Arrhythmia mechanism dependent pulmonary vein ablation in paroxysmal atrial fibrillation.

Atrial fibrillation (AF) often requires invasive treatment by ablation to decrease symptom burden. The pulmonary veins (PV) are thought to trigger paroxysms of AF, and ablative PV isolation (PVI) is a cornerstone in AF treatment. However, incomplete PVI, where electrical conduction between the PV and left atrium (LA) is maintained, is curative of AF in a subset of patients. This implies that an antiarrhythmic effect other than electrical isolation between the PV and LA plays a role in AF prevention in these patients. We reason that the PV myocardium constitutes an arrhythmogenic substrate conducive to reentry in the patients with curative incomplete PVI. This PV substrate is amenable to ablation, even when conduction between the LA and PV persists. We propose that PV ablation strategies are differentiated to fit the arrhythmogenic mechanisms in the individual patient. PV substrate modification in patients with PV reentry may constitute a new therapeutic approach that is potentially simpler and more effective, in this subgroup of patients.

Translational implications of bradyarrhythmia in hibernating brown bears.

The brown bear Ursus arctos undergoes exceptional physiological adaptions during annual hibernation that minimize energy consumption, including profound decrease in heart rate, cardiac output, and respiratory rate. These changes are completely reversible after the bears reenter into the active state in spring. In this case report, we show episodes of sinus arrest in a hibernating Scandinavian brown bear and in humans, recorded by implantable loop recorders and discuss the possible underlying mechanisms. Lessons learned from cardiac adaptations in hibernating bears might prove useful in the treatment of patients with sinus node dysfunction.

Reduction in atrial and pulmonary vein stretch as a therapeutic target for prevention of atrial fibrillation.

Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with increased mortality. Heart failure, hypertension, valvular disease, and obstructive sleep apnea are risk factors for incident AF. A common characteristic of these diseases is that they increase atrial wall stretch. Multiple experimental studies confirm a proarrhythmic effect of atrial stretch. Conversely, a reduction in stretch is antiarrhythmic. A therapeutic target for AF, therefore, lies in local reduction of atrial stretch. This review focuses on atrial stretch and its clinical associations in patients with AF and its downstream effects on electrophysiology. We discuss the possible application of targeted atrial stretch reduction in AF prevention. We conclude that a reduction in local atrial stretch should be considered an essential element in rhythm control.

Profibrillatory Structural and Functional Properties of the Atrial-Pulmonary Junction in the Absence of Remodeling.

Background: Sole pulmonary vein (PV) isolation by ablation therapy prevents atrial fibrillation (AF) in patients with short episodes of AF and without comorbidities. Since incomplete PV isolation can be curative, we tested the hypothesis that the PV in the absence of remodeling and comorbidities contains structural and functional properties that are proarrhythmic for AF initiation by reentry. Methods: We performed percutaneous transvenous in vivo endocardial electrophysiological studies and quantitative histological analysis of PV from healthy sheep. Results: The proximal PV contained more myocytes than the distal PV and a higher percentage of collagen and fat tissue relative to myocytes than the left atrium. Local fractionated electrograms occurred in both the distal and proximal PVs, but a large local activation (>0.75 mV) was more often present in the proximal PV than in the distal PV (86 vs. 50% of electrograms, respectively, p = 0.017). Atrial arrhythmias (run of premature atrial complexes) occurred more often following the premature stimulation in the proximal PV than in the distal PV (p = 0.004). The diastolic stimulation threshold was higher in the proximal PV than in the distal PV (0.7 [0.3] vs. 0.4 [0.2] mA, (median [interquartile range]), p = 0.004). The refractory period was shorter in the proximal PV than in the distal PV (170 [50] vs. 248 [52] ms, p < 0.001). A linear relation existed between the gradient in refractoriness (distal-proximal) and atrial arrhythmia inducibility in the proximal PV. Conclusion: The structural and functional properties of the native atrial-PV junction differ from those of the distal PV. Atrial arrhythmias in the absence of arrhythmia-induced remodeling are caused by reentry in the atrial-PV junction. Ablative treatment of early paroxysmal AF, rather than complete isolation of focal arrhythmia, may be limited to inhibition of reentry.

Reduction in left atrial and pulmonary vein dimensions after ablation therapy is mediated by scar.

BACKGROUND: Ablative pulmonary vein isolation (PVI) decreases pulmonary vein (PV) and left atrial (LA) dimensions in atrial fibrillation (AF) patients. These changes are attributed to reverse structural remodeling following sinus rhythm restoration but evidence is lacking. We hypothesized that the downsizing is directly caused by the ablative energy and subsequent scar formation. METHODS: We studied cardiac magnetic resonance imaging in 21 paroxysmal AF patients before and 3 months after successful PVI and in healthy sheep (n = 12) before and after PVI of the right PV only. RESULTS: PVI decreased the PV diameter in patients and sheep by 11.0(10.3) and 9.2(11.0)%, (p < 0.001 and p = 0.020), respectively. The control left PV in sheep were unchanged. A linear correlation existed between the extent of PV scar and PVI-induced decrease in PV diameter in patients.After PVI, the LA volume decreased (103(38) vs. 92(31)ml, pre- vs. post-ablation, respectively, p = 0.006), while the right atrial (RA) volume was unchanged in patients. A decrease in active emptying fraction after ablation (26.5(10.7) vs. 21.8(10.6)%, pre- vs. post-ablation, p = 0.031) was associated with reduced contractility of the PV walls (p = 0.004). The contractility of the LA walls was unaltered (p = 0.749). CONCLUSION: The ablation-induced PV diameter reduction was similar in patients with AF and healthy sheep without AF and was associated with PV scar extent. The volume only decreased in LA and not RA after PVI, and wall contractility decreased only in ablated sites. Therefore, the PVI-induced atrial downsizing is caused by the ablative energy and subsequent scar formation.

Localized Pulmonary Vein Scar Promotes Atrial Fibrillation in High Left Atrial Pressure.

BACKGROUND: Pulmonary vein (PV) ablation is unsuccessful in atrial fibrillation (AF) patients with high left atrial (LA) pressure. Increased atrial stretch by increased pressure is proarrhythmic for AF, and myocardial scar alters wall deformation. We hypothesized that localized PV scar is proarrhythmic for AF in high LA pressure. METHODS: Radiofrequency energy was delivered locally in the right PV of healthy sheep. The sheep recovered for 4 months. Explanted hearts (n = 9 PV scar, n = 9 controls) were perfused with 1:4 blood:Tyrode's solution in a four-chamber working heart setup. Programmed PV stimulation was performed during low (∼12 mmHg) and high (∼25 mmHg) LA pressure. An AF inducibility index was calculated based on the number of induction attempts and the number of attempts causing AF (run of ≥ 20 premature atrial complexes). RESULTS: In high LA pressure, the presence of PV scar increased the AF inducibility index compared with control hearts (0.83 ± 0.20 vs. 0.38 ± 0.40 arb. unit, respectively, p = 0.014). The diastolic stimulation threshold in high LA pressure was higher (108 ± 23 vs. 77 ± 16 mA, respectively, p = 0.006), and its heterogeneity was increased in hearts with PV scar compared with controls. In high LA pressure, the refractory period was shorter in PV scar than in control hearts (178 ± 39 vs. 235 ± 48 ms, p = 0.011). CONCLUSION: Localized PV scar only in combination with increased LA pressure facilitated the inducibility of AF. This was associated with changes in tissue excitability remote from the PV scar. Localized PV ablation is potentially proarrhythmic in patients with increased LA pressure.

A left lateral body position increases pulmonary vein stress in healthy humans.

Pulmonary vein (PV) stretch is proarrhythmic for atrial fibrillation (AF). AF patients often report that a left lateral (LL) body position can trigger arrhythmia symptoms. Because the PV myocardium is thought to trigger AF, we hypothesized that the LL compared to the supine body position increases PV wall stress. Functional cardiac magnetic resonance imaging was performed in supine and LL recumbent body position in awake condition in healthy human volunteers (n = 20). Following a change from supine to LL position, the heart moved in an anterior-LL direction in the thorax. The right superior PV diameter was increased by 19% (24.6 ± 3.1 vs. 20.7 ± 3.2 mm, p = 0.009) and left atrial (LA) volume was larger by 17% (61.7[15.4] vs. 51.0[17.8] ml, p = 0.015) in LL than supine position, respectively. The passive LA conduit fraction (normalized difference between maximum and pre-contraction LA volume) increased by 25% in LL compared to supine position (19.6 ± 9.0 vs. 15.7 ± 7.6%, respectively, p = 0.016). Local wall stress in the PV regions increased in LL compared to supine position (overall mean: 1.01 ± 0.12 vs. 1.10 ± 0.10 arb. unit, LL vs. supine, position effect p = 0.041), whereas this was not the case in the LA walls (overall mean: 1.18 ± 0.31 vs. 1.21 ± 0.21 arb. unit, LL vs. supine, position effect p = 0.381). In conclusion, a left lateral body position increases PV myocardial stress during the atrial relaxation phase of healthy volunteers. These results have implications for the mechanisms of posture-triggered AF.

Self-Reported Onset of Paroxysmal Atrial Fibrillation Is Related to Sleeping Body Position.

Background: Because stretch of the atrial myocardium is proarrhythmic for atrial fibrillation (AF) and a left lateral body position increases atrial dimensions in humans, we hypothesized that left lateral recumbence is a frequent AF-triggering body position in AF patients. Methods: We performed a questionnaire study of symptomatic paroxysmal AF (episodes of AF < 1 week) patients scheduled for a first AF ablation therapy at Catharina Hospital, Eindhoven, the Netherlands and at University Hospital, Bordeaux, France. Results: Ninety-four symptomatic paroxysmal AF patients were included [mean age 61 ± 11 years, median AF history of 29(48) months, 31% were females]. Twenty-two percent of patients reported a specific body position as a trigger of their AF symptoms. The triggering body position was left lateral position in 57% of cases, supine position in 33%, right lateral position in 10%, and prone position in 5% (p = 0.003 overall difference in prevalence). Patients with positional AF had a higher body mass index compared to patients without nocturnal/positional AF [28.7(4.2) and 25.4(5.2) kg/m2, respectively, p = 0.025], but otherwise resembled these patients. Conclusion: Body position, and the left lateral position, in particular, is a common trigger of AF in symptomatic AF patients. Moreover, positional AF is associated with overweight. Understanding of the underlying mechanisms of positional AF can contribute to AF treatment and prevention.

Prolonged QT intervals in mice with cardiomyocyte-specific deficiency of the molecular clock.

AIM: Cardiac arrhythmias and sudden deaths have diurnal rhythms in humans. The underlying mechanisms are unknown. Mice with cardiomyocyte-specific disruption of the molecular clock genes have lower heart rate than control. Because changes in the QT interval on the electrocardiogram is a clinically used marker of risk of arrhythmias, we sought to test if the biological rhythms of QT intervals are dependent on heart rate and if this dependency is changed when the molecular clock is disrupted. METHODS: We implanted radio transmitters in male mice with cardiomyocyte-specific Bmal1 knockout (CBK) and in control mice and recorded 24-h ECGs under diurnal and circadian conditions. We obtained left ventricular monophasic action potentials during pacing in hearts ex vivo. RESULTS: Both RR and QT intervals were longer in conscious CBK than control mice (RR: 117 ± 7 vs 110 ± 9 ms, P < .05; and QT: 53 ± 4 vs 48 ± 2 ms, P < .05). The prolonged QT interval was independent of the slow heart rate in CBK mice. The QT interval exhibited diurnal and circadian rhythms in both CBK and control mice. The action potential duration was longer in CBK than in control mice, indicating slower repolarization. Action potential alternans occurred at lower pacing rate in hearts from CBK than control mice (12 ± 3 vs 16 ± 2 Hz, respectively, P < .05). CONCLUSION: The bradycardic CBK mice have prolonged ventricular repolarization independent of the heart rate. Diurnal and circadian rhythms in repolarization are preserved in CBK mice and are not a consequence of the 24-h rhythm in heart rate. Arrhythmia vulnerability appears to be increased when the cardiac clock is disrupted.

The Blinding Period Following Ablation Therapy for Atrial Fibrillation: Proarrhythmic and Antiarrhythmic Pathophysiological Mechanisms.

Atrial fibrillation (AF) causes heart failure, ischemic strokes, and poor quality of life. The number of patients with AF is estimated to increase to 18 million in Europe in 2050. Pharmacological therapy does not cure AF in all patients. Ablative pulmonary vein isolation is recommended for patients with drug-resistant symptomatic paroxysmal AF but is successful in only about 60%. In patients in whom ablative therapy is successful on the long term, recurrence of AF may occur in the first weeks to months after pulmonary vein ablation. The early recurrence (or delayed cure) of AF is not understood but forms the basis for the generally accepted 3-month blinding (or blanking) period after ablation therapy, which is not included in the evaluation of the eventual success rate of the procedures. The underlying pathophysiological processes responsible for early recurrence and the delayed cure are unknown. The implicit assumption of the blinding period is that the AF mechanism in this period is different from the ablation-targeted AF mechanism (ectopy from the pulmonary veins). In this review, we evaluate the temporary and long-lasting pro- and antiarrhythmic effects of each of the pathophysiological processes and interventions (necrosis, ischemia, oxidative stress, edema, inflammation, autonomic nervous activity, tissue repair, mechanical remodeling, and use of antiarrhythmic drugs) occurring in the blinding period that can modulate AF mechanisms. We propose that stretch-reducing ablation scar is a permanent antiarrhythmic mechanism that develops during the blinding period and is the reason for delayed cure.

Aberrant sinus node firing during ß-adrenergic stimulation leads to cardiac arrhythmias in diabetic mice.

AIM: Cardiovascular complications, including cardiac arrhythmias, result in high morbidity and mortality in patients with type-2 diabetes mellitus (T2DM). Clinical and experimental data suggest electrophysiological impairment of the natural pacemaker of the diabetic heart. The present study examined sinoatrial node (SAN) arrhythmias in a mouse model of T2DM and physiologically probed their underlying cause. METHODS: Electrocardiograms were obtained from conscious diabetic db/db and lean control db/+ mice. In vivo SAN function was probed through pharmacological autonomic modulation with isoprenaline, atropine and carbachol. Blood pressure stability and heart rate variability (HRV) were evaluated. Intrinsic SAN function was evaluated through ex vivo imaging of spontaneous Ca2+ transients in isolated SAN preparations. RESULTS: While lean control mice showed constant RR intervals during isoprenaline challenge, the diabetic mice experienced SAN arrhythmias with large RR fluctuations in a dose-dependent manner. These arrhythmias were completely abolished by atropine pre-treatment, while carbachol pretreatment significantly increased SAN arrhythmia frequency in the diabetic mice. Blood pressure and HRV were comparable in db/db and db/+ mice, suggesting that neither augmented baroreceptor feedback nor autonomic neuropathy is a likely arrhythmia mechanism. Cycle length response to isoprenaline was comparable in isolated SAN preparations from db/db and db/+ mice; however, Ca2+ spark frequency was significantly increased in db/db mice compared to db/+ at baseline and after isoprenaline. CONCLUSION: Our results demonstrate a dysfunction of cardiac pacemaking in an animal model of T2DM upon challenge with a ß-adrenergic agonist. Ex vivo, higher Ca2+ spark frequency is present in diabetic mice, which may be directly linked to in vivo arrhythmias.

Circadian rhythm in QT interval is preserved in mice deficient of potassium channel interacting protein 2.

Potassium Channel Interacting Protein 2 (KChIP2) is suggested to be responsible for the circadian rhythm in repolarization duration, ventricular arrhythmias, and sudden cardiac death. We investigated the hypothesis that there is no circadian rhythm in QT interval in the absence of KChIP2. Implanted telemetric devices recorded electrocardiogram continuously for 5 days in conscious wild-type mice (WT, n = 9) and KChIP2-/- mice (n = 9) in light:dark periods and in complete darkness. QT intervals were determined from all RR intervals and corrected for heart rate (QT100 = QT/(RR/100)1/2). Moreover, QT intervals were determined from complexes within the RR range of mean-RR ± 1% in the individual mouse (QTmean-RR). We find that RR intervals are 125 ± 5 ms in WT and 123 ± 4 ms in KChIP2-/- (p = 0.81), and QT intervals are 52 ± 1 and 52 ± 1 ms, respectively(p = 0.89). No ventricular arrhythmias or sudden cardiac deaths were observed. We find similar diurnal (light:dark) and circadian (darkness) rhythms of RR intervals in WT and KChIP2-/- mice. Circadian rhythms in QT100 intervals are present in both groups, but at physiological small amplitudes: 1.6 ± 0.2 and 1.0 ± 0.3 ms in WT and KChIP2-/-, respectively (p = 0.15). A diurnal rhythm in QT100 intervals was only found in WT mice. QTmean-RR intervals display clear diurnal and circadian rhythms in both WT and KChIP2-/-. The amplitude of the circadian rhythm in QTmean-RR is 4.0 ± 0.3 and 3.1 ± 0.5 ms in WT and KChIP2-/-, respectively (p = 0.16). In conclusion, KChIP2 expression does not appear to underlie the circadian rhythm in repolarization duration.

Preservation of cardiac function by prolonged action potentials in mice deficient of KChIP2.

Inherited ion channelopathies and electrical remodeling in heart disease alter the cardiac action potential with important consequences for excitation-contraction coupling. Potassium channel-interacting protein 2 (KChIP2) is reduced in heart failure and interacts under physiological conditions with both Kv4 to conduct the fast-recovering transient outward K(+) current (Ito,f) and with CaV1.2 to mediate the inward L-type Ca(2+) current (ICa,L). Anesthetized KChIP2(-/-) mice have normal cardiac contraction despite the lower ICa,L, and we hypothesized that the delayed repolarization could contribute to the preservation of contractile function. Detailed analysis of current kinetics shows that only ICa,L density is reduced, and immunoblots demonstrate unaltered CaV1.2 and CaVß2 protein levels. Computer modeling suggests that delayed repolarization would prolong the period of Ca(2+) entry into the cell, thereby augmenting Ca(2+)-induced Ca(2+) release. Ca(2+) transients in disaggregated KChIP2(-/-) cardiomyocytes are indeed comparable to wild-type transients, corroborating the preserved contractile function and suggesting that the compensatory mechanism lies in the Ca(2+)-induced Ca(2+) release event. We next functionally probed dyad structure, ryanodine receptor Ca(2+) sensitivity, and sarcoplasmic reticulum Ca(2+) load and found that increased temporal synchronicity of the Ca(2+) release in KChIP2(-/-) cardiomyocytes may reflect improved dyad structure aiding the compensatory mechanisms in preserving cardiac contractile force. Thus the bimodal effect of KChIP2 on Ito,f and ICa,L constitutes an important regulatory effect of KChIP2 on cardiac contractility, and we conclude that delayed repolarization and improved dyad structure function together to preserve cardiac contraction in KChIP2(-/-) mice.