Effect of electroacupuncture on myocardial electrical remodeling in rats with acute myocardial infarction. / ç”µé’ˆå¯¹æ€¥æ€§å¿ƒè‚Œæ¢—æ­»å¤§é¼ å¿ƒè‚Œç”µé‡æž„çš„å½±å“åŠå ¶æœºåˆ¶ç ”ç©¶.

OBJECTIVES: To investigate the mechanism of electroacupuncture (EA) at "Neiguan" (PC6) in impro-ving myocardial electrical remodeling in rats with acute myocardial infarction (AMI) by enhancing transient outward potassium current. METHODS: A total of 30 male SD rats were randomly divided into control, model and EA groups, with 10 rats in each group. The AMI model was established by subcutaneous injection with isoprenaline (ISO, 85 mg/kg). EA was applied to left PC6 for 20 min, once daily for 5 days. Electrocardiogram (ECG) was recorded after treatment. TTC staining was used to observe myocardial necrosis. HE staining was used to observe the pathological morphology of myocardial tissue and measure the cross-sectional area of myocardium. Potassium ion-related genes in myocardial tissue were detected by RNA sequencing. The mRNA and protein expressions of Kchip2 and Kv4.2 in myocardial tissue were detected by real-time fluorescence quantitative PCR and Western blot, respectively. RESULTS: Compared with the control group, cardiomyocyte cross-sectional area in the model group was significantly increased (P<0.01), the ST segment was significantly elevated (P<0.01), and QT, QTc, QTd and QTcd were all significantly increased (P<0.05, P<0.01). After EA treatment, cardiomyocyte cross-sectional area was significantly decreased (P<0.01), the ST segment was significantly reduced (P<0.01), and the QT, QTc, QTcd and QTd were significantly decreased (P<0.01, P<0.05). RNA sequencing results showed that a total of 20 potassium ion-related genes co-expressed by the 3 groups were identified. Among them, Kchip2 expression was up-regulated most notablely in the EA group. Compared with the control group, the mRNA and protein expressions of Kchip2 and Kv4.2 in the myocardial tissue of the model group were significantly decreased (P<0.01, P<0.05), while those were increased in the EA group (P<0.01, P<0.05). CONCLUSIONS: EA may improve myocardial electrical remodeling in rats with myocardial infarction, which may be related to its functions in up-regulating the expressions of Kchip2 and Kv4.2.

[Effect of Zhenwu Decoction on electrical remodeling of cardiomyocytes in heart failure via I_(to)/Kv channels].

This study aimed to investigate the underlying mechanism of Zhenwu Decoction in the treatment of heart failure by regulating electrical remodeling through the transient outward potassium current(I_(to))/voltage-gated potassium(Kv) channels. Five normal SD rats were intragastrically administered with Zhenwu Decoction granules to prepare drug-containing serum, and another seven normal SD rats received an equal amount of distilled water to prepare blank serum. H9c2 cardiomyocytes underwent conventional passage and were treated with angiotensin Ⅱ(AngⅡ) for 24 h. Subsequently, 2%, 4%, and 8% drug-containing serum, simvastatin(SIM), and BaCl_2 were used to interfere in H9c2 cardiomyocytes for 24 h. The cells were divided into a control group [N, 10% blank serum + 90% high-glucose DMEM(DMEM-H)], a model group(M, AngⅡ + 10% blank serum + 90% DMEM-H), a low-dose Zhenwu Decoction-containing serum group(Z1, AngⅡ + 2% drug-containing serum of Zhenwu Decoction + 8% blank serum + 90% DMEM-H), a medium-dose Zhenwu Decoction-containing serum group(Z2, AngⅡ + 4% drug-containing serum of Zhenwu Decoc-tion + 6% blank serum + 90% DMEM-H), a high-dose Zhenwu Decoction-containing serum group(Z3, AngⅡ + 8% drug-containing serum of Zhenwu Decoction + 2% blank serum + 90% DMEM-H), an inducer group(YD, AngⅡ + SIM + 10% blank serum + 90% DMEM-H), and an inhibitor group(YZ, AngⅡ + BaCl_2 + 10% blank serum + 90% DMEM-H). The content of ANP in cell extracts of each group was detected by ELISA. The relative mRNA expression levels of ANP, Kv1.4, Kv4.2, Kv4.3, DPP6, and KChIP2 were detected by real-time quantitative PCR. The protein expression of Kv1.4, Kv4.2, Kv4.3, DPP6, and KChIP2 was detected by Western blot. I_(to) was detected by the whole cell patch-clamp technique. The results showed that Zhenwu Decoction at low, medium, and high doses could effectively reduce the surface area of cardiomyocytes. Compared with the M group, the Z1, Z2, Z3, and YD groups showed decreased ANP content and mRNA level, increased protein and mRNA expression of Kv4.2, Kv4.3, DPP6, and KChIP2, and decreased protein and mRNA expression of Kv1.4, and the aforementioned changes were the most notable in the Z3 group. Compared with the N group, the Z1, Z2, and Z3 groups showed significantly increased peak current and current density of I_(to). The results indicate that Zhenwu Decoction can regulate myocardial remodeling and electrical remodeling by improving the expression trend of Kv1.4, Kv4.2, Kv4.3, KChIP2, and DPP6 proteins and inducing I_(to) to regulate Kv channels, which may be one of the mechanisms of Zhenwu Decoction in treating heart failure and related arrhythmias.

Histological validation of atrial structural remodelling in patients with atrial fibrillation.

BACKGROUND AND AIMS: This study aimed to histologically validate atrial structural remodelling associated with atrial fibrillation. METHODS AND RESULTS: Patients undergoing atrial fibrillation ablation and endomyocardial atrial biopsy were included (n = 230; 67 ± 12 years old; 69 women). Electroanatomic mapping was performed during right atrial pacing. Voltage at the biopsy site (Vbiopsy), global left atrial voltage (VGLA), and the proportion of points with fractionated electrograms defined as ≥5 deflections in each electrogram (%Fractionated EGM) were evaluated. SCZtotal was calculated as the total width of slow conduction zones, defined as regions with a conduction velocity of <30 cm/s. Histological factors potentially associated with electroanatomic characteristics were evaluated using multiple linear regression analyses. Ultrastructural features and immune cell infiltration were evaluated by electron microscopy and immunohistochemical staining in 33 and 60 patients, respectively. Fibrosis, intercellular space, myofibrillar loss, and myocardial nuclear density were significantly associated with Vbiopsy (P = .014, P < .001, P < .001, and P = .002, respectively) and VGLA (P = .010, P < .001, P = .001, and P < .001, respectively). The intercellular space was associated with the %Fractionated EGM (P = .001). Fibrosis, intercellular space, and myofibrillar loss were associated with SCZtotal (P = .028, P < .001, and P = .015, respectively). Electron microscopy confirmed plasma components and immature collagen fibrils in the increased intercellular space and myofilament lysis in cardiomyocytes, depending on myofibrillar loss. Among the histological factors, the severity of myofibrillar loss was associated with an increase in macrophage infiltration. CONCLUSION: Histological correlates of atrial structural remodelling were fibrosis, increased intercellular space, myofibrillar loss, and decreased nuclear density. Each histological component was defined using electron microscopy and immunohistochemistry studies.

Effects and pharmacological mechanism of Zhigancao Decoction on electrical and structural remodeling of the atrium of rabbits induced by rapid atrial pacing.

BACKGROUND: Zhigancao decoction (ZD) has a long history in China as a traditional Chinese medicine compound for the treatment of tachyarrhythmias. This study mainly explored the pharmacological mechanism of Zhigancao Decoction in preventing atrial fibrillation by altering the electrical and structural remodeling of the atrial in rabbits. METHODS: In total, 30 male New Zealand white rabbits were randomly divided into 3 groups (ten rabbits for each). The first group was sham-operated (control group). The second group was intervened by the rapid right atrium pacing (RAP) to induce atrial fibrillation (AF group), while the third group was given ZD gavage and RAP (AF + ZD group). All rabbits were anesthetized before two monophasic action potential (MAP) catheters were sequentially inserted into the right atrium. After 8 h of rapid right atrial pacing, the electrophysiological indexes and the induction rate of atrial fibrillation were observed in the three groups of rabbits, and the left atrial myocardium samples were taken to observe the ultrastructure. Single atrial myocytes were separated by enzymolysis, and the L-type calcium current (ICa-L) of atrial myocytes in different experimental groups was observed by whole-cell patch clamp technique. The fluorescence intensity of Ca2+ in atrial myocytes was observed after Fluo-3/AM fluorescent staining. The main components of ZD were identified by liquid chromatography-mass spectrometry-mass spectrometry (LC-MS/MS) method. RESULTS: Compared with the AF group, the maximum ascent rate (Max dV/dt) and plateau potential were significantly reduced in the ZD group, the action potential duration at 10% and 20% (APD10, APD20) were significantly shortened (P < 0.01), action potential duration at 50%, 70%, and 90% (APD50, APD70, APD90) were significantly prolonged, and atrial effective refractory period (AERP) was significantly prolonged (P < 0.01) in the ZD group. In the ZD group, the ICa-L amplitudes of rabbit atrial myocytes under each clamping voltage were significantly smaller than those in the AF group (P < 0.01) and the control group (P < 0.05). The Ca2+ fluorescence intensity in the rabbit atrial myocytes in the ZD group was significantly weaker than that in the AF group (P < 0.01) and the control group (P < 0.05). Electron microscopy displayed that the control group had neatly arranged atrial tissue myofilaments and intact mitochondria. However, the ultrastructural damage of the AF group was severe compared with that of the ZD group. LC-MS/MS analysis confirmed that ZD contained several antiarrhythmic compounds including ginsenoside, isoliensinine, catalpol, glycyrrhizinate and hesperetin. CONCLUSION: Rapid atrial pacing (RAP) could cause the electrical and structural remodeling of rabbit atrial myocytes. ZD might reverse the atrial electrical remodeling but could have little effect on structural remodeling, which might be the mechanism of ZD treatment on atrial fibrillation.

Effect of Zhenwu Decoction on electrical remodeling of cardiomyocytes in heart failure via I_(to)/Kv channels / 中国中药杂志

This study aimed to investigate the underlying mechanism of Zhenwu Decoction in the treatment of heart failure by regulating electrical remodeling through the transient outward potassium current(I_(to))/voltage-gated potassium(Kv) channels. Five normal SD rats were intragastrically administered with Zhenwu Decoction granules to prepare drug-containing serum, and another seven normal SD rats received an equal amount of distilled water to prepare blank serum. H9c2 cardiomyocytes underwent conventional passage and were treated with angiotensin Ⅱ(AngⅡ) for 24 h. Subsequently, 2%, 4%, and 8% drug-containing serum, simvastatin(SIM), and BaCl_2 were used to interfere in H9c2 cardiomyocytes for 24 h. The cells were divided into a control group [N, 10% blank serum + 90% high-glucose DMEM(DMEM-H)], a model group(M, AngⅡ + 10% blank serum + 90% DMEM-H), a low-dose Zhenwu Decoction-containing serum group(Z1, AngⅡ + 2% drug-containing serum of Zhenwu Decoction + 8% blank serum + 90% DMEM-H), a medium-dose Zhenwu Decoction-containing serum group(Z2, AngⅡ + 4% drug-containing serum of Zhenwu Decoc-tion + 6% blank serum + 90% DMEM-H), a high-dose Zhenwu Decoction-containing serum group(Z3, AngⅡ + 8% drug-containing serum of Zhenwu Decoction + 2% blank serum + 90% DMEM-H), an inducer group(YD, AngⅡ + SIM + 10% blank serum + 90% DMEM-H), and an inhibitor group(YZ, AngⅡ + BaCl_2 + 10% blank serum + 90% DMEM-H). The content of ANP in cell extracts of each group was detected by ELISA. The relative mRNA expression levels of ANP, Kv1.4, Kv4.2, Kv4.3, DPP6, and KChIP2 were detected by real-time quantitative PCR. The protein expression of Kv1.4, Kv4.2, Kv4.3, DPP6, and KChIP2 was detected by Western blot. I_(to) was detected by the whole cell patch-clamp technique. The results showed that Zhenwu Decoction at low, medium, and high doses could effectively reduce the surface area of cardiomyocytes. Compared with the M group, the Z1, Z2, Z3, and YD groups showed decreased ANP content and mRNA level, increased protein and mRNA expression of Kv4.2, Kv4.3, DPP6, and KChIP2, and decreased protein and mRNA expression of Kv1.4, and the aforementioned changes were the most notable in the Z3 group. Compared with the N group, the Z1, Z2, and Z3 groups showed significantly increased peak current and current density of I_(to). The results indicate that Zhenwu Decoction can regulate myocardial remodeling and electrical remodeling by improving the expression trend of Kv1.4, Kv4.2, Kv4.3, KChIP2, and DPP6 proteins and inducing I_(to) to regulate Kv channels, which may be one of the mechanisms of Zhenwu Decoction in treating heart failure and related arrhythmias.

Novel preventive effect of isorhamnetin on electrical and structural remodeling in atrial fibrillation.

Isorhamnetin, a natural flavonoid, has strong antioxidant and antifibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). The present study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII- and isorhamnetin-treated group. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using atrial tissue and HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Isorhamnetin decreased AF inducibility compared with the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. The findings of the present study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling, highlighting its therapeutic potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.

Icariin attenuates excessive alcohol consumption-induced susceptibility to atrial fibrillation through SIRT3 signaling.

Excessive alcohol consumption has long been identified as a risk factor for adverse atrial remodeling and atrial fibrillation (AF). Icariin is a principal active component from traditional Chinese medicine Herba Epimedii and has been demonstrated to exert potential antiarrhythmic effect. The present study was designed to evaluate the effect of icariin against alcohol-induced atrial remodeling and disruption of mitochondrial dynamics and furthermore, to elucidate the underlying mechanisms. Excessive alcohol-treated C57BL/6 J mice were infected with serotype 9 adeno-associated virus (AAV9) carrying mouse SIRT3 gene or negative control virus. Meanwhile, icariin (50 mg/kg/d) was administered to the animals in the presence or absence of AAV9 carrying SIRT3 shRNA. We noted that 8 weeks of icariin treatment effectively attenuated alcohol consumption-induced atrial structural and electrical remodeling as evidenced by reduced AF inducibility and reversed atrial electrical conduction pattern as well as atrial enlargement. Furthermore, icariin-treated group exhibited significantly enhanced atrial SIRT3-AMPK signaling, decreased atrial mitoSOX fluorescence and mitochondrial fission markers, elevated mitochondrial fusion markers (MFN1, MFN2) as well as NRF-1-Tfam-mediated mitochondrial biogenesis. Importantly, these beneficial effects were mimicked by SIRT3 overexpression while abolished by SIRT3 knockdown. These data revealed that targeting atrial SIRT3-AMPK signaling and preserving mitochondrial dynamics might serve as the novel therapeutic strategy against alcohol-induced AF genesis. Additionally, icariin ameliorated atrial remodeling and mitochondrial dysfunction by activating SIRT3-AMPK signaling, highlighting the use of icariin as a promising antiarrhythmic agent in this circumstance.

Danqi soft caspule prevents atrial fibrillation by ameliorating left atrial remodeling through inhibiting cardiac fibroblasts differentiation and function.

BACKGROUND: Danqi soft capsule (DQ) is a Chinese herb medicine with a remarkable protective effect on cardio-cerebrovascular diseases. PURPOSE: The study aimed to investigate the role and mechanism of DQ on left atrial (LA) remodeling and atrial fibrillation (AF) occurrence in rats with post-myocardial infarction (MI) induced heart failure (HF). METHODS: MI in rats was established by ligation of the left anterior descending coronary artery. DQ was administered to the post-MI induced HF rats over a 4-week period. AF inducibility was detected using the transesophageal programmed electrical stimulation technology. Echocardiogram, histology, and western blot analysis were performed. Meanwhile, cardiac fibroblasts (CFs) were performed to determine the effects of DQ on CFs function by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT), flow cytometry, transwell assay and ELISA. RESULTS: The DQ-treated rats showed lower rates of AF inducibility and shorter AF durations than the MI rats. Moreover, DQ inhibited fibrosis and increased the expression of Cx43 in the left atrium; it also inhibited the myofibroblasts differentiation by reducing the expression of cytokines TNF-α, IL-6, and TGF-ß1 via the TGF-ß1/Smad 3 pathway. In addition, DQ inhibited the proliferation, migration, and collagen secretion of CFs in vitro. CONCLUSIONS: DQ reduces the risk of AF in post-MI HF rats by ameliorating LA arrhythmogenic substrate via inhibiting the function of proliferation, migration, collagen secretion, and myofibroblasts differentiation of CFs. Together, these results indicate the therapeutic potential of DQ in AF by delaying the progression of LA remodeling in post-MI-induced HF. Targeting CFs may be a novel prospective therapeutic avenue for AF after MI.

Shensong Yangxin attenuates metabolic syndrome-induced atrial fibrillation via inhibition of ferroportin-mediated intracellular iron overload.

BACKGROUND: Shensong Yangxin (SSYX) is a traditional Chinese medicine been widely used clinically to treat various arrhythmias including atrial fibrillation (AF). However, the role and precise mechanism of SSYX in MS-induced AF have not yet been elucidated. PURPOSE: To elucidate the protective effects of SSYX on MS-induced AF and its possible mechanisms of action. METHODS: Male Wistar rats (180-220 g) were fed a 16-week high-carbohydrate, high-fat (HCHF) diet together with 25% fructose in drinking water to produce a MS model. Low-concentration (SSYX-L, 0.4 g/kg) and high-concentration (SSYX-H, 0.8 g/kg) of SSYX were given by daily gavage 8-weeks following HCHF diet for 8-weeks. In vivo electrophysiological study, histological analysis, RNA-sequence (RNA-Seq) and gene ontology (GO) analysis, qRT-PCR and western blot were performed. RESULTS: Both low-concentration and high-concentration of SSYX could inhibit MS-induced AF susceptibility, electrical remodeling and structural remodeling. Results from RNA-sequence analysis revealed intracellular iron homeostasis mediated the protective effect of SSYX against MS. In vivo and in vitro experiments both demonstrated that SSYX up-regulated ferroportin (Fpn) expression and ameliorated intracellular iron overload induced by MS. To verified whether Fpn is the target of SSYX and intracellular iron overload mediated the protective effect of SSYX against MS, adeno-associated virus type 9 (AAV9) delivery system was used. Knocking down Fpn (AAV9-shFpn) markedly aggravated the reactive oxygen species (ROS) production, electrical remodeling and atrial fibrosis induced by MS, leading to a further increase of AF susceptibility induced by MS. CONCLUSION: Our study demonstrated for the first time that SSYX reduced AF susceptibility, inhibited electrical remodeling and structural remodeling via up-regulating Fpn, decreasing intracellular iron overload and reducing ROS production. These results suggest that SSYX might be a potential therapeutic agent for the treatment of MS-induced AF.

Sex-Related Differences in Atrial Remodeling in Patients With Atrial Fibrillation: Relationship to Ablation Outcomes.

BACKGROUND: Population studies have demonstrated a range of sex differences including a higher prevalence of atrial fibrillation (AF) in men and a higher risk of AF recurrence in women. However, the underlying reasons for this higher recurrence are unknown. This study evaluated whether sex-based electrophysiological substrate differences exist to account for worse AF ablation outcomes in women. METHODS: High-density electroanatomic mapping of the left atrium was performed in 116 consecutive patients with AF. Regional analysis was performed across 6 left atrium segments. High-density maps were created using a multipolar catheter (Biosense Webster) during distal coronary sinus pacing at 600 and 300 ms. Mean voltage and conduction velocity was determined. Complex fractionated signals and double potentials were manually annotated. RESULTS: Overall, 42 (36%) were female, mean age was 61±8 years and AF was persistent in 52%. Global mean voltage was significantly lower in females compared with males at 600 ms (1.46±0.17 versus 1.84±0.15 mV, P<0.001) and 300 ms (1.27±0.18 versus 1.57±0.18 mV, P=0.013) pacing. These differences were seen uniformly across the left atrium. Females demonstrated significant conduction velocity slowing (34.9±6.1 versus 44.1±6.9 cm/s, P=0.002) and greater proportion of complex fractionated signals (9.9±1.7% versus 6.0±1.7%, P=0.014). After a median follow-up of 22 months (Q1-Q3: 15-29), females had significantly lower single-procedure (22 [54%] versus 54 [75%], P=0.029) and multiprocedure (24 [59%] versus 60 [83%], P=0.005) arrhythmia-free survival. Female sex and persistent AF were independent predictors of single and multiprocedure arrhythmia recurrence. CONCLUSIONS: Female patients demonstrated more advanced atrial remodeling on high-density electroanatomic mapping and greater post-AF ablation arrhythmia recurrence compared with males. These changes may contribute to sex-based differences in the clinical course of females with AF and in part explain the higher risk of recurrence. Graphic Abstract: A graphic abstract is available for this article.

Clinical Outcomes of low-voltage area-guided left atrial linear ablation for non-paroxysmal atrial fibrillation patients.

BACKGROUND: The therapeutic effect of low-voltage area (LVA)-guided left atrial (LA) linear ablation for non-paroxysmal atrial fibrillation (non-PAF) is uncertain. We aimed to investigate the efficacy of LA linear ablation based on the preexisting LVA and its effects on LA reverse remodeling in non-PAF patients. METHODS: We retrospectively evaluated 145 consecutive patients who underwent radiofrequency catheter ablation for drug-refractory non-PAF. CARTO-guided bipolar voltage mapping was performed in atrial fibrillation (AF). LVA was defined as sites with voltage ≤ 0.5 mV. If circumferential pulmonary vein isolation couldn't convert AF into sinus rhythm, additional LA linear ablation was performed preferentially at sites within LVA. RESULTS: After a mean follow-up duration of 48 ± 33 months, 29 of 145 patients had drugs-refractory AF/LA tachycardia recurrence. Low LA emptying fraction, large LA size and high extent of LVA were associated with AF recurrence. There were 136 patients undergoing LA linear ablation. The rate of linear block at the mitral isthmus was significantly higher via LVA-guided than non-LVA-guided linear ablation. Patients undergoing LVA-guided linear ablation had larger LA size and higher extent of LVA, but the long-term AF/LA tachycardia-free survival rate was higher than the non-LVA-guided group. The LA reverse remodeling effects by resuming sinus rhythm were noted even in patients with a diseased left atrium undergoing extensive LA linear ablation. CONCLUSIONS: LVA-guided linear ablation through targeting the arrhythmogenic LVA and reducing LA mass provides a better clinical outcome than non-LVA guided linear ablation, and outweighs the harmful effects of iatrogenic scaring in non-PAF patients.

Understanding PITX2-Dependent Atrial Fibrillation Mechanisms through Computational Models.

Atrial fibrillation (AF) is a common arrhythmia. Better prevention and treatment of AF are needed to reduce AF-associated morbidity and mortality. Several major mechanisms cause AF in patients, including genetic predispositions to AF development. Genome-wide association studies have identified a number of genetic variants in association with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene for the homeobox transcription PITX2. Because of the inherent complexity of the human heart, experimental and basic research is insufficient for understanding the functional impacts of PITX2 variants on AF. Linking PITX2 properties to ion channels, cells, tissues, atriums and the whole heart, computational models provide a supplementary tool for achieving a quantitative understanding of the functional role of PITX2 in remodelling atrial structure and function to predispose to AF. It is hoped that computational approaches incorporating all we know about PITX2-related structural and electrical remodelling would provide better understanding into its proarrhythmic effects leading to development of improved anti-AF therapies. In the present review, we discuss advances in atrial modelling and focus on the mechanistic links between PITX2 and AF. Challenges in applying models for improving patient health are described, as well as a summary of future perspectives.

Neuroscientific therapies for atrial fibrillation.

The cardiac autonomic nervous system (ANS) plays an integral role in normal cardiac physiology as well as in disease states that cause cardiac arrhythmias. The cardiac ANS, comprised of a complex neural hierarchy in a nested series of interacting feedback loops, regulates atrial electrophysiology and is itself susceptible to remodelling by atrial rhythm. In light of the challenges of treating atrial fibrillation (AF) with conventional pharmacologic and myoablative techniques, increasingly interest has begun to focus on targeting the cardiac neuraxis for AF. Strong evidence from animal models and clinical patients demonstrates that parasympathetic and sympathetic activity within this neuraxis may trigger AF, and the ANS may either induce atrial remodelling or undergo remodelling itself to serve as a substrate for AF. Multiple nexus points within the cardiac neuraxis are therapeutic targets, and neuroablative and neuromodulatory therapies for AF include ganglionated plexus ablation, epicardial botulinum toxin injection, vagal nerve (tragus) stimulation, renal denervation, stellate ganglion block/resection, baroreceptor activation therapy, and spinal cord stimulation. Pre-clinical and clinical studies on these modalities have had promising results and are reviewed here.

Renal denervation prevents myocardial structural remodeling and arrhythmogenicity in a chronic kidney disease rabbit model.

BACKGROUND: The electrophysiological (EP) effects and safety of renal artery denervation (RDN) in chronic kidney disease (CKD) are unclear. OBJECTIVE: The purpose of this study was to investigate the arrhythmogenicity of RDN in a rabbit model of CKD. METHODS: Eighteen New Zealand white rabbits were randomized to control (n = 6), CKD (n = 6), and CKD-RDN (n = 6) groups. A 5/6 nephrectomy was selected for the CKD model. RDN was applied in the CKD-RDN group. All rabbits underwent cardiac EP studies for evaluation. Immunohistochemistry, myocardial fibrosis, and renal catecholamine levels were evaluated. RESULTS: The CKD group (34.8% ± 9.2%) had a significantly higher ventricular arrhythmia (VA) inducibility than the control (8.6% ± 3.8%; P <.01) and CKD-RDN (19.5% ± 6.3%; P = .01) groups. In the CKD-RDN group, ventricular fibrosis was significantly decreased compared to the CKD group (7.4% ± 2.0 % vs 10.4% ± 3.7%; P = .02). Sympathetic innervation in the CKD group was significantly increased compared to the control and CKD-RDN groups [left ventricle: 4.1 ± 1.8 vs 0.8 ± 0.5 (102 µm2/mm2), P <.01; 4.1 ± 1.8 vs 0.9± 0.6 (102 µm2/mm2), P <.01; right ventricle: 3.6 ± 1.0 vs 1.0 ± 0.4 (102 µm2/mm2), P <.01; 3.6 ± 1.0 vs 1.0 ± 0.5 (102 µm2/mm2), P <.01]. CONCLUSION: Neuromodulation by RDN demonstrated protective effects with less structural and electrical remodeling, leading to attenuated VAs. In a rabbit model of CKD, RDN plays a therapeutic role by lowering the risk of VA caused by autonomic dysfunction.

Increased body mass index, age, and left atrial size are associated with altered intracardiac atrial electrograms in persistent atrial fibrillation patients.

BACKGROUND: There are limited studies evaluating whether atrial fibrillation (AF) patients with increased BMI, age, and left atrial (LA) size have altered intracardiac electrogram (EGM) morphology. METHODS: We analyzed left atrial intracardiac EGMs acquired during invasive electrophysiology study in 54 patients with AF. EGM correlations were assessed among AF risk factors including age, left atrial size, and BMI. RESULTS: BMI correlated positively with DF (r2 = 0.17, p = 0.009) and MP (r2 = 0.16, p = 0.01) with dominant frequency (DF) and mean spectral profile (MP) greater among obese individuals. Age was negatively associated with mean amplitude (r2 = 0.42, p < 0.001) and width (r2 = 0.32, p < 0.001); age was positively correlated with MP (r2 = 0.24, p < 0.001). LA size was negatively correlated with mean amplitude (r2 = 0.18, p = 0.03) and width (r2 = 0.23, p = 0.01); LA size was positively correlated with DF (r2 = 0.22, p = 0.01) and MP (r2 = 0.23, p = 0.01). Mean amplitude and width were decreased among subjects with a severely enlarged LA; DF and MP were increased in those with severely enlarged LA. The associations with BMI and LA size remained significant in multiple regression models that included age, male gender, time since AF diagnosis, and LVEF. CONCLUSIONS: EGM morphology of AF patients with increased BMI, older age, and an enlarged LA possessed decreased amplitude and decreased width and increased DF and MP. These findings suggest that atrial remodeling due to increased age, LA size, and BMI is associated with differences in local atrial activation, decreased refractoriness, and more heterogeneous activation. These novel findings point out clinical risk factors for atrial fibrillation that may affect electrogram characteristics.

Canagliflozin Suppresses Atrial Remodeling in a Canine Atrial Fibrillation Model.

Background Recent clinical trials have demonstrated the possible pleiotropic effects of SGLT2 (sodium-glucose cotransporter 2) inhibitors in clinical cardiovascular diseases. Atrial electrical and structural remodeling is important as an atrial fibrillation (AF) substrate. Methods and Results The present study assessed the effect of canagliflozin (CAN), an SGLT2 inhibitor, on atrial remodeling in a canine AF model. The study included 12 beagle dogs, with 10 receiving continuous rapid atrial pacing and 2 acting as the nonpacing group. The 10 dogs that received continuous rapid atrial pacing for 3 weeks were subdivided as follows: pacing control group (n=5) and pacing+CAN (3 mg/kg per day) group (n=5). The atrial effective refractory period, conduction velocity, and AF inducibility were evaluated weekly through atrial epicardial wires. After the protocol, atrial tissues were sampled for histological examination. The degree of reactive oxygen species expression was evaluated by dihydroethidium staining. The atrial effective refractory period reduction was smaller (P=0.06) and the degree of conduction velocity decrease was smaller in the pacing+CAN group compared with the pacing control group (P=0.009). The AF inducibility gradually increased in the pacing control group, but such an increase was suppressed in the pacing+CAN group (P=0.011). The pacing control group exhibited interstitial fibrosis and enhanced oxidative stress, which were suppressed in the pacing+CAN group. Conclusions CAN and possibly other SGLT2 inhibitors might be useful for preventing AF and suppressing the promotion of atrial remodeling as an AF substrate.

Cardiac electrical remodeling and neurodegenerative diseases association.

Cardiac impairment contributes significantly to the mortality associated with several neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), primarily recognized as brain pathologies. These diseases may be caused by aggregation of a misfolded protein, most often, in the brain, although new evidence also reveals peripheral abnormalities. After characterization of the cardiac involvement in neurodegenerative diseases, several studies concentrated on elucidating the cause of the impaired cardiac function. However, most of the current knowledge is focused on the mechanical aspects of the heart rather than the electrical disturbances. The main objective of this review is to summarize the most recent advances in the elucidation of cardiac electrical remodeling in the neurodegenerative environment. We aimed to determine a crosstalk between the heart and the brain in three neurodegenerative conditions: AD, PD, and HD. We found that the most studies demonstrated important alterations in the electrocardiogram (ECG) of patients with neurodegeneration and in animal models of the conditions. We also showed that little is described when considering excitability disruptions in cardiomyocytes, for example, action potential impairments. It is a matter of contention whether central nervous system abnormalities or the peripheral ones increase the risk of heart diseases in patients with neurodegenerative conditions. To determine this notion, there is a need for new heart studies focusing specifically on the cardiac electrophysiology (e.g., ECG and cardiomyocyte excitability). This review could serve as an important guide in designing novel accurate approaches targeting the heart in neuronal conditions.

Untargeted metabolomics and lipidomics uncovering the cardioprotective effects of Huanglian Jiedu Decoction on pathological cardiac hypertrophy and remodeling.

ETHNOPHARMACOLOGICAL RELEVANCE: As a classic herbal prescription, Huanglian Jiedu Decoction (HLJDD) exhibits positive effects against cardiac dysfunction. However, its cardioprotective effects and potential mechanism(s) of action still need to be systematically investigated. AIM OF THE STUDY: This study aimed to reveal the underlying therapeutic mechanism of HLJDD on transverse aortic constriction (TAC)-induced pathological cardiac hypertrophy and remodeling. MATERIALS AND METHODS: TAC-induced cardiac hypertrophy and remodeling mice model was established to evaluate the therapeutic effects of HLJDD. Serum untargeted metabolomics and lipidomic profiling were performed using ultra-performance liquid chromatography quadrupole-time-of-flight mass spectrometry coupled with multivariate statistical analyses. RESULTS: Oral administration of HLJDD (2.5 g/kg/day, 5.0 g/kg/day) significantly improved the heart morphology, enhanced the heart function, and alleviated the accumulation of fibrosis in the interstitial space and the infiltration of inflammatory cells in TAC-stimulated mice. Serum untargeted metabolomics analysis showed that significant alterations were observed in metabolic signatures between the TAC-model and sham group. Principal component analysis and orthogonal partial least-squares discriminant analysis screened 59 differential metabolic features and 13 metabolites were identified. The disturbed metabolic pathways in TAC group mainly related to lipid metabolism. Further serum lipidomic profiling showed that most lipids including cholesterol esters, ceramides, glycerides, fatty acids and phospholipids were decreased in TAC group and these alterations were reversed after HLJDD intervention. CONCLUSION: HLJDD alleviates TAC-induced pathological cardiac hypertrophy and remodeling, and its potential therapeutic mechanism involves the regulation of lipid metabolism.

Decreased bioavailability of hydrogen sulfide links vascular endothelium and atrial remodeling in atrial fibrillation.

Oxidative stress drives the pathogenesis of atrial fibrillation (AF), the most common arrhythmia. In the cardiovascular system, cystathionine γ-lyase (CSE) serves as the primary enzyme producing hydrogen sulfide (H2S), a mammalian gasotransmitter that reduces oxidative stress. Using a case control study design in patients with and without AF and a mouse model of CSE knockout (CSE-KO), we evaluated the role of H2S in the etiology of AF. Patients with AF (n = 51) had significantly reduced plasma acid labile sulfide levels compared to patients without AF (n = 65). In addition, patients with persistent AF (n = 25) showed lower plasma free sulfide levels compared to patients with paroxysmal AF (n = 26). Consistent with an important role for H2S in AF, CSE-KO mice had decreased atrial sulfide levels, increased atrial superoxide levels, and enhanced propensity for induced persistent AF compared to wild type (WT) mice. Rescuing H2S signaling in CSE-KO mice by Diallyl trisulfide (DATS) supplementation or reconstitution with endothelial cell specific CSE over-expression significantly reduced atrial superoxide, increased sulfide levels, and lowered AF inducibility. Lastly, low H2S levels in CSE KO mice was associated with atrial electrical remodeling including longer effective refractory periods, slower conduction velocity, increased myocyte calcium sparks, and increased myocyte action potential duration that were reversed by DATS supplementation or endothelial CSE overexpression. Our findings demonstrate an important role of CSE and H2S bioavailability in regulating electrical remodeling and susceptibility to AF.

Evaluation of left atrial remodeling by 2D-speckle-tracking echocardiography versus by high-density voltage mapping in patients with atrial fibrillation.

BACKGROUND: Strain imaging during left atrial (LA) reservoir phase (LASr) is used as a surrogate for LA structural remodeling and fibrosis. Atrial fibrillation (AF) patients with >5% low-voltage zones (LVZs) obtained by 3D-electro-anatomical-mapping have higher recurrence rate post-ablation. We investigated the relationship between LA remodeling using two-dimensional-speckle-tracking echocardiography (2D-STE) and high-density voltage mapping in AF patients. METHODS: A prospective study of 42 consecutive patients undergoing AF ablation. 2D-echo, 2D-STE, and high-density contact LA bipolar voltage maps were constructed before ablation. LVZs were determined with different bipolar amplitudes and their ratio per patient's LA area were investigated for correlation with LASr. We compared 2D-LASr results in patients with LVZs ≥ 5% (LVZs group) versus those with LVZ < 5% (non-LVZs group). RESULTS: Compared with non-LVZs group (n = 15), LVZs group (n = 27) included significantly older patients, more women, more persistent AF, higher CHA2 DS2 -VASc score, higher E/A ratio and higher LA volume index (p < .05). LVZs group had lower %LASr values (12.4 ± 5.9% vs. 21.1 ± 6.3, respectively; p<.001). LVZs% in different amplitudes (<0.1 mV, <0.2 mV, and <0.5 mV) were negatively correlated with %LASr (r = -.63, r = -.68, and r = -.72, respectively; p< .001). Atrial strain thresholds for LVZs ≥ 5% in amplitudes <0.1 mV, <0.2 mV, and <0.5 mV were associated with %LASr 12.98, 16.16 and 19.55, respectively; p< .05). In a multivariate analysis, %LASr was the only independent indicator of LVZs (OR, 0.8; 95% CI, 0.6-0.9; p= .04). CONCLUSIONS: LVZs ≥ 5% has a negative association with atrial %LASr. Thus, a simple 2D-STE measurement of %LASr can be used as a noninvasive method to evaluate significant LA remodeling and fibrosis in AF patients.