Tachypacing-induced Heart Failure Research Articles

Transseptal Conduction as an Important Determinant for Cardiac Resynchronization Therapy, as Revealed by Extensive Electrical Mapping in the Dyssynchronous Canine Heart

Simple conceptual ideas about cardiac resynchronization therapy assume that biventricular (BiV) pacing results in collision of right and left ventricular (LV) pacing-derived wavefronts. However, this concept is contradicted by the minor reduction in QRS duration usually observed. We investigated the electric mechanisms of cardiac resynchronization therapy by performing detailed electric mapping during extensive pacing protocols in dyssynchronous canine hearts. Studies were performed in anesthetized dogs with acute left bundle-branch block (LBBB, n=10) and chronic LBBB with tachypacing-induced heart failure (LBBB+HF, n=6). Activation times (AT) were measured using LV endocardial contact and noncontact mapping and epicardial contact mapping. BiV pacing reduced QRS duration by 21±10% in LBBB but only by 5±12% in LBBB+HF hearts. Transseptal impulse conduction was significantly slower in LBBB+HF than in LBBB hearts (67±9 versus 44±16 ms, respectively), and in both groups significantly slower than transmural LV conduction (≈30 ms). In both groups QRS duration and vector and the epicardial AT vector amplitude and angle were significantly different between LV and BiV pacing, whereas the endocardial AT vector was similar. During variation of atrioventricular delay while LV pacing, and ventriculo-ventricular delay while BiV pacing, the optimal hemodynamic effect was achieved when epicardial AT and QRS vectors were minimal and endocardial AT vector indicated LV preexcitation. Due to slow transseptal conduction, the LV electric activation sequence is similar in LV and BiV pacing, especially in failing hearts. Optimal hemodynamic cardiac resynchronization therapy response coincides with minimal epicardial asynchrony and QRS vector and LV preexcitation.

Atrial Electrophysiologic Remodeling in Canine Heart Failure: Modulation by Atrial Fibrillation

Background Heart failure (HF) is a common antecedent to atrial fibrillation (AF). Concomitant HF and AF increases morbidity and mortality over that of either disease alone. AF- and HF-induced atrial electrophysiologic remodeling is known to favor the progression of AF. AF results in accelerated repolarization and reductions in multiple ion currents, including transient outward K + current (I to ), changes associated with AF maintenance. Methods Dogs had tachypacing-induced HF for 10 weeks and then were assigned to 6 weeks of atrial tachypacing (60 seconds of pacing at 10 Hz, repeated every 70 seconds) until sustained AF/atrial flutter was induced (HF+AF, n=3), or continued right ventricular tachypacing (n = 6). Baseline LVFS was reduced ( P to were made at 35° ± 0.5°C. Results HF significantly increased I to vs control, whereas HF+AF significantly reduced I to vs control and HF (Figure A). At 2 Hz, HF shortened action potential durations at 50% repolarization (APD 50 ); HF+AF lengthened APD 50 vs HF alone, and did not differ from control (Figure B). HF shortened APD at 90% repolarization (APD 90 ) vs controls, whereas HF+AF had similar shortening of APD 90 . Conclusions Chronic HF results in increased I to and faster repolarization of left atrial appendage myocytes. The addition of AF to chronic HF reduced I to and lengthened APD 50 without changing APD 90 . The effects of chronic HF and chronic HF+AF on I to and APD morphology are variable, suggesting complex disease-induced effects on the substrate for AF.

Transient Receptor Potential Canonical-3 Channel–Dependent Fibroblast Regulation in Atrial Fibrillation

Fibroblast proliferation and differentiation are central in atrial fibrillation (AF)-promoting remodeling. Here, we investigated fibroblast regulation by Ca(2+)-permeable transient receptor potential canonical-3 (TRPC3) channels. Freshly isolated rat cardiac fibroblasts abundantly expressed TRPC3 and had appreciable nonselective cation currents (I(NSC)) sensitive to a selective TPRC3 channel blocker, pyrazole-3 (3 μmol/L). Pyrazole-3 suppressed angiotensin II-induced Ca(2+) influx, proliferation, and α-smooth muscle actin protein expression in fibroblasts. Ca(2+) removal and TRPC3 blockade suppressed extracellular signal-regulated kinase phosphorylation, and extracellular signal-regulated kinase phosphorylation inhibition reduced fibroblast proliferation. TRPC3 expression was upregulated in atria from AF patients, goats with electrically maintained AF, and dogs with tachypacing-induced heart failure. TRPC3 knockdown (based on short hairpin RNA [shRNA]) decreased canine atrial fibroblast proliferation. In left atrial fibroblasts freshly isolated from dogs kept in AF for 1 week by atrial tachypacing, TRPC3 protein expression, currents, extracellular signal-regulated kinase phosphorylation, and extracellular matrix gene expression were all significantly increased. In cultured left atrial fibroblasts from AF dogs, proliferation rates, α-smooth muscle actin expression, and extracellular signal-regulated kinase phosphorylation were increased and were suppressed by pyrazole-3. MicroRNA-26 was downregulated in canine AF atria; experimental microRNA-26 knockdown reproduced AF-induced TRPC3 upregulation and fibroblast activation. MicroRNA-26 has NFAT (nuclear factor of activated T cells) binding sites in the 5' promoter region. NFAT activation increased in AF fibroblasts, and NFAT negatively regulated microRNA-26 transcription. In vivo pyrazole-3 administration suppressed AF while decreasing fibroblast proliferation and extracellular matrix gene expression. TRPC3 channels regulate cardiac fibroblast proliferation and differentiation, likely by controlling the Ca(2+) influx that activates extracellular signal-regulated kinase signaling. AF increases TRPC3 channel expression by causing NFAT-mediated downregulation of microRNA-26 and causes TRPC3-dependent enhancement of fibroblast proliferation and differentiation. In vivo, TRPC3 blockade prevents AF substrate development in a dog model of electrically maintained AF. TRPC3 likely plays an important role in AF by promoting fibroblast pathophysiology and is a novel potential therapeutic target.

TRV120027, a Novel β-Arrestin Biased Ligand at the Angiotensin II Type I Receptor, Unloads the Heart and Maintains Renal Function When Added to Furosemide in Experimental Heart Failure

TRV120027 is a novel β-arrestin biased ligand of the angiotensin II type 1 receptor; it antagonizes canonical G-protein-mediated coupling while, in contrast to classical angiotensin II type 1 receptor antagonists, it engages β-arrestin-mediated signaling. Consequently, TRV120027 inhibits angiotensin II-mediated vasoconstriction while, via β-arrestin coupling, it increases cardiomyocyte contractility. We hypothesized that TRV120027 would elicit beneficial cardiorenal actions when added to furosemide in experimental heart failure. Two groups of anesthetized dogs (n=6 each) with tachypacing-induced heart failure were studied. After a baseline clearance, 1 group (F+V) received furosemide (1 mg/kg per hour) plus saline for 90 minutes, whereas the other (F+T) received the same dose of furosemide plus TRV120027 (0.3 and 1.5 µg/kg per minute for 45 minutes each); 2 clearances were done during drug infusion. After a washout, a postinfusion clearance was done; *P<0.05 between groups. F+V and F+T increased diuresis and natriuresis to a similar extent during drug administration, but urine flow* and urinary sodium excretion* were higher in the postinfusion clearance with F+T. Glomerular filtration rate was preserved in both groups. Renal blood flow increased with F+T but this was not significant versus F+V. Compared with F+V, F+T decreased mean arterial pressure*, systemic* and pulmonary* vascular resistances, and atrial natriuretic peptide*. Pulmonary capillary wedge pressure* decreased to a larger extent with F+T than with F+V. When added to furosemide, TRV120027, a novel β-arrestin biased angiotensin II type 1 receptor ligand, preserved furosemide-mediated natriuresis and diuresis, while reducing cardiac preload and afterload. These results provide support for TRV120027 as a promising novel therapeutic for the treatment of heart failure.

Short-term memory in the heart: A road map for channel trafficking required

Short-term memory in the heart: A road map for channel trafficking required

Physiological consequences of transient outward K+ current activation during heart failure in the canine left ventricle

Remodeling of ion channel expression is well established in heart failure (HF). We determined the extent to which I(to) is reduced in tachypacing-induced HF and assessed the ability of an I(to) activator (NS5806) to recover this current. Whole-cell patch clamp was used to record I(to) in epicardial (Epi) ventricular myocytes. Epi- and endocardial action potentials were recorded from left ventricular wedge preparations. Right ventricular tachypacing-induced heart failure reduced I(to) density in Epi myocytes (Control=22.1±1.9pA/pF vs 16.1±1.4 after 2weeks and 10.7±1.4pA/pF after 5 weeks, +50mV). Current decay as well as recovery of I(to) from inactivation progressively slowed with the development of heart failure. Reduction of I(to) density was paralleled by a reduction in phase 1 magnitude, epicardial action potential notch and J wave amplitude recorded from coronary-perfused left ventricular wedge preparations. NS5806 increased I(to) (at +50mV) from 16.1±1.4 to 23.9±2.1pA/pF (p<0.05) at 2weeks and from 10.7±1.4 to 14.4±1.9pA/pF (p<0.05) in 5 weeks tachypaced dogs. NS5806 increased both fast and slow phases of I(to) recovery in 2 and 5-week HF cells and restored the action potential notch and J wave in wedge preparations from HF dogs. The I(to) agonist NS5806 increases the rate of recovery and density of I(to), thus reversing the HF-induced reduction in these parameters. In wedge preparations from HF dogs, NS5806 restored the spike-and-dome morphology of the Epi action potential providing proof of principal that some aspects of electrical remodelling during HF can be pharmacologically reversed.

Physiological Effects of Transient Outward K+ Current Activation during Heart Failure in the Canine Left Ventricle

Introduction: Remodeling of ion channel expression is well established in heart failure (HF). Loss of transient outward current (Ito) during HF contributes to repolarization abnormalities. We determined the extent to which Ito is reduced in tachypacing-induced HF and assessed the ability of an Ito activator (NS5806) to recover this current. Methods: Whole cell patch clamp was used to record Ito in epicardial (Epi) ventricular myocytes. Epi- and endocardial action potentials were recorded from left ventricular (LV) wedge preparations. Results: Rapid pacing resulted in a reduction in the size of Ito in Epi myocytes (Control= 22.13±1.9 pA/pF vs 16.12±1.4 after 2-weeks and 10.69±1.4 pA/pF after 5-weeks, +50 mV). HF also slowed the recovery of Ito. Recovery of Ito showed a fast and slow phase as follows: i) 1=28.4±2.54 ms and 2= 177.5±7.82 ms for Control Epi, ii) 1=56.6±5.92 ms and 2=337.8±28.9 ms for 2-week Epi, and iii) 1=73.4±3.52 ms and 2=546.3±38.6ms for 5-week Epi. In 2-week paced dogs, NS5806 increased Ito (at +50 mV) from 16.12±1.4 pA/pF to 23.85±2.1 pA/pF (p<0.05). In 5-week paced dogs, application of NS5806 increased Ito from 10.69±1.4 pA/pF to 14.35±1.9 pA/pF (p<0.05). In the presence of NS5806, both the fast and slow phase of Ito recovery increased in 2 and 5-week paced cells. Application of NS5806 to HF wedges restored phase 1 repolarization. Conclusions: HF produces a time dependent reduction in the size of Ito and a slowing in recovery from inactivation. Application of an Ito agonist to HF cells increased the magnitude of Ito and rate of Ito recovery. In HF wedge preparations, NS5806 restored the spike-and-dome morphology of the Epi action potential providing proof of principal that some aspects of electrical remodelling during HF can be pharmacologically reversed.

Abnormal Intra-Store Calcium Handling and Arrhythmogenesis in Heart Failure

Heart failure (HF) patients are known to have increased susceptibility to ventricular arrhythmias. Although abnormal intracellular calcium (Ca) cycling is recognized as an important contributor to the pathogenesis of ventricular arrhythmias, the specific cellular and molecular mechanisms of these arrhythmias remain to be defined. The objective of present study was to investigate the sub-cellular mechanisms of Ca-dependent arrhythmia using time-resolved Ca imaging in the cytosolic and sarcoplasmic reticulum (SR) luminal compartments and the patch-clamp technique in a canine model of tachypacing-induced HF. When rhythmically paced in the presence of the β-adrenergic agonist, isoproterenol, HF myocytes displayed a higher frequency of diastolic Ca waves than control myocytes. In both HF and control myocytes, diastolic Ca waves occurred when [Ca]SR rose above a certain threshold level, which was significantly lower in HF than in control myocytes. Ca signaling refractoriness determined as the time delay between systolic SR Ca depletion and Ca wave initiation was significantly reduced in HF myocytes. Electrical and Ca signaling activities exhibited several distinct potentially arrhythmogenic patterns, including: 1) delayed afterdepolarizations and extrasystolic action potentials (APs) linked to diastolic spontaneous Ca waves; 2) intermittent prolongations of AP duration associated with pre-systolic spontaneous Ca waves and post-systolic triggered Ca waves; and 3) disorganized release uncoupled from myocyte electrical activity. The level of [Ca]SR threshold for spontaneous Ca waves and the time to attain the threshold during the pacing cycle were critical in determining the type of arrhythmogenic abnormality. These experiments suggest a common mechanistic framework for apparently different arrhythmic phenotypes and provide new insights into the relationship between abnormal Ca release and arrhythmogenesis in HF.

Chronic heart failure and the substrate for atrial fibrillation

We sought to define the underlying mechanisms for atrial fibrillation (AF) during chronic heart failure (HF). Preliminary studies showed that 4 months of HF resulted in irreversible systolic dysfunction (n = 9) and a substrate for sustained inducible AF (>3 months, n = 3). We used a chronic (4-month) canine model of tachypacing-induced HF (n = 10) to assess atrial electrophysiological remodelling, relative to controls (n = 5). Left ventricular fractional shortening was reduced from 37.2 +/- 0.83 to 13.44 +/- 2.63% (P < 0.05). Left atrial (LA) contractility (fractional area change) was reduced from 34.9 +/- 7.9 to 27.9 +/- 4.23% (P < 0.05). Action potential durations (APDs) at 50 and 90% repolarization were shortened by approximately 60 and 40%, respectively, during HF (P < 0.05). HF-induced atrial remodelling included increased fibrosis, increased I(to), and decreased I(K1), I(Kur), and I(Ks) (P < 0.05). HF induced increases in LA Kv channel interacting protein 2 (P < 0.05), no change in Kv4.3, Kv1.5, or Kir2.3, and reduced Kir2.1 (P < 0.05). When I(Ca-L) was elicited by action potential (AP) clamp, HF APs reduced the integral of I(Ca) in control myocytes, with a larger reduction in HF myocytes (P < 0.05). I(CaL) measured with standard voltage clamp was unchanged by HF. Incubation of myocytes with N-acetylcysteine (a glutathione precursor) attenuated HF-induced electrophysiological alterations. LA angiotensin-1 receptor expression was increased in HF. Chronic HF causes alterations in ion channel expression and ion currents, resulting in attenuation of the APD and atrial contractility and a substrate for persistent AF.

Is echocardiographic assessment of dyssynchrony useful to select candidates for cardiac resynchronization therapy?

Cardiac resynchronization therapy (CRT) has emerged as one of the few therapies available for patients with advanced heart failure (HF) that favorably affects symptoms, functional status, hospitalization rates, and mortality rate.1,2 It is thought that CRT achieves these benefits by coordinating contraction between ventricular segments that at baseline are dyssynchronous.3 Synchronized electrical excitation of the ventricles leads to near-simultaneous mechanical activation of the normal and delayed segments, resulting in greater stroke volume and reduction of mitral regurgitation with improved neurohormonal profile and reversal of adverse ventricular remodeling. The early large-scale clinical trials that established these benefits of CRT were limited to patients with prolonged QRS duration, a simple and convenient marker of delayed electrical activation. On the basis of these data, current guidelines recommend CRT for patients with ejection fraction 120 ms. Response by Prinzen and Auricchio p 79 A consistent finding from all trials of CRT, however, is a lack of clinical or echocardiographic benefit in approximately one third of patients (“nonresponders”).4 Unlike pharmacological therapy, CRT is complex, invasive, and costly; therefore, improved identification of patients likely to benefit is a clinical imperative. One factor among many underlying this high rate of nonresponse is that QRS duration is an imperfect surrogate for the disorder actually targeted by CRT: mechanical dyssynchrony. Mechanical dyssynchrony may involve delay in mechanical activation of the left ventricle (LV) relative to the right ventricle (RV) (interventricular dyssynchrony) or of one LV region relative to another (intraventricular dyssynchrony). Several lines of evidence suggest that QRS duration may not always be concordant with mechanical dyssynchrony. Leclercq et al5 used an experimental model of tachypacing-induced HF with left bundle-branch block to demonstrate improvement in invasive indices of ventricular contractility …

Diminished Left Ventricular Dyssynchrony and Impact of Resynchronization in Failing Hearts With Right Versus Left Bundle Branch Block

We compared mechanical dyssynchrony and the impact of cardiac resynchronization therapy (CRT) in failing hearts with a pure right (RBBB) versus left bundle branch block (LBBB). Cardiac resynchronization therapy is effective for treating failing hearts with conduction delay and discoordinate contraction. Most data pertain to LBBB delays. With RBBB, the lateral wall contracts early so that biventricular (BiV) pre-excitation may not be needed. Furthermore, the magnitude of dyssynchrony and impact of CRT in pure RBBB versus LBBB remains largely unknown. Dogs with tachypacing-induced heart failure combined with right or left bundle branch radiofrequency ablation were studied. Basal dyssynchrony and effects of single and BiV CRT on left ventricular (LV) function were assessed by pressure-volume catheter and tagged magnetic resonance imaging, respectively. Left bundle branch block and RBBB induced similar QRS widening, and LV function (ejection fraction, maximum time derivative of LV pressure [dP/dt(max)]) was similarly depressed in failing hearts with both conduction delays. Despite this, mechanical dyssynchrony was less in RBBB (circumferential uniformity ratio estimate [CURE] index: 0.80 +/- 0.03 vs. 0.58 +/- 0.09 for LBBB, p < 0.04; CURE 0-->1 is dyssynchronous-->synchronous). Cardiac resynchronization therapy had correspondingly less effect on hearts with RBBB than those with LBBB (i.e., 5.5 +/- 1.1% vs. 29.5 +/- 5.0% increase in dP/dt(max), p < 0.005), despite similar baselines. Furthermore, right ventricular-only pacing enhanced function and synchrony in RBBB as well or better than did BiV, whereas LV-only pacing worsened function. Less mechanical dyssynchrony is induced by RBBB than LBBB in failing hearts, and the corresponding impact of CRT on the former is reduced. Right ventricular-only pacing may be equally efficacious as BiV CRT in hearts with pure right bundle branch conduction delay.

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts.

Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K(+) current (I(K1)) was homogeneously reduced by approximately 41% (at -60 mV) in the three cell types. Transient outward K(+) current (I(to1)) was decreased by 43-45% at +30 mV, and the slow component of the delayed rectifier K(+) current (I(Ks)) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K(+) current was not altered. The results indicate that HF remodels electrophysiology in all layers of the left ventricle, and the downregulation of I(K1), I(to1), and I(Ks) increases APD and favors occurrence of EADs.