AimsAngiotensin-converting enzyme (ACE), which metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling, is expressed as a type-1 membrane glycoprotein on the surface of different cells, including endothelial cells of the heart. We hypothesized that the local conformation and, therefore, the properties of heart ACE could differ from lung ACE due to different microenvironment in these organs.Methods and resultsWe performed ACE phenotyping (ACE levels, conformation and kinetic characteristics) in the human heart and compared it with that in the lung. ACE activity in heart tissues was 10–15 lower than that in lung. Various ACE effectors, LMW endogenous ACE inhibitors and HMW ACE-binding partners, were shown to be present in both heart and lung tissues. “Conformational fingerprint” of heart ACE (i.e., the pattern of 17 mAbs binding to different epitopes on the ACE surface) significantly differed from that of lung ACE, which reflects differences in the local conformations of these ACEs, likely controlled by different ACE glycosylation in these organs. Substrate specificity and pH-optima of the heart and lung ACEs also differed. Moreover, even within heart the apparent ACE activities, the local ACE conformations, and the content of ACE inhibitors differ in atria and ventricles.ConclusionsSignificant differences in the local conformations and kinetic properties of heart and lung ACEs demonstrate tissue specificity of ACE and provide a structural base for the development of mAbs able to distinguish heart and lung ACEs as a potential blood test for predicting atrial fibrillation risk.

Postoperative cognitive dysfunction (POCD) is a mild form of perioperative ischemic brain injury, which emerges as memory decline, decreased attention, and decreased concentration during several months, or even years, after surgery. Here we present results of our three neuropsychological studies, which overall included 145 patients after on-pump operations. We found that the auditory memory span test (digit span) was more effective as a tool for registration of POCD, in comparison with the word-list learning and story-learning tests. Nonverbal memory or visuoconstruction tests were sensitive to POCD in patients after intraoperative opening of cardiac chambers with increased cerebral air embolism. Psychomotor speed tests (digit symbol, or TMT A) registered POCD, which was characteristic for elderly atherosclerotic patients. Finally, we observed that there were significant effects of the order of position of a test on the performance on this test. For example, the postoperative performance on the core tests (digit span and digit symbol) showed minimal impairment when either of these tests was administered at the beginning of testing. Overall, our data shows that the selection of tests, and the order of which these tests are administered, may considerably influence the results of studies of POCD.

BackgroundThe pattern of binding of monoclonal antibodies (mAbs) to 18 epitopes on human angiotensin I-converting enzyme (ACE)–“conformational fingerprint of ACE”–is a sensitive marker of subtle conformational changes of ACE due to mutations, different glycosylation in various cells, the presence of ACE inhibitors and specific effectors, etc.Methodology/Principal findingsWe described in detail the methodology of the conformational fingerprinting of human blood and tissue ACEs that allows detecting differences in surface topography of ACE from different tissues, as well detecting inter-individual differences. Besides, we compared the sensitivity of the detection of ACE inhibitors in the patient’s plasma using conformational fingerprinting of ACE (with only 2 mAbs to ACE, 1G12 and 9B9) and already accepted kinetic assay and demonstrated that the mAbs-based assay is an order of magnitude more sensitive. This approach is also very effective in detection of known (like bilirubin and lysozyme) and still unknown ACE effectors/inhibitors which nature and set could vary in different tissues or different patients.Conclusions/SignificancePhenotyping of ACE (and conformational fingerprinting of ACE as a part of this novel approach for characterization of ACE) in individuals really became informative and clinically relevant. Appreciation (and counting on) of inter-individual differences in ACE conformation and accompanying effectors make the application of this approach for future personalized medicine with ACE inhibitors more accurate. This (or similar) methodology can be applied to any enzyme/protein for which there is a number of mAbs to its different epitopes.

О коло 50 % всех случаев смерти от сердечно-сосудистых заболеваний происходят внезапно [1]. На долю ишемической болезни сердца (ИБС) и острого коронарного синдрома приходится около 80 % всех внезапных сердечных смертей (ВСС) [2]. Согласно результатам Российского многоцентрового эпидемиологического исследования заболеваемости, смертности, качества диагностики и лечения острых форм ИБС (РЕЗОНАНС), частота ВСС у пациентов с ИБС составила 72 на 100 000 женского населения и 156 на 100 000 мужского населения [3]. Для сравнения число зарегистрированных случаев ВСС от любых причин в США составляет 50-100 на 100 000 населения [4]. Непосредственной причиной ВСС принято считать желудочковые тахиаритмии-фибрилляцию желудочков (ФЖ) или устойчивую желудочковую тахикардию (ЖТ),

The article covers the development of the problem of sudden cardiac death prevention with the implantable cardioverter­defibrillators from the moment of creation of these devices to our days. The current concept of primary prevention of sudden cardiac death, based on the severity of manifestation of heart failure and left ventricular dysfunction, is not effective enough. Its practical application is difficult because it requires mass application of implantable defibrillators, with low predictive accuracy of these criteria in terms of development of life­threatening arrhythmias. The development of methods for visualizing the myocardium, allowing to assess the severity of myocardial fibrosis, as well as the possibilities of medical genetics, at the present stage, allows us to clarify indications for implantation of cardioverter­defibrillators and thereby significantly improve the concept of preventing sudden cardiac death with these instruments.