Translation of experimental cardioprotective capability of P2Y12 inhibitors into clinical outcome in patients with ST-elevation myocardial infarction.

We studied the translational cardioprotective potential of P2Y12 inhibitors against acute myocardial ischemia/reperfusion injury (IRI) in an animal model of acute myocardial infarction and in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). P2Y12 inhibitors may have pleiotropic effects to induce cardioprotection against acute myocardial IRI beyond their inhibitory effects on platelet aggregation. We compared the cardioprotective effects of clopidogrel, prasugrel, and ticagrelor on infarct size in an in vivo rat model of acute myocardial IRI, and investigated the effects of the P2Y12 inhibitors on enzymatic infarct size (48-h area-under-the-curve (AUC) troponin T release) and clinical outcomes in a retrospective study of STEMI patients from the CONDI-2/ERIC-PPCI trial using propensity score analyses. Loading with ticagrelor in rats reduced infarct size after acute myocardial IRI compared to controls (37 ± 11% vs 52 ± 8%, p < 0.01), whereas clopidogrel and prasugrel did not (50 ± 11%, p > 0.99 and 49 ± 9%, p > 0.99, respectively). Correspondingly, troponin release was reduced in STEMI patients treated with ticagrelor compared to clopidogrel (adjusted 48-h AUC ratio: 0.67, 95% CI 0.47-0.94). Compared to clopidogrel, the composite endpoint of cardiac death or hospitalization for heart failure within 12 months was reduced in STEMI patients loaded with ticagrelor (HR 0.63; 95% CI 0.42-0.94) but not prasugrel (HR 0.84, 95% CI 0.43-1.63), prior to PPCI. Major adverse cardiovascular events did not differ between clopidogrel, ticagrelor, or prasugrel. The cardioprotective effects of ticagrelor in reducing infarct size may contribute to the clinical benefit observed in STEMI patients undergoing PPCI.

Multielectrode Unipolar Voltage Mapping and Electrogram Morphology to Identify Post-Infarct Scar Geometry: Validation by Histology.

OBJECTIVES: This study sought to evaluate the ability of uni- and bipolar electrograms collected with a multielectrode catheter with smaller electrodes to: 1) delineate scar; and 2) determine local scar complexity. BACKGROUND: Early reperfusion results in variable endocardial scar, often overlaid with surviving viable myocardium. Although bipolar voltage (BV) mapping is considered the pillar of substrate-based ablation, the role of unipolar voltage (UV) mapping has not been sufficiently explored. It has been suggested that bipolar electrograms collected with small electrode catheters can better identify complex scar geometries. METHODS: Twelve swine with early reperfusion infarctions were mapped with the 48-electrode OctaRay catheter and a conventional catheter during sinus rhythm. BV electrograms with double components were identified. Transmural (n = 933) biopsy specimens corresponding to mapping points were obtained, histologically assessed, and classified by scar geometry. RESULTS: OctaRay UV (UVOcta) and BV (BVOcta) amplitude were associated with the amount of viable myocardium at a given location, with a stronger association for UVOcta (R2 = 0.767 vs 0.473). Cutoff values of 3.7 mV and 1.0 mV could delineate scar (area under the curve: 0.803 and 0.728 for UVOcta and BVOcta, respectively). The morphology of bipolar electrograms collected with the OctaRay catheter more frequently identified areas with 2 layers of surviving myocardium than electrograms collected with the conventional catheter (84% vs 71%). CONCLUSIONS: UV mapping can generate a map to delineate the area of interest when using a multielectrode catheter. Within this area of interest, the morphology of bipolar electrograms can identify areas in which a surviving epicardial layer may overlay a poorly coupled, potentially arrhythmogenic, endocardium.

Cardioprotective effect of combination therapy by mild hypothermia and local or remote ischemic preconditioning in isolated rat hearts.

A multitargeted strategy to treat the consequences of ischemia and reperfusion (IR) injury in acute myocardial infarction may add cardioprotection beyond reperfusion therapy alone. We investigated the cardioprotective effect of mild hypothermia combined with local ischemic preconditioning (IPC) or remote ischemic conditioning (RIC) on IR injury in isolated rat hearts. Moreover, we aimed to define the optimum timing of initiating hypothermia and evaluate underlying cardioprotective mechanisms. Compared to infarct size in normothermic controls (56 ± 4%), mild hypothermia during the entire or final 20 min of the ischemic period reduced infarct size (34 ± 2%, p < 0.01; 35 ± 5%, p < 0.01, respectively), while no reduction was seen when hypothermia was initiated at reperfusion (51 ± 4%, p = 0.90). In all groups with effect of mild hypothermia, IPC further reduced infarct size. In contrast, we found no additive effect on infarct size between hypothermic controls (20 ± 3%) and the combination of mild hypothermia and RIC (33 ± 4%, p = 0.09). Differences in temporal lactate dehydrogenase release patterns suggested an anti-ischemic effect by mild hypothermia, while IPC and RIC preferentially targeted reperfusion injury. In conclusion, additive underlying mechanisms seem to provide an additive effect of mild hypothermia and IPC, whereas the more clinically applicable RIC does not add cardioprotection beyond mild hypothermia.

Remote ischemic conditioning in active ulcerative colitis: An explorative randomized clinical trial.

Remote ischemic conditioning (RIC) by repetitive brief periods of limb ischemia and reperfusion renders organs more resistant to ischemic injury. The protection is partly through down-regulation of the inflammatory response. Our aim was to investigate the clinical and anti-inflammatory effects of RIC in patients with active ulcerative colitis (UC). We included 22 patients with active UC in this explorative, randomized, sham-controlled clinical trial. The patients were randomly assigned 1:1 to RIC (induced in the arm through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff) or sham (incomplete inflation of the blood-pressure cuff) once daily for 10 days. Outcome variables were measured at baseline and on day 11. When compared with sham, RIC did not affect inflammation in the UC patients measured by fecal calprotectin, plasma C-reactive protein, Mayo Score, Mayo Endoscopic Subscore, Nancy Histological Index or inflammatory cytokines involved in UC and RIC. The mRNA and miRNA expression profiles in the UC patients were measured by RNA sequencing and multiplexed hybridization, respectively, but were not significantly affected by RIC. We used the Langendorff heart model to assess activation of the organ protective mechanism induced by RIC, but could not confirm activation of the organ protective mechanism in the UC patients.