Ventricular Electrical Remodeling Research Articles

LEFT VENTRICULAR REPOLARIZATION ANOMALIES AFTER EXERCISE TESTING IN ASYMPTOMATIC MODERATE AORTIC REGURGITATION

Aortic regurgitation (AR) results in a volume overload of the left ventricle. Although this volume-load brings on left ventricular eccentric hypertrophy and fibrosis, it may remain asymptomatic and have no effect on function as assed by echocardiography. Symptoms or reduced function are the result of a more advanced stage of the pathophysiological process and are not the earliest indicators of worsening ventricular adaptation. Heterogeneity in ventricular repolarization is reflected by QT dispersion (d-QT), which increases with the transvalvular pressure gradient. It has not been studied in AR at rest or during exercise testing. We sought to determine the pattern of QT and d-QT response to exercise testing in children with moderate AR in order to evaluate the impact of volume overload on ventricular repolarization. 9 patients with moderate AR were compared with 17 controls of similar age (12.9±3.7 vs 11.9±2.3 years; p=0.31) and gender distributions (55 vs 53 % male; p=0.97). All subjects underwent a treadmill exercise testing with 12-lead electrocardiograph recording. Similar METS were achieved between groups (11.8±2.8 vs 13.7±1.9 METS; p=0.11), with similar resting systolic BP, but lower diastolic BP in AR subjects (Table1). QT was measured from the onset of QRS to the end (QTe) at rest, at peak exercise, and at 1 and 3 minutes upon recovery. QT was corrected using the Fridericia equation (QTeF), and d-QT was calculated. Resting QTeF was similar at rest in both groups (p=0.968) but increased significantly in AR group compared to controls (CTL) during exercise (p<0.001) and remained so after 1 minute (p<0.001) of recovery with largest difference being observed then (374 vs 302msec). d-QT was found to be significantly higher in AR group compared to controls at rest, maximal effort and 1 minute of recovery with largest difference at 1 minute recovery (101 vs 45 msec). At 3 minutes, neither QTeF nor d-QT were significantly different (Figure1). Ventricular repolarization is prolonged and more heterogeneous in asymptomatic moderate AR. Changes are mostly detectible with exercise. Although d-QT is higher at rest in AR, QT prolongation is only observed after exercise testing and becomes more pronounced in early recovery. Using QT response to exercise could be beneficial for a better understanding of left ventricular electrical remodeling response to volume overload.View Large Image Figure ViewerDownload (PPT)

CT-1-CP-induced ventricular electrical remodeling in mice.

The chronic effects of carboxyl-terminal polypeptide of Cardiotrophin-1 (CT-1-CP) on ventricular electrical remodeling were investigated. CT-1-CP, which contains 16 amino acids in sequence of the C-terminal of Cardiotrophin-1, was selected and synthesized, and then administered to Kunming mice (aged 5 weeks) by intraperitoneal injection (500 ng·g⁻¹·day⁻¹) (4 groups, n=10 and female: male=1:1 in each group) for 1, 2, 3 and 4 weeks, respectively. The control group (n=10, female: male=1:1) was injected by physiological saline for 4 weeks. The epicardial monophasic action potential (MAP) was recorded by using a contact-type MAP electrode placed vertically on the left ventricular (LV) epicardium surface, and the electrocardiogram (ECG) signal in lead II was monitored synchronously. ECG intervals (RR, PR, QRS and QT) and the amplitude of MAP (Am), the maximum upstroke velocity (Vmax), as well as action potential durations (APDs) at different repolarization levels (APD30, APD50, APD70, and APD90) of MAP were determined and analyzed in detail. There were no significant differences in RR and P intervals between CT-1-CP-treated groups and control group, but the PR segment and the QRS complex were greater in the former than in the latter (F=2.681 and 5.462 respectively, P<0.05). Though QT interval and the corrected QT interval (QTc) were shorter in CT-1-CP-treated groups than in control group, the QT dispersion (QTd) of them was greater in the latter than in the former (F=3.090, P<0.05) and increased with the time. The ECG monitoring synchronously with the MAP showed that the compression of MAP electrode on the left ventricular epicardium induced performance similar to myocardium ischemia. As compared with those before chest-opening, the PR segment and QT intervals remained basically unchanged in control group, but prolonged significantly in all CT-1-CP-treated groups and the prolongation of QT intervals increased gradually along with the time of exposure to CT-1-CP. The QRS complex had no significant change in control group, one-week and three-week CT-1-CP-treated groups, but prolonged significantly in two-week and four-week CT-1-CP-treated groups. Interestingly, the QTd after chest-opening was significantly greater than that before chest-opening in control group (t=5.242, P<0.01), but decreased along with the time in CT-1-CP-treated groups. The mean MAP amplitude, Vmax and APD were greater in CT-1-CP-treated groups than those in control group, and became more obvious along with the time. The APD in four CT-1-CP-treat groups was prolonged mainly in middle to final repolarization phase. The difference among these groups became significant in middle phase (APD50) (F=6.076, P<0.01) and increased furthermore in late and final phases (APD70: F=10.054; APD90: F=18.691, P<0.01) along with the time of injection of CT-1-CP. The chronic action of CT-1-CP might induce the adapting alteration in cardiac conductivity and ventricular repolarization. The amplitude and the Vmax of the anterior LV epicardial MAP increased obviously, and the APD prolonged mainly in late and final phase of repolarization.

0244: Pro-arrhythmic ventricular remodeling in a porcine model of repaired tetralogy of Fallot

Ventricular arrhythmias are frequent in patients with repaired tetralogy of Fallot but their underlying mechanisms remain unclear. In this study, ventricular electrical and structural remodelling was assessed in an animal model that mimics postoperative tetralogy of Fallot. Piglets underwent a tetralogy of Fallot repair-like surgery (rTOF N=6) or were sham-operated (Sham N=5). Following cardiac function assessment in vivo by MRI 3-4 months after surgery, pigs were euthanized and their hearts rapidly excised. Electrophysiological properties of right (RV) and left ventricles (LV) were obtained by optical mapping. Fibrosis was assessed histologically. RV dysfunction was evident while LV function remained unaltered in rTOF pigs. LV action potential duration (APD) was significantly longer on the epicardium (Sham 280±50ms; rTOF 390±76ms) and endocardium (Sham 301±20ms; rTOF 403±34ms) of rTOF animals (P<0.05). RV epicardial and endocardial APD were not different between rTOF and Sham RVs. LV conduction velocity (CV) was significantly reduced in the longitudinal direction in rTOF pigs (65.37 ±6.76 cm/s vs 51.27±0.57 cm/s; P<0.05) but remained unchanged in the transverse direction compared to Sham animals (27.34±3.08 cm/s vs 30.19±1.97 cm/s). In the RV both longitudinal and transverse CVs were significantly in rTOF compared to Sham (P<0.05). An elevated collagen content was found in both the LV and RV of rTOF pigs (P<0.05). A trend for a lateralization of Connexin43 was found in the LV of rTOFs which, together with the increased fibrosis, may account for the reduced longitudinal conduction velocity in this ventricle. Altogether, these findings highlight the presence of an arrhytmic substrate in the ventricles of rTOF pigs. Interestingly, the remodeling in LV is reminiscent to that observed in LV failure, despite no functional alterations, and is likely to contribute to ventricular arrhythmias in patients with rTOF.

Effects of Cardiac Resynchronization Therapy on Ventricular Electrical Remodeling in Patients With Heart Failure.

Cardiac resynchronization therapy (CRT) reverses structural remodeling of the left ventricle. We investigated whether CRT reverses left-ventricular electrical remodeling.Eighty patients were enrolled and implanted with CRT-devices. Echocardiography and electrocardiography data were obtained from each patient prior to implantation and two years after implantation. At two years after implantation, the patients were classified into a responder group and a non-responder group based on echocardiography.Over the next 2 years, 75 patients completed follow-up, and 5 patients had died. Echocardiography results showed that 23 patients could be classified as non-responders and 52 as responders. Larger numbers of non-responders were diagnosed with either ischemic cardiomyopathy (ICM) or nonspecific intraventricular conduction delay (NICD). The intrinsic QRS duration was not changed in responders, patients with dilated cardiomyopathy, or in the patient categories of male and female. However, the intrinsic QRS duration was significantly prolonged in non-responders and patients with ischemic cardiomyopathy (P = 0.041). The mean left ventricular end-diastolic diameter in the responder group was significantly decreased by CRT (P < 0.05), while there was no significant change in intrinsic QRS duration.While CRT does not reduce the intrinsic QRS duration, it can delay negative ventricular electrical remodeling. Continuous CRT is necessary.

0354: Pro-arrhythmic ventricular remodeling in a porcine model of repaired tetralogy of Fallot

Ventricular arrhythmias are frequent in patients with repaired tetralogy of Fallot but their underlying mechanisms remain unclear. In this study, ventricular electrical and structural remodelling was assessed in an animal model that mimics postoperative tetralogy of Fallot. Piglets underwent a tetralogy of Fallot repair-like surgery (rTOF N=6) or were sham-operated (Sham N=5). Following cardiac function assessment in vivo by MRI 3–4 months after surgery, pigs were euthanized and their hearts rapidly excised. Electrophysiological properties of right (RV) and left ventricles (LV) were obtained by optical mapping. Fibrosis was assessed histologically. RV dysfunction was evident while LV function remained unaltered in rTOF pigs. LV action potential duration (APD) was significantly longer on the epicardium (Sham 280±50 ms; rTOF 390±76 ms) and endocardium (Sham 301±20 ms; rTOF 403±34 ms) of rTOF animals (P<0.05). RV epicardial and endocardial APD were not different between rTOF and Sham RVs. LV conduction velocity (CV) was significantly reduced in the longitudinal direction in rTOF pigs (65.37±6.76 cm/s vs 51.27±0.57 cm/s; P<0.05) but remained unchanged in the transverse direction compared to Sham animals (27.34±3.08 cm/s vs 30.19±1.97 cm/s). In the RV both longitudinal and transverse CVs were significantly decreased in rTOF compared to Sham (P<0.05). An elevated collagen content was found in both the LV and RV of rTOF pigs (P<0.05). A trend for a lateralization of Connexin43 was found in the LV of rTOFs which, together with the increased fibrosis, may account for the reduced longitudinal conduction velocity in this ventricle. Altogether, these findings highlight the presence of an arrhytmic substrate in the ventricles of rTOF pigs. Interestingly, the remodeling in LV is reminiscent to that observed in LV failure, despite no functional alterations, and is likely to contribute to ventricular arrhythmias in patients with rTOF.

Nicorandil improves electrical remodelling, leading to the prevention of electrically induced ventricular tachyarrhythmia in a mouse model of desmin-related cardiomyopathy

1. Transgenic (TG) mice overexpressing an arg120gly missense mutation in heat shock protein B5 (HSPB5; i.e. R120G TG mice) exhibit desmin-related cardiomyopathy. Recently, the cardioprotective effect of nicorandil has been shown to prolong the survival of R120G TG mice. However, whether the TG mice exhibit ventricular arrhythmias and whether nicorandil can inhibit these arrhythmias remain unknown. In the present study we examined the effects of chronic nicorandil administration on ventricular electrical remodelling and arrhythmias in R120G TG mice. 2. Mice were administered nicorandil (15 mg/kg per day) or vehicle (water) orally from 5 to 30 weeks of age. Electrocardiograms (ECG) and optical action potentials were recorded from R120G TG mouse hearts. In addition, the expression of ventricular connexin 43 and the cardiac Na(+) channel Nav1.5 was examined in TG mice. 3. All ECG parameters tested were prolonged in R120G TG compared with non-transgenic (NTG) mice. Nicorandil improved the prolonged P, PQ and QRS intervals in R120G TG mice. Interestingly, impulse conduction slowing and increases in the expression of total and phosphorylated connexin 43 and Nav1.5 were observed in ventricles from R120G TG compared with NTG mice. Nicorandil improved ventricular impulse conduction slowing and normalized the increased protein expression levels of total and phosphorylated connexin 43, but not of Nav1.5, in R120G TG mouse hearts. Electrical rapid pacing at the ventricle induced ventricular tachyarrhythmias (VT) in six of eight R120G TG mouse hearts, but not in any of the eight nicorandil-treated R120G TG mouse hearts (P < 0.05). 4. These findings demonstrate that nicorandil inhibits cardiac electrical remodelling and that the prevention of VT by nicorandil is associated with normalization of connexin 43 expression in this model.

Ionic bases for electrical remodeling of the canine cardiac ventricle

Emerging evidence suggests that ventricular electrical remodeling (VER) is triggered by regional myocardial strain via mechanoelectrical feedback mechanisms; however, the ionic mechanisms underlying strain-induced VER are poorly understood. To determine its ionic basis, VER induced by altered electrical activation in dogs undergoing left ventricular pacing (n = 6) were compared with unpaced controls (n = 4). Action potential (AP) durations (APDs), ionic currents, and Ca(2+) transients were measured from canine epicardial myocytes isolated from early-activated (low strain) and late-activated (high strain) left ventricular regions. VER in the early-activated region was characterized by minimal APD prolongation, but marked attenuation of the AP phase 1 notch attributed to reduced transient outward K(+) current. In contrast, VER in the late-activated region was characterized by significant APD prolongation. Despite marked APD prolongation, there was surprisingly minimal change in ion channel densities but a twofold increase in diastolic Ca(2+). Computer simulations demonstrated that changes in sarcolemmal ion channel density could only account for attenuation of the AP notch observed in the early-activated region but failed to account for APD remodeling in the late-activated region. Furthermore, these simulations identified that cytosolic Ca(2+) accounted for APD prolongation in the late-activated region by enhancing forward-mode Na(+)/Ca(2+) exchanger activity, corroborated by increased Na(+)/Ca(2+) exchanger protein expression. Finally, assessment of skinned fibers after VER identified altered myofilament Ca(2+) sensitivity in late-activated regions to be associated with increased diastolic levels of Ca(2+). In conclusion, we identified two distinct ionic mechanisms that underlie VER: 1) strain-independent changes in early-activated regions due to remodeling of sarcolemmal ion channels with no changes in Ca(2+) handling and 2) a novel and unexpected mechanism for strain-induced VER in late-activated regions in the canine arising from remodeling of sarcomeric Ca(2+) handling rather than sarcolemmal ion channels.

Effects of Spironolactone Alone and in Addition to a Beta-blocker on Myocardial Histological and Electrical Remodeling in Chronic Severe Failing Rat Hearts

Aldosterone antagonists (AAs) have beneficial effects on ventricular histological and electrical remodeling and improve noradrenaline uptake. Adding an AA to a beta-blocker (BB) further improves cardiac mortality in heart failure patients. We investigated if adjunction of a BB modifies beneficial effects of spironolactone on different parameters of the ventricular remodeling. A severe myocardial infarction (MI) was produced in rats. Three months after surgery, left ventricular (LV) function was assessed by echocardiography. Fifty-five rats with heart failure were then randomized in 5 groups: sham, MI, and MI treated for 4 weeks with spironolactone (10 mg·kg·d), atenolol (1 mg·kg·d), or both. Holter transducers were implanted to record 24-hour ventricular electrical parameters, mean cycle length (RR) and SD of RR. Before killing, invasive left ventricular end diastolic pressure (LVEDP) was recorded. LV samples were used for histological analysis and catecholamine assay. Rats with MI had significantly increased LVEDP (32 ± 3 vs. 14 ± 1 mm Hg), LV, collagen content (5.8% ± 1.4% vs. 3.6% ± 0.7%), ventricular premature complexes (2.5 10 ± 10 vs. 30 ± 13), and decreased meanRR (164 ± 2 vs. 169 ± 1 milliseconds) and SDRR (3.9 ± 0.2 vs. 5.4 ± 0.2 milliseconds) compared with sham. At nonhypotensive doses, spironolactone and atenolol similarly improved LVEDP. Compared with MI, although spironolactone significantly decreased ventricular premature complexes, LV collagen and noradrenaline contents, and improved meanRR and SDRR, atenolol had effects only on meanRR and SDRR. Addition of atenolol to spironolactone further improved spironolactone effects on all these parameters. AA improved, independently of the cardiac function, histological and electrical remodeling after MI. A BB added to an AA did not blunt these beneficial effects; furthermore, it improved these effects related to spironolactone.

The zebrafish as a novel animal model to study the molecular mechanisms of mechano-electrical feedback in the heart

Altered mechanical loading of the heart leads to hypertrophy, decompensated heart failure and fatal arrhythmias. However, the molecular mechanisms that link mechanical and electrical dysfunction remain poorly understood. Growing evidence suggest that ventricular electrical remodeling (VER) is a process that can be induced by altered mechanical stress, creating persistent electrophysiological changes that predispose the heart to life-threatening arrhythmias. While VER is clearly a physiological property of the human heart, as evidenced by “T wave memory”, it is also thought to occur in a variety of pathological states associated with altered ventricular activation such as bundle branch block, myocardial infarction, and cardiac pacing. Animal models that are currently being used for investigating stretch-induced VER have significant limitations. The zebrafish has recently emerged as an attractive animal model for studying cardiovascular disease and could overcome some of these limitations. Owing to its extensively sequenced genome, high conservation of gene function, and the comprehensive genetic resources that are available in this model, the zebrafish may provide new insights into the molecular mechanisms that drive detrimental electrical remodeling in response to stretch. Here, we have established a zebrafish model to study mechano-electrical feedback in the heart, which combines efficient genetic manipulation with high-precision stretch and high-resolution electrophysiology. In this model, only 90 min of ventricular stretch caused VER and recapitulated key features of VER found previously in the mammalian heart. Our data suggest that the zebrafish model is a powerful platform for investigating the molecular mechanisms underlying mechano-electrical feedback and VER in the heart.

The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy

The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy

Abstract P170: Nicorandil Inhibits Gáq-Induced Chronic Heart Failure in Transgenic Mice

Introduction: Beneficial effects of nicorandil on the treatment of hypertensive heart failure (HF) and ischemic heart disease have been suggested. However, whether nicorandil has inhibitory effects on HF and ventricular arrhythmias caused by the activation of G protein alpha q (Gαq) -coupled receptor (GPCR) signaling pathway still remains unknown. We examined effects of chronic and acute administration of nicorandil on the development of HF and ventricular action potential (VAP) in transgenic mice with transient cardiac expression of activated Gαq (Gαq-TG), respectively. Method and Results: Nicorandil (6 mg/kg/day) or vehicle was chronically administered in Gαq-TG mice for 24 weeks from 8 weeks of age, and then ventricular function, and electrical and structural changes were investigated in the hearts. Chronic nicorandil administration improved the reduction of left ventricular fractional shortening (p &lt; 0.001) in Gαq-TG hearts. During 10 min of electrocardiogram recording, premature ventricular contractions (more than 20 beats/min) were observed in 7 of 10 vehicle-treated Gαq-TG but in none of 10 nicorandil-treated Gαq-TG hearts (p &lt; 0.01). QT interval was significantly shorter in nicorandil-treated Gαq-TG than in vehicle-treated Gαq-TG hearts (p &lt; 0.05). Chronic nicorandil administration improved the increased ventricular interstitial fibrosis (p &lt; 0.05) but not cardiac hypertrophy in Gαq-TG left ventricles. Real time RT-PCR revealed that mRNA expression levels of s sulfonylurea receptor 2B (SUR-2B) were decreased in vehicle-treatd Gαq-TG but not in nicorandil-treated Gαq-TG. In addition, chronic nicorandil increased endotherial nitric oxide syntheses gene expression in Gαq-TG hearts (p &lt; 0.05). Acute nicorandil administration (1 microM) significantly shortened the prolonged VAP duration and reduced the number of PVCs in vehicle treated Gαq-TG hearts. Conclusions: These findings suggest that nicorandil inhibits ventricular electrical and structural remodeling and arrhythmias through the shortening of VAP duration and the increased expression of SUR-2B and eNOS in a mouse model of HF.

Sympathetic storm aggravate abnormal Kv4.2 ion channel membrane transposition in rat cardiomyocytes through endoplasmic reticulum stress

ObjectivesThe excessive activation of sympathetic nerve can lead to heart failure which causes heart remodelling, including both electrical and structural remodelling. Whether the endoplasmic reticulum (ER) stress mechanism on the...

Interlead Distance and Left Ventricular Lead Electrical Delay Predict Reverse Remodeling During Cardiac Resynchronization Therapy

Both anatomic interlead separation and left ventricle lead electrical delay (LVLED) have been associated with outcomes following cardiac resynchronization therapy (CRT). However, the relationship between interlead distance and electrical delay in predicting CRT outcomes has not been defined. We studied 61 consecutive patients undergoing CRT for standard clinical indications. All patients underwent intraprocedural measurement of LVLED. Interlead distances in the horizontal (HD), vertical (VD), and direct (DD) dimensions were measured from postprocedure chest radiographs (CXR). Remodeling indices [percent change in left ventricle (LV) ejection fraction, end-diastolic, end-systolic dimensions] were assessed by transthoracic echocardiogram. There was a positive correlation between corrected LVLED and HD on lateral CXR (r = 0.361, P = 0.004) and a negative correlation between LVLED and VD on posteroanterior (PA) CXR (r =-0.281, P = 0.028). To account for this inverse relationship, we developed a composite anatomic distance (defined as: lateral HD-PA VD), which correlated most closely with LVLED (r = 0.404, P = 0.001). Follow-up was available for 48 patients. At a mean of 4.1 +/- 3.2 months, patients with optimal values for both corrected LVLED (>or=75%) and composite anatomic distance (>or=15 cm) demonstrated greater reverse LV remodeling than patients with either one or neither of these optimized values. We identified a significant correlation between LV-right ventricular interlead distance and LVLED; additionally, both parameters act synergistically in predicting LV anatomic reverse remodeling. Efforts to optimize both interlead distance and electrical delay may improve CRT outcomes.

Long-term blockade of L/N-type Ca(2+) channels by cilnidipine ameliorates repolarization abnormality of the canine hypertrophied heart.

The heart of the canine model of chronic atrioventricular block is known to have a ventricular electrical remodelling, which mimics the pathophysiology of long QT syndrome. Using this model, we explored a new pharmacological therapeutic strategy for the prevention of cardiac sudden death. The L-type Ca(2+) channel blocker amlodipine (2.5 mg.day(-1)), L/N-type Ca(2+) channel blocker cilnidipine (5 mg.day(-1)), or the angiotensin II receptor blocker candesartan (12 mg.day(-1)) was administered orally to the dogs with chronic atrioventricular block for 4 weeks. Electropharmacological assessments with the monophasic action potential (MAP) recordings and blood sample analyses were performed before and 4 weeks after the start of drug administration. Amlodipine and cilnidipine decreased the blood pressure, while candesartan hardly affected it. The QT interval, MAP duration and beat-to-beat variability of the ventricular repolarization period were shortened only in the cilnidipine group, but such effects were not observed in the amlodipine or candesartan group. Plasma concentrations of adrenaline, angiotensin II and aldosterone decreased in the cilnidipine group. In contrast, plasma concentrations of angiotensin II and aldosterone were elevated in the amlodipine group, whereas in the candesartan group an increase in plasma levels of angiotensin II and a decrease in noradrenaline and adrenaline concentrations were observed. Long-term blockade of L/N-type Ca(2+) channels ameliorated the ventricular electrical remodelling in the hypertrophied heart which causes the prolongation of the QT interval. This could provide a novel therapeutic strategy for the treatment of cardiovascular diseases.

Aldosterone blockade attenuates development of an electrophysiological substrate associated with ventricular tachyarrhythmias in heart failure

Aldosterone blockade reduces sudden cardiac death in heart failure, but the underlying mechanism is unclear. This study's aim was to determine whether chronic eplerenone treatment protects against detrimental ventricular electrical remodeling and development of an arrhythmogenic substrate in a rapid ventricular pacing (RVP)-induced heart failure model. Dogs were assigned randomly to oral placebo or eplerenone treatment and divided into 4 groups: 2 sham-operated (no RVP) and 2 RVP groups. After 5 weeks of no RVP or RVP along with concurrent placebo or eplerenone treatment, dogs underwent echocardiographic assessments of systolic function and chamber size and electrophysiologic measurements of ventricular repolarization, refractoriness, conduction, tachyarrhythmia inducibility, and myocardial activation delays after premature stimulation. Eplerenone failed to prevent left ventricular systolic dysfunction or chamber enlargement in RVP dogs. Eplerenone attenuated prolongation of ventricular repolarization and refractoriness, increases in dispersion of repolarization and refractoriness, fractionation of ventricular electrograms, and delays in myocardial activation after premature stimulation at short coupling intervals and improved arrhythmia vulnerability score in RVP dogs with heart failure. Ventricular tachyarrhythmia inducibility in heart failure dogs was predicted by activation delays after premature stimulation at short coupling intervals, which were prevented by eplerenone. Eplerenone did not alter electrophysiological parameters in no-RVP dogs without heart failure. Eplerenone attenuates heart failure-related ventricular electrical remodeling and tachyarrhythmia vulnerability. Inhibition of myocardial activation delays during premature excitation may contribute to preventing development of an arrhythmogenic ventricular substrate in heart failure.

Beneficial effects of delayed ivabradine treatment on cardiac anatomical and electrical remodeling in rat severe chronic heart failure

We tested the hypothesis that heart rate (HR) reduction, induced by the selective hyperpolarization-activated current inhibitor ivabradine (Iva), might improve left ventricular (LV) function, structure, and electrical remodeling in severe post-myocardial infarction (MI) chronic heart failure (HF). MI was produced in adult male Wistar rats. After 2 mo, echocardiography was performed before the randomization into MI and MI + Iva (10 mg x kg(-1) x day(-1)) groups. After 3 mo of treatment, echocardiography and 24-h telemetry were recorded. Cardiac collagen, mRNA, and protein expressions of angiotensin-converting enzyme (ACE) and ANG II type 1 (AT(1)) receptor were quantified. As a result, at 2 mo post-MI, all rats displayed severe congestive HF signs (ejection fraction < 30%). At 5 mo post-MI, body and heart weights were similar in the MI and MI + Iva groups. LV ejection fraction and LV end-diastolic pressure were worsened in the MI group, whereas both were improved with Iva. Iva reduced HR by 10.4% (P < 0.03 vs. MI) and ventricular premature complexes by 89% (P < 0.03) and improved HR variability (standard deviation of the RR interval) by 22% (P < 0.05). There were no effects of Iva on PR, QRS, and QT durations. Interstitial fibrosis in the MI-remote LV was markedly reduced by Iva (4.0 +/- 0.1 vs. 1.8 +/- 0.1%, P < 0.005). Increases in ventricular gene and protein expressions of ACE and AT(1) receptor in MI were completely blunted by Iva. In conclusion, these data indicated that HR reduction by Iva prevents the worsening of LV dysfunction and remodeling that may be related to a downregulation of cardiac renin-angiotensin-aldosterone system transcripts. Such beneficial effects of Iva on cardiac remodeling open new clinical perspectives for the treatment of severe HF.

Atrial and Ventricular Electrical and Contractile Remodeling and Reverse Remodeling Owing to Short‐Term Pacing‐Induced Atrial Fibrillation in Horses

In humans, atrial fibrillation (AF) induces electrical, contractile, and structural remodeling leading to AF stabilization. Little is known about AF-induced atrial remodeling in horses. Induced AF produces rapid atrial electrical and contractile remodeling in horses. Six horses, 5 animals completed the study. Each horse was instrumented with a pulse generator and pacemaker to maintain AF by burst pacing and to study atrial and ventricular electrophysiology (AF cycle length [AFCL], AF duration, and atrial/ventricular effective refractory period [AERP/VERP] at different pacing cycle lengths [PCL]). Left atrial and ventricular contractile remodeling were assessed echocardiographically by calculation of fractional changes in atrial and ventricular dimensions, respectively, during the cardiac cycle. Measurements were performed at baseline, a 7-day AF period and a 2-day recovery period. Atrial electrical and contractile remodeling could be demonstrated after 4 and 12 hours of AF, respectively. A progressive shortening of the AERP (261 +/- 39-171 +/- 18 ms at a PCL of 1,000 ms, P < .0001), an attenuation of the AERP rate adaptation, a decrease in AFCL (239 +/- 39-194 +/- 7 ms, P < .0001), and a decrease in atrial FS (12 +/- 3% to 0 +/- 2%, P < .05) occurred. AF duration increased progressively and became persistent in 2 animals. VERP did not change significantly. Upon restoration of sinus rhythm, values returned to baseline within 48 hours. Atrial electrical and contractile remodeling appears rapidly. After 7 days of AF, reverse remodeling occurred within 2 days. These observations suggest that early conversion of AF might be beneficial for success rate and early return to training.

Mechanisms and management of electrical remodeling

Altered electrical activation of the heart by pacing or disease induces profound ventricular electrical remodeling (VER), manifested electrocardiographically as T-wave memory, and ultimately as deleterious mechanical remodeling from heterogeneous strain. This has important clinical implications to post-infarction cardiac remodeling, cardiac resynchronization therapies, and cardiac development. Although T-wave memory is associated with altered expression of sarcolemmal ion channels, the biophysical mechanisms responsible for triggering remodeling of cardiac ion channels are unknown.

High-Septal Pacing Reduces Ventricular Electrical Remodeling and Proarrhythmia in Chronic Atrioventricular Block Dogs

This study was designed to analyze the relevance of ventricular activation patterns for ventricular electrical remodeling after atrioventricular (AV) block in dogs. Bradycardia is thought to be the main contributor to ventricular electrical remodeling after complete AV block. However, an altered ventricular activation pattern or AV dyssynchrony may also contribute. For 4 weeks, AV block dogs were either paced from the high-ventricular septum near the His bundle at lowest captured rate (n = 9, high-septal pacing [HSP]) or kept at idioventricular rate without controlled activation (n = 14, chronic AV block [CAVB]). Multiple electrocardiographic and electrophysiological parameters were measured under anesthesia at 0 and 4 weeks. Proarrhythmia was tested at 4 weeks by I(Kr) block (25 mug/kg dofetilide intravenous). At 0 weeks, the 2 groups were comparable, whereas after 4 weeks of similar bradycardia, QT duration at unpaced conditions had increased from 300 +/- 5 to 395 +/- 18 ms in CAVB (+32 +/- 6%) and from 307 +/- 8 ms to 357 +/- 11 ms in HSP (+17 +/- 4%; p < 0.05). Frequency dependency of repolarization was less steep in HSP compared to CAVB dogs after 4 weeks remodeling. Beat-to-beat variability of repolarization, a proarrhythmic parameter, increased only in CAVB from 0 to 4 weeks. Torsades de pointes arrhythmias were induced at 4 weeks in 44% HSP versus 78% CAVB dogs (p = 0.17). Cumulative duration of arrhythmias per inducible dog was 87 +/- 36 s in CAVB and 30 +/- 21 s in HSP (p < 0.05). High-septal pacing reduces the magnitude of ventricular electrical remodeling and proarrhythmia in AV block dogs, suggesting a larger role for altered ventricular activation pattern in the generation of ventricular electrical remodeling than previously assumed.

Mechanoelectrical Feedback as Novel Mechanism of Cardiac Electrical Remodeling

Altered electrical activation of the heart by pacing or disease induces profound ventricular electrical remodeling (VER), manifested electrocardiographically as T-wave memory and ultimately as deleterious mechanical remodeling from heterogeneous strain. Although T-wave memory is associated with altered expression of sarcolemmal ion channels, the biophysical mechanisms responsible for triggering remodeling of cardiac ion channels are unknown. To test the hypothesis that mechanoelectrical feedback triggered by regional strain is a mechanism for VER, dogs (n=6) underwent 4 weeks of ventricular pacing to induce VER. Multisegment transmural optical action potential imaging of left ventricular wedges revealed profound and selective prolongation of action potential duration in late-activated (288+/-29 ms) compared with early-activated (250+/-9 ms) myocardial segments (P<0.05), providing the first experimental evidence that amplification of repolarization gradients between segments of left ventricle is the electrophysiological basis for T-wave memory. In vivo tagged magnetic resonance imaging revealed a 2-fold and preferential increase in circumferential strain in late-activated segments of myocardium, which exactly coincided with segments undergoing VER. VER could not be attributed to structural remodeling because it occurred without any histological evidence of cellular hypertrophy. The mechanism responsible for triggering remodeling of ion channel function in VER was locally enhanced circumferential strain. These data suggest a novel mechanoelectrical feedback mechanism for inducing physiological and potentially deleterious electrical heterogeneities in the heart.