Dataset Information

Mechanical dyssynchrony precedes QRS widening in ATP-sensitive K? channel-deficient dilated cardiomyopathy.

ABSTRACT: Contractile discordance exacerbates cardiac dysfunction, aggravating heart failure outcome. Dissecting the genesis of mechanical dyssynchrony would enable an early diagnosis before advanced disease.High-resolution speckle-tracking echocardiography was applied in a knockout murine surrogate of adult-onset human cardiomyopathy caused by mutations in cardioprotective ATP-sensitive K(+) (K(ATP)) channels. Preceding the established criteria of cardiac dyssynchrony, multiparametric speckle-based strain resolved nascent erosion of dysfunctional regions within cardiomyopathic ventricles of the K(ATP) channel-null mutant exposed to hemodynamic stress. Not observed in wild-type counterparts, intraventricular disparity in wall motion, validated by the degree, direction, and delay of myocardial speckle patterns, unmasked the disease substrate from asymptomatic to overt heart failure. Mechanical dyssynchrony preceded widening of the QRS complex and exercise intolerance and progressed into global myocardial discoordination and decompensated cardiac pump function, precipitating a low output syndrome.The present study, with the use of high-resolution imaging, prospectively resolved the origin and extent of intraventricular motion disparity in a K(ATP) channel-knockout model of dilated cardiomyopathy. Mechanical dyssynchrony established as an early marker of cardiomyopathic disease offers novel insight into the pathodynamics of dyssynchronous heart failure.

SUBMITTER: Yamada S

PROVIDER: S-EPMC3886734 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Mechanical dyssynchrony precedes QRS widening in ATP-sensitive K⁺ channel-deficient dilated cardiomyopathy.

Yamada Satsuki S Arrell D Kent DK Kane Garvan C GC Nelson Timothy J TJ Perez-Terzic Carmen M CM Behfar Atta A Purushothaman Saranya S Prinzen Frits W FW Auricchio Angelo A Terzic Andre A

Journal of the American Heart Association 20131205 6

<h4>Background</h4>Contractile discordance exacerbates cardiac dysfunction, aggravating heart failure outcome. Dissecting the genesis of mechanical dyssynchrony would enable an early diagnosis before advanced disease.<h4>Methods and results</h4>High-resolution speckle-tracking echocardiography was applied in a knockout murine surrogate of adult-onset human cardiomyopathy caused by mutations in cardioprotective ATP-sensitive K(+) (K(ATP)) channels. Preceding the established criteria of cardiac dy ...[more]

PMID: 24308936

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Project description:Transplantation of pluripotent stem cells has proven beneficial in heart failure, yet the proteomic landscape underlying repair remains largely uncharacterized. In a genetic model of dilated cardiomyopathy elicited by pressure overload in the KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11) null mutant, proteome-wide profiles were here resolved by means of a systems approach prior to and following disease manifestation in the absence or presence of embryonic stem cell treatment. Comparative two-dimensional gel electrophoresis revealed a unique cardiomyopathic proteome in the absence of therapy, remodeled in response to stem cell treatment. Specifically, linear ion trap quadrupole-Orbitrap mass spectrometry determined the identities of 93 and 109 differentially expressed proteins from treated and untreated cardiomyopathic hearts, respectively. Mapped protein-protein relationships and corresponding neighborhoods incorporated the stem cell-dependent subproteome into a nonstochastic network with divergent composition from the stem cell-independent counterpart. Stem cell intervention produced a distinct proteome signature across a spectrum of biological processes ranging from energetic metabolism, oxidoreductases, and stress-related chaperones to processes supporting protein synthesis/degradation, signaling, and transport regulation, cell structure and scaffolding. In the absence of treatment, bioinformatic interrogation of the disease-only proteome network prioritized adverse cardiac outcomes, ablated or ameliorated following stem cell transplantation. Functional and structural measurements validated improved myocardial contractile performance, reduced ventricular size and decreased cardiac damage in the treated cohort. Unbiased systems assessment unmasked "cardiovascular development" as a prioritized biological function in stem cell-reconstructed cardiomyopathic hearts. Thus, embryonic stem cell treatment transformed the cardiomyopathic proteome to demote disease-associated adverse effects and sustain a procardiogenic developmental response, supplying a regenerative substrate for heart failure repair.

Project description:We investigated the effects of cell therapy on local mechanical dyssynchrony (LMD) in patients with nonischemic dilated cardiomyopathy (NICM). We analyzed electromechanical data of 30 NICM patients undergoing CD34+ cell transplantation. All patients underwent bone marrow stimulation; CD34+ cells were collected by apheresis and injected transendocardially. At baseline and at 6 months after therapy, we performed electromechanical mapping and measured unipolar voltage (UV) and LMD at cell injection sites. LMD was defined as a temporal difference between global and segmental peak systolic displacement normalized to the average duration of the RR interval. Favorable clinical response was defined as increase in the left ventricular ejection fraction (LVEF) ≥5% between baseline and 6 months. Using paired electromechanical point-by-point analysis, we were able to identify 233 sites of CD34+ cell injections in 30 patients. We found no overall differences in local UV between baseline and 6 months (10.7 ± 4.1 mV vs 10.0 ± 3.6 mV, P = 0.42). In contrast, LMD decreased significantly (17 ± 17% at baseline vs 13 ± 12% at 6 months, P = 0.00007). Favorable clinical response at 6 months was found in 19 (63%) patients (group A), and 11 (37%) patients did not respond to cell therapy (group B). At baseline, the two groups did not differ in age, gender, LVEF, or N terminal-pro brain natriuretic peptide (NT-proBNP) levels. Similarly, we found no differences in baseline UV (9.5 ± 2.9 mV in group A vs 8.6 ± 2.4 mV in group B, P = 0.41) or LMD at cell injection sites (17 ± 19% vs 16 ± 14%, P = 0.64). In contrast, at 6 months, we found higher UV in group A (10.0 ± 3.1 mV vs 7.4 ± 1.9 mV in group B, P = 0.04). Furthermore, when compared with group B, patients in group A displayed a significantly lower LMD (11 ± 12% vs 16 ± 10%, P = 0.002). Thus, it appears that favorable clinical effects of cell therapy in NICM patients may be associated with a decrease of LMD at cell injection sites.

Dataset Information

Mechanical dyssynchrony precedes QRS widening in ATP-sensitive K? channel-deficient dilated cardiomyopathy.

Publications

Mechanical dyssynchrony precedes QRS widening in ATP-sensitive K⁺ channel-deficient dilated cardiomyopathy.

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