The link between repolarisation alternans and ventricular arrhythmia: Does the cellular phenomenon extend to the clinical problem?

T-wave alternans is considered a potentially useful clinical marker for the risk of ventricular arrhythmia in patients with heart disease. Cellular repolarisation alternans is thought to underlie T-wave alternans, and moreover, to cause re-entrant ventricular arrhythmia. This review examines the experimental and clinical evidence linking repolarisation alternans and T-wave alternans with the occurrence of ventricular arrhythmia. Repolarisation alternans, manifest as alternating changes in action potential duration, is observed in isolated ventricular cardiomyocytes and in multicellular preparations. Its underlying causes are discussed particularly with respect to the role of intracellular Ca2+. The repolarisation alternans observed at the single cell level is compared to the alternating behaviour observed in isolated multicellular preparations including the perfused ventricular wedge and Langendorff perfused heart. The evidence concerning spatial differences in repolarisation alternans is considered, particularly the situation where adjacent regions of myocardium exhibit repolarisation alternans of different phases. This extreme behaviour, known as discordant alternans, is thought to produce marked gradients of repolarisation that can precipitate unidirectional block and re-entrant ventricular arrhythmias. Finally, the difficulties in extrapolating between experimental models of alternans and arrhythmias and the clinical manifestation are discussed. The areas where experimental evidence is weak are highlighted, and areas for future research are outlined

Local β-adrenergic stimulation overcomes source-sink mismatch to generate focal arrhythmia

<b>Rationale:</b> β-Adrenergic receptor stimulation produces sarcoplasmic reticulum Ca<sup>2+</sup> overload and delayed afterdepolarizations in isolated ventricular myocytes. How delayed afterdepolarizations are synchronized to overcome the source-sink mismatch and produce focal arrhythmia in the intact heart remains unknown. <b>Objective:</b> To determine whether local β-adrenergic receptor stimulation produces spatiotemporal synchronization of delayed afterdepolarizations and to examine the effects of tissue geometry and cell-cell coupling on the induction of focal arrhythmia. <b>Methods and Results:</b> Simultaneous optical mapping of transmembrane potential and Ca<sup>2+</sup> transients was performed in normal rabbit hearts during subepicardial injections (50 μ) of norepinephrine (NE) or control (normal Tyrode's solution). Local NE produced premature ventricular complexes (PVCs) from the injection site that were dose-dependent (low-dose [30-60 μmol/L], 0.45±0.62 PVCs per injection; high-dose [125-250 μmol/L], 1.33±1.46 PVCs per injection; P<0.0001) and were inhibited by propranolol. NE-induced PVCs exhibited abnormal voltage-Ca<sup>2+</sup> delay at the initiation site and were inhibited by either sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup>-ATPase inhibition or reduced perfusate [Ca<sup>2+</sup>], which indicates a Ca<sup>2+</sup>-mediated mechanism. NE-induced PVCs were more common at right ventricular than at left ventricular sites (1.48±1.50 versus 0.55±0.89, P<0.01), and this was unchanged after chemical ablation of endocardial Purkinje fibers, which suggests that source-sink interactions may contribute to the greater propensity to right ventricular PVCs. Partial gap junction uncoupling with carbenoxolone (25 μmol/L) increased focal activity (2.18±1.43 versus 1.33±1.46 PVCs per injection, P<0.05), which further supports source-sink balance as a critical mediator of Ca<sup>2+</sup>-induced PVCs. <b>Conclusions:</b> These data provide the first experimental demonstration that localized β-adrenergic receptor stimulation produces spatiotemporal synchronization of sarcoplasmic reticulum Ca<sup>2+</sup> overload and release in the intact heart and highlight the critical nature of source-sink balance in initiating focal arrhythmias

Ermittlung der Schwingfestigkeiten von Schweissverbindungen auf der Grundlage von FE-Rechnungen im elastisch-plastischen Bereich. T. 1

TIB: RO 1533 (1983,4) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

The vascular effects of rotigaptide in vivo in man

En dothelium-derived hyperpolarising factor (EDHF) causes vasorelaxation and may contribute to the release of the endogenous fibrinolytic factor, tissue-plasminogen activator (t-PA). Rotigaptide enhances communication via the connexin 43 gap junction subunit and may potentiate the vascular actions of EDHF. The aims of the present study were therefore to determine whether rotigaptide influences basal and stimulated endothelium-dependent vasodilatation and t-PA release in vivo in man. Using venous occlusion plethysmography, forearm blood flow was measured in 27 healthy volunteers during intra-brachial infusions of rotigaptide (0.25-25 nmol/min) alone, or co-administered with endothelium-dependent (acetylcholine [5-20 mu g/min] and bradykinin [30-300 pmol/min]) and independent (sodium nitroprusside 12-8 mu g/min])) vasodilators in the presence or absence of aspirin and the 'nitric oxide clamp'. The 'nitric oxide clamp' inhibits endogenous nitric oxide synthesis with L-N-monomethylarginine and restores resting blood flow with the exogenous nitric oxide donor, sodium nitroprusside. Basal blood flow was unaffected by rotigaptide (P = NS). Acetylcholine, bradykinin and sodium nitroprusside all caused dose-dependent vasodilatation in the presence and absence of aspirin and the 'nitric oxide clamp' (P <= 0.005 for all). These responses were unaffected by rotigaptide (P = NS). Bradykinin caused t-PA antigen and activity release (P = 0.04, P <= 0.0001, respectively) that was unaffected by rotigaptide. Augmentation of connexin 43 communication has no effect on basal vascular tone and does not enhance endothelium-dependent or independent vasodilatation, or t-PA release in the forearm arterial circulation of healthy men. It remains to be established whether augmentation of connexin 43 communication improves endothelial function in patients with vascular diseas

Subepicardial action potential characteristics are a function of depth and activation sequence in isolated rabbit hearts

<p>Background—Electric excitability in the ventricular wall is influenced by cellular electrophysiology and passive electric properties of the myocardium. Action potential (AP) rise time, an indicator of myocardial excitability, is influenced by conduction pattern and distance from the epicardial surface. This study examined AP rise times and conduction velocity as the depolarizing wavefront approaches the epicardial surface.</p> <p>Methods and Results—Two-photon excitation of di-4-aminonaphthenyl-pyridinum-propylsulfonate was used to measure electric activity at discrete epicardial layers of isolated Langendorff-perfused rabbit hearts to a depth of 500 μm. Endo-to-epicardial wavefronts were studied during right atrial or ventricular endocardial pacing. Similar measurements were made with epi-to-endocardial, transverse, and longitudinal pacing protocols. Results were compared with data from a bidomain model of 3-dimensional (3D) electric propagation within ventricular myocardium. During right atrial and endocardial pacing, AP rise time (10%–90% of upstroke) decreased by ≈50% between 500 and 50 μm from the epicardial surface, whereas conduction velocity increased and AP duration was only slightly shorter (≈4%). These differences were not observed with other conduction patterns. The depth-dependent changes in rise time were larger at higher pacing rates. Modeling data qualitatively reproduced the behavior seen experimentally and demonstrated a parallel reduction in peak INa and electrotonic load as the wavefront approaches the epicardial surface.</p> <p>Conclusions—Decreased electrotonic load at the epicardial surface results in more rapid AP upstrokes and higher conduction velocities compared with the bulk myocardium. Combined effects of tissue depth and pacing rate on AP rise time reduce conduction safety and myocardial excitability within the ventricular wall.</p&gt

Feasibility/eligibility of T-wave alternans testing in patients with heart failure: should we rethink our current modus operandi?: reply

We appreciate the interest of Dr Madias in our study regarding microvolt T-wave alternans testing. He addresses the important issue of eligibility for MTWA testing and identifies several recent studies where a large proportion of unselected patients have been ineligible for MTWA testing. However, Dr Madias suggests that implantable cardioverter-defibrillators (ICDs) may be recommended for certain patients including those ineligible for MTWA testing and proposes that MTWA testing may have a role in specific settings. There is no evidence to support any role for MTWA in the contemporary risk stratification of patients with heart failure. At present the use of MTWA testing can be justified for research purposes only. Patients should not be exposed to a test that has never been shown to be of any clinical value. An ICD should only be considered in patients fulfilling the evidence-based criteria laid out in guidelines

Microvolt T-wave alternans (MTWA) testing in 'real world' heart failure (HF): a study of prevalence and incremental prognostic value

Background Ventricular arrhythmias contribute to the high risk of death in heart failure (HF) and can be treated with an implantable cardioverter-defibrillator (ICD). Microvolt T-wave alternans (MTWA) testing examines beat-to-beat fluctuations in the morphology of the T-wave. Alternans is believed to reflect dynamic instability of repolarisation and to be linked, mechanistically, to ventricular arrhythmias. Observational studies in highly selected populations have suggested that MTWA testing may identify individuals likely to benefit from a primary prevention ICD. The aims of this study were to evaluate the applicability of MTWA testing in an unselected cohort of patients recently hospitalised with HF and determine the prevalence and incremental prognostic value of an abnormal test.<p></p> Methods Consecutive admissions with confirmed HF (typical clinical findings and BNP>100 pg/ml) were recruited in three hospitals from 1 December 2006 to 12 January 2009. Survivors were invited to attend 1-month post-discharge for MTWA testing (HearTWave II, Cambridge Heart).<p></p> Results 648 of 1003 patients recruited returned for MTWA testing (58% males, mean age 70.8 years). 318 patients (49%) were ineligible for MTWA testing due to atrial fibrillation (AF), pacemaker-dependency or inability to exercise. Of the 330 patients who underwent MTWA treadmill testing, 100 (30%) were positive, 78 (24%) were negative and 152 (46%) were indeterminate. Failure to achieve the target heart rate due to chronotropic incompetence, secondary to β-blocker therapy or physical limitations, accounted for 75% of indeterminate tests. 131 deaths occurred during a mean follow-up of 18 months. 23% of ineligible patients died vs 17% of eligible patients. 12%, 20% and 19% of patients with a positive, negative and indeterminate test, respectively, died (p=0.24). MTWA results were analysed in the accepted way of non-negative (positive and indeterminate) and negative, but there was still no difference in mortality between the groups (p=0.39). MTWA showed no incremental prognostic value in a multivariable mortality model. The independent predictors of mortality were: lower body mass index (HR 0.96 [95% CI 0.93 to 0.99], p=0.01), New York Heart Association class III–IV (1.72 [95% CI 1.2 to 2.47], p=0.003), previous myocardial infarction (1.68 [95% CI 1.18 to 2.4], p=0.004), elevated B-type natriuretic peptide concentration (1.36 [95% CI 1.12 to 1.65], p=0.002) and elevated troponin (1.57 [95% CI 1.04 to 2.37], p=0.03).<p></p> Conclusion MTWA treadmill-testing was not widely applicable in typical patients with HF and failed to predict mortality risk. At present MTWA cannot be endorsed as a tool for improving risk stratification in HF.<p></p&gt

Changes in regional cerebral blood flow elicited by craving memories in abstinent opiate-dependent subjects

Objective: The brain circuitry of opiate craving was investigated with positron emission tomography (PET) imaging of regional cerebral blood flow (rCBF)

Brain dopamine response in human opioid addiction

BACKGROUND: Drugs of dependence cause dopamine release in the rat striatum. Human neuroimaging studies have shown an increase in dopamine in the equivalent region in response to stimulants and other drugs. AIMS: We tested whether opioids provoke dopamine release and its relationship to the subjective experience. METHOD: In two combined studies 14 heroin addicts on methadone maintenance treatment underwent two positron emission tomography brain scans of the dopamine system using [(11)C]-raclopride following an injection of placebo and either 50 mg intravenous diamorphine or 10 mg subcutaneous hydromorphone in a double-blind, random order design. RESULTS: Both opioids produced marked subjective and physiological effects, but no measurable change in [(11)C]-raclopride binding. CONCLUSIONS: The absence of a dopamine response to opioid agonists contrasts with that found with stimulant drugs and suggests dopamine may not play the same role in addiction to opioids. This questions the role of dopamine in the subjective experience of heroin in opioid addicts

Rationale, objectives, and design of the EUTrigTreat clinical study: A prospective observational study for arrhythmia risk stratification and assessment of interrelationships among repolarization markers and genotype

Aims The EUTrigTreat clinical study has been designed as a prospective multicentre observational study and aims to (i) risk stratify patients with an implantable cardioverter defibrillator (ICD) for mortality and shock risk using multiple novel and established risk markers, (ii) explore a link between repolarization biomarkers and genetics of ion (Ca 2, Na, K) metabolism, (iii) compare the results of invasive and non-invasive electrophysiological (EP) testing, (iv) assess changes of non-invasive risk stratification tests over time, and (v) associate arrythmogenomic risk through 19 candidate genes. Methods and resultsPatients with clinical ICD indication are eligible for the trial. Upon inclusion, patients will undergo non-invasive risk stratification, including beat-to-beat variability of repolarization (BVR), T-wave alternans, T-wave morphology variables, ambient arrhythmias from Holter, heart rate variability, and heart rate turbulence. Non-invasive or invasive programmed electrical stimulation will assess inducibility of ventricular arrhythmias, with the latter including recordings of monophasic action potentials and assessment of restitution properties. Established candidate genes are screened for variants. The primary endpoint is all-cause mortality, while one of the secondary endpoints is ICD shock risk. A mean follow-up of 3.3 years is anticipated. Non-invasive testing will be repeated annually during follow-up. It has been calculated that 700 patients are required to identify risk predictors of the primary endpoint, with a possible increase to 1000 patients based on interim risk analysis. ConclusionThe EUTrigTreat clinical study aims to overcome current shortcomings in sudden cardiac death risk stratification and to answer several related research questions. The initial patient recruitment is expected to be completed in July 2012, and follow-up is expected to end in September 2014. © The Author 2011