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BACKGROUND: Idiopathic epicardial premature ventricular contractions (PVCs) originating from the left ventricular summit are difficult to eliminate. OBJECTIVE: The purpose of this study was to describe the feasibility and procedural safety of monopolar biphasic focal pulsed field ablation (F-PFA) from within the great cardiac vein (GCV) for treatment of idiopathic epicardial PVCs. METHODS: In 4 pigs, F-PFA (Centauri, CardioFocus) was applied from within the GCV followed by macroscopic gross analysis. In 4 patients with previously failed radiofrequency ablation, electroanatomic mapping was used to guide F-PFA from within the GCV and the ventricular outflow tracts. Coronary angiography and optical coherence tomography (OCT) were performed in 2 patients. RESULTS: In pigs, F-PFA from within the GCV (5 mm away from the coronary arteries) resulted in myocardial lesions with a maximal depth of 4 mm, which was associated with nonobstructive transient coronary spasms. In patients, sequential delivery of F-PFA in the ventricular outflow tracts and from within the GCV eliminated the PVCs. During F-PFA delivery from within the GCV with prophylactic nitroglycerin application, coronary angiography showed no coronary spasm when F-PFA was delivered >5 mm away from the coronary artery and a transient coronary spasm without changes in a subsequent OCT, when F-PFA was delivered directly on the coronary artery. Intracardiac echocardiography and computed tomography integration was used to monitor F-PFA delivery from within the GCV. There were no immediate or short-term complications. CONCLUSION: Sequential mapping-guided F-PFA from endocardial ventricular outflow tracts and from within the GCV is feasible with a favorable procedural safety profile for treatment of epicardial PVCs.
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AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to treat type 2 diabetes and obesity. Albeit cardiovascular outcomes generally improve, treatment with GLP-1 RAs is associated with increased heart rate, the mechanism of which is unclear. METHODS AND RESULTS: We employed a large animal model, the female landrace pig, and used multiple in-vivo and ex-vivo approaches including pharmacological challenges, electrophysiology and high-resolution mass spectrometry to explore how GLP-1 elicits an increase in heart rate. In anaesthetized pigs, neither cervical vagotomy, adrenergic blockers (alpha, beta or combined alpha-beta blockade), ganglionic blockade (hexamethonium) nor inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (ivabradine) abolished the marked chronotropic effect of GLP-1. GLP-1 administration to isolated perfused pig hearts also increased heart rate, which was abolished by GLP-1 receptor blockade. Electrophysiological characterization of GLP-1 effects in vivo and in isolated perfused hearts localized electrical modulation to the atria and conduction system. In isolated sinus nodes, GLP-1 administration shortened action potential cycle length of pacemaker cells and shifted the site of earliest activation. The effect was independent of HCN blockade. Collectively, these data support a direct effect of GLP-1 on GLP-1 receptors within the heart. Consistently, single nucleus RNA sequencing (snRNAseq) showed GLP-1 receptor expression in porcine pacemaker cells. Quantitative phosphoproteomics analyses of sinus node samples revealed that GLP-1 administration leads to phosphorylation changes of calcium cycling proteins of the sarcoplasmic reticulum, known to regulate heart rate. CONCLUSION: GLP-1 has direct chronotropic effects on the heart mediated by GLP-1 receptors in pacemaker cells of the sinus node, inducing changes in action potential morphology and the leading pacemaker site through a calcium signaling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pace making. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in GLP-1 RA recipients.
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AIMS: Pulmonary vein isolation (PVI) is the corner stone of modern rhythm control strategies in patients with atrial fibrillation (AF). Sleep-disordered breathing (SDB) is prevalent in more than 50% of patients undergoing AF ablation, and studies have indicated a greater recurrence rate after PVI in patients with SDB. Herein, we study the effect of catheter-based PVI on AF in a pig model for SDB. METHODS AND RESULTS: In 11 sedated spontaneously breathing pigs, obstructive apnoeas were simulated by 75â s of intermittent negative upper airway pressure (INAP) applied by a negative pressure device connected to the endotracheal tube. Intermittent negative upper airway pressures were performed before and after PVI. AF-inducibility and atrial effective refractory periods (aERPs) were determined before and during INAP by programmed atrial stimulation. Pulmonary vein isolation prolonged the aERP by 48 ± 27â ms in the right atrium (RA) (P < 0.0001) and by 40 ± 34â ms in the left atrium (LA) (P = 0.0004). Following PVI, AF-inducibility dropped from 28 ± 26% to 0% (P = 0.0009). Intermittent negative upper airway pressure was associated with a transient aERP-shortening (ΔaERP) in both atria, which was not prevented by PVI (INAP indued ΔaERP after PVI in the RA: -57 ± 34â ms, P = 0.0002; in the LA: -42 ± 24â ms, P < 0.0001). Intermittent negative upper airway pressure was associated with a transient increase in AF-inducibility (from 28 ± 26% to 69 ± 21%; P = 0.0008), which was not attenuated by PVI [INAP-associated AF-inducibility after PVI: 58 ± 33% (P = 0.5)]. CONCLUSION: Transient atrial arrhythmogenic changes related to acute obstructive respiratory events are not prevented by electrical isolation of the pulmonary veins, which partially explains the increased AF recurrence in patients with SDB after PVI procedures.
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Fibrilação Atrial , Ablação por Cateter , Modelos Animais de Doenças , Veias Pulmonares , Animais , Veias Pulmonares/cirurgia , Veias Pulmonares/fisiopatologia , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/cirurgia , Fibrilação Atrial/prevenção & controle , Fibrilação Atrial/diagnóstico , Suínos , Ablação por Cateter/métodos , Apneia Obstrutiva do Sono/fisiopatologia , Falha de Tratamento , Frequência Cardíaca , Átrios do Coração/fisiopatologia , Átrios do Coração/cirurgiaRESUMO
BACKGROUND: More than 50% of patients with atrial fibrillation (AF) suffer from sleep disordered breathing (SDB). Obstructive respiratory events contribute to a transient, vagally mediated atrial arrhythmogenic substrate, which is resistant to most available antiarrhythmic drugs. OBJECTIVE: The purpose of this study was to investigate the effect of pharmacologic inhibition of the G-protein-gated acetylcholine-regulated potassium current (IK,ACh) with and without acute autonomic nervous system activation by nicotine in a pig model for obstructive respiratory events. METHODS: In 21 pigs, SDB was simulated by applying an intermittent negative upper airway pressure (INAP). AF inducibility and atrial effective refractory periods (aERPs) were determined before and during INAP by an S1S2 atrial pacing-protocol. Pigs were randomized into 3 groups-group 1: vehicle (n = 4); group 2: XAF-1407 (IK,ACh inhibitor) (n = 7); and group 3: nicotine followed by XAF-1407 (n = 10). RESULTS: In group 1, INAP shortened aERP (ΔaERP -42.6 ms; P = .004) and transiently increased AF inducibility from 0% to 31%. In group 2, XAF-1407 prolonged aERP by 25.2 ms (P = .005) during normal breathing and prevented INAP-induced aERP shortening (ΔaERP -3.6 ms; P = .3) and AF inducibility. In group 3, INAP transiently shortened aERP during nicotine perfusion (ΔaERP -33.6 ms; P = .004) and increased AF inducibility up to 61%, which both were prevented by XAF-1407. CONCLUSION: Simulated obstructive respiratory events transiently shorten aERP and increase AF inducibility, which can be prevented by the IK,ACh-inhibitor XAF-1407. XAF-1407 also prevents these arrhythmogenic changes induced by obstructive respiratory events during nicotine perfusion. Whether IK,ACh channels represent a target for SDB-related AF in humans warrants further study.
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Fibrilação Atrial , Modelos Animais de Doenças , Animais , Suínos , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/etiologia , Fibrilação Atrial/prevenção & controle , Átrios do Coração/fisiopatologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Acetilcolina/farmacologia , Nicotina/farmacologia , Síndromes da Apneia do Sono/fisiopatologia , Síndromes da Apneia do Sono/complicaçõesRESUMO
Aim: To propose a standardized workflow for 3D-electroanatomical mapping guided pulmonary vein isolation in pigs. Materials and methods: Danish female landrace pigs were anaesthetized. Ultrasound-guided puncture of both femoral veins was performed and arterial access for blood pressure measurement established. Fluoroscopy- and intracardiac ultrasound-guided passage of the patent foramen ovale or transseptal puncture was performed. Then, 3D-electroanatomical mapping of the left atrium was conducted using a high-density mapping catheter. After mapping all pulmonary veins, an irrigated radiofrequency ablation catheter was used to perform ostial ablation to achieve electrical pulmonary vein isolation. Entrance- and exit-block were confirmed and re-assessed after a 20-min waiting period. Lastly, animals were sacrificed to perform left atrial anatomical gross examination. Results: We present data from 11 consecutive pigs undergoing pulmonary vein isolation. Passage of the fossa ovalis or transseptal puncture was uneventful and successful in all animals. Within the inferior pulmonary trunk 2-4 individual veins as well as 1-2 additional left and right pulmonary veins could be cannulated. Electrical isolation by point-by-point ablation of all targeted veins was successful. However, pitfalls including phrenic nerve capture during ablation, ventricular arrhythmias during antral isolation close to the mitral valve annulus and difficulties in accessing right pulmonary veins were encountered. Conclusion: Fluoroscopy- and intracardiac ultrasound-guided transseptal puncture, high-density electroanatomical mapping of all pulmonary veins and complete electrical pulmonary vein isolation can be achieved reproducibly and safely in pigs when using current technologies and a step-by-step approach.
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BACKGROUND: Obstructive sleep apnea (OSA) creates a complex substrate for atrial fibrillation (AF), which is refractory to many clinically available pharmacological interventions. We investigated atrial antiarrhythmogenic properties and ventricular electrophysiological safety of small-conductance Ca2+ -activated K+ (SK)-channel inhibition in a porcine model for obstructive respiratory events. METHODS: In spontaneously breathing pigs, obstructive respiratory events were simulated by intermittent negative upper airway pressure (INAP) applied via a pressure device connected to the intubation tube. INAP was applied for 75 s, every 10 min, three times before and three times during infusion of the SK-channel inhibitor AP14145. Atrial effective refractory periods (AERP) were acquired before (pre-INAP), during (INAP) and after (post-) INAP. AF-inducibility was determined by a S1S2 atrial pacing protocol. Ventricular arrhythmicity was evaluated by heart rate adjusted QT-interval duration (QT-paced) and electromechanical window (EMW) shortening. RESULTS: During vehicle infusion, INAP transiently shortened AERP (pre-INAP: 135 ± 10 ms vs. post-INAP 101 ± 11 ms; p = .008) and increased AF-inducibility. QT-paced prolonged during INAP (pre-INAP 270 ± 7 ms vs. INAP 275 ± 7 ms; p = .04) and EMW shortened progressively throughout INAP and post-INAP (pre-INAP 80 ± 4 ms; INAP 59 ± 6 ms, post-INAP 46 ± 10 ms). AP14145 prolonged baseline AERP, partially prevented INAP-induced AERP-shortening and reduced AF-susceptibility. AP14145 did not alter QT-paced at baseline (pre-AP14145 270 ± 7 ms vs. AP14145 268 ± 6 ms, p = .83) or QT-paced and EMW-shortening during INAP. CONCLUSION: In a pig model for obstructive respiratory events, the SK-channel-inhibitor AP14145 prevented INAP-associated AERP-shortening and AF-susceptibility without impairing ventricular electrophysiology. Whether SK-channels represent a target for OSA-related AF in humans warrants further study.
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Fibrilação Atrial , Apneia Obstrutiva do Sono , Humanos , Suínos , Animais , Fibrilação Atrial/prevenção & controle , AcetamidasRESUMO
Excessive drinking has detrimental effects on the cardiovascular system. Atrial fibrillation (AF) after alcohol binge drinking, also named "holiday heart syndrome," is well established. However, chronic lower levels of alcohol intake also may increase AF risk. In this review, we aim to provide a comprehensive overview of the epidemiology and pathophysiology by which alcohol may be responsible for AF and discuss whether alcohol abstinence is required for optimal rhythm control as well as to maintain sinus rhythm in patients with AF. The pathophysiologic mechanisms responsible for the relationship between alcohol consumption and AF may include both direct and chronic effects increasing AF burden. Acute effects may include arrhythmogenic changes (such as shortening in atrial refractoriness, slowing in conduction velocity, and increased atrial ectopy) and an autonomic imbalance. Chronic changes contributing to the development of an arrhythmogenic substrate involve atrial structural and functional remodelling processes due to atrial dilation, elevated pressures, and fibrosis formation. In addition, alcohol consumption contributes to developing concomitant AF risk factors such as obesity, sleep-disordered breathing, and hypertension. Alcohol abstinence is associated with a reduction in AF recurrence and overall burden and moreover improves AF risk factor development such as obesity, hypertension, sleep apnea, and AF-related consequences such as stroke. In conclusion, alcohol consumption is associated with atrial arrhythmia and a wide range of cardiovascular comorbidities. Although further evidence is needed, current knowledge indicates that there might not be a safe level of alcohol consumption that does not increase AF risk.
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Fibrilação Atrial , Hipertensão , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/etiologia , Etanol , Átrios do Coração , Humanos , Obesidade/complicações , Fatores de RiscoRESUMO
BACKGROUND: In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase atrial fibrillation (AF) susceptibility by cholinergic activation. OBJECTIVE: To investigate short-term atrial electrophysiological consequences of obstructive respiratory events, simulated by intermittent negative upper airway pressure (INAP), and the role of atrial acetylcholine-regulated potassium current (I K,ACh) activated by the M2 receptor. METHODS: In sedated (2% isoflurane), spontaneously breathing rats, INAP was applied noninvasively by a negative pressure device for 1 minute, followed by a resting period of 4 minutes. INAP was applied repeatedly throughout 70 minutes, followed by a 2-hour recovery period. Atrial effective refractory period (AERP) and AF inducibility were determined throughout the protocol. To study INAP-induced I K,ACh activation, protein levels of protein kinase C (PKCÆ) were determined in membrane and cytosolic fractions of left atrial (LA) tissue by Western blotting. Moreover, an I K,ACh inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 µg/kg) were investigated. RESULTS: In vehicle-treated rats, repetitive INAP shortened AERP (37 ± 3 ms vs baseline 44 ± 3 ms; P = .001) and increased LA membrane PKCÆ content relative to cytosolic levels. Upon INAP recovery, ratio of PKCÆ membrane to cytosol content normalized and INAP-induced AERP shortening reversed. Both XAF-1407 and atropine increased baseline AERP (control vs XAF-1407: 61 ± 4 ms; P > .001 and control vs atropine: 58 ± 3 ms; P = .011) and abolished INAP-associated AERP shortening. CONCLUSION: Short-term simulated OSA is associated with a progressive, but transient, AERP shortening and a PKCÆ translocation to LA membrane. Pharmacological I K,ACh and muscarinic receptor inhibition prevented transient INAP-induced AERP shortening, suggesting an involvement of I K,ACh in the transient arrhythmogenic AF substrate in OSA.
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BACKGROUND: In patients with chronic kidney disease (CKD), atrial fibrillation (AF) is highly prevalent and represents a major risk factor for stroke and death. CKD is associated with atrial proarrhythmic remodeling and activation of the sympathetic nervous system. Whether reduction of the sympathetic nerve activity by renal denervation (RDN) inhibits AF vulnerability in CKD is unknown. METHODS: Left atrial (LA) fibrosis was analyzed in samples from patients with AF and concomitant CKD (estimated glomerular filtration rate [eGFR], <60 mL/min per 1.73 m2) using picrosirius red and compared with AF patients without CKD and patients with sinus rhythm with and without CKD. In a translational approach, male Sprague Dawley rats were fed with 0.25% adenine (AD)-containing chow for 16 weeks to induce CKD. At week 5, AD-fed rats underwent RDN or sham operation (AD). Rats on normal chow served as control. After 16 weeks, cardiac function and AF susceptibility were assessed by echocardiography, radiotelemetry, electrophysiological mapping, and burst stimulation, respectively. LA tissue was histologically analyzed for sympathetic innervation using tyrosine hydroxylase staining, and LA fibrosis was determined using picrosirius red. RESULTS: Sirius red staining demonstrated significantly increased LA fibrosis in patients with AF+CKD compared with AF without CKD or sinus rhythm. In rats, AD demonstrated LA structural changes with enhanced sympathetic innervation compared with control. In AD, LA enlargement was associated with prolonged duration of induced AF episodes, impaired LA conduction latency, and increased absolute conduction inhomogeneity. RDN treatment improved LA remodeling and reduced LA diameter compared with sham-operated AD. Furthermore, RDN decreased AF susceptibility and ameliorated LA conduction latency and absolute conduction inhomogeneity, independent of blood pressure reduction and renal function. CONCLUSIONS: In an experimental rat model of CKD, RDN inhibited progression of atrial structural and electrophysiological remodeling. Therefore, RDN represents a potential therapeutic tool to reduce the risk of AF in CKD, independent of changes in renal function and blood pressure.
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Fibrilação Atrial , Remodelamento Atrial , Insuficiência Renal Crônica , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/prevenção & controle , Denervação , Feminino , Fibrose , Humanos , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/complicaçõesRESUMO
INTRODUCTION: Sleep-disordered breathing (SDB) is present in 21-74% of all patients with atrial fibrillation (AF). Treatment of SDB by positive airway pressure may help to prevent recurrence of AF after electrical cardioversion and help to improve AF ablation success rates in non-randomized studies. AREAS COVERED: In this review, the current understanding of the atrial arrhythmogenic pathophysiology of SDB is summarized, and diagnostic and therapeutic challenges in AF patients are discussed. Current international recommendations are presented, and a comprehensive literature search is undertaken. EXPERT OPINION: AF patients with SDB rarely report SDB-related symptoms such as daytime sleepiness. Therefore, systematic home sleep testing evaluation should be considered for all patients eligible for rhythm control strategy. A close interdisciplinary collaboration between the electrophysiologist/cardiologist, nurses and sleep-specialists are required for the management of SDB in AF patients. An arrhythmia-orientated assessment of SDB may better quantify SDB-related AF risk in an individual patient and may help to better guide targeted and personalized SDB treatment in AF patients as a component of rhythm and symptom control strategies. Finally, randomized controlled trials are needed to confirm the relationship between SDB and AF, and the benefits of routine testing and treatment of SDB in AF patients.
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Fibrilação Atrial , Ablação por Cateter , Síndromes da Apneia do Sono , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/terapia , Humanos , Polissonografia , Síndromes da Apneia do Sono/complicações , Síndromes da Apneia do Sono/diagnóstico , Síndromes da Apneia do Sono/terapia , Pesquisa Translacional BiomédicaRESUMO
BACKGROUND: Obstructive sleep apnea is associated with increased risk of sudden cardiac death. OBJECTIVE: The purpose of this study was to elucidate changes in ventricular repolarization and electromechanical interaction during obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) in pigs. We also investigated the effect of a reduced repolarization reserve in drug-induced long QT (LQT) following INAP-induced changes in ventricular repolarization. METHODS: In sedated spontaneously breathing pigs, 75 seconds of INAP was applied by a negative pressure device connected to the endotracheal tube. Ventricular electromechanical coupling was determined by the electromechanical window (EMW) before (pre-INAP), during (INAP), and after INAP (post-INAP). Incidence rates of premature ventricular contractions (PVCs) were measured respectively. A drug-induced LQT was modeled by treating the pigs with the hERG1 blocker dofetilide (DOF). RESULTS: Whereas QT interval increased during and decreased after INAP (pre-INAP: 273 ± 5 ms; INAP 281 ± 6 ms; post-INAP 254 ± 9 ms), EMW shortened progressively throughout INAP and post-INAP periods (pre-INAP 81 ± 4 ms; post-INAP 44 ± 7 ms). DOF shortened EMW at baseline. Throughout INAP, EMW decreased in a comparable fashion as before DOF (pre-INAP/+DOF 61 ± 7 ms; post-INAP/+DOF 14 ± 9 ms) but resulted in shorter absolute EMW levels. Short EMW levels were associated with increased occurrence of PVCs (pre-INAP 7 ± 2 ms vs post-INAP 26 ± 6 ms; P = .02), which were potentiated in DOF pigs (pre-INAP/+DOF 5 ± 2 ms vs post-INAP/+DOF 40 ± 8 ms; P = .006). Administration of atenolol prevented post-INAP EMW shortening and decreased occurrence of PVCs. CONCLUSION: Transient dissociation of ventricular electromechanical coupling during simulated obstructive respiratory events creates a dynamic ventricular arrhythmogenic substrate, which is sympathetically mediated and aggravated by drug-induced LQT.
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Eletrocardiografia , Frequência Cardíaca/fisiologia , Síndrome do QT Longo/fisiopatologia , Apneia Obstrutiva do Sono/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/complicações , Apneia Obstrutiva do Sono/etiologia , SuínosRESUMO
INTRODUCTION: Nocturnal hypoxemia is associated with increased cardiovascular mortality. Here, we assess whether positive airway pressure by adaptive servo-ventilation (ASV) reduces nocturnal hypoxemic burden in patients with primary central sleep apnea (primary CSA), or heart failure related central sleep apnea (CSA-HF) and treatment emergent central sleep apnea (TECSA). METHODS: Overnight oximetry data from 328 consecutive patients who underwent ASV initiation between March 2010 and May 2018 were retrospectively analyzed. Patients were stratified into three groups: primary CSA (n = 14), CSA-HF (n = 31), TECSA (n = 129). Apnea hypopnea index (AHI) and time spent below 90% SpO2 (T90) was measured. Additionally, T90 due to acute episodic desaturations (T90Desaturation) and due to non-specific and non-cyclic drifts of SpO2 (T90Non-specific) were assessed. RESULTS: ASV reduced the AHI below 15/h in all groups. ASV treatment significantly shortened T90 in all three etiologies to a similar extent. T90Desaturation, but not T90Non-specific, was reduced by ASV across all three patient groups. AHI was identified as an independent modulator for ΔT90Desaturation upon ASV treatment (B (95% CI: -1.32 (-1.73; -0.91), p < 0.001), but not for ΔT90 or ΔT90Non-specific. Body mass index was one independent predictor of T90. CONCLUSIONS: Across different central sleep apnea etiologies, ASV reduced AHI, but nocturnal hypoxemic burden remained high due to a non-specific component of T90 not related to episodic desaturation. Whether adjunct risk factor management such as weight-loss can further reduce T90 warrants further study.
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Insuficiência Cardíaca , Apneia do Sono Tipo Central , Pressão Positiva Contínua nas Vias Aéreas , Humanos , Respiração , Estudos Retrospectivos , Apneia do Sono Tipo Central/etiologia , Apneia do Sono Tipo Central/terapia , Resultado do TratamentoRESUMO
BACKGROUND: High night-to-night variability in obstructive sleep apnea (OSA) is associated with atrial fibrillation (AF). Obstructive apneas are characterized by intermittent deoxygenation-reoxygenation and intrathoracic pressure swings during ineffective inspiration against occluded upper airways. OBJECTIVE: We elucidated the effect of repeated exposure to transient OSA conditions simulated by intermittent negative upper airway pressure (INAP) on the development of an AF substrate. METHODS: INAP (48 events/4 h; apnea-hypopnea index 12 events/h) was applied in sedated spontaneously breathing rats (2% isoflurane) to simulate mild-to-moderate OSA. Rats without INAP served as a control group (CTR). In an acute test series (ATS), rats were either killed immediately (n = 9 per group) or after 24 hours of recovery (ATS-REC: n = 5 per group). To simulate high night-to-night variability in OSA, INAP applications (n = 10; 24 events/4 h; apnea-hypopnea index 6/h) were repeated every second day for 3 weeks in a chronic test series (CTS). RESULTS: INAP increased atrial oxidative stress acutely, represented in decreases of reduced to oxidized glutathione ratio (ATS: INAP: 0.33 ± 0.05 vs CTR: 1 ± 0.26; P = .016), which was reversible after 24 hours (ATS-REC: INAP vs CTR; P = .274). Although atrial oxidative stress did not accumulate in the CTS, atrial histological analysis revealed increased cardiomyocyte diameters, reduced connexin 43 expression, and increased interstitial fibrosis formation (CTS: INAP 7.0% ± 0.5% vs CTR 5.1% ± 0.3%; P = .013), which were associated with longer inducible AF episodes (CTS: INAP: 11.65 ± 4.43 seconds vs CTR: 0.7 ± 0.33 seconds; P = .033). CONCLUSION: Acute simulation of OSA was associated with reversible atrial oxidative stress. Cumulative exposure to these transient OSA-related conditions resulted in AF substrates and was associated with increased AF susceptibility. Mild-to-moderate OSA with high night-to-night variability may deserve intensive management to prevent atrial substrate development.
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Remodelação das Vias Aéreas/fisiologia , Fibrilação Atrial/etiologia , Átrios do Coração/fisiopatologia , Apneia Obstrutiva do Sono/complicações , Animais , Fibrilação Atrial/fisiopatologia , Doença Crônica , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Arterial hypertension is one of the main contributors to cardiovascular diseases, including stroke, heart failure, and coronary heart disease. Salt plays a major role in the regulation of blood pressure and is one of the most critical factors for hypertension and stroke. At the individual level, effective salt reduction is difficult to achieve and available methods for managing sodium balance are lacking for many patients. As part of the ingested food, salt is absorbed in the gastrointestinal tract by the sodium proton exchanger subtype 3 (NHE3 also known as Slc9a3), influencing extracellular fluid volume and blood pressure. In this review, we discuss the beneficial effects of pharmacological inhibition of NHE3-mediated sodium absorption in the gut and focus on the effect on blood pressure and end-organ damage.
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In the heart, the serine carboxypeptidase cathepsin A (CatA) is distributed between lysosomes and the extracellular matrix (ECM). CatA-mediated degradation of extracellular peptides may contribute to ECM remodeling and left ventricular (LV) dysfunction. Here, we aimed to evaluate the effects of CatA overexpression on LV remodeling. A proteomic analysis of the secretome of adult mouse cardiac fibroblasts upon digestion by CatA identified the extracellular antioxidant enzyme superoxide dismutase (EC-SOD) as a novel substrate of CatA, which decreased EC-SOD abundance 5-fold. In vitro, both cardiomyocytes and cardiac fibroblasts expressed and secreted CatA protein, and only cardiac fibroblasts expressed and secreted EC-SOD protein. Cardiomyocyte-specific CatA overexpression and increased CatA activity in the LV of transgenic mice (CatA-TG) reduced EC-SOD protein levels by 43%. Loss of EC-SOD-mediated antioxidative activity resulted in significant accumulation of superoxide radicals (WT, 4.54 µmol/mg tissue/min; CatA-TG, 8.62 µmol/mg tissue/min), increased inflammation, myocyte hypertrophy (WT, 19.8 µm; CatA-TG, 21.9 µm), cellular apoptosis, and elevated mRNA expression of hypertrophy-related and profibrotic marker genes, without affecting intracellular detoxifying proteins. In CatA-TG mice, LV interstitial fibrosis formation was enhanced by 19%, and the type I/type III collagen ratio was shifted toward higher abundance of collagen I fibers. Cardiac remodeling in CatA-TG was accompanied by an increased LV weight/body weight ratio and LV end diastolic volume (WT, 50.8 µl; CatA-TG, 61.9 µl). In conclusion, CatA-mediated EC-SOD reduction in the heart contributes to increased oxidative stress, myocyte hypertrophy, ECM remodeling, and inflammation, implicating CatA as a potential therapeutic target to prevent ventricular remodeling.
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Catepsina A/metabolismo , Miócitos Cardíacos/metabolismo , Proteólise , Superóxido Dismutase/metabolismo , Remodelação Ventricular , Animais , Catepsina A/genética , Masculino , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/patologia , Superóxido Dismutase/genéticaRESUMO
BACKGROUND: Increased sodium uptake has been shown to contribute to hypertension and cardiac end-organ damage. The sodium-proton-exchanger subtype 3 (NHE3) is an important mediator of intestinal sodium absorption. Whether a reduction in intestinal sodium absorption can prevent the development of an atrial arrhythmogenic substrate in hypertension is unknown. METHODS: Eight-week-old obese spontaneously hypertensive rats (SHR-ob) were treated for six weeks with the gut-specific NHE3-inhibitor SAR (1-(ß-D-glucopyranosyl)-3-{3-[(4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroiso-chinolin-4-yl]phenyl}urea, 1 mg/kg/d in chow, SHR-ob SAR, n = 7) and compared to aged-matched placebo-treated SHR-ob (SHR-ob PLAC, n = 8). Cardiac magnetic resonance imaging was performed at the end of the treatment period to assess atrial emptying function. Afterwards, local conduction disturbances and inducible atrial fibrillation (AF) duration were determined and histological analysis to quantify atrial fibrosis amount were performed. RESULTS: Inhibition of intestinal NHE3 by SAR increased fecal sodium excretion, resulted in marked changes in feces electrolyte concentrations and water content, reduced blood pressure and preserved atrial emptying function (active total percent emptying: SHR-ob SAR: 0.47 ± 0.05% vs. SHR-ob PLAC: 0.38 ± 0.007, p < 0.0001). Atrial fibrosis content was lower (21.4 ± 2.5% vs. 36.7 ± 1.2%, p < 0.0001) and areas of slow conduction were smaller (2.5 ± 0.09% vs. 5.3 ± 0.2%, p < 0.0001) in SHR-ob SAR compared to SHR-ob PLAC. Left atrial burst stimulation resulted in shorter inducible AF-durations in SHR-ob SAR compared to SHR-ob PLAC. CONCLUSIONS: Reduction of intestinal sodium absorption and subsequent changes in feces milieu by pharmacological NHE3 inhibition in the gut preserved atrial emptying function and reduced AF susceptibility. Whether pharmacological NHE3 inhibition in the gut prevents AF in humans warrants further study.