Arterial hypertension drives arrhythmia progression via specific structural remodeling in a porcine model of atrial fibrillation

Manninger, Martin; Zweiker, David; Hunnik, Arne van; Alogna, Alessio; Prassl, Anton J.; Schipke, Julia; Zeemering, Stef; Zirngast, B.; Schönleitner, Patrick; Schwarzl, Michael; Herbst, Viktoria; Thon-Gutschi, Eva; Huber, Stefan; Rohrer, Ursula; Ebner, Jakob; Brussee, Helmut; Pieske, Burkert; Heinzel, Frank R.; Verheule, Sander; Antoons, Gudrun; Lueger, Andreas; Mühlfeld, Christian; Plank, Gernot; Schotten, Ulrich; Post, Heiner; Scherr, Douglas S.

doi:10.1016/j.hrthm.2018.05.016

Cited by 19 publications

(18 citation statements)

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“…Our observations are in line with a strong role of renin–angiotensin system activation as a trigger for atrial fibrosis 7 . In a previous study, however, we demonstrated that DOCA‐induced arterial hypertension does promote atrial fibrosis in the presence of atrial tachycardia 9 . Thus, combining our results provides evidence that common risk factors such as arterial hypertension and atrial tachyarrhythmia—while similarly promoting an arrhythmogenic substrate (see Figure and Manninger et al 9 …”

Section: Discussionsupporting

confidence: 89%

“…We have shown that in the presence of AF, the induction of arterial hypertension worsens atrial remodelling and arrhythmogeneity, however, without further shortening of AERP. 9 Arterial hypertension also promotes atrial remodelling independent of AERP in aged rats. 10 While systemic arterial hypertension is sufficient to initiate maladaptive LA and RA remodelling, 5,6,11 cellular mechanisms have not yet been investigated in a large animal model.…”

Section: Introductionmentioning

confidence: 99%

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Cellular contribution to left and right atrial dysfunction in chronic arterial hypertension in pigs

et al. 2020

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Aims Atrial contractile dysfunction contributes to worse prognosis in hypertensive heart disease (HHD), but the role of cardiomyocyte dysfunction in atrial remodelling in HHD is not well understood. We investigated and compared cellular mechanisms of left (LA) and right atrial (RA) contractile dysfunction in pigs with HHD. Methods and results In vivo electrophysiological and magnetic resonance imaging studies were performed in control and pigs treated with 11‐deoxycorticosterone acetate (DOCA)/high‐salt/glucose diet (12 weeks) to induce HHD. HHD leads to significant atrial remodelling and loss of contractile function in LA and a similar trend in RA (magnetic resonance imaging). Atrial remodelling was associated with a higher inducibility of atrial fibrillation but unrelated to changes in atrial refractory period or fibrosis (histology). Reduced atrial function in DOCA pigs was related to reduced contraction amplitude of isolated LA (already at baseline) and RA myocytes (at higher frequencies) due to reduced intracellular Ca release (Fura 2‐AM, field stimulation). However, Ca regulation differed in LA and RA cardiomyocytes: LA cardiomyocytes showed reduced sarcoplasmic reticulum (SR) [Ca], whereas in RA, SR [Ca] was unchanged and SR Ca2+‐ATPase activity was increased. Sodium–calcium exchanger (NCX) activity was not significantly altered. We used ORM‐10103 (3 μM), a specific NCX inhibitor to improve Ca availability in LA and RA cardiomyocytes from DOCA pigs. Partial inhibition of NCX increased Ca2+ transient amplitude and SR Ca in LA, but not RA cells. Conclusions In this large animal model of HHD, atrial remodelling in sinus rhythm in vivo was related to differential LA and RA cardiomyocyte dysfunction and Ca signalling. Selective acute inhibition of NCX improved Ca release in diseased LA cardiomyocytes, suggesting a potential therapeutic approach to improve atrial inotropy in HHD.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Cellular contribution to left and right atrial dysfunction in chronic arterial hypertension in pigs

et al. 2020

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“…Experimental setup. The experimental setup has been described before [12][13][14] . Briefly, landrace pigs (n = 9, 54 ± 6 kg) were fasted overnight, premedicated with midazolam and ketamine, intubated and mechanically ventilated.…”

Section: Methodsmentioning

confidence: 99%

“…Atrial effective refractory period (AERP) was determined using a S1–S2 stimulation protocol (1 ms pulse at twice diastolic threshold at cycle lengths 400 ms, 350 ms, 300 ms, 250 ms and 200 ms) as described before 14 .…”

Section: Methodsmentioning

confidence: 99%

Acute hyperglycaemia is not associated with the development of atrial fibrillation in healthy pigs

Manninger

Zweiker

Dobrovnik

et al. 2020

Sci Rep

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Development and progression of atrial fibrillation (AF) is driven by comorbidities such as arterial hypertension and diabetes mellitus. In animal models of chronic hyperglycaemia, progression of AF has been proposed to be triggered by oxidative stress, apoptosis and fibrosis. Acute glycosylation of CaMKII has been associated with increased susceptibility to arrhythmias in acute hyperglycaemia. However, the proarrhythmogenic effect of acute hyperglycaemia has not been investigated. Nine healthy, anesthetized pigs (54 ± 6 kg) were instrumented with electrophysiologic catheters and a multielectrode array on the epicardium of the left atrial anterior wall. Left and right atrial effective refractory periods (AERP), inducibility of AF and left atrial epicardial conduction velocities (CV) were measured at baseline (BL), increasing steps of blood glucose (200-500 mg/dL in steps of 100 mg/ dL by glucose infusion) and repeated after normalisation of blood glucose levels (recovery). Serum electrolytes were kept constant during measurements by means of sodium and potassium infusion. There were no significant differences in AERP, CV or AF inducibility between BL and recovery. Heart rate remained constant regardless of blood glucose levels (BL: 103 ± 18 bpm, 500 mg/dL: 103 ± 18 bpm, r = 0.02, p = 0.346). Mean left as well as right AERP increased with higher glucose levels. CV increased with glucose levels (1.25 (1.04, 1.67) m/s at BL vs. 1.53 (1.22, 2.15) m/s at 500 mg/dL, r = 0.85, p = 0.034). Rate of AF inducibility in the left atrium remained constant throughout the whole protocol (AF episodes > 10 s: mean inducibility of 80% at BL vs. 69% at 500 mg/dL, p = 0.32, episodes > 30 s: 0% at BL vs. 0% at 500 mg/dL, p = 0.17). Our data imply that acute hyperglycaemia is associated with lower arrhythmogenic substrate and does not promote AF inducibility.

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“…Currently, atrial cardiopathy is discussed as a precursor condition of AF, which is characterized by endothelial dysfunction, fibrosis, impaired myocyte function and dilatation of the left atrium, and might also cause a thromboembolic state in the left atrium in the absence of AF. 10 The morphological changes within the left atrium are accompanied by electrical changes, 11,12 premature beats 13 and supraventricular runs, 14,15 the latter shown to be associated with increased risk of cerebral re-ischemia, 14 supporting the clinical relevance of an intensified analysis of ECG data. In addition to clinical variables, automated software-based analysis might be capable of identifying the aforementioned ECG variations and could further individualize the allocation of prolonged ECG monitorings.…”

Section: Annals Of Clinical and Translational Neurology Published By mentioning

confidence: 95%

Software‐based analysis of 1‐hour Holter ECG to select for prolonged ECG monitoring after stroke

Gröschel

Lange

Wasser

et al. 2020

Ann Clin Transl Neurol

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Objective: Identification of ischemic stroke patients at high risk for paroxysmal atrial fibrillation (pAF) during 72 hours Holter ECG might be useful to individualize the allocation of prolonged ECG monitoring times, currently not routinely applied in clinical practice. Methods: In a prospective multicenter study, the first analysable hour of raw ECG data from prolonged 72 hours Holter ECG monitoring in 1031 patients with acute ischemic stroke/TIA presenting in sinus rhythm was classified by an automated software (AA) into "no risk of AF" or "risk of AF" and compared to clinical variables to predict AF during 72 hours Holter-ECG. Results: pAF was diagnosed in 54 patients (5.2%; mean age: 78 years; female 56%) and was more frequently detected after 72 hours in patients classified by AA as "risk of AF" (n = 21, 17.8%) compared to "no risk of AF" (n = 33, 3.6%). AA-based risk stratification as "risk of AF" remained in the prediction model for pAF detection during 72 hours Holter ECG (OR3.814, 95% CI 2.024-7.816, P < 0.001), in addition to age (OR1.052, 95% CI 1.021-1.084, P = 0.001), NIHSS (OR 1.087, 95% CI 1.023-1.154, P = 0.007) and prior treatment with thrombolysis (OR2.639, 95% CI 1.313-5.306, P = 0.006). Similarly, risk stratification by AA significantly increased the area under the receiver operating characteristic curve (AUC) for prediction of pAF detection compared to a purely clinical risk score (AS5F alone: AUC 0.751; 95% CI 0.724-0.778; AUC for the combination: 0.789, 95% CI 0.763-0.814; difference between the AUC P = 0.022). Interpretation: Automated software-based ECG risk stratification selects patients with high risk of AF during 72 hours Holter ECG and adds predictive value to common clinical risk factors for AF prediction.

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Arterial hypertension drives arrhythmia progression via specific structural remodeling in a porcine model of atrial fibrillation

Cited by 19 publications

References 34 publications

Cellular contribution to left and right atrial dysfunction in chronic arterial hypertension in pigs

Cellular contribution to left and right atrial dysfunction in chronic arterial hypertension in pigs

Acute hyperglycaemia is not associated with the development of atrial fibrillation in healthy pigs

Software‐based analysis of 1‐hour Holter ECG to select for prolonged ECG monitoring after stroke

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