miRNA-200b-A Potential Biomarker Identified in a Porcine Model of Cardiogenic Shock and Mechanical Unloading.

Background: Cardiogenic shock (CS) alters whole body metabolism and circulating biomarkers serve as prognostic markers in CS patients. Percutaneous ventricular assist devices (pVADs) unload the left ventricle by actively ejecting blood into the aorta. The goal of the present study was to identify alterations in circulating metabolites and transcripts in a large animal model that might serve as potential prognostic biomarkers in acute CS and additional left ventricular unloading by Impella ® pVAD support. Methods: CS was induced in a preclinical large animal model by injecting microspheres into the left coronary artery system in six pigs. After the induction of CS, mechanical pVAD support was implemented for 30 min total. Serum samples were collected under basal conditions, after the onset of CS, and following additional pVAD unloading. Circulating metabolites were determined by metabolomic analysis, circulating RNA entities by RNA sequencing. Results: CS and additional pVAD support alter the abundance of circulating metabolites involved in Aminoacyl-tRNA biosynthesis and amino acid metabolism. RNA sequencing revealed decreased abundance of the hypoxia sensitive miRNA-200b following the induction of CS, which was reversed following pVAD support. Conclusion: The hypoxamir miRNA-200b is a potential circulating marker that is repressed in CS and is restored following pVAD support. The early transcriptional response with increased miRNA-200b expression following only 30 min of pVAD support suggests that mechanical unloading alters whole body metabolism. Future studies are required to delineate the impact of serum miRNA-200b levels as a prognostic marker in patients with acute CS and pVAD unloading.

Proteomic Discovery and Validation of the Confounding Effect of Heparin Administration on the Analysis of Candidate Cardiovascular Biomarkers.

BACKGROUND: Several plasma proteins have been suggested as markers for a variety of cardiovascular conditions but fail to qualify in independent patient cohorts. This may relate to interference of medication on plasma protein concentrations. We used proteomics to identify plasma proteins that changed in concentration with heparin administration and therefore potentially may confound their evaluation as biomarkers in situations in which heparin is used. METHODS: We used a proteomic approach based on isobaric tagging and nano-LC-MS/MS analysis to quantify several hundred proteins in a discovery study in which individual plasma samples from 9 patients at intravascular ultrasound follow-up 12 months after an acute myocardial infarction before heparin administration and 2, 15, and 60 min after heparin administration; we validated our findings in 500 individual plasma samples obtained at admission from patients with suspected ST segment elevation myocardial infarction (STEMI), of whom 363 were treated with heparin before admission. RESULTS: In the discovery study, 25 of 653 identified plasma proteins displayed a changed concentration after heparin administration (Bonferroni-corrected P value at P < 7.66 × 10-5). Fourteen of the proteins changed significantly among heparin-treated patients in the validation study (nominal significance level of P < 6.92 × 10-5). Among heparin-affected proteins in both the discovery study and the validation study were midkine, spondin 1, secreted frizzled-like protein 1, lipoprotein lipase, and follistatin, all previously associated with STEMI. CONCLUSIONS: Medications such as heparin administration given before blood sampling may confound biomarker discovery and should be carefully considered in such studies.

Large Porcine Model of Profound Acute Ischemic Cardiogenic Shock.

Cardiogenic shock is one of the leading causes of death following acute myocardial infarction affecting 10% of patients with large myocardial infarcts with a subsequent mortality rate of 50%. Here we describe a large porcine model of acute ischemic cardiogenic shock. Acute left or right ventricular failure can be achieved with close to a 100% success rate by stepwise injection of microspheres into the left or right coronary artery, respectively, and the method allows for titration of heart failure to a prespecified level.

Support with intra-aortic balloon pump vs. Impella2.5® and blood flow to the heart, brain and kidneys - an experimental porcine model of ischaemic heart failure.

BACKGROUND: Cardiogenic shock as a complication to an acute myocardial infarction has an unacceptably high death rate that has not changed for the last 15years. Mortality is partly related to organ hypoperfusion and mechanical assist devices are used for the most severe cases but we do not know which assist device is the best option. Therefore, we have investigated how an IABP and an Impella®-pump influenced blood flow to the brain, heart and kidneys, in a closed-chest porcine model of severe left ventricular failure. METHODS: 13 pigs were anesthetised and left ventricular failure was induced by occluding the proximal LAD for 45min followed by 30min of reperfusion. Blood flow was measured in the carotid artery, the LAD, and the renal artery. The Impella® and IABP were inserted via the femoral arteries, and the two devices were tested individually and combined after induction of heart failure. RESULTS: Carotid- (p=0.01) and renal blood flow (p=0.045) were higher on Impella®-support, compared to no support. None of the devices altered the blood flow in the LAD. Cardiac power output (p<0.005) and left ventricular work (p<0.00) were also higher on Impella®-support compared to no support. CONCLUSION: Haemodynamics and blood flow to the brain and kidneys were significantly better on Impella®-support, suggesting that the Impella® is superior to the IABP in a state of ischaemia induced left ventricular failure. These data, however, needs to be confirmed in a proper clinical trial with patients in cardiogenic shock.