scholarly journals Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling

2008 ◽  
Vol 35 (3) ◽  
pp. 222-230 ◽  
Author(s):  
Zhong Gao ◽  
Andreas S. Barth ◽  
Deborah DiSilvestre ◽  
Fadi G. Akar ◽  
Yanli Tian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Action Potential ◽  
Action Potential Duration ◽  
Expression Patterns ◽  
Left Ventricular ◽  
Ventricular Pacing ◽  
Extracellular Matrix Components ◽  
Transcriptional Changes ◽  
Rapid Ventricular Pacing

Heart failure (HF) is the leading cause of morbidity and mortality in the industrialized world. While the transcriptomic changes in end-stage failing myocardium have received much attention, no information is available on the gene expression patterns associated with the development of HF in large mammals. Therefore, we used a well-controlled canine model of tachycardia-induced HF to examine global gene expression in left ventricular myocardium with Affymetrix canine oligonucleotide arrays at various stages after initiation of rapid ventricular pacing ( days 3, 7, 14, and 21). The gene expression data were complemented with measurements of action potential duration, conduction velocity, and left ventricular end diastolic pressure, and dP/d t(max) over the time course of rapid ventricular pacing. As a result, we present a phenotype-centered gene association network, defining molecular systems that correspond temporally to hemodynamic and electrical remodeling processes. Gene Ontology analysis revealed an orchestrated regulation of oxidative phosphorylation, ATP synthesis, cell signaling pathways, and extracellular matrix components, which occurred as early as 3 days after the initiation of ventricular pacing, coinciding with the early decline in left ventricular pump function and prolongation of action potential duration. The development of clinically overt left ventricular dysfunction was associated with few additional changes in the myocardial transcriptome. We conclude that the majority of tachypacing-induced transcriptional changes occur early after initiation of rapid ventricular pacing. As the transition to overt HF is characterized by few additional transcriptional changes, posttranscriptional modifications may be more critical in regulating myocardial structure and function during later stages of HF.

Activation of cardiorenal and pulmonary tissue endothelin-1 in experimental heart failure

2000 ◽  
Vol 279 (3) ◽  
pp. R974-R979 ◽  
Author(s):  
A. Luchner ◽  
M. Jougasaki ◽  
E. Friedrich ◽  
D. D. Borgeson ◽  
T. L. Stevens ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Left Atrial ◽  
Plasma Concentrations ◽  
Left Ventricular ◽  
Moderate Increase ◽  
Ventricular Pacing ◽  
Pulmonary Tissue ◽  
Endothelin 1 ◽  
Rapid Ventricular Pacing

Endothelin-1 (ET-1) is a peptide that has been implicated in congestive heart failure (CHF). Although increased concentrations of circulating ET-1 have been repeatedly demonstrated, the activation of local ET-1 in target tissues of CHF remains poorly defined. Our objective was to characterize ET-1 tissue concentrations and gene expression of prepro ET-1 in myocardial, renal, and pulmonary tissue in rapid ventricular pacing-induced canine CHF. Progressive rapid ventricular pacing (38 days) resulted in impaired cardiovascular hemodynamics, increased atrial and left ventricular mass, decreased renal sodium excretion, and increased ET-1 plasma concentrations (all P < 0.05). Tissue analysis revealed significant increases in local ET-1 during CHF in left ventricular, renal, and pulmonary tissue, whereas a moderate increase in left atrial ET-1 did not reach statistical significance. In contrast, prepro-ET-1 gene expression was increased more than threefold in pulmonary tissue and more than twofold in left atrial myocardium with no increase in left ventricular or renal gene expression. The present studies demonstrate a differential pattern of ET-1 activation in cardiorenal and pulmonary tissue with a strong accumulation of ET-1 in kidney and lung during CHF. Although the observed increase in left ventricular and renal ET-1 in association with unaltered gene expression is consistent with increased uptake, pulmonary and atrial tissue may contribute to increased circulating and local ET-1 in CHF.

scholarly journals Remodeling of the Purkinje Network in Congestive Heart Failure in the Rabbit

2021 ◽  
Author(s):  
Sunil Jit R.J. Logantha ◽  
Xue J. Cai ◽  
Joseph Yanni ◽  
Caroline B. Jones ◽  
Robert S. Stephenson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Computed Tomography ◽  
Action Potential ◽  
Action Potential Duration ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Micro Computed Tomography ◽  
Left And Right ◽  
Upstroke Velocity

Background: Purkinje fibers (PFs) control timing of ventricular conduction and play a key role in arrhythmogenesis in heart failure (HF) patients. We investigated the effects of HF on PFs. Methods: Echocardiography, electrocardiography, micro-computed tomography, quantitative polymerase chain reaction, immunohistochemistry, volume electron microscopy, and sharp microelectrode electrophysiology were used. Results: Congestive HF was induced in rabbits by left ventricular volume- and pressure-overload producing left ventricular hypertrophy, diminished fractional shortening and ejection fraction, and increased left ventricular dimensions. HF baseline QRS and corrected QT interval were prolonged by 17% and 21% (mean±SEMs: 303±6 ms HF, 249±11 ms control; n=8/7; P =0.0002), suggesting PF dysfunction and impaired ventricular repolarization. Micro-computed tomography imaging showed increased free-running left PF network volume and length in HF. mRNA levels for 40 ion channels, Ca 2+ -handling proteins, connexins, and proinflammatory and fibrosis markers were assessed: 50% and 35% were dysregulated in left and right PFs respectively, whereas only 12.5% and 7.5% changed in left and right ventricular muscle. Funny channels, Ca 2+ -channels, and K + -channels were significantly reduced in left PFs. Microelectrode recordings from left PFs revealed more negative resting membrane potential, reduced action potential upstroke velocity, prolonged duration (action potential duration at 90% repolarization: 378±24 ms HF, 249±5 ms control; n=23/38; P <0.0001), and arrhythmic events in HF. Similar electrical remodeling was seen at the left PF-ventricular junction. In the failing left ventricle, upstroke velocity and amplitude were increased, but action potential duration at 90% repolarization was unaffected. Conclusions: Severe volume- followed by pressure-overload causes rapidly progressing HF with extensive remodeling of PFs. The PF network is central to both arrhythmogenesis and contractile dysfunction and the pathological remodeling may increase the risk of fatal arrhythmias in HF patients.

scholarly journals His resynchronization therapy produces more physiological ventricular repolarisation compared with biventricular pacing

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
TC Cheng ◽  
ADA Arnold ◽  
JC Chow ◽  
MJS-S Shun-Shin ◽  
JPH Howard ◽  
...  
Keyword(s):  
Heart Failure ◽  
Action Potential ◽  
Action Potential Duration ◽  
Biventricular Pacing ◽  
Left Ventricular ◽  
Cardiac Resynchronization ◽  
Resynchronization Therapy ◽  
Activation Time ◽  
Ventricular Repolarisation ◽  
Non Invasive

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation BACKGROUND Biventricular pacing (BVP) is known to shorten activation time in patients with heart failure and left bundle branch block (LBBB) but its effects on repolarisation are not well studied. His bundle pacing (HBP) can correct LBBB to deliver cardiac resynchronization therapy (HBP-CRT), producing more physiological ventricular activation time and pattern than BVP. It is not known whether this translates to more physiological repolarisation, and if so whether the effect is mediated through its effects on activation. PURPOSE We measured the effects of HBP-CRT and BVP on left ventricular repolarisation using non-invasive epicardial mapping (ECGI). METHODS Patients were recruited in two groups. 1) Patients scheduled for clinically indicated BVP procedures for heart failure with LBBB, 2) Individuals with narrow QRS, normal ventricular function and intact conduction systems. Using non-invasive electrocardiographic imaging, we identified patients with LBBB in whom HBP shortened ECGI-derived left ventricular (LV) activation time by &gt;10ms. We compared the effects of HBP and BVP on ECGI-derived dispersion of LV repolarisation times and activation-recovery intervals (a surrogate for action potential duration). RESULTS 21 patients in whom HBP shortened LV activation time by &gt;10ms and an equal number of individuals with narrow intrinsic QRS were recruited. LV repolarisation dispersion was reduced by HBP-CRT (-42.0 ms, 95% confidence interval (CI): -52.3 to -31.7 ms, p &lt;0.001) but not by BVP (11.9 ms, 95% CI: -6.24 to 30.1 ms, p = 0.182). The mean within-patient change in LV repolarisation dispersion from BVP to HBP-CRT was -56.5 ms (95% CI: -70.5 to -42.5 ms, p &lt; 0.001). LV repolarisation dispersion with HBP-CRT was not different from individuals with narrow intrinsic QRS (2.75 ms, 95% CI: -16.2 to 21.7 ms, p = 0.981). The magnitude of reduction in LV repolarisation dispersion with HBP-CRT from intrinsic LBBB appeared similar to the magnitude of LV activation time shortening (-54.9 ms, 95% CI: -68.2 to -41.6 ms, p &lt; 0.001). However, LV activation-recovery interval dispersion was also reduced by HBP-CRT (-44.3 ms, 95% CI: -69.2 to -19.3 ms, p &lt; 0.001). Repolarisation mapping demonstrated normalisation of repolarisation pattern by HBP-CRT. CONCLUSIONS HBP-CRT can normalise repolarisation dispersion, producing more physiological repolarisation compared with BVP, which does not resolve the repolarisation abnormality of LBBB. HBP-CRT improves repolarisation through both activation resynchronization and modulation of action-potential duration. If these acute results translate to longer term outcomes, HBP-CRT may reduce the risk of ventricular arrhythmias in heart failure with LBBB to a greater extent than BVP. Abstract Figure. Epicardial Repolarisation Maps

Altered connexin43 expression produces arrhythmia substrate in heart failure

2004 ◽  
Vol 287 (4) ◽  
pp. H1762-H1770 ◽  
Author(s):  
Steven Poelzing ◽  
David S. Rosenbaum
Keyword(s):  
Heart Failure ◽  
Action Potential ◽  
Action Potential Duration ◽  
Expression Patterns ◽  
Canine Model ◽  
Cx43 Expression ◽  
Dispersion Of Repolarization ◽  
Myocardial Layers ◽  
Junction Protein ◽  
Space Constant

Recently, we found that repolarization heterogeneities between subepicardial and midmyocardial cells can form a substrate for reentrant ventricular arrhythmias in failing myocardium. We hypothesized that the mechanism responsible for maintaining transmural action potential duration heterogeneities in heart failure is related to intercellular uncoupling from downregulation of cardiac gap junction protein connexin43 (Cx43). With the use of the canine model of pacing-induced heart failure, left ventricles were sectioned to expose the transmural surface ( n = 5). To determine whether heterogeneous Cx43 expression influenced electrophysiological function, high-resolution transmural optical mapping of the arterially perfused canine wedge preparation was used to measure conduction velocity (θTM), effective transmural space constant (λTM), and transmural gradients of action potential duration (APD). Absolute Cx43 expression in failing myocardium, quantified by confocal immunofluorescence, was uniformly reduced (by 40 ± 3%, P < 0.01) compared with control. Relative Cx43 expression was heterogeneously distributed and lower (by 32 ± 18%, P < 0.05) in the subepicardium compared with deeper layers. Reduced Cx43 expression in heart failure was associated with significant reductions in intercellular coupling between transmural muscle layers, as evidenced by reduced θTM (by 18.9 ± 4.9%) and λTM (by 17.2 ± 1.4%; P < 0.01) compared with control. Heterogeneous transmural distribution of Cx43 in failing myocardium was associated with lower subepicardial θTM (by 12 ± 10%) and λTM (by 13 ± 7%), compared with deeper transmural layers ( P < 0.05). APD dispersion was greatest in failing myocardium, and the largest transmural APD gradients were consistently found in regions exhibiting lowest relative Cx43 expression. These data demonstrate that reduced Cx43 expression produces uncoupling between transmural muscle layers leading to slowed conduction and marked dispersion of repolarization between epicardial and deeper myocardial layers. Therefore, Cx43 expression patterns can potentially contribute to an arrhythmic substrate in failing myocardium.

Rapid ventricular pacing of dogs to heart failure: biochemical and physiological studies

1990 ◽  
Vol 68 (1) ◽  
pp. 34-39 ◽  
Author(s):  
Peter James O'Brien ◽  
C. David Ianuzzo ◽  
Gordon W. Moe ◽  
Terry P. Stopps ◽  
Paul W. Armstrong
Keyword(s):  
Heart Failure ◽  
Glycolytic Enzyme ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Pacing ◽  
Ventricular Ejection Fraction ◽  
Biochemical Alterations ◽  
Rapid Ventricular Pacing

Chronic, rapid ventricular pacing produces congestive heart failure in dogs. The objectives of this study were to determine whether or not (i) in vitro myocardial biochemical alterations reported for heart failure by volume or pressure overload also occurred with heart failure due to rate overload, and (ii) these biochemical alterations were related to relevant in vivo cardiac physiologic alterations. We compared 27 dogs that were paced to advanced heart failure with 21 sham-operated dogs. Dogs with heart failure had 55% lower left ventricular ejection fraction (22.5 ± 7.6 vs. 50.5 ± 5.1%) and cardiac index (81 ± 22 vs. 178 ± 48 mL∙min−1∙kg−1), 287% higher pulmonary capillary wedge pressure (27.5 ± 6.8 vs. 7.1 ± 3.4 mmHg; 1 mmHg = 133.3 Pa), and 64% greater left ventricular diastolic area (18.4 ± 3.7 vs. 11.2 ± 1.3 cm2) (all p < 0.05). Dogs with heart failure also had (i) 69% lower norepinephrine (232 ± 139 vs. 747 ± 220 ng/g protein), (ii) 25–50% lower activities of myofibrillar Ca ATPase (0.188 ± 0.026 vs. 0.253 ± 0.051 U/mg myofibrils), sarcoplasmic reticulum Ca-transport ATPase (0.155 ± 0.074 vs. 0.288 ± 0.043 U/mg membrane), and the glycolytic enzyme phosphofructokinase (33.4 ± 10.0 and 47.7 ± 15.8 U/g), (iii) 32% higher activity of the β-oxidation enzyme hydroxyacyl-CoA dehydrogenase (11.43 ± 1.48 vs. 8.67 ± 1.70 U/g), and (iv) 60% higher activity of Krebs cycle oxoglutarate dehydrogenase (2.89 ± 0.77 vs. 1.81 ± 0.95 U/g) (all p < 0.05). No differences between groups were observed for isozyme patterns and ATPase activity of myosin. The pacing-induced alterations in left ventricular norepinephrine and sarcoplasmic reticular and myofibrillar Ca ATPase best correlated with in vivo physiological alterations. Biochemical alterations produced by rate overload were similar to those reported for volume or pressure overload.Key words: heart disease, chronic tachycardia, biochemical changes.

Identification of Nogo as a novel indicator of heart failure

2008 ◽  
Vol 32 (2) ◽  
pp. 182-189 ◽  
Author(s):  
Tara A. Bullard ◽  
Tricia L. Protack ◽  
Frédérick Aguilar ◽  
Suveer Bagwe ◽  
H. Todd Massey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Animal Models ◽  
Expression Patterns ◽  
Left Ventricular ◽  
Cell Type ◽  
Cell Type Specificity ◽  
Novel Genes ◽  
Specific Expression ◽  
Adrenergic Signaling

Numerous genetically engineered animal models of heart failure (HF) exhibit multiple characteristics of human HF, including aberrant β-adrenergic signaling. Several of these HF models can be rescued by cardiac-targeted expression of the Gβγ inhibitory carboxy-terminus of the β-adrenergic receptor kinase (βARKct). We recently reported microarray analysis of gene expression in multiple animal models of HF and their βARKct rescue, where we identified gene expression patterns distinct and predictive of HF and rescue. We have further investigated the muscle LIM protein knockout model of HF (MLP−/−), which closely parallels human dilated cardiomyopathy disease progression and aberrant β-adrenergic signaling, and their βARKct rescue. A group of known and novel genes was identified and validated by quantitative real-time PCR whose expression levels predicted phenotype in both the larger HF group and in the MLP−/− subset. One of these novel genes is herein identified as Nogo, a protein widely studied in the nervous system, where it plays a role in regeneration. Nogo expression is altered in HF and normalized with rescue, in an isoform-specific manner, using left ventricular tissue harvested from both animal and human subjects. To investigate cell type-specific expression of Nogo in the heart, immunofluorescence and confocal microscopy were utilized. Nogo expression appears to be most clearly associated with cardiac fibroblasts. To our knowledge, this is the first report to demonstrate the relationship between Nogo expression and HF, including cell-type specificity, in both mouse and human HF and phenotypic rescue.

A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure

2003 ◽  
Vol 284 (3) ◽  
pp. H1035-H1042 ◽  
Author(s):  
Masateru Kohno ◽  
Masafumi Yano ◽  
Shigeki Kobayashi ◽  
Masahiro Doi ◽  
Tetsuro Oda ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ryanodine Receptors ◽  
Channel Gating ◽  
Rapid Change ◽  
Left Ventricular ◽  
Ventricular Pacing ◽  
Channel Opening ◽  
Rapid Ventricular Pacing ◽  
A Site ◽  
Possible Cause

Defective interaction between FKBP12.6 and ryanodine receptors (RyR) is a possible cause of cardiac dysfunction in heart failure (HF). Here, we assess whether the new cardioprotective agent JTV519 can correct it in tachycardia-induced HF. HF was induced in dogs by 4-wk rapid ventricular pacing, and sarcoplasmic reticulum (SR) was isolated from left ventricular muscles. In failing SR, JTV519 increased the rate of Ca2+ release and [3H]ryanodine binding. RyR were then labeled in a site-directed fashion with the fluorescent conformational probe methylcoumarin acetamide. In failing SR, the polylysine induced a rapid change in methylcoumarin acetamide fluorescence, presumably because the channel opening preceding the Ca2+ release was smaller than in normal SR (consistent with a decreased rate of Ca2+ release in failing SR), and JTV519 increased it. In conclusion, JTV519, a new 1,4-benzothiazepine derivative, corrected the defective channel gating in RyR (increase in both the rapid conformational change and the subsequent Ca2+ release rate) in HF.

Rapid ventricular pacing in pigs: an experimental model of congestive heart failure

1990 ◽  
Vol 258 (5) ◽  
pp. H1603-H1605 ◽  
Author(s):  
E. Chow ◽  
J. C. Woodard ◽  
D. J. Farrar
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Diastolic Pressure ◽  
Weight Ratio ◽  
Total Body Weight ◽  
Realistic Model ◽  
Left Ventricular ◽  
Heart Weight ◽  
Ventricular Pacing ◽  
Rapid Ventricular Pacing

To develop an improved animal model of congestive heart failure, 11 female farm pigs (wt, 42-46 kg) underwent rapid ventricular pacing at 230 beats/min for 7 days with a modified Medtronic unipolar pacemaker connected to an apical pacing lead. After 7 days the pacemaker was turned off, anesthesia induced, the chest opened, and cardiac hemodynamic and dimensional studies were performed. Results were subsequently compared with data from 12 control pigs that received no pacing. Two pigs died before measurements could be determined. Cardiac output in the paced animals (0.061 +/- 0.018 l.min-1.kg-1) was significantly less (P less than 0.05) than in control pigs (0.085 +/- 0.016 l.min-1.kg-1), when compared at the same resting heart rate. Left ventricular (LV) end-diastolic pressure (23.2 +/- 7.7 vs. 8.6 +/- 3.6 mmHg, P less than 0.01) and right ventricular (RV) end-diastolic pressure (9.0 +/- 3.1 vs. 4.4 +/- 1.7 mmHg, P less than 0.01) were significantly greater in the paced pigs. Significant increases in both septal-lateral LV end-diastolic dimension (60.3 +/- 3.9 vs. 52.1 +/- 7.2 mm, P less than 0.01) and RV end-diastolic dimension (47.2 +/- 5.7 vs. 40.8 +/- 4.7 mm, P less than 0.05) indicated biventricular dilation in the paced pigs. They also exhibited a significantly greater heart weight-to-total body weight ratio and clinical evidence of congestive heart failure, with hepatomegaly and ascites. These results demonstrate that 1 wk of rapid ventricular pacing at 230 beats/min produces a realistic model of congestive heart failure in the pig.

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