neonatal rat cardiomyocytes, DEP provoked ROS generation in dose dependant manner. DEP (12.5 μg/ml) induced apoptosis, and this effect was prevented by NAC and KN 93. Thus, this study shows that in vivo and vitro exposure of PM induced APD prolongation, EAD and ventricular arrhythmia. These effects might be caused by oxidative stress and CaMKII activation.     

Predictor of rehabilitation outcome for dysphagia

Objective

Predicting whether dysphagia will resolve is very difficult, but is obviously important for patients and their families as well as for physicians. This study retrospectively evaluated potential prognostic indicators for dysphagia in order to examine the feasibility of predicting the outcome.

Methods

Data on 123 patients who received initial treatment for dysphagia between April 2008 and March 2010 were reviewed. The patient population included 63 men and 60 women, with a mean age of 81.4 years. All the patients underwent physical examination and video-endoscopy (VE) at the initial assessment, and video-fluorography (VF) was also done if necessary. We used the “Food Intake Level Scale” (FILS) to classify the severity of dysphagia as follows: “no oral intake” (FILS score: 1–3), “oral intake and alternative nutrition” (FILS score: 4–6), and “oral intake alone” (FILS score: 7–10). The patient's age, primary disease, cognitive ability, and general condition were evaluated as potential factors associated with the severity of dysphagia. Each patient underwent assessment at every 2 weeks to evaluate the progress of their dysphagia.

Results

Forty-six patients were classified as “no oral intake” (FILS score: 1–3) at the initial examination and subsequently showed improvement to “oral intake and alternative nutrition” (FILS score: 4–6) or “oral intake alone” (FILS score: 7–10). They were compared with 43 patients who were also “no oral intake” at the second examination after training in swallowing. The combination of stroke and cognitive dysfunction showed a sensitivity of 75.9% (22/29) and specificity of 78.3% (18/23) for predicting no improvement of dysphagia, and was a statistically significant parameter. The presence of disuse syndrome showed a sensitivity of 66.0% (31/47) and specificity of 71.4% (30/42) for predicting no improvement of dysphagia, and this was also a significant parameter.

Conclusion

The results of this study suggest that a combination of factors other than stroke, including cognitive dysfunction and a decrease in activity of daily living (ADL) influence the outcome of dysphagia. It is not rare for patients who resume oral intake to be readmitted within a year for symptoms such as fever. Therefore, effective rehabilitation programs should be developed for the impairments of elderly patients and common disabilities such as dysphagia.     

Prevention of sudden cardiac death beyond the ICD: Have we reached the boundary or are we just burning the surface?

Preventing sudden cardiac death (SCD) remains a major unsolved problem in contemporary medical practice. As the most common cause of SCD, treatment for ventricular arrhythmias is the target area of interest in research field. While implantable cardioverter-defibrillator (ICD) effectively decreases death from ventricular arrhythmias in highly selected patients, risk of inappropriate shocks, mortality from frequent therapy, chance of failing in abortion of arrhythmias despite having a defibrillator, and our inability to recognize which of several hundreds of thousands of patients at risk for sudden death but do not meet current criteria for defibrillator, limit ICD effectiveness. In this article, a brief review of mechanism leading to SCD, the existing evidence for a defibrillator and the lacunae in present guidelines for patients clearly at risk for sudden death but without proven benefit from a defibrillator are presented in Section I. Following this, interventional approaches, both catheter-based and general measures that may serve as adjuncts to a defibrillator in preventing this all too common catastrophic end event, are summarized in Section II.     

The Pyhäjärvi Cataract Study II. Criteria for cataract surgery

Purpose: It is necessary to develop tools for patient selection to target cataract surgery to patients with the best expected outcomes. We used visual acuity, visual functioning 14 (VF‐14) test, the 15‐dimension health‐related quality‐of‐life questionnaire (15D) and the New Zealand priority criteria to evaluate the criteria for cataract surgery in a post hoc setting. Material and methods: Ninety‐three consecutive patients living in a defined rural area in Finland had cataract surgery as a part of the Pyhäjärvi Cataract Study in 2003. Success of cataract surgery was defined as improvement of visual acuity by at least 2 lines and/or improvement of visual function measured by questionnaires. Results: The patients with a visual acuity of 0.30 logMAR (0.5 Snellen decimal) or worse in the better eye and/or 0.52 logMAR (0.3 Snellen decimal) in the worse eye had successful surgery in 59–83% of cases depending on the definition of success. When subjective judgement was added, the success rates varied between 63% and 91%. Conclusion: Setting indication criteria, it seems sufficient to use two global questions in addition to visual acuity: one on the subjective view on disability, and one on a more neutral view on visual function, such as the 15D item on vision. The VF‐14 did not perform any better than the single item counterparts.