Relationship of Echocardiographic Dyssynchrony to Long-Term Survival After Cardiac Resynchronization Therapy

Gorcsan, John; Oyenuga, Olusegun; Habib, Phillip; Tanaka, Hidekazu; Adelstein, Evan; Hara, Hideyuki; McNamara, Dennis M.; Saba, Samir

doi:10.1161/circulationaha.110.954768

Cited by 170 publications

(87 citation statements)

References 36 publications

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“…Its improvement of systolic function occurs within 1 beat (3) and is associated with negligible or even reduced myocardial oxygen consumption, indicating improved chamber efficiency (4,5). While dyssynchrony is an independent risk factor in patients with HF, successful CRT reduces mortality (6,7), perhaps to levels even below those of HF patients without dyssynchrony (8,9).…”

Section: Introductionmentioning

confidence: 99%

Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β

Kirk¹,

Holewinski²,

Kooij³

et al. 2013

J. Clin. Invest.

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Cardiac resynchronization therapy (CRT), the application of biventricular stimulation to correct discoordinate contraction, is the only heart failure treatment that enhances acute and chronic systolic function, increases cardiac work, and reduces mortality. Resting myocyte function also increases after CRT despite only modest improvement in calcium transients, suggesting that CRT may enhance myofilament calcium responsiveness. To test this hypothesis, we examined adult dogs subjected to tachypacing-induced heart failure for 6 weeks, concurrent with ventricular dyssynchrony (HF dys ) or CRT. Myofilament force-calcium relationships were measured in skinned trabeculae and/or myocytes. Compared with control, maximal calcium-activated force and calcium sensitivity declined globally in HF dys ; however, CRT restored both. Phosphatase PP1 induced calcium desensitization in control and CRT-treated cells, while HF dys cells were unaffected, implying that CRT enhances myofilament phosphorylation. Proteomics revealed phosphorylation sites on Z-disk and M-band proteins, which were predicted to be targets of glycogen synthase kinase-3β (GSK-3β). We found that GSK-3β was deactivated in HF dys and reactivated by CRT. Mass spectrometry of myofilament proteins from HF dys animals incubated with GSK-3β confirmed GSK-3β-dependent phosphorylation at many of the same sites observed with CRT. GSK-3β restored calcium sensitivity in HF dys , but did not affect control or CRT cells. These data indicate that CRT improves calcium responsiveness of myofilaments following HF dys through GSK-3β reactivation, identifying a therapeutic approach to enhancing contractile function.

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Section: Introductionmentioning

confidence: 99%

Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β

Kirk¹,

Holewinski²,

Kooij³

et al. 2013

J. Clin. Invest.

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“…Gorcsan et al 35 have recently evaluated the relationship between several indices of mechanical dyssynchrony and long-term survival after CRT. 36 There was a strong trend for more female patients and significantly more patients with non-ischemic cardiomyopathy in the patients who showed mechanical dyssynchrony, independent of the selected echocardiographic parameter. This observation further substantiates that the value of mechanical dyssynchrony cannot be entirely dissected from other very important clinical characteristics.…”

Section: Predictors Of Crt Responsementioning

confidence: 85%

Non-Responders to Cardiac Resynchronization Therapy - The Magnitude of the Problem and the Issues -

Auricchio

Prinzen

2011

Circ J

199

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A variable proportion of cardiac resynchronization therapy (CRT) patients do not benefit from treatment (termed 'non-responders'). The problem of non-response to CRT might become increasingly important, because it is anticipated that larger groups of heart failure patients are indicated to the therapy. This article will discuss the definition of response to CRT, the parameters related to response to CRT, and finally whether response to CRT might be predicted. The effort to improve patient selection in order to maximize human and financial resource utilization has fallen short so far. It is, however, conceivable that rather than the identification of a 'universally' applicable cut-off value, risk strata - in which inclusion of method for determination of left ventricular volumes, etiology, QRS duration and morphology, etc - might better serve the goal of defining non-responders. Potentially simple clinical scores might help in refining outcome and by doing so, allow to more precisely measure response to CRT in daily practice in the individual patient at the time of CRT implantation. Although sophisticated cardiac imaging modalities have been intensively utilized for improving patient outcome, it seems that many mechanical dyssynchrony measures suffer from technical limitations and from difficult interpretation of the complex signals, which lack reproducibility outside highly specialized laboratories. (Circ J 2011; 75: 521 - 527)

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“…Resynchronization either by treatment of underlying pathology or cardiac resynchronization therapy (CRT) has been shown to improve mortality and morbidity in this patient population. [1][2][3][4] In MADIT-CRT study, patients with LBBB who had improvement in their dyssynchrony with CRT were also less likely to experience ventricular arrhythmias compared to those who did not have an improvement. 5 This raises the question if dyssynchronous contraction of the left ventricle is arrhythmogenic?…”

Section: See Related Article Pp 555-569mentioning

confidence: 99%

Dyssynchrony: a risk marker for ventricular arrhythmias?

Kumar

2018

Journal of Nuclear Cardiology

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Mechanical left ventricular dyssynchrony can result from conduction system abnormalities like left bundle branch block (LBBB), scarring in the left ventricle from ischemic or non-ischemic cardiomyopathy, and significant left ventricular dilatation resulting in changes in gap junctions and ion channels thereby affecting conduction velocity. The end result of these processes is dyssynchronous contraction of the left ventricle, causing inefficient pump function. Resynchronization either by treatment of underlying pathology or cardiac resynchronization therapy (CRT) has been shown to improve mortality and morbidity in this patient population.1-4 In MADIT-CRT study, patients with LBBB who had improvement in their dyssynchrony with CRT were also less likely to experience ventricular arrhythmias compared to those who did not have an improvement.5 This raises the question if dyssynchronous contraction of the left ventricle is arrhythmogenic? Dyssynchrony in patients with purely conduction system abnormality and no myopathy as seen in right ventricular pacing or LBBB with normal left ventricular structure and function does not seem to be associated with increased risk of arrhythmias. 6,7 In the presence of abnormal substrate, several studies have showed increased risk of adverse cardiovascular outcomes in patients with dyssynchrony but data on arrhythmic events are less convincing.8-11 A sub-study of MADIT-CRT showed no difference in the occurrence of ventricular arrhythmias in patients undergoing CRT implantation with or without baseline dyssynchrony. 10In REVERSE trial there was no difference in occurrence of ventricular arrhythmias in patients with CRT ON vs CRT OFF implying resynchronization had little impact on occurrence of ventricular arrhythmias. The study population in this trial included patients with mild heart failure (NYHA classes I and II) with QRS greater than 120 ms and since there was no baseline assessment of dyssynchrony it is plausible that most of these patients did not have significant dyssynchrony to begin with. 12 In the InSync ICD trial, there was reduction in ventricular arrhythmias, which was related to the degree of the remodeling after CRT implantation. 13 Most of these studies used strain imaging to assess and quantify dyssynchrony, which, in itself is limited by temporal resolution of echocardiography.In the current study, Saurabh et al studied the impact of dyssynchrony as assessed by phase analysis of gated SPECT on ventricular arrhythmias in patients undergoing CRT. There results showed that most ventricular arrhythmias occurred in patients with dyssynchrony and at least some degree of myocardial scarring. Reversal of dyssynchrony was seen in only few patients post CRT-implant and these patients had decreased risk of ventricular arrhythmias. There are several limitations of the study including small sample size, retrospective design, significantly poor response to CRT, and lack of effect on mortality despite higher incidence of ventricular arrhythmias. But in spite of these limitations, ...

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Relationship of Echocardiographic Dyssynchrony to Long-Term Survival After Cardiac Resynchronization Therapy

Cited by 170 publications

References 36 publications

Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β

Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β

Non-Responders to Cardiac Resynchronization Therapy - The Magnitude of the Problem and the Issues -

Dyssynchrony: a risk marker for ventricular arrhythmias?

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