Reappraisal of Atrial fibrillation: interaction between hyperCoagulability, Electrical remodelling and Vascular destabilisation in the progression of AF (RACE V) Tissue Bank Project: study design.

BACKGROUND: The development of atrial fibrillation (AF) is a complex multifactorial process. Over the past few decades, much has been learned about the pathophysiological processes that can lead to AF from a variety of specific disease models in animals. However, our ability to recognise these disease processes in AF patients is still limited, which has contributed to the limited progress in improving rhythm control in AF. AIMS/OBJECTIVES: We believe that a better understanding and detection of the individual pathophysiological mechanisms underlying AF is a prerequisite for developing patient-tailored therapies. The RACE V Tissue Bank Project will contribute to the unravelling of the main molecular mechanisms of AF by studying histology and genome-wide RNA expression profiles and combining this information with detailed phenotyping of patients undergoing cardiac surgery. METHODS: As more and more evidence suggests that AF may occur not only during the first days but also during the months and years after surgery, we will systematically study the incidence of AF during the first years after cardiac surgery in patients with or without a history of AF. Both the overall AF burden as well as the pattern of AF episodes will be studied. Lastly, we will study the association between the major molecular mechanisms and the clinical presentation of the patients, including the incidence and pattern of AF during the follow-up period. CONCLUSION: The RACE V Tissue Bank Project combines deep phenotyping of patients undergoing cardiac surgery, including rhythm follow-up, analysis of molecular mechanisms, histological analysis and genome-wide RNA sequencing. This approach will provide detailed insights into the main pathological alterations associated with AF in atrial tissue and thereby contribute to the development of individualised, mechanistically informed patient-tailored treatment for AF.

Stroke risk in patients with device-detected atrial high-rate episodes.

Cardiovascular implantable electronic devices (CIEDs) can detect atrial arrhythmias, i. e. atrial high-rate episodes (AHRE). The thrombo-embolic risk in patients showing AHRE appears to be lower than in patients with clinical atrial fibrillation (AF) and it is unclear whether the former will benefit from oral anticoagulants. Based on currently available evidence, it seems reasonable to consider antithrombotic therapy in patients without documented AF showing AHRE >24 hours and a CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes mellitus, prior stroke [doubled], vascular disease, age 65-74 years and female sex) ≥1, awaiting definite answers from ongoing randomised clinical trials. In patients with AHRE <24 hours, current literature does not support starting oral anticoagulation. In these patients, intensifying CIED read-outs can be considered to find progression in AHRE duration sooner, enhancing timely stroke prevention. The notion that AHRE and stroke coincide perseveres but should be abandoned since CIED data show a clear disconnect.

Current controversies in determining the main mechanisms of atrial fibrillation.

Despite considerable basic research into the mechanisms of atrial fibrillation (AF), not much progress has been made in the prognosis of patients with AF. With the exception of anticoagulant therapy, current treatments for AF still do not improve major cardiovascular outcomes. This may be due partly to the diverse aetiology of AF with increasingly more factors found to contribute to the arrhythmia. In addition, a strong increase has been seen in the technological complexity of the methods used to quantify the main pathophysiological alterations underlying the initiation and progression of AF. Because of the lack of standardization of the technological approaches currently used, the perception of basic mechanisms of AF varies widely in the scientific community. Areas of debate include the role of Ca(2+) -handling alterations associated with AF, the contribution and noninvasive assessment of the degree of atrial fibrosis, and the best techniques to identify electrophysiological drivers of AF. In this review, we will summarize the state of the art of these controversial topics and describe the diverse approaches to investigating and the scientific opinions on leading AF mechanisms. Finally, we will highlight the need for transparency in scientific reporting and standardization of terminology, assumptions, algorithms and experimental conditions used for the development of better AF therapies.

Tailored treatment strategies: a new approach for modern management of atrial fibrillation.

Atrial fibrillation (AF) is not benign. Cardiovascular diseases and risk factors differ importantly amongst patients. Careful phenotyping with the aim to start tailored therapy may improve outcome and quality of life. Furthermore, structural remodelling plays an important role in initiation and progression of AF. Therapies that interfere in the remodelling processes are promising because they may modify the atrial substrate. However, success is still limited probably due to variations in the underlying substrate in individual patients. The most favourable effects of lifestyle changes on success of rhythm control have been demonstrated in obese patients with AF. Differences in genotype may also play an important role. Common gene variants have been associated with recurrence of AF after electrical cardioversion, antiarrhythmic drug therapy and catheter ablation. Therefore, both phenotyping and genotyping may become useful for patient selection in the future. Beside the choice of rate or rhythm control, and type of rhythm control, prevention of complications associated with AF may also differ depending on genotype and phenotype. Efficacy of stroke prevention has been well established, but bleeding remains a clinically relevant problem. Risk stratification is still cumbersome, especially in low-risk patients and in those with a high bleeding risk. The decision whether to start anticoagulation (and if so which type of anticoagulant) or, alternatively, to implant an occlusion device of the left atrial appendage may also be improved by genotyping and phenotyping. In this review, we will summarize new insights into the roles of phenotype and genotype in generating more tailored treatment strategies in patients with AF and discuss several patient-tailored treatment options.

Smartphone and wearable detected atrial arrhythmias in Older Adults: Results of a fully digital European Case finding study.

Aims: Simplified detection of atrial arrhythmias via consumer-electronics would enable earlier therapy in at-risk populations. Whether this is feasible and effective in older populations is not known. Methods and results: The fully remote, investigator-initiated Smartphone and wearable detected atrial arrhythmia in Older Adults Case finding study (Smart in OAC-AFNET 9) digitally enrolled participants ≥65 years without known atrial fibrillation, not receiving oral anticoagulation in Germany, Poland, and Spain for 8 weeks. Participants were invited by media communications and direct contacts. Study procedures adhered to European data protection. Consenting participants received a wristband with a photoplethysmography sensor to be coupled to their smartphone. The primary outcome was the detection of atrial arrhythmias lasting 6 min or longer in the first 4 weeks of monitoring. Eight hundred and eighty-two older persons (age 71 ± 5 years, range 65-90, 500 (57%) women, 414 (47%) hypertension, and 97 (11%) diabetes) recorded signals. Most participants (72%) responded to adverts or word of mouth, leaflets (11%) or general practitioners (9%). Participation was completely remote in 469/882 persons (53%). During the first 4 weeks, participants transmitted PPG signals for 533/696 h (77% of the maximum possible time). Atrial arrhythmias were detected in 44 participants (5%) within 28 days, and in 53 (6%) within 8 weeks. Detection was highest in the first monitoring week [incidence rates: 1st week: 3.4% (95% confidence interval 2.4-4.9); 2nd-4th week: 0.55% (0.33-0.93)]. Conclusion: Remote, digitally supported consumer-electronics-based screening is feasible in older European adults and identifies atrial arrhythmias in 5% of participants within 4 weeks of monitoring (NCT04579159).

JavaCyte, a novel open-source tool for automated quantification of key hallmarks of cardiac structural remodeling.

Many cardiac pathologies involve changes in tissue structure. Conventional analysis of structural features is extremely time-consuming and subject to observer bias. The possibility to determine spatial interrelations between these features is often not fully exploited. We developed a staining protocol and an ImageJ-based tool (JavaCyte) for automated histological analysis of cardiac structure, including quantification of cardiomyocyte size, overall and endomysial fibrosis, spatial patterns of endomysial fibrosis, fibroblast density, capillary density and capillary size. This automated analysis was compared to manual quantification in several well-characterized goat models of atrial fibrillation (AF). In addition, we tested inter-observer variability in atrial biopsies from the CATCH-ME consortium atrial tissue bank, with patients stratified by their cardiovascular risk profile for structural remodeling. We were able to reproduce previous manually derived histological findings in goat models for AF and AV block (AVB) using JavaCyte. Furthermore, strong correlation was found between manual and automated observations for myocyte count (r = 0.94, p < 0.001), myocyte diameter (r = 0.97, p < 0.001), endomysial fibrosis (r = 0.98, p < 0.001) and capillary count (r = 0.95, p < 0.001) in human biopsies. No significant variation between observers was observed (ICC = 0.89, p < 0.001). We developed and validated an open-source tool for high-throughput, automated histological analysis of cardiac tissue properties. JavaCyte was as accurate as manual measurements, with less inter-observer variability and faster throughput.

Cardioversion of persistent atrial fibrillation by a combination of atrial specific and non-specific class III drugs in the goat.

OBJECTIVE: In electrically remodeled atria the effect of blockers of the delayed rectifier K+ current I(Kr) on repolarization is reduced, whereas the efficacy of 'early' class III drugs (I(Kur)/I(to)/I(Kach) blockers) is enhanced. We evaluated the electrophysiological and antifibrillatory effects of AVE0118, dofetilide, and ibutilide (alone and in combination) on persistent atrial fibrillation (AF) in the goat. METHODS AND RESULTS: The effects of separate and combined administration of AVE0118, dofetilide, and ibutilide were determined before and after 48 h of AF. AVE0118 alone markedly prolonged the atrial refractory period (400 ms cycle length) (AERP400) before and after 48 h of AF. The prolongation of AERP(400) by dofetilide and ibutilide, respectively, was reduced by AF from 22+/-2 to 7+/-2 ms (p<0.01) and 25+/-5 to 5+/-2 ms (p=0.01). Pre-treatment with AVE0118 restored the prolongation of AERP400 by dofetilide or ibutilide (to 20+/-3 and 30+/-6 ms; p<0.01). This effect was atrial specific since the QT-interval was not changed. The antifibrillatory action was evaluated in 10 goats that were in persistent AF for 57+/-7 days. Dofetilide (20 microg/kg/h) or ibutilide (4 mg/h) alone restored sinus rhythm in only 20% of the animals. AVE0118 (1, 3 and 10 mg/kg/h) [DOSAGE ERROR CORRECTED] terminated AF in 11, 30, and 60%, respectively. Additional infusion of I(Kr) blockers caused an additional number of cardioversions, resulting in a final cardioversion rate of 56, 80, and 100%, respectively. AVE0118 alone prolonged the AF cycle length (AFCL) while the conduction velocity during AF (CV(AF)) remained unchanged (70+/-1 vs. 68+/-2 cm/s; p=0.3). Addition of dofetilide or ibutilide caused a synergistic increase in AFCL and a slight increase in CV(AF) to 74+/-1 cm/s (p<0.001). The length of the reentrant trajectories increased from 7.6+/-0.3 (control) to 11.6+/-0.5 cm after AVE0118 alone (p<0.001) and 14.8+/-0.8 cm after addition of dofetilide or ibutilide (p<0.001). CONCLUSIONS: In electrically remodeled atria, blockade of I(Kur)/I(to)/I(KAch) restored the class III action of I(Kr) blockers. Persistent AF could be effectively cardioverted by infusion of a combination of AVE0118 and dofetilide or ibutilide. This antifibrillatory action was associated with an almost twofold lengthening of the intra-atrial pathways for reentry.

[New antiarrhythmic drugs for therapy of atrial fibrillation: I. Ion channel blockers]. / Neue Antiarrhythmika in der Therapie des Vorhofflimmerns--I. Ionenkanalblocker.

During the last ten years we have made substantial progress in our understanding of the underlying mechanisms of atrial fibrillation. The high rate associated alterations in electrical and structural properties of the atria, referred to as atrial remodeling, promote the progression of atrial fibrillation. The development of new therapeutic approaches addresses three different directions: (i) prevention of atrial remodeling, especially of structural remodeling; (ii) increase of long-term efficacy of currently used drugs and improvement of their side-effect profile; and (iii) design of atria- and pathology-specific antiarrhythmic drugs without concomitant proarrhythmic effects in the ventricles. The current review outlines the pathophysiology of atrial fibrillation and focuses on electrical remodeling. The properties of new antiarrhythmic drugs for atrial fibrillation are discussed in detail.

"Early" class III drugs for the treatment of atrial fibrillation: efficacy and atrial selectivity of AVE0118 in remodeled atria of the goat.

BACKGROUND: Currently available antiarrhythmic drugs are only moderately effective against atrial fibrillation (AF) and may cause ventricular proarrhythmia. AVE0118 is a blocker of atrium-specific early K+ currents (I(Kur)/I(to)). METHODS AND RESULTS: Effects of intravenous AVE0118 and dofetilide on atrial effective refractory period (AERP) and inducibility of AF were measured before and after 48-hours of AF-induced electrical remodeling in the goat. During persistent AF (53+/-19 days), the cardioversion efficacy and effects on atrial wavelength of AVE0118, dofetilide, and ibutilide were evaluated. QT durations were measured during atrial pacing and persistent AF. After 48 hours of AF, the effect of dofetilide on AERP was reduced, and induction of AF was not prevented. In contrast, the class III action of AVE0118 was enhanced, and AF inducibility decreased from 100% to 32% (P<0.001). At 1, 3, and 10 mg x kg(-1) x h(-1), AVE0118 terminated persistent AF in 1 of 8, 3 of 8, and 5 of 8 goats, respectively. Dofetilide and ibutilide terminated AF in 1 of 5 and 2 of 7 goats. AVE0118 0.5, 1.5, and 5 mg/kg prolonged the AERP during AF and increased the fibrillation wavelength from 6.7+/-0.6 to 8.5+/-0.5, 9.7+/-0.5, and 11.2+/-0.9 cm (P<0.01). Whereas dofetilide and ibutilide prolonged QT duration, AVE0118 had no appreciable effect. CONCLUSIONS: AVE0118 markedly prolongs the AERP during AF without affecting QT duration. Cardioversion of AF was due to an approximately 2-fold increase in fibrillation wavelength. Atrium-selective class III drugs like AVE0118 may be a promising new option for safe and effective cardioversion of AF.

Cellular mechanisms of depressed atrial contractility in patients with chronic atrial fibrillation.

BACKGROUND: After cardioversion of atrial fibrillation (AF), the contractile function of the atria is temporarily impaired. Although this has significant clinical implications, the underlying cellular mechanisms are poorly understood. METHODS AND RESULTS: Forty-nine consecutive patients submitted for mitral valve surgery were investigated. Twenty-three were in persistent AF (>/=3 months); the others were in sinus rhythm. Before extracorporal circulation, the right atrial appendage was excised. ss-Adrenoceptors were quantified by radioligand binding, and G proteins were quantified by Western blot analysis. The isometric contractile response to Ca(2+), isoproterenol, Bay K8644, and the postrest potentiation of contractile force were investigated in thin atrial trabeculae, which were also examined histologically. The contractile force of the atrial preparations obtained from AF patients was 75% less than that in preparations from patients in sinus rhythm. Also, the positive inotropic effect of isoproterenol was impaired, and Bay K8644 failed to increase atrial contractile force. In contrast, the response to extracellular Ca(2+) was maintained, and the postrest potentiation was preserved. Beta-adrenoceptor density and G-protein expression were unchanged. Histological examination revealed 14% more myolysis in the atria of AF patients. CONCLUSIONS: After prolonged AF, atrial contractility was reduced by 75%. The impairment of beta-adrenergic modulation of contractile force cannot be explained by downregulation of ss-adrenoceptors or changes in G proteins. Dysfunction of the sarcoplasmic reticulum does not occur after prolonged AF. Failure of Bay K8644 to restore contractility suggests that the L-type Ca(2+) channel is responsible for the contractile dysfunction. The restoration of contractile force by high extracellular Ca(2+) shows that the contractile apparatus itself is nearly completely preserved after prolonged AF.

Pathophysiology of idiopathic atrial fibrillation - prognostic and treatment implications.

The term idiopathic or lone atrial fibrillation (AF) is commonly used in the young and apparently healthy individual who suffers from AF. Although there is conflicting evidence concerning prognosis, these patients are at risk to develop (vascular) comorbidities in the years following AF onset. It is conceivable that early stages of vascular disease, undetectable by the routine diagnostics, may contribute to the pathophysiology of "apparently" idiopathic AF. At present, more advanced diagnostics have become available that can be deployed at low threshold in order to detect early stage or yet subclinical cardiovascular disease. In this respect one could raise the question whether idiopathic AF exists at all or that the arrhythmia acts as a harbinger of as yet undetected underlying vascular disease in this specific population. Assuming that idiopathic AF is the final arrhythmic expression of underlying genetic mutations and/or vascular diseases, high priority should be given to trace identifiable predisposing factors or the presence of early stages of underlying disease in order to treat these, or prevent their complications. A more comprehensive quest for potential hidden causes of idiopathic AF creates new therapeutic dilemmas, but also encourages further research regarding pathophysiology and new early treatment opportunities in patients with atrial fibrillation in general. The present review provides more insight regarding diverse pathophysiological mechanisms in the fundamental basis for idiopathic AF, outlines prognostic and treatment implications, and questions the robustness of its definition.

Hypertrophic cardiomyopathy: a desensitized cardiac beta-adrenergic system in the presence of normal plasma catecholamine concentrations.

Only few data are available concerning the biochemical and functional state of the beta-adrenergic system in hypertrophied human myocardium. The present study was to investigate the myocardial beta-adrenergic signal transduction system in hypertrophic obstructive cardiomyopathy (HOCM). Thin myocardial strips were prepared from surgically excised, septal myocardium from 7 patients with HOCM and their force of contraction was measured in vitro. The positive inotropic effects of calcium and dihydro-ouabain, both acting independently of beta-adrenoceptors and cAMP, were similar in these preparations to those, previously published, seen with nonfailing myocardium. In contrast, the beta-adrenoceptor agonist isoprenaline and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) had reduced positive inotropic effects. Their EC50-values were about 10 fold higher than the respective EC50-values published for nonfailing myocardium. The positive inotropic potencies of isoprenaline and IBMX were reduced in HOCM by as much as they were in the additionally investigated myocardium from 6 patients with severe mitral regurgitation (MR, NYHA III). In order to clarify whether the functional alterations are related to changes in the beta-adrenoceptors, beta-adrenoceptor density and beta 1: beta 2-adrenoceptor subtype distribution were determined in the same myocardium using 125I-Iodocyanopindolol saturation binding. Myocardial beta-adrenoceptor density was reduced to 68% in HOCM and to 56% in MR compared to nonfailing myocardium controls (NF: 64.8 +/- 6.5 fmol/mg protein). In HOCM, this reduction was due to a selective down regulation of beta 1-adrenoceptors (24.9 +/- 3.7 fmol/mg protein vs NF: 46.4 +/- 6.8 fmol/mg protein, P < 0.05), whereas beta 2-adrenoceptor density was unchanged (19.0 +/- 1.9 fmol/mg protein vs NF: 18.4 +/- 3.3 fmol/mg protein, n.s.). In MR both beta-adrenoceptor subtypes were reduced (beta 1: 26.9 +/- 1.4 fmol/mg protein, beta 2: 9.6 +/- 1.7 fmol/mg protein; both P < 0.05 vs NF). Electrochemically determined plasma catecholamine levels were elevated in MR. However, plasma catecholamine levels were normal or slightly below normal in HOCM. In summary, myocardial beta-adrenoceptors are downregulated and their function is impaired in HOCM. This desensitization is not caused by a negative feedback regulation due to increased plasma catecholamines. The present results show that the desensitizations of the beta-adrenergic system associated with HOCM has characteristics that indicate a major deviation in its development from that of the beta-adrenergic desensitization previously described to occur in congestive heart failure.

Post-operative Atrial Fibrillation - Pathophysiology, Treatment and Prevention.

Atrial fibrillation occurring after cardiac surgery has been the subject of intensive research over the past decades. However, the incidence remains high, despite numerous preventive and treatment strategies. In addition, several reports show that the impact of post-operative atrial fibrillation (POAF) is high. It is an independent risk factor for mortality after several years. These findings make clear that the pathophysiology of POAF is not fully understood and POAF-associated risks to some extent might be underestimated. On the one hand, excessive triggers during the acute post operative phase after cardiac surgery might initiate AF even in atria with low vulnerability. On the other hand, many patients undergoing surgery have an atrial substrate at the time of operation promoting AF not only in the post-operative phase but also in the days and weeks thereafter. Progress in our understanding of the AF mechanisms in general has provided valuable insights into processes involved in atrial structural remodeling due to advanced age, hypertension, obesity, and congestive heart failure. These patient characteristics strongly contribute to cardiac disease, predict POAF and likely have an impact on the risk of thrombus formation in the weeks and months after cardiac surgery. For a better understanding of the mechanisms involved, it is important to not only recognize the occurrence of POAF by continuous monitoring after surgery, but also to identity the extent of atrial vulnerability to AF in these patients.

Identification of recurring wavefront propagation patterns in atrial fibrillation using basis pursuit.

High density contact electrogram data of atrial fibrillation (AF) contain detailed information on recurring activation patterns and dominant signaling pathways. Current methods to analyze these patterns and pathways rely mainly on supervised atrial deflection annotation and wave reconstruction. In this study, we developed a new algorithm to automatically identify recurring patterns and dominant pathways without the need for annotation. A sparse multivariate autoregression model was estimated on short segments of synchronous unipolar electrograms to extract the dominant interactions between electrograms at different recording electrodes. Sparsity of the electrode interaction matrices at several time-lags was maximized by applying a distance-weighted basis pursuit algorithm. Dominant interactions were identified by computing the mean interaction matrix over a number of consecutive time segments. The algorithm was evaluated on high-density recordings with 234 electrodes and 2.4mm electrode spacing in the left and right atrial free wall of a goat model of AF. The method was able to identify relevant patterns of AF, including wave trains, repetitive breakthrough waves and rotating wave activity.

Automated quantification of atrial fibrillation complexity by probabilistic electrogram analysis and fibrillation wave reconstruction.

The analysis of high-density activation maps of atrial fibrillation (AF) provides fundamental insights into the fibrillation wave propagation patterns and thus the mechanisms of AF. Current annotation of local activations in unipolar atrial electrograms and the construction of fibrillation waves require labor-intensive manual editing. To enhance the possibilities for spatiotemporal analysis of AF, we developed a rapid and fully automated procedure to accurately identify local, intrinsic atrial deflections and construct fibrillation waves based on these deflections. In this study, the automated procedure was validated using manually annotated electrograms and wave maps. We show that the novel procedure accurately detects intrinsic deflections (sensitivity=87%, positive predictive value=89%) and that reconstructed wave maps correlate well with manually edited wave maps in terms of number of waves (r=0.96), intra-wave conduction velocity (r=0.97), AF cycle length (r=0.97), and wave size (r=0.96) (p<0.01 in all cases). The automated procedure is therefore an adequate substitute for manual annotation.

Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): standardised reporting for model reproducibility, interoperability, and data sharing.

Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step towards establishing this, we present a draft standard, called Minimum Information about a Cardiac Electrophysiology Experiment (MICEE). The ultimate goal is to develop a useful tool for cardiac electrophysiologists which facilitates and improves dissemination of the minimum information necessary for reproduction of cardiac electrophysiology research, allowing for easier comparison and utilisation of findings by others. It is hoped that this will enhance the integration of individual results into experimental, computational, and conceptual models. In its present form, this draft is intended for assessment and development by the research community. We invite the reader to join this effort, and, if deemed productive, implement the Minimum Information about a Cardiac Electrophysiology Experiment standard in their own work.

Verapamil prevents stretch-induced shortening of atrial effective refractory period in langendorff-perfused rabbit heart.

INTRODUCTION: Atrial dilation and rapid pacing reduce atrial effective refractory periods (AERPs), thereby increasing the susceptibility to sustained atrial fibrillation (AF) in Langendorff-perfused rabbit hearts. It is unclear whether similar pathophysiologic mechanisms are operative in short-term electrophysiologic changes caused by dilation and rapid pacing. Therefore, we analyzed whether both forms of short-term electrophysiologic changes are similarly affected by pharmacologic interventions acting on different potential mechanisms underlying these changes. METHODS AND RESULTS: Thirty Langendorff-perfused rabbit hearts underwent a protocol with stepwise increase of intra-atrial pressure from 0 to 12 cm H2O followed by 10 minutes of rapid pacing at 4 cm H2O. The protocol was repeated after addition of glibenclamide (10 micromol/L, n = 7), cariporide (1 micromol/L, n = 7), or verapamil (1 micromol/L, n = 9). In the basal state, increase of intra-atrial pressure from 0 to 12 cm H2O decreased AERPs from 85 +/- 11 to 55 +/- 9 msec (P < 0.01), rapid pacing at low intra-atrial pressure (4 cmH2O) decreased AERP to a similar extent, from 81 +/- 11 to 60 +/- 10 (P < 0.01). At higher intra-atrial pressure, decrease of AERP was more pronounced (10 cm H2O: 37 +/- 2 msec) (n = 7). Addition of verapamil decreased basal AERP from 86 +/- 10 msec to 68 +/- 11 msec (P < 0.05). Short-term electrophysiologic changes due to atrial dilation were abolished; changes due to rapid pacing were reduced but still present. Glibenclamide and cariporide had no significant effect. CONCLUSION: Langendorff-perfused rabbit heart is a suitable model for studying short-term electrophysiologic changes due to both rapid pacing and atrial dilation. AERPs are shortened to a similar extent by both mechanisms, whereas a combination of the two leads to more pronounced AERP reduction. Calcium overload plays a crucial role in short-term electrophysiologic changes caused by atrial dilation, whereas atrial ischemia or acidosis has no significant impact.

Effect of volatile anesthetics on the force-frequency relation in human ventricular myocardium: the role of the sarcoplasmic reticulum calcium-release channel.

BACKGROUND: In human ventricular myocardium, contractile force increases at higher stimulation frequencies (positive force-frequency relation). In failing hearts, the force-frequency relation (FFR) is negative. Data on the effect of volatile anesthetics on FFR are very limited. METHODS: The authors obtained left ventricular tissue from 18 explanted hearts from patients undergoing cardiac transplantation and tissue of 8 organ donors. The negative inotropic effect of halothane, isoflurane, and sevoflurane on isometric force of contraction of isolated muscle preparations at a stimulation frequency of 1 and 3 Hz and the effect of each anesthetic on the FFR were studied. Ryanodine and verapamil were studied for comparison. In addition, the effect of the anesthetics on Ca(2+)-dependent (3)H-ryanodine binding was investigated. RESULTS: In nonfailing myocardium, halothane was the strongest negative inotropic compound, and the positive FFR was not affected by either drug. In failing myocardium, halothane also showed the strongest negative inotropic effect, but the positive shape of FFR was restored by halothane and ryanodine. In contrast, isoflurane, sevoflurane, and verapamil did not change FFR. Only halothane shifted the Ca(2+)-dependent (3)H-ryanodine binding curve toward lower Ca(2+) concentrations. CONCLUSION: In nonfailing human myocardium, none of the anesthetics affect FFR, but halothane is the strongest negative inotropic compound. In failing myocardium, halothane, but not isoflurane or sevoflurane, restores the positive shape of FFR. Both the more pronounced negative inotropic effect of halothane and the restoration of the positive shape of FFR in failing myocardium in the presence of halothane can be explained by its interaction with the myocardial sarcoplasmic reticulum calcium-release channel.

Changes of beta-adrenergic signaling in compensated human cardiac hypertrophy depend on the underlying disease.

In human heart failure, desensitization of the beta-adrenergic signal transduction has been reported to be one of the main pathophysiological alterations. However, data on the beta-adrenergic system in human compensated cardiac hypertrophy are very limited. Therefore, we studied the myocardial beta-adrenergic signaling in patients suffering from hypertrophic obstructive cardiomyopathy (HOCM, n = 9) or from aortic valve stenosis (AoSt, n = 8). beta-Adrenoceptor density determined by [(125)I]iodocyanopindolol binding was reduced in HOCM and AoSt compared with nonhypertrophied, nonfailing myocardium (NF) of seven organ donors. In HOCM the protein expression of stimulatory G protein alpha-subunit (G(s)alpha) measured by immunoblotting was unchanged, whereas the inhibitory G protein alpha-subunit (Galpha(i-2)) was increased. In contrast, in AoSt, Galpha(i-2) protein was unchanged, but G(s)alpha protein was increased. Adenylyl cyclase stimulation by isoproterenol was reduced in HOCM but not in AoSt. Plasma catecholamine levels were normal in all patients. In conclusion, both forms of hypertrophy are associated with beta-adrenoceptor downregulation but with different changes at the G protein level that occur before symptomatic heart failure due to progressive dilatation of the left ventricle develops and are not due to elevated plasma catecholamine levels.

Calcium-sensitivity of the SR calcium release channel in failing and nonfailing human myocardium.

BACKGROUND: Altered Ca2+ metabolism of the sarcoplasmic reticulum results in changes of the contractile behavior in failing human myocardium. The ryanodine-sensitive Ca2+ release channel of the sarcoplasmic reticulum plays a key role in the intracellular Ca2+ handling in cardiac myocytes. Recently, we showed that the density of 3H-ryanodine binding sites which correspond to the SR Ca2+ release channel in human myocardial homogenates is unchanged in failing human myocardium. However, the sensitivity of the channel towards Ca2+, which acts as the trigger signal of channel activation and thereby initiates contraction, has not yet been investigated in failing and nonfailing myocardium. METHODS: Homogenates (100 micrograms protein) from hearts with dilated (DCM, n = 10) or ischemic (ICM, n = 9) cardiomyopathy were incubated with a saturating concentration of 3H-ryanodine (12 nM) in the presence of different Ca2+ concentrations ranging from 1 nM to 10 mM. For comparison, myocardium of 8 nonfailing hearts which could not be transplanted for technical reasons was investigated. Non-specific binding was determined in the presence of a high concentration (10 microM) of unlabeled ryanodine. RESULTS: 3H-ryanodine binding to the Ca2+ release channel showed a bell-shaped pattern with an increase in specific binding at submicromolar Ca2+ concentrations and a decrease at higher Ca2+ concentrations than 0.5 mM, whereas nonspecific binding was not influenced by different Ca2+ concentrations. In nonfailing myocardium, maximal 3H-ryanodine binding (Bmax) was 85.2 +/- 3.1 fmol/mg protein and half-maximal binding was reached at a free Ca2+ concentration of 0.25 (0.22-0.30) microM (EC50). Neither EC50 values nor maximal specific 3H-ryanodine binding differed between nonfailing and failing myocardium of both etiologies. EC50 values were 0.24 (0.23-0.26) microM (DCM, n = 10) or 0.28 (0.25-0.31) microM (ICM, n = 9), respectively. Caffeine (2 mM) and the ATP-analogon AMP-PCP (1 mM) led to a shift towards lower Ca2+ concentrations consistent with an activation of the channel by these compounds, whereas Mg2+ (0.7 mM) shifted the Ca(2+)-dependence of 3H-ryanodine binding towards higher Ca2+ concentrations indicating inhibition of channel opening. After activation of the Ca2+ release channel by caffeine or AMP-PCP as well as after the inhibition with Mg2+ EC50 values were the same in failing and nonfailing myocardium. CONCLUSION: Caffeine and AMP-PCP sensitize, whereas Mg2+ desensitizes the myocardial Ca2+ release channel to Ca2+. The determination of Ca(2+)-dependent 3H-ryanodine binding to the human myocardial Ca2+ release channel is a useful tool to investigate its open probability. Furthermore, the Ca(2+)-sensitivity and the pharmacological behavior of the human SR Ca2+ release channel are similar in failing and nonfailing myocardium.