Nesbitt, Lisa

Background Soluble urokinase plasminogen activator receptor (su PAR ) is a proinflammatory biomarker associated with immune activation and fibrinolysis inhibition. Plasminogen activator inhibitor ( PAI ‐1) is associated with excessive fibrin accumulation, thrombus formation, and atherosclerosis. The relationship between cross‐coronary su PAR and PAI ‐1 production and endothelial dysfunction remains unknown. Methods and Results Seventy‐nine patients (age 53±10 years, 75% women) with angina and normal coronary arteries or mild coronary artery disease (<40% stenosis) on angiogram underwent acetylcholine assessment of epicardial endothelial dysfunction (mid–left anterior descending coronary artery diameter decrease >20% after acetylcholine) and mircovascular endothelial dysfunction (coronary blood flow change <50% after acetylcholine). Simultaneous left main and coronary sinus su PAR and PAI ‐1 levels were measured in each patient before acetylcholine administration, and cross‐coronary su PAR and PAI ‐1 production rates were calculated. Patients’ characteristics, except for age (51±10 versus 57±9, P =0.02), and resting coronary hemodynamics were not significantly different between patients with (26%) versus without (74%) epicardial endothelial dysfunction. Patients’ characteristics and resting coronary hemodynamics were not significantly different between those with (62%) and those without (38%) mircovascular endothelial dysfunction. Patients with mircovascular endothelial dysfunction demonstrated local coronary su PAR production versus su PAR extraction in patients with normal microvascular function (median 25.8 [interquartile range 121.6, −23.7] versus −12.7 [52.0, −74.8] ng/min, P =0.03). Patients with epicardial endothelial dysfunction had higher median coronary PAI ‐1 production rates compared with those with normal epicardial endothelial function (1224.7 [12 940.7, −1915.4] versus −187.4 [4444.7, −4535.8] ng/min, P =0.03). Conclusions su PAR is released in coronary circulation of patients with mircovascular endothelial dysfunction and extracted in those with normal microvascular function. Cross‐coronary PAI ‐1 release is higher in humans with epicardial endothelial dysfunction.

Abstract Aims The proteasome prevents the intracellular accumulation of proteins and its impairment can lead to structural and functional alterations, as noted for the coronary vasculature in a previous study. Utilizing the same model, this study was designed to test the hypothesis that chronic proteasome inhibition (PSI) also leads to structural and functional changes of the heart. Methods and results Female domestic pigs were randomized to a normal diet without (N) or with twice-weekly subcutaneous injections of the proteasome inhibitor MLN-273 (0.08 mg/kg, N + PSI, n = 5 each group). In vivo data on cardiac structure and function as well as myocardial perfusion and microvascular permeability response to adenosine and dobutamine were obtained by electron beam computed tomography after 11 weeks. Subsequent ex vivo myocardial analyses included immunoblotting, immunostaining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labelling), Masson trichrome, and Congo red staining. Compared with N, an increase in LV mass was observed in N + PSI (106.5 ± 16.4 g vs. 183.1 ± 24.2 g, P &lt; 0.05). The early to late diastolic filling ratio was increased in N + PSI vs. N (3.5 ± 0.6 vs. 1.8 ± 0.1, P &lt; 0.05). The EF tended to be lower (46 ± 12% and 53 ± 9%, respectively) and cardiac output was significantly lower in N + PSI than in N (2.9 ± 1.1 vs. 4.7 ± 1.1 L/min, P &lt; 0.05). Tissue analyses demonstrated an accumulation of proteasome substrates, apoptosis, and fibrosis in the PSI group. Compared with N, the myocardial perfusion response was reduced and microvascular permeability was increased in N + PSI. Conclusion The current study demonstrates that chronic proeasome inhibition affects the cardiovascular system, leading to functional and structural alteration of the heart consistent with a hypertrophic–restrictive cardiomyopathy phenotype.