Published online before print March 3, 2008, doi: 10.1161/CIRCULATIONAHA.107.706291
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2008;117:1369-1377.)
© 2008 American Heart Association, Inc.
Heart Failure |
Reversal of Global Apoptosis and Regional Stress Kinase Activation by Cardiac Resynchronization
From the Division of Cardiology, School of Medicine, Department of Biomedical Engineering, Johns Hopkins University Medical Institutions, Baltimore, Md.
Correspondence to David A. Kass, MD, Division of Cardiology, Ross Bldg 835, Johns Hopkins University Medical Institutions, 720 Rutland Ave, Baltimore, Md 21205. E-mail dkass{at}jhmi.edu
Received March 28, 2007; accepted January 8, 2008.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
Background— Cardiac dyssynchrony in the failing heart worsens global function and efficiency and generates regional loading disparities that may exacerbate stress-response molecular signaling and worsen cell survival. We hypothesized that cardiac resynchronization (CRT) from biventricular stimulation reverses such molecular abnormalities at the regional and global levels.
Methods and Results— Adult dogs (n=27) underwent left bundle-branch radiofrequency ablation, prolonging the QRS by 100%. Dogs were first subjected to 3 weeks of atrial tachypacing (200 bpm) to induce dyssynchronous heart failure (DHF) and then randomized to either 3 weeks of additional atrial tachypacing (DHF) or biventricular tachypacing (CRT). At 6 weeks, ejection fraction improved in CRT (2.8±1.8%) compared with DHF (–4.4±2.7; P=0.02 versus CRT) dogs, although both groups remained in failure with similarly elevated diastolic pressures and reduced dP/dtmax. In DHF, mitogen-activated kinase p38 and calcium-calmodulin–dependent kinase were disproportionally expressed/activated (50% to 150%), and tumor necrosis factor-
increased in the late-contracting (higher-stress) lateral versus septal wall. These disparities were absent with CRT. Apoptosis assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, caspase-3 activity, and nuclear poly ADP-ribose polymerase cleavage was less in CRT than DHF hearts and was accompanied by increased Akt phosphorylation/activity. Bcl-2 and BAD protein diminished with DHF but were restored by CRT, accompanied by marked BAD phosphorylation, enhanced BAD–14-3-3 interaction, and reduced phosphatase PP1, consistent with antiapoptotic effects. Other Akt-coupled modulators of apoptosis (FOXO-3 and GSK3β) were more phosphorylated in DHF than CRT and thus less involved.
Conclusions— CRT reverses regional and global molecular remodeling, generating more homogeneous activation of stress kinases and reducing apoptosis. Such changes are important benefits from CRT that likely improve cardiac performance and outcome.
Key Words: cardiac pacing, artificial • apoptosis • heart failure • molecular biology • pacing
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
Chronic heart failure involves a progressive decline in cardiac performance accompanied by chamber dilation and multiple abnormalities of molecular signaling that adversely affect cell function and survival.1–3 These processes and clinical outcomes are further worsened if hearts develop dyssynchronous contraction resulting from an intraventricular conduction delay.4–6 Mechanical dyssynchrony generates marked disparities in regional loading7,8 and reduces systolic function at similar or higher metabolic demand compared with synchronous failing hearts.9 The early activated region is less loaded because its shortening reciprocally stretches the still inactive opposing wall, whereas the late-stimulated region must operate at higher loads because of prestretch and late contraction against already stiffened muscle.10,11 Such unequal loading can affect localized expression/activity of calcium handling, stress kinases, and electric conduction proteins in the high-load lateral wall.12 Dyssynchrony also triggers global changes by adversely affecting chamber mechanoenergetics.13
Clinical Perspective p 1377
Biventricular stimulation, now called cardiac resynchronization therapy (CRT), offsets underlying conduction delay to homogenize loading and shortening. Its development as a clinical therapy marked an important advance for heart failure, and it remains arguably the only treatment to date that enhances systolic function while improving long-term outcome and survival.14–16 Studies exploring the mechanisms for CRT have focused primarily on chamber mechanics and energetics,13,17–21 with virtually all the work being performed in patients. No prior studies have tested whether and how CRT affects regional and/or global molecular protein signaling abnormalities induced by dyssynchronous heart failure (DHF).
The present study tested the hypothesis that CRT reverses chronic regional and global molecular stress cell-survival signaling abnormalities in failing hearts with electromechanical dyssynchrony. To this end, we developed a novel canine model in which animals first undergo radiofrequency ablation of the left bundle branch and are then subjected to either 6 weeks of atrial tachypacing (DHF) or 3 weeks of such pacing followed by 3 weeks of biventricular tachypacing. Both models involve tachypacing for 6 weeks, with the primary difference being the synchrony of contraction during the latter half-period, allowing a more focused analysis of the impact of CRT. We report that CRT restores normal homogeneity of stress proteins, reducing their differential expression and activation in the late-contracting lateral wall of dyssynchronous hearts. Most strikingly, we reveal a potent effect of CRT on globally reducing apoptosis via the Akt-BAD signaling pathway.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
Experimental Model
Adult mongrel dogs (n=22) underwent left bundle-branch radiofrequency ablation as previously described.12,22 Left bundle-branch block was confirmed by intracardiac electrograms, with surface QRS widening from 50±7 to 104±7 ms (P<0.001). Eleven animals were paced from the right atrium for 6 weeks at
200 bpm (AAO pacing, DHF); the remaining dogs were subjected first to 3 weeks of atrial pacing (dyssynchrony) followed by 3 weeks of biventricular tachypacing (VOO) at the same rate (CRT). Biventricular pacing was achieved by simultaneous lateral epicardial and right ventricular anteroapical free wall stimulation. Echo and tissue Doppler studies were performed at 3 and 6 weeks in conscious animals to assess left ventricular (LV) dyssynchrony, chamber dimensions, and ejection fraction. Tachypacing was suspended for 1 hour before data acquisition, and then DHF or CRT was restarted at 30 bpm above sinus rhythm (190 bpm) to measure function at a similar rate among the animals. At the end of the study, animals were anesthetized with pentobarbital, pacing was suspended, and invasive LV pressures were recorded. Hearts were then extracted under cold cardioplegia, dissected into endocardial and mid/epicardial segments from the septum (ie, LV and right ventricular septum) and LV lateral wall,12 and frozen in liquid nitrogen or placed in 10% formalin.
In Vivo Cardiac Function Assessments
Transthoracic echocardiography and tissue Doppler examination were performed (GE Vivid-7, 3.5-MHz multifrequency broadband transducer, GE Healthcare, Piscataway, NJ) to measure end-diastolic and end-systolic volumes, ejection fraction, and dyssynchrony index (SD of radial strains from 12 different regions). In a subgroup of animals (n=5 in each group), dyssynchrony also was measured from magnetic resonance–tagged images (GE Signa, 1.5 T, GE Healthcare) by the circumferential uniformity ration estimate.11
To assess short-term cardiac effects of biventricular pacing in our model of DHF, a separate group of 5 animals were instrumented long term for pressure–volume analysis as previously described.23 Pressure–volume relations were measured after 3 weeks of dyssynchronous tachypacing, and atrial versus short-term biventricular stimulation were compared. Pacing was first suspended for at least 1 hour; then, heart rate was maintained constant at just above the sinus rate for the comparisons. Load-independent measures of systolic function were obtained.23 All of the animal protocols and procedures were approved by the Animal Care and Use Committee of Johns Hopkins University.
Protein Expression and Activity Analysis
Myocardial tissue was homogenized in lysis buffer (Cell Signaling Technology, Danvers, Mass), and gel electrophoresis was performed with 50 to 100 µg total protein per lane. Proteins were transferred to nitrocellulose membranes that were blocked, probed overnight at 4°C with primary antibodies, and then exposed to horseradish peroxidase–conjugated secondary antibodies for 2 hours at 27°C. Protein was detected by chemiluminescence (ECL, Amersham BioSciences, Piscataway, NJ), and autoradiograms were analyzed with ImageJ software (National Institutes of Health, Bethesda, Md). Antibodies used were as follows: total Akt, P-Akt (T308), P-Akt (S473), p38, extracellular response kinase (ERK1/2), Jun n-terminal kinase (JNK), Bcl-2 antagonist of cell death (BAD) and phosphorylated BAD (pBAD; S136, S112), calcium-calmodulin–dependent kinase II (CaMKII), p90 ribosomal S6 kinase (p90RSK, P-p90RSK T359/S363, T356/S360), 14-3-3 protein, pFOXO3a (T32), p-glycogen synthase kinase GSK3β (S9), nuclear poly ADP-ribose polymerase (PARP), caspase-3 (all at 1:1000, Cell Signaling Technology), and PP1- (1:500, Santa Cruz Biotechnology, Santa Cruz, Calif). GAPDH (1:10000, Imagenex, San Diego, Calif) was probed in each membrane as a loading control. Displayed results are from 6 to 8 different dogs in each experimental group, with immunoblots performed in duplication and results averaged. Myocardial tumor necrosis factor- (TNF-) was assayed by quantitative ELISA (Quantikine, R&D Systems, Minneapolis, Minn) and spectrophotometry (M5, Molecular Devices, Carlsbad, Calif). Enzymatic activity assays were performed for p38 mitogen-activated protein (MAP), CaMKII, and Akt kinases (CycLex CY1177, CY1173, and CY-1168, respectively; MBL International) following the manufacturer’s instructions.
Analysis of Apoptosis
Ventricular myocardial apoptosis was assessed using several complementary methods. First, we assessed terminal deoxynucleotide transferase–mediated dUTP nick-end labeling (TUNEL) in formalin-fixed myocardial samples (CardioTACS In Situ Apoptosis Detection Kit, TA5353) according to the manufacturer’s instructions. Apoptotic myocytes were counted under x400 magnification and expressed as a fraction of cells per field. Second, apoptosis was assessed by caspase-3 proteolytic activity with a spectrophotometric assay (Fiena kit, Roche Applied Science, Indianapolis, Ind) normalized to total lysate protein and incubation time (FU · mg–1 · h–1). Third, we determined PARP cleavage as a marker of activated apoptotic cascades.
Statistical Analysis
Comparisons between groups (unpaired samples) were performed by 1-way ANOVA with Bonferroni correction; comparisons between regions or myocardial layers or over time (ie, paired samples) were performed by repeated-measures ANOVA. Data are presented as mean±SEM.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
Mechanical Dyssynchrony and Heart Failure in DHF and CRT Hearts
Figure 1A shows representative anterior and lateral strain tracings from dogs with a left bundle-branch block after 3 weeks of atrial tachypacing. Early septal shortening with concomitant lateral stretch was followed by the opposite patterns in later systole. In DHF dogs, dyssynchrony persisted for the ensuing 3 weeks of tachypacing, whereas it declined markedly in dogs receiving CRT during this period (Figure 1A and 1B). Similar differences were confirmed by magnetic resonance imaging (circumferential uniformity ratio estimate index: 1=synchronous, 0=maximal dyssynchrony; normal controls, 0.97±0.01; CRT, 0.87±0.06; DHF, 0.58±0.09; P<0.01 versus other groups).
|
P=0.058), and a trend toward less rise in end-systolic volume (ESV) was present. LBBB indicates left bundle-branch block; RAP, right atrial pressure; and EDV, end-diastolic volume.Both groups developed similar LV dysfunction after 3 weeks of pacing (ie, before randomization; Table 1), whereas by 6 weeks, ejection declined further in DHF (–4.7±2.7%) but rose slightly in CRT animals (2.8±1.8%; P=0.02 versus DHF; Figure 1B), associated with a borderline higher stroke volume (P=0.058). Despite these changes, both groups had substantial persistent heart failure with similarly elevated end-diastolic pressures (36±9.7 and 33.5±3.2 mm Hg, DHF versus CRT, respectively; 9.1±2.0 mm Hg, reference control) and reduced dP/dtmax (1031±86.2 and 1062±80 mm Hg/s, DHF versus CRT, respectively; 2891.3±39 mm Hg/s, controls).
|
To confirm that biventricular stimulation (CRT mode) produced a short-term improvement in systolic function as in clinical studies,4 a separate group of long-term–instrumented animals with DHF were studied. Biventricular stimulation led to short-term improvement in load-independent measures of systolic function on the basis of pressure–volume analysis (Table 2).
|
Regional Heterogeneity of Stress Kinases With DHF Is Homogenized by CRT
DHF hearts had locally enhanced protein expression and activation of multiple stress-response proteins. For example, p38 MAP kinase (MAPK) and CaMKII increased in the late-contracting lateral wall compared with septum of DHF hearts (both endocardial and epicardial layers), but this was reduced and rendered more homogeneous by CRT (Figure 2A). These results closely correlated with enzyme activity (Figure 2B). Regional expression disparities also were observed for JNK and ERK1/2 MAPK in DHF hearts, and again these were homogenized by CRT (Figure I of the online-only Data Supplement). Regional stimulation disparities also were observed in TNF- in DHF but not CRT hearts (Figure 2C). We previously showed that disproportionate regional activation is not observed in synchronous heart failure12,24 or in normal controls (online-only Data Supplement Figure II).
|
P<0.001 vs control and CRT, P<0.05 vs septum; *P<0.001 vs control;
DHF Myocardium Has Increased Apoptosis That Is Reduced by CRT
One potential consequence of p38, JNK, CaMKII, and TNF- activation is increased apoptosis.3 Figure 3A shows TUNEL staining in myocardium from control, DHF, and CRT hearts; positive nuclei increased 3- to 4-fold in DHF versus control hearts but declined with CRT. Proapoptotic caspase-3 activity was greater in DHF than CRT myocardium (Figure 3B), accompanied by an increase in PARP cleavage (Figure 3C). PARP is a 116-kDa protein involved in DNA repair that is cleaved by caspase-3 to yield 89- and 24-kDa fragments. DHF hearts displayed substantial PARP fragmentation, whereas CRT ventricles displayed less PARP fragmentation.
|
0.05 vs DHF;
Akt Kinase Is Activated by CRT
Unlike the regional amplification of stress kinases, apoptosis changes were more global in nature, leading us to speculate that alternative pathways might be involved. One prominent cell-survival pathway is linked to activated (phosphorylated) Akt (PKB) kinase. pAkt was markedly and globally reduced in DHF in both myocardial layers (Figure 4A) yet rose to control levels with CRT (Figure 4B). Total Akt was unaltered (Figure 4A). Akt activity was further tested by an in vitro assay, which confirmed the pAkt expression findings.
|
CRT Modifies BAD/Bcl-2 Expression and BAD Phosphorylation
Akt regulates apoptosis by phosphorylating several negative modulators, notably BAD, GSK3β, and forkhead proteins (eg, FOXO3). Given the marked disparity of Akt activity in DHF and CRT ventricles, we examined these downstream cascades to assess their potential role in the decline in apoptosis. BAD binding to the Bcl-x(L) complex triggers apoptosis,25 but on phosphorylation, BAD dissociates and binds to 14-3-3 protein, suppressing apoptosis.26 In DHF hearts, S136-pBAD (Akt site) was markedly and globally reduced (in both myocardial layers) but returned to control levels with CRT (Figure 5A). Total BAD also declined with DHF (Figure 5B) but was similarly reduced in CRT hearts, so the disparity in pBAD could not be attributed to differences in total protein per se.
|
We next examined 14-3-3 protein, which binds to pBAD to suppress apoptosis. As shown in Figure 5C, full-length 14-3-3 declined in both DHF and CRT conditions, much like total BAD. However, 14-3-3 also underwent cleavage in DHF hearts, a phenomenon linked to caspase-3 activation and thought to be proapoptotic by reducing pBAD–14-3-3 interaction.27 The 14-3-3 cleavage declined in CRT hearts. Finally, we performed immunoprecipitation to BAD and then probed for 14-3-3 binding (Figure 5D), which declined in DHF hearts but rose again with CRT. Interpretation of this assay, however, also was influenced by the changes in both total proteins.
BAD expression changes were paralleled by Bcl-2 (Figure 6A), which also binds to BAD, suggesting coordinated modification. Intriguingly, mRNA expression assessed by quantitative polymerase chain reaction was unaltered for either protein (data not shown), indicating that this regulation occurred at the translational and/or posttranslational level. We further examined BAD and Bcl-2 levels in isolated mitochondrial fractions (Figure 6B) because increases there would be considered proapoptotic. With DHF, mitochondrial BAD and Bcl-2 increased but declined with CRT. Mitochondrial cytochrome c oxidase-IV served as a loading control.
|
BAD also can be phosphorylated at S112 to confer antiapoptotic effects. Phosphorylation at this site was depressed in DHF hearts and recovered toward control with CRT (Figure 7A). Rather than Akt, BAD S112 phosphorylation is induced by p90RSK, which in turn is stimulated by MAPKs28 and protein kinase C.29 Therefore, we tested whether p90RSK was differentially activated in CRT hearts. However, p90RSK phosphorylation was actually higher in DHF than CRT hearts (Figure 7B; changes in total protein followed a similar pattern [data not shown]), making it unlikely to explain altered S112-pBAD. An alternative mechanism could be reduced S112 dephosphorylation by phosphatase PP1 in CRT, and this was observed (Figure 7C). PP1β and PP1
were unaltered by either condition (data not shown).
|
Finally, we assess 2 other proteins that can negatively modulate apoptosis when phosphorylated by Akt: FOXO3 and GSK3β. Unlike BAD, however, these proteins were more phosphorylated (inactivated) in DHF hearts, whereas thy returned to normal levels with CRT (Figure 8). This finding is opposite to what we observed with Akt or BAD, suggesting that the latter dominated.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
Cardiac resynchronization directly alters the timing of electric activation with the goal of rendering contraction more homogeneous. This affects regional loading and shortening and chamber function and efficiency. To date, the consequences of CRT have been revealed almost entirely at the chamber level, with studies showing its capacity to suppress progressive dilation.30,31 Here, we show that CRT also potently influences regional and global molecular abnormalities in dyssynchronous failing hearts, lowering regional activation of stress-response kinases and globally enhancing cell-survival signaling. As all of these changes occurred despite persistent albeit slightly mitigated heart failure, they may reflect primary factors contributing to CRT benefits.
In a prior study, we first reported that DHF induces localized changes in activity and/or expression of stress-response kinases, calcium handling, and gap junction proteins in the late-activated endocardium.12 This was not observed in synchronous heart failure, normal hearts, or nonfailing dyssynchronous hearts,24 the last case highlighting the importance of combining heart failure pathophysiology with discoordinate contraction. The present study extends these observations, confirming amplified stress kinase activation mostly in the late-contracting lateral wall; however, the exact proteins involved differed somewhat from those in our earlier study (eg, p38 was not activated previously), and the changes were transmural. The only real difference between models was the duration of tachypacing, which was doubled for the present study, and this could underlie the disparities.
The present results are the first to show that CRT homogenizes local stress kinase expression and activity, and this is potentially important given the impact of these proteins on muscle function, survival, and fibrosis. p38 MAPK stimulates fibrosis and apoptosis and is associated with contractile failure.32,33 CaMKII is important to β-adrenergic–stimulated toxicity and apoptosis,34 hypertrophy coupled to histone deacetylase,35,36 and cardiac arrhythmia.37,38 TNF- stimulates fibrosis and apoptosis, and overexpression induces dilated cardiomyopathy.39 It can be triggered by abnormal loading,40 and its decline solely in the lateral wall of CRT hearts supports this mechanism. This change is supported by recent human data reporting lower LV TNF- (localization was not defined) after 6 months of CRT.41
More striking than regional modifications by CRT was the decline in global apoptosis and enhanced cell-survival signaling. Reduced LV TUNEL positive staining also has been found in humans treated with long-term CRT,41 and the present findings reveal key pathways likely involved. The fall in Akt activity in DHF hearts is consistent with an earlier study using tachypacing-induced heart failure,42 with dyssynchrony generated by right ventricular pacing. The presumption was that lower pAkt was due to cardiac failure itself; however, our data suggest that it may be more specific to dyssynchrony because pAkt recovered with CRT even though hearts had persistent failure. The global distribution of altered Akt activation supports a more general impact of CRT, perhaps on mechanoenergetics.
Among the major targets of Akt that modulate cell survival, BAD phosphorylation best correlated. BAD is a member of the Bcl-2 family, which normally interacts with and suppresses antiapoptotic proteins Bcl-2/Bcl-X located at the mitochondrial membrane. This action depends on its phosphorylation state, and when phosphorylated by Akt (or p90RSK), BAD dissociates from the complex, binds to 14-3-3 protein, and suppresses apoptosis. The present study supports an important role of BAD modulation by CRT, revealed by differential phosphorylation, mitochondrial levels, and 14-3-3 modulation. BAD also is phosphorylated at S112 by several kinases, including p90RSK linked to the activity of ERK1/228 and protein kinase C.29 Although this site was also preferentially phosphorylated by CRT over DHF, p90RSK did not appear to be the culprit. One alternative is mitogen and stress kinase-1 linked to p38 activity,43 although our finding that p38 activation was lowered by CRT suggested that this is unlikely. Rather, we found that the major BAD phosphatase PP1 was reduced in CRT hearts, which could increase BAD phosphorylation.44,45
Total BAD in cell lysates declined in both DHF and CRT hearts. This was not due to transcriptional regulation at the mRNA level, and intriguingly, mitochondrial BAD rose with DHF (not CRT). Analogous disparities between total cellular and mitochondrial protein levels for Bcl-2 also were observed. The markedly reduced BAD phosphorylation with DHF would support relative Bcl-2 inhibition and a proapoptotic effect. Little is known about how BAD expression and Bcl-2 protein expression are regulated, although oxidative stress46 and hypoxia, coupled with opening of a mitochondrial ATP-sensitive potassium channel,47 may contribute. Whether such mechanisms apply to DHF or CRT remains to be determined. Finally, it is intriguing that phosphorylation of 2 other regulators of apoptosis that are inactivated by Akt (ie, antiapoptotic effect)—FOXO3 and GSK3β—did not correlate with Akt activity or CRT antiapoptotic effects. Signaling by these proteins, however, is complex,48 and their changes could reflect other influences (ie, worse failure with DHF) and phosphorylation by alternative kinases such as protein kinase A, protein kinase C, and MAPK.48,49
Our study has several limitations. The model requires continued tachypacing to maintain heart failure while concomitantly applying resynchronization to examine its impact on the pathophysiology. Although different from what is found in the typical clinical setting, this model has advantages in that it helps isolate the influence of resynchronization per se from more general heart failure influences. The similarity between the TNF- and apoptosis in the present study and a previous human CRT study41 supports its clinical relevance. The model is nonischemic, and it remains unknown whether identical results would be observed with ischemic cardiomyopathy. However, CRT is effective in both ischemic and nonischemic cardiomyopathy, and regional stress effects from dyssynchrony and its improvement by biventricular pacing are similar in both forms of failure. Another limitation is that we could not directly test the role of a given molecular change given the lack of specific pharmacological inhibitors usable in vivo and difficulties in genetically targeting these pathways in the intact canine heart.
|
Conclusions |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
We demonstrated both localized abnormalities in stress-response enzymes and global changes in cell-survival signaling that develop in the LV myocardium of the dyssynchronous failing heart and find that they can be favorably affected by biventricular stimulation to resynchronize contraction. These findings correlated with a very modest improvement in global function, suggesting that they may reflect more primary CRT effects from enhanced contractile synchrony that contribute to the long-term benefits of this treatment.
|
Acknowledgments |
|---|
Sources of Funding
This study was supported by National Institutes of Health National Heart, Lung, and Blood Institute grants PO1-HL077180 (Drs Kass and Tomaselli) and T32-HL07227 (Drs Kass and Helm), the Peter Belfer Laboratory, and the Abraham and Virginia Weiss Professorship (Dr Kass).
Disclosures
Dr Lardo has received a research grant from and served as a consultant or on the advisory board for Boston Scientific/Guidant. The other authors report no conflicts.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
|---|
1. Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol. 2006; 7: 589–600.[CrossRef][Medline] [Order article via Infotrieve]
2. Dorn GW, Force T. Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest. 2005; 115: 527–537.[CrossRef][Medline] [Order article via Infotrieve]
3. Baines CP, Molkentin JD. STRESS signaling pathways that modulate cardiac myocyte apoptosis. J Mol Cell Cardiol. 2005; 38: 47–62.[CrossRef][Medline] [Order article via Infotrieve]
4. Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B, Nevo E. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation. 1999; 99: 1567–1573.
5. Spragg DD, Kass DA. Pathobiology of left ventricular dyssynchrony and resynchronization. Prog Cardiovasc Dis. 2006; 49: 26–41.[CrossRef][Medline] [Order article via Infotrieve]
6. Bader H, Garrigue S, Lafitte S, Reuter S, Jais P, Haissaguerre M, Bonnet J, Clementy J, Roudaut R. Intra-left ventricular electromechanical asynchrony: a new independent predictor of severe cardiac events in heart failure patients. J Am Coll Cardiol. 2004; 43: 248–256.
7. Prinzen FW, Augustijn CH, Arts T, Allessie MA, Reneman RS. Redistribution of myocardial fiber strain and blood flow by asynchronous activation. Am J Physiol. 1990; 259: H300–H308.[Medline] [Order article via Infotrieve]
8. Prinzen FW, Hunter WC, Wyman BT, McVeigh ER. Mapping of regional myocardial strain and work during ventricular pacing: experimental study using magnetic resonance imaging tagging. J Am Coll Cardiol. 1999; 33: 1735–1742.
9. Owen CH, Esposito DJ, Davis JW, Glower DD. The effects of ventricular pacing on left ventricular geometry, function, myocardial oxygen consumption, and efficiency of contraction in conscious dogs. Pacing Clin Electrophysiol. 1998; 21: 1417–1429.[CrossRef][Medline] [Order article via Infotrieve]
10. Kawaguchi M, Murabayashi T, Fetics BJ, Nelson GS, Samejima H, Nevo E, Kass DA. Quantitation of basal dyssynchrony and acute resynchronization from left or biventricular pacing by novel echo-contrast variability imaging. J Am Coll Cardiol. 2002; 39: 2052–2058.
11. Helm RH, Leclercq C, Faris OP, Ozturk C, McVeigh E, Lardo AC, Kass DA. Cardiac dyssynchrony analysis using circumferential versus longitudinal strain: implications for assessing cardiac resynchronization. Circulation. 2005; 111: 2760–2767.
12. Spragg DD, Leclercq C, Loghmani M, Faris OP, Tunin RS, DiSilvestre D, McVeigh ER, Tomaselli GF, Kass DA. Regional alterations in protein expression in the dyssynchronous failing heart. Circulation. 2003; 108: 929–932.
13. Nelson GS, Berger RD, Fetics BJ, Talbot M, Hare JM, Spinelli JC, Kass DA. Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block. Circulation. 2000; 102: 3053–3059.
14. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005; 352: 1539–1549.
15. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the Cardiac Resynchronization-Heart Failure (CARE-HF) trial extension phase]. Eur Heart J. 2006; 27: 1928–1932.
16. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004; 350: 2140–2150.
17. Spragg DD, Kass DA. Pathobiology of left ventricular dyssynchrony and resynchronization. Prog Cardiovasc Dis. 2006; 49: 26–41.[CrossRef][Medline] [Order article via Infotrieve]
18. Nowak B, Sinha AM, Schaefer WM, Koch KC, Kaiser HJ, Hanrath P, Buell U, Stellbrink C. Cardiac resynchronization therapy homogenizes myocardial glucose metabolism and perfusion in dilated cardiomyopathy and left bundle branch block. J Am Coll Cardiol. 2003; 41: 1523–1528.
19. Auricchio A, Stellbrink C, Block M, Sack S, Vogt J, Bakker P, Klein H, Kramer A, Ding J, Salo R, Tockman B, Pochet T, Spinelli J. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure: the Pacing Therapies for Congestive Heart Failure Study Group: the Guidant Congestive Heart Failure Research Group. Circulation. 1999; 99: 2993–3001.
20. Vernooy K, Verbeek XA, Peschar M, Crijns HJ, Arts T, Cornelussen RN, Prinzen FW. Left bundle branch block induces ventricular remodelling and functional septal hypoperfusion. Eur Heart J. 2005; 26: 91–98.
21. Nishijima Y, Feldman DS, Bonagura JD, Ozkanlar Y, Jenkins PJ, Lacombe VA, Abraham WT, Hamlin RL, Carnes CA. Canine nonischemic left ventricular dysfunction: a model of chronic human cardiomyopathy. J Card Fail. 2005; 11: 638–644.[CrossRef][Medline] [Order article via Infotrieve]
22. Leclercq C, Faris O, Tunin R, Johnson J, Kato R, Evans F, Spinelli J, Halperin H, McVeigh E, Kass DA. Systolic improvement and mechanical resynchronization does not require electrical synchrony in the dilated failing heart with left bundle-branch block. Circulation. 2002; 106: 1760–1763.
23. Senzaki H, Isoda T, Paolocci N, Ekelund U, Hare JM, Kass DA. Improved mechanoenergetics and cardiac rest and reserve function of in vivo failing heart by calcium sensitizer EMD-57033. Circulation. 2000; 101: 1040–1048.
24. Spragg DD, Akar FG, Helm RH, Tunin RS, Tomaselli GF, Kass DA. Abnormal conduction and repolarization in late-activated myocardium of dyssynchronously contracting hearts. Cardiovasc Res. 2005; 67: 77–86.
25. Matsui T, Nagoshi T, Rosenzweig A. Akt and PI 3-kinase signaling in cardiomyocyte hypertrophy and survival. Cell Cycle. 2003; 2: 220–223.[Medline] [Order article via Infotrieve]
26. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997; 91: 231–241.[CrossRef][Medline] [Order article via Infotrieve]
27. Won J, Kim DY, La M, Kim D, Meadows GG, Joe CO. Cleavage of 14-3-3 protein by caspase-3 facilitates bad interaction with Bcl-x(L) during apoptosis. J Biol Chem. 2003; 278: 19347–19351.
28. Takeishi Y, Huang Q, Abe J, Che W, Lee JD, Kawakatsu H, Hoit BD, Berk BC, Walsh RA. Activation of mitogen-activated protein kinases and p90 ribosomal S6 kinase in failing human hearts with dilated cardiomyopathy. Cardiovasc Res. 2002; 53: 131–137.
29. Tan Y, Ruan H, Demeter MR, Comb MJ. p90(RSK) blocks bad-mediated cell death via a protein kinase C-dependent pathway. J Biol Chem. 1999; 274: 34859–34867.
30. Sutton MG, Plappert T, Hilpisch KE, Abraham WT, Hayes DL, Chinchoy E. Sustained reverse left ventricular structural remodeling with cardiac resynchronization at one year is a function of etiology: quantitative Doppler echocardiographic evidence from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). Circulation. 2006; 113: 266–272.
31. Yu CM, Chau E, Sanderson JE, Fan K, Tang MO, Fung WH, Lin H, Kong SL, Lam YM, Hill MR, Lau CP. Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation. 2002; 105: 438–445.
32. Liao P, Wang SQ, Wang S, Zheng M, Zheng M, Zhang SJ, Cheng H, Wang Y, Xiao RP. p38 Mitogen-activated protein kinase mediates a negative inotropic effect in cardiac myocytes. Circ Res. 2002; 90: 190–196.
33. Liao P, Georgakopoulos D, Kovacs A, Zheng M, Lerner D, Pu H, Saffitz J, Chien K, Xiao RP, Kass DA, Wang Y. The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy. Proc Natl Acad Sci U S A. 2001; 98: 12283–12288.
34. Zhu WZ, Wang SQ, Chakir K, Yang D, Zhang T, Brown JH, Devic E, Kobilka BK, Cheng H, Xiao RP. Linkage of beta1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase II. J Clin Invest. 2003; 111: 617–625.[CrossRef][Medline] [Order article via Infotrieve]
35. Wu X, Zhang T, Bossuyt J, Li X, McKinsey TA, Dedman JR, Olson EN, Chen J, Brown JH, Bers DM. Local InsP3-dependent perinuclear Ca2+ signaling in cardiac myocyte excitation-transcription coupling. J Clin Invest. 2006; 116: 675–682.[CrossRef][Medline] [Order article via Infotrieve]
36. Backs J, Song K, Bezprozvannaya S, Chang S, Olson EN. CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy. J Clin Invest. 2006; 116: 1853–1864.[CrossRef][Medline] [Order article via Infotrieve]
37. Grueter CE, Colbran RJ, Anderson ME. CaMKII, an emerging molecular driver for calcium homeostasis, arrhythmias, and cardiac dysfunction. J Mol Med. 2007; 85: 5–14.[CrossRef][Medline] [Order article via Infotrieve]
38. Zhang R, Khoo MS, Wu Y, Yang Y, Grueter CE, Ni G, Price EE Jr, Thiel W, Guatimosim S, Song LS, Madu EC, Shah AN, Vishnivetskaya TA, Atkinson JB, Gurevich VV, Salama G, Lederer WJ, Colbran RJ, Anderson ME. Calmodulin kinase II inhibition protects against structural heart disease. Nat Med. 2005; 11: 409–417.[CrossRef][Medline] [Order article via Infotrieve]
39. Feldman AM, Combes A, Wagner D, Kadakomi T, Kubota T, Li YY, McTiernan C. The role of tumor necrosis factor in the pathophysiology of heart failure. J Am Coll Cardiol. 2000; 35: 537–544.
40. Kapadia SR, Oral H, Lee J, Nakano M, Taffet GE, Mann DL. Hemodynamic regulation of tumor necrosis factor-alpha gene and protein expression in adult feline myocardium. Circ Res. 1997; 81: 187–195.
41. D’Ascia C, Cittadini A, Monti MG, Riccio G, Sacca L. Effects of biventricular pacing on interstitial remodelling, tumor necrosis factor-alpha expression, and apoptotic death in failing human myocardium. Eur Heart J. 2006; 27: 201–206.
42. Ananthakrishnan R, Moe GW, Goldenthal MJ, Marin-Garcia J. Akt signaling pathway in pacing-induced heart failure. Mol Cell Biochem. 2005; 268: 103–110.[CrossRef][Medline] [Order article via Infotrieve]
43. Nagy N, Shiroto K, Malik G, Huang CK, Gaestel M, Abdellatif M, Tosaki A, Maulik N, Das DK. Ischemic preconditioning involves dual cardio-protective axes with p38MAPK as upstream target. J Mol Cell Cardiol. 2007; 42: 981–990.[CrossRef][Medline] [Order article via Infotrieve]
44. Garcia A, Cayla X, Guergnon J, Dessauge F, Hospital V, Rebollo MP, Fleischer A, Rebollo A. Serine/threonine protein phosphatases PP1 and PP2A are key players in apoptosis. Biochimie. 2003; 85: 721–726.[Medline] [Order article via Infotrieve]
45. Ayllon V, Martinez A, Garcia A, Cayla X, Rebollo A. Protein phosphatase 1alpha is a Ras-activated Bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis. EMBO J. 2000; 19: 2237–2246.[CrossRef][Medline] [Order article via Infotrieve]
46. Maroto R, Perez-Polo JR. BCL-2-related protein expression in apoptosis: oxidative stress versus serum deprivation in PC12 cells. J Neurochem. 1997; 69: 514–523.[Medline] [Order article via Infotrieve]
47. Nishikawa S, Tatsumi T, Shiraishi J, Matsunaga S, Takeda M, Mano A, Kobara M, Keira N, Okigaki M, Takahashi T, Matsubara H. Nicorandil regulates Bcl-2 family proteins and protects cardiac myocytes against hypoxia-induced apoptosis. J Mol Cell Cardiol. 2006; 40: 510–519.[CrossRef][Medline] [Order article via Infotrieve]
48. Grimes CA, Jope RS. The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol. 2001; 65: 391–426.[CrossRef][Medline] [Order article via Infotrieve]
49. van der HA, Burgering BM. Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol. 2007; 8: 440–450.[CrossRef][Medline] [Order article via Infotrieve]
|
Footnotes |
|---|
The online-only Data Supplement can be found with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.706291/DC1.
Related Article:
Circulation 2008 117: 1353.
This article has been cited by other articles:
 |
|
 |
|
  A. Cheng, R. H. Helm, and T. P. Abraham Pathophysiological mechanisms underlying ventricular dyssynchrony Europace, November 1, 2009; 11(suppl_5): v10 - v14. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Barth, T. Aiba, V. Halperin, D. DiSilvestre, K. Chakir, C. Colantuoni, R. S. Tunin, V. L. Dimaano, W. Yu, T. P. Abraham, et al. Cardiac Resynchronization Therapy Corrects Dyssynchrony-Induced Regional Gene Expression Changes on a Genomic Level Circ Cardiovasc Genet, August 1, 2009; 2(4): 371 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Chua, L.-T. Chang, C.-K. Sun, J.-J. Sheu, F.-Y. Lee, A. A. Youssef, C.-H. Yang, C.-J. Wu, and H.-K. Yip Time Courses of Subcellular Signal Transduction and Cellular Apoptosis in Remote Viable Myocardium of Rat Left Ventricles Following Acute Myocardial Infarction: Role of Pharmacomodulation Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2009; 14(2): 104 - 115. [Abstract] [PDF]
|
|
|
|
 |
|
 J. A. Dixon and F. G. Spinale Large Animal Models of Heart Failure: A Critical Link in the Translation of Basic Science to Clinical Practice Circ Heart Fail, May 1, 2009; 2(3): 262 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Chakir, S. K. Daya, T. Aiba, R. S. Tunin, V. L. Dimaano, T. P. Abraham, K. Jaques, E. W. Lai, K. Pacak, W.-Z. Zhu, et al. Mechanisms of Enhanced {beta}-Adrenergic Reserve From Cardiac Resynchronization Therapy Circulation, March 10, 2009; 119(9): 1231 - 1240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Aiba, G. G. Hesketh, A. S. Barth, T. Liu, S. Daya, K. Chakir, V. L. Dimaano, T. P. Abraham, B. O'Rourke, F. G. Akar, et al. Electrophysiological Consequences of Dyssynchronous Heart Failure and Its Restoration by Resynchronization Therapy Circulation, March 10, 2009; 119(9): 1220 - 1230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Castellant, M. Fatemi, E. Orhan, Y. Etienne, and J. J. Blanc Patients with non-ischaemic dilated cardiomyopathy and hyper-responders to cardiac resynchronization therapy: characteristics and long-term evolution Europace, March 1, 2009; 11(3): 350 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. N. Faddis A dose response for cardiac resynchronization therapy? J. Am. Coll. Cardiol., January 27, 2009; 53(4): 361 - 362. [Full Text] [PDF]
|
|
|
|
 |
|
 G.-C. Fan, X. Zhou, X. Wang, G. Song, J. Qian, P. Nicolaou, G. Chen, X. Ren, and E. G. Kranias Heat Shock Protein 20 Interacting With Phosphorylated Akt Reduces Doxorubicin-Triggered Oxidative Stress and Cardiotoxicity Circ. Res., November 21, 2008; 103(11): 1270 - 1279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Chakir, R. S Tunin, T. Aiba, G. Tomaselli, and D. A Kass Abstract 4341: Dyssynchrony is a Prerequisite condition for Beta Reserve Upregulation By Cardiac Resynchronization Therapy Circulation, October 28, 2008; 118(18_MeetingAbstracts): S_868 - S_868.
|
|
|
|
 |
|
 J. Abraham and T. P. Abraham Is echocardiographic assessment of dyssynchrony useful to select candidates for cardiac resynchronization therapy?: Echocardiography Is Useful Before Cardiac Resynchronization Therapy if QRS Duration Is Available Circ Cardiovasc Imaging, July 1, 2008; 1(1): 79 - 85. [Full Text] [PDF]
|
|
|
|
|
|
A. Auricchio and F. W. Prinzen Update on the pathophysiological basics of cardiac resynchronization therapy Europace, July 1, 2008; 10(7): 797 - 800. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||