Abstract
Aims
The primary goal in the treatment of symptomatic atrial fibrillation/flutter (AF) is to restore sinus rhythm by cardioversion. Electrical shocks are highly effective, but have to be ...applied under analgo-sedation and can further harm the heart. In order to develop a novel pain-free and less harmful approach, we explored herein the optogenetic cardioversion by light-induced depolarization.
Methods and results
Hearts from mice expressing Channelrhodopsin-2 (ChR2) and the AF-promoting loss-of-function Connexin 40 Ala96Ser mutation were explanted and perfused with low K+ Tyrode's solution and an atrial KATP-channel activator. This new protocol shortened atrial refractoriness as well as slowed atrial conduction and thereby enabled the induction of sustained AF. AF episodes could be terminated by epicardial illumination of the atria with focussed blue light (470 nm, 0.4 mW/mm2) with an efficacy of ∼97% (n = 17 hearts). In > 80% of cases, light directly terminated the AF episode with onset of illumination. Because similar illumination intensity was able to locally inhibit atrial activity, we propose that a light-induced block of electrical activity is responsible for reliable AF termination. The success rate was strongly depending on the illuminated area, applied light intensity and duration of illumination. Importantly, we were also able to demonstrate optogenetic termination of AF in vivo, using epicardial illumination through the open chest (n = 3 hearts). To point towards a translational potential, we systemically injected an adeno-associated virus to express ChR2 in wild type hearts. After 6-8 months, we found robust ChR2 expression in the atria, enabling light-mediated AF termination in six of seven mice tested.
Conclusion
We provide the first evidence for optogenetic termination of atrial tachyarrhythmia in intact hearts from transgenic as well as wild type mice ex and in vivo. Thus, this report could lay the foundation for the development of implantable devices for pain-free termination of AF.
Recent observational clinical and ex-vivo studies suggest that inflammation and in particular leukocyte activation predisposes to atrial fibrillation (AF). However, whether local binding and ...extravasation of leukocytes into atrial myocardium is an essential prerequisite for the initiation and propagation of AF remains elusive. Here we investigated the role of atrial CD11b/CD18 mediated infiltration of polymorphonuclear neutrophils (PMN) for the susceptibility to AF.
C57bl/6J wildtype (WT) and CD11b/CD18 knock-out (CD11b(-/-)) mice were treated for 14 days with subcutaneous infusion of angiotensin II (Ang II), a known stimulus for PMN activation. Atria of Ang II-treated WT mice were characterized by increased PMN infiltration assessed in immunohistochemically stained sections. In contrast, atrial sections of CD11b(-/-) mice lacked a significant increase in PMN infiltration upon Ang II infusion. PMN infiltration was accompanied by profoundly enhanced atrial fibrosis in Ang II treated WT as compared to CD11b(-/-) mice. Upon in-vivo electrophysiological investigation, Ang II treatment significantly elevated the susceptibility for AF in WT mice if compared to vehicle treated animals given an increased number and increased duration of AF episodes. In contrast, animals deficient of CD11b/CD18 were entirely protected from AF induction. Likewise, epicardial activation mapping revealed decreased electrical conduction velocity in atria of Ang II treated WT mice, which was preserved in CD11b(-/-) mice. In addition, atrial PMN infiltration was enhanced in atrial appendage sections of patients with persistent AF as compared to patients without AF.
The current data critically link CD11b-integrin mediated atrial PMN infiltration to the formation of fibrosis, which promotes the initiation and propagation of AF. These findings not only reveal a mechanistic role of leukocytes in AF but also point towards a potential novel avenue of treatment in AF.
Aging is a progressive decline of body function, during which many tissues accumulate few cells with high levels of deleted mitochondrial DNA (mtDNA), leading to a defect of mitochondrial functions. ...Whether this mosaic mitochondrial deficiency contributes to organ dysfunction is unknown. To investigate this, we generated mice with an accelerated accumulation of mtDNA deletions in the myocardium, by expressing a dominant-negative mutant mitochondrial helicase. These animals accumulated few randomly distributed cardiomyocytes with compromised mitochondrial function, which led to spontaneous ventricular premature contractions and AV blocks at 18 months. These symptoms were not caused by a general mitochondrial dysfunction in the entire myocardium, and were not observed in mice at 12 months with significantly lower numbers of dysfunctional cells. Therefore, our results suggest that the disposition to arrhythmia typically found in the aged human heart might be due to the random accumulation of mtDNA deletions and the subsequent mosaic respiratory chain deficiency.
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•Cardiomyocytes steadily accumulate mitochondrial DNA deletions with aging•This leads to the development of a tissue mosaic of mitochondrial deficiency•Impaired mitochondrial function in few cells promotes cardiac arrhythmia
Baris et al. test the idea of mosaic respiratory chain deficiency contributing to aging-related human cardiac disease. Using a genetic mouse model of accelerated accumulation of mtDNA deletions in the heart, they show that a few cardiomyocytes with mitochondrial DNA deletions progressively accumulate during aging, leading to cardiac arrhythmias.
Atrioesophageal Fistula After Cryoballoon PV Isolation. The risk of atrioesophageal fistula after cryoballoon pulmonary vein isolation is thought to be much lower than after radiofrequency ablation, ...seeing that no data exist on this complication so far. We report for the first time on the occurrence of an atrioesophageal fistula 4 weeks after cryoballoon ablation at the site of the left inferior pulmonary vein. We suggest that even when using cryothermal ablation technique, an imaging modality to assess the proximity of esophagus and left atrium should be routinely performed to avoid this fatal complication. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1254–1257, November 2012)
In patients with liver cirrhosis, cardiac dysfunction is frequent and is associated with increased morbidity and mortality. Cardiac dysfunction in cirrhosis seems to be linked to autonomic ...dysfunction. This study investigates the role of autonomic dysfunction assessed by Heart Rate Turbulence (HRT) analyses in patients with liver cirrhosis.
Inclusion criteria was (1) diagnosis of cirrhosis by clinical, imaging or biopsy and (2) evaluation by standard 12-lead-ECG and 24h holter monitoring and (3) at least 3 premature ventricular contractions. The exclusion criterion was presence of cardiac diseases, independent of liver cirrhosis. Biochemical parameters were analysed using standard methods. HRT was assessed using Turbulence onset (TO) and slope (TS). The endpoint was deterioration of liver cirrhosis defined as increased MELD and readmission for complications of liver cirrhosis.
Out of 122 cirrhotic patients, 82 patients (63% male) with median Child score of 6 (range 5-12) and median MELD score of 10 (range 6-32) were included. Increasing Child score, INR and decreasing albumin were correlated with TO. In addition, decompensated patients with ascites showed more abnormal TO and TS. During the observation period, patients with more abnormal TO showed significantly higher rate of rising MELD Score at 6 months (p = 0.03). Nevertheless, at least in our collective HRT-parameters were not independent predictors of deterioration of cirrhosis.
Parameters of HRT are closely associated with deterioration of cirrhosis and might be helpful in its prediction.
Cryoballoon (CB) ablation has become a popular method for pulmonary vein isolation (PVI) in atrial fibrillation (AF) treatment. This study aimed to compare the intraprocedural ablation ...characteristics of two cryoballoons, Arctic Front Advance Pro™ (AFA-Pro, Medtronic) and POLARx™ (Boston Scientific).
In this retrospective single-center study, 230 symptomatic paroxysmal or persistent AF patients underwent CB ablation with either AFA-Pro or POLARx. Propensity-score matching resulted in two cohorts of 114 patients each. Baseline and procedural characteristics were comparable between both CBs. POLARx achieved lower minimal temperatures (e.g., left superior pulmonary vein, LSPV: AFA-Pro - 49.0 °C vs. POLARx - 59.5 °C) and lower temperatures at time-to-isolation (TTI). Additionally, POLARx reached lower temperatures faster, as evidenced by lower temperatures after 40 and 60 s, and a larger mean temperature change between 20 and 40 s. POLARx also had a greater area under the curve below 0 °C and a longer thawing phase. Both CBs achieved comparable high rates of final PV-isolation. TTI, minimal esophagus temperature, and first-pass isolation rates were similar between groups. Periprocedural complications, including phrenic nerve injuries, were comparable. Troponin levels in the left atrium were elevated with both systems. Values and change in troponin were numerically higher in the POLARx group (delta troponin: AFA-Pro 36.3 (26.4, 125.4) ng/L vs. POLARx 104.9 (49.5, 122.2) ng/L), p = 0.077).
AFA-Pro and POLARx are both highly effective and safe CB systems for PVI. POLARx exhibited significant faster and lower freezing characteristics, and numerically higher troponin levels might indicate greater myocardial injury. However, these differences did not translate into improved performance, procedural efficiency, or safety.
Psychosocial stress is one of the main environmental factors contributing to the development of psychiatric disorders. In humans and rodents, chronic stress is associated with elevated inflammatory ...responses, indicated by increased numbers of circulating myeloid cells and activation of microglia, the brain-resident immune cells. The endocannabinoid system (ECS) regulates neuronal and endocrine stress responses via the cannabinoid receptor 1 (CB1). CB1-deficient mice (Cnr1
) are highly sensitive to stress, but if this involves altered inflammatory responses is not known. To test this, we exposed Cnr1
and Cnr1
mice to chronic social defeat stress (CSDS). Cnr1
mice were extremely sensitive to a standard protocol of CSDS, indicated by an increased mortality rate. Therefore, a mild CSDS protocol was established, which still induced a behavioural phenotype in susceptible Cnr1
mice. These mice also showed altered glucocorticoid levels after mild CSDS, suggesting dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Mild CSDS induced weak myelopoiesis in the periphery, but no recruitment of myeloid cells to the brain. In contrast, mild CSDS altered microglial activation marker expression and morphology in Cnr1
mice. These microglial changes correlated with the severity of the behavioural phenotype. Furthermore, microglia of Cnr1
mice showed increased expression of Fkbp5, an important regulator of glucocorticoid signalling. Overall, the results confirm that CB1 signalling protects the organism from the physical and emotional harm of social stress and implicate endocannabinoid-mediated modulation of microglia in the development of stress-related pathologies.
Ventricular tachyarrhythmias are the main cause of sudden death in patients after myocardial infarction. Here we show that transplantation of embryonic cardiomyocytes (eCMs) in myocardial infarcts ...protects against the induction of ventricular tachycardia (VT) in mice. Engraftment of eCMs, but not skeletal myoblasts (SMs), bone marrow cells or cardiac myofibroblasts, markedly decreased the incidence of VT induced by in vivo pacing. eCM engraftment results in improved electrical coupling between the surrounding myocardium and the infarct region, and Ca2+ signals from engrafted eCMs expressing a genetically encoded Ca2+ indicator could be entrained during sinoatrial cardiac activation in vivo. eCM grafts also increased conduction velocity and decreased the incidence of conduction block within the infarct. VT protection is critically dependent on expression of the gap-junction protein connexin 43 (Cx43; also known as Gja1): SMs genetically engineered to express Cx43 conferred a similar protection to that of eCMs against induced VT. Thus, engraftment of Cx43-expressing myocytes has the potential to reduce life-threatening post-infarct arrhythmias through the augmentation of intercellular coupling, suggesting autologous strategies for cardiac cell-based therapy.
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