Pacing therapy for atrioventricular dromotropathy: A combined computational-experimental-clinical study

AIMS: Investigate haemodynamic effects, and their mechanisms, of restoring atrioventricular (AV)-coupling using pacemaker therapy in normal and failing hearts in a combined computational-experimental-clinical study. METHODS AND RESULTS: Computer simulations were performed in the CircAdapt model of the normal and failing human heart and circulation. Experiments were performed in a porcine model of AV dromotropathy. In a proof-of-principle clinical study, left ventricular (LV) pressure and volume were measured in 22 heart failure (HF) patients (LV ejection fraction \u3c35%) with prolonged PR interval (\u3e230 ms) and narrow or non-left bundle branch block QRS complex. Computer simulations and animal studies in normal hearts showed that restoring of AV-coupling with unchanged ventricular activation sequence significantly increased LV filling, mean arterial pressure, and cardiac output by 10-15%. In computer simulations of failing hearts and in HF patients, reducing PR interval by biventricular (BiV) pacing (patients: from 300 ± 61 to 137 ± 30 ms) resulted in significant increases in LV stroke volume and stroke work (patients: 34 ± 40% and 26 ± 31%, respectively). However, worsening of ventricular dyssynchrony by using right ventricular (RV) pacing abrogated the benefit of restoring AV-coupling. In model simulations, animals and patients, the increase of LV filling and associated improvement of LV pump function coincided with both larger mitral inflow (E- and A-wave area) and reduction of diastolic mitral regurgitation. CONCLUSION: Restoration of AV-coupling by BiV pacing in normal and failing hearts with prolonged AV conduction leads to considerable haemodynamic improvement. These results indicate that BiV or physiological pacing, but not RV pacing, may improve cardiac function in patients with HF and prolonged PR interval

Pre-Stressor Interference Control and Intrusive Memories

Although intrusive imagery is a common response in the aftermath of a stressful or traumatic event, only a minority of trauma victims show persistent re-experiencing and related psychopathology. Individual differences in pre-trauma executive control possibly play a critical role. Therefore, this study investigated whether a relatively poor pre-stressor ability to resist proactive interference in working memory might increase risk for experiencing undesirable intrusive memories after being exposed to a stressful event. Non-clinical participants (N = 85) completed a modified version of a widely used test of interference control in working memory (CVLT; Kramer and Delis 1991) and subsequently watched an emotional film fragment. Following presentation of the fragment, intrusive memories were recorded in a 1-week diary and at a follow up session 7 days later. A relatively poor ability to resist proactive interference was related to a relatively high frequency of film-related intrusive memories. This relationship was independent of neuroticism and gender. These findings are consistent with the idea that a pre-morbid deficit in the ability to resist proactive interference reflects a vulnerability factor for experiencing intrusive memories after trauma exposure

Cardiac Electrical Dyssynchrony is Accurately Detected by Noninvasive Electrocardiographic Imaging

Poor identification of electrical dyssynchrony is postulated to be a major factor contributing to the low success rate for cardiac resynchronization therapy (CRT). To evaluate body surface mapping and electrocardiographic imaging (ECGi) to detect electrical dyssynchrony noninvasively. Langendorff-perfused pig hearts (n=11) were suspended in a human torso-shaped tank, with LBBB induced through ablation. Recordings were taken simultaneously from a 108-electrode epicardial sock and 128 electrodes embedded in the tank surface during sinus rhythm and ventricular pacing. CT provided electrode and heart positions in the tank. Epicardial unipolar electrograms were reconstructed from torso potentials using ECGi. Dyssynchrony markers from torso potentials (e.g. QRS-duration) or ECGi (total activation time (TAT), interventricular delay (D-LR) and intraventricular markers) were correlated with those recorded from the sock. LBBB was induced (n=8) and sock-derived activation maps demonstrated interventricular dyssynchrony (D-LR and TAT) in all cases (p 0.05). Although ECGi markers were significantly lower than recorded (p <0.05) there was a significant strong linear relationship between ECGi and recorded values. ECGi correctly diagnosed electrical dyssynchrony, and interventricular resynchronization in all cases. The latest site of activation was identified to 9.1±0.6 mm by ECGi. ECGi reliably and accurately detects electrical dyssynchrony, resynchronization by biventricular pacing, and the site of latest activation, providing more information than body surface potential

Response to cardiac resynchronization therapy is determined by intrinsic electrical substrate rather than by its modification

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Electrical Substrates Driving Response to Cardiac Resynchronization Therapy: A Combined Clinical–Computational Evaluation

BACKGROUND: The predictive value of interventricular versus intraventricular dyssynchrony for response to cardiac resynchronization therapy (CRT) remains unclear. We investigated the relative importance of both ventricular electrical substrate components for left ventricular (LV) hemodynamic function. METHODS AND RESULTS: First, we used the cardiovascular computational model CircAdapt to characterize the isolated effect of intrinsic interventricular and intraventricular activation on CRT response (Delta LVdP/dt(max)). Simulated Delta LVdP/dt(max) (range: 1.3%-26.5%) increased considerably with increasing interventricular dyssynchrony. In contrast, the isolated effect of intraventricular dyssynchrony in either the LV or right ventricle was limited (Delta LVdP/dt(max) range: 12.3%-18.3% and 14.1%-15.7%, respectively). Effects of activation during biventricular pacing on Delta LVdP/dt(max) were small. Second, electrocardiographic imaging-derived activation characteristics of 51 CRT candidates were used to personalize ventricular activation in CircAdapt. The individualized models were subsequently used to assess the accuracy of Delta LVdP/dt(max) prediction based on the electrical data. The model-predicted Delta LVdP/dt(max) was close to the actual value in patients with left bundle branch block (measured-simulated: 2.7 +/- 9.0%) when only intrinsic interventricular dyssynchrony was personalized. Among patients without left bundle branch block, Delta LVdP/dt(max) was systematically overpredicted by CircAdapt (measured-simulated: 9.2 +/- 7.1%). Adding intraventricular activation to the model did not improve the accuracy of the response prediction. CONCLUSIONS: Computer simulations revealed that intrinsic interventricular dyssynchrony is the dominant component of the electrical substrate driving the response to CRT. Intrinsic intraventricular dyssynchrony and any dyssynchrony during biventricular pacing play a minor role in this respect. This may facilitate patient-specific modeling for prediction of CRT response

Distinct lipid droplet characteristics and distribution unmask the apparent contradiction of the athlete's paradox

Objective: Intramyocellular lipid (IMCL) storage negatively associates with insulin resistance, albeit not in endurance-trained athletes. We investigated the putative contribution of lipid droplet (LD) morphology and subcellular localization to the so-called athlete's paradox. Methods: We performed quantitative immunofluorescent confocal imaging of muscle biopsy sections from endurance Trained, Lean sedentary, Obese, and Type 2 diabetes (T2DM) participants (n = 8/group). T2DM patients and Trained individuals were matched for IMCL content. Furthermore we performed this analysis in biopsies of T2DM patients before and after a 12-week exercise program (n = 8). Results: We found marked differences in lipid storage morphology between trained subjects and T2DM: the latter group mainly store lipid in larger LDs in the subsarcolemmal (SS) region of type II fibers, whereas Trained store lipid in a higher number of LDs in the intramyofibrillar (IMF) region of type I fibers. In addition, a twelve-week combined endurance and strength exercise program resulted in a LD phenotype shift in T2DM patients partly towards an ‘athlete-like’ phenotype, accompanied by improved insulin sensitivity. Proteins involved in LD turnover were also more abundant in Trained than in T2DM and partly changed in an ‘athlete-like’ fashion in T2DM patients upon exercise training. Conclusions: Our findings provide a physiological explanation for the athlete's paradox and reveal LD morphology and distribution as a major determinant of skeletal muscle insulin sensitivity. Keywords: Insulin sensitivity, Athlete's paradox, Intramyocellular lipid, Lipid droplet