Impact of left ventricular assist device therapy on the cardiac proteome and metabolome composition in ischemic cardiomyopathy.

The changes in the myocardial proteome and metabolome associated with left ventricular assist device (LVAD) therapy in patients with ischemic cardiomyopathy (ICM) are poorly characterized. We investigated the impact of mechanical unloading following LVAD therapy on the myocardial proteome and metabolome. Matched samples of 5 patients' myocardial tissue, harvested at the time of LVAD implant ("pre-LVAD") or heart transplant ("post-LVAD"), were studied by quantitative proteomics and metabolomics as well as being probed for T-tubule structure and connexin-43 distribution. Moreover, pre-LVAD proteome profiles of ICM context were bioinformatically compared to pre-LVAD proteome profiles of dilated cardiac myopathy (DCM). More than 2120 proteins were reliably identified and quantified in paired patient samples. LVAD therapy led to proteomic remodeling, including reduced levels of α-1-antichymotrypsin together with an overall decrease of immune response proteins and an increase of proteins involved in membrane biology. Metabolomics highlighted increased glucose and glucose-6-phosphate levels in the left ventricle upon LVAD therapy. Wheat germ agglutinin staining demonstrated improved T-tubule structure. Connexin-43 displayed a trend for more pronounced intercalated disc localization. In comparing pre-LVAD proteome profiles of ICM context with pre-LVAD proteome profiles of dilated cardiac myopathy (DCM), we noticed an overrepresentation in ICM of proteins associated with humoral immune response. Our findings underline an impact of LVAD therapy on left ventricular biology in ICM. The proteomic, metabolomic, and structural alterations described here are typically associated with cardiac recovery. On the molecular level, our findings indicate the possibility of cardiac remodeling under LVAD therapy in ICM.

Cathepsin A inhibition attenuates myocardial infarction-induced heart failure on the functional and proteomic levels.

BACKGROUND: Myocardial infarction (MI) is a major cause of heart failure. The carboxypeptidase cathepsin A is a novel target in the treatment of cardiac failure. We aim to show that recently developed inhibitors of the protease cathepsin A attenuate post-MI heart failure. METHODS: Mice were subjected to permanent left anterior descending artery (LAD) ligation or sham operation. 24 h post-surgery, LAD-ligated animals were treated with daily doses of the cathepsin A inhibitor SAR1 or placebo. After 4 weeks, the three groups (sham, MI-placebo, MI-SAR1) were evaluated. RESULTS: Compared to sham-operated animals, placebo-treated mice showed significantly impaired cardiac function and increased plasma BNP levels. Cathepsin A inhibition prevented the increase of plasma BNP levels and displayed a trend towards improved cardiac functionality. Proteomic profiling was performed for the three groups (sham, MI-placebo, MI-SAR1). More than 100 proteins were significantly altered in placebo-treated LAD ligation compared to the sham operation, including known markers of cardiac failure as well as extracellular/matricellular proteins. This ensemble constitutes a proteome fingerprint of myocardial infarction induced by LAD ligation in mice. Cathepsin A inhibitor treatment normalized the marked increase of the muscle stress marker CA3 as well as of Igγ 2b and fatty acid synthase. For numerous further proteins, cathepsin A inhibition partially dampened the LAD ligation-induced proteome alterations. CONCLUSIONS: Our proteomic and functional data suggest that cathepsin A inhibition has cardioprotective properties and support a beneficial effect of cathepsin A inhibition in the treatment of heart failure after myocardial infarction.

Unexpected collateral impact after out of hospital resuscitation using LUCAS system.

BACKGROUND: Mechanical chest compression using a piston device during reanimation is often the only way to ensure stable chest compression at a constant rate and force. However, its use can be associated with severe fractures of the thoracic rib cage and endanger the clinical course of the patient. Thus, the usage of such a piston device during the reanimation has currently been classified as a mere Class IIB indication. CASE PRESENTATION: We present a case of a 66-year-old male who underwent emergent CABG surgery after receiving out-of-hospital resuscitation as a result of myocardial infarction using the LUCAS system. Due to severe bilateral rib fractures a concomitant emergency chest-wall stabilization surgery had to be performed to ensure uncompromised graft flow to obtain stable cardiac function and hemodynamics. CONCLUSIONS: Reanimation using LUCAS-System might enable stable resuscitation conditions. However, it is crucial not to underestimate potential collateral damage which can in turn aggravate patient's clinical condition.

Proteomics highlights decrease of matricellular proteins in left ventricular assist device therapy†.

OBJECTIVES: We investigated the impact of mechanical unloading with a left ventricular assist device (LVAD) on the myocardial proteome. METHODS: We collected 11 patient-matched samples of myocardial left ventricular tissue of patients with non-ischaemic dilate cardiomyopathy, harvested at time of LVAD implant ('pre-LVAD') and heart transplant ('post-LVAD'). Samples were studied by quantitative proteomics. Further we performed histological assessment of deposited collagens and immune infiltration in both pre- and post-LVAD samples. RESULTS: A core set of >1700 proteins was identified and quantified at a false discovery rate <1%. The previously established decrease post-LVAD of alpha-1-antichymotrypsin was corroborated. We noted a post-LVAD decrease of matricellular proteins and proteoglycans such as periostin and versican. Also, proteins of the complement system and precursors of cardiac peptide hormones were decreased post-LVAD. An increase post-LVAD was evident for individual proteins linked to the innate immune response, proteins involved in diverse metabolic pathways, and proteins involved in protein synthesis. Histological analysis did not reveal significant alterations post-LVAD of deposited collagens or immune infiltration. The proteomic data further highlighted a pronounced inter-patient heterogeneity with regards to the impact of LVAD therapy on the left ventricular myocardial proteome. Finally, the proteomic data showed differential proteolytic processing in response to LVAD therapy. CONCLUSIONS: Our findings underline a strong impact of LVAD therapy on the left ventricular myocardial proteome. Together with previous studies, protein markers of LVAD therapy such as alpha-1-antichymotrypsin are becoming apparent. Further, matricellular proteins are emerging as important components in response to LVAD therapy.