ASSESSMENT OF SEGMENTAL MYOCARDIAL STRAIN OF THE LEFT VENTRICULAR MYOCARDIUM IN CHILDREN WITH HYPERTROPHIC CARDIOMYOPATHY

Assessment of segmental myocardial strain is a promising and relevant direction in the diagnosis of early impairments of left ventricular (LV) contractility in children with hypertrophic cardiomyopathy (HCM). Objective of the study: to assess the indicators of segmental myocardial strain in children with HCM. Materials and methods of research: prospective, open-label, nonrandomized, controlled. 61 patients with asymmetric HCM aged 7 to 17 years (median 9 [7,6; 13,2]) underwent echocardiography according to the standard technique with the determination of segmental longitudinal, radial, circular LV myocardium in 2D speckle tracking mode. 45 (74%) children had a non-obstructive form (NF) of HCM, 16 (26%) children had an obstructive form (OF). Obstruction was detected at the level of the LV outflow tract with a pressure gradient of 30-50 mm Hg. Results: when assessing segmental myocardial strain, a decrease in longitudinal strain was found less than the normative values in the antero-septal, anterior, antero-lateral segments in children with NF HCM with a compensatory increase in strain values in the contralateral segments (inferior septal, inferior lateral and lower ). In similar segments in children with OF, there was a significant decrease in deformity, while in the contralateral segments a less pronounced compensatory increase in deformity was determined, as well as a decrease in the minimum values of strain indicators. Assessment of segmental radial and circular strain, a statistically significant predominance of indicators in all segments, except for anterolateral, in the group with NF compared to the OF HCM was determined. A decrease in strain in the antero-septal, anterior, antero-lateral segments was found, but less pronounced compared to the indicators of longitudinal strain, as well as a compensatory increase in strain in the antero-septal values in the contralateral segments (inferior septal, inferior lateral and inferior). It has been found that the assessment of global strain values widely used in clinical practice might not be optimal enough, since too many segmental strain values are discarded and averaged, which are unevenly distributed, and therefore the assessment of strain in each segment of the myocardium in children with an asymmetric form of HCM acquires important diagnostic value. Conclusion: changes in the indicators of segmental myocardial strain reflect violations of LV contractile function and are most pronounced in OF compared with NF HCM. Their study in children is important for the timely initiation of therapy and improving the prognosis of the disease.

МАРКЕРИ ОБМІНУ СПОЛУЧНОЇ ТКАНИНИ У ХВОРИХ З ДІАБЕТИЧНИМИ АРТРОПАТІЯМИ

The aim of study was to investigate markers of connective tissue metabolism (COMP level) and indicators that reflect the synthetic and catabolic phases of the metabolism of the main components of connective tissue - collagen and glycosaminoglycans in patients with diabetic arthropathy.The study involved 87 patients with diabetes. Patients were examined using a visual analogue scale of the Leken index and WOMAK. Cartilage oligomeric matrix Protein (COMP) was determined using enzyme immunoassay.Results. The presence of diabetic arthropathy was detected in 78% of patients with type 1 diabetes and in 80% of patients with type 2 diabetes. In the vast majority of patients, the joints of the upper extremities were involved in the pathological process. A direct correlation was established between the presence of arthropathy and the COMP level (r = 0.76, p = 0.001), the Leken index (r = 0.76, p = 0.001), YOUR scale (r = 0.88 , p = 0.001) and WOMAK (R = 0.88, p = 0.001). Patients with type 1 diabetes with joint damage are characterized by a compensatory increase in the synthesis of subchondral bone in response to increased collagen breakdown. For patients with type 1 diabetes with joint damage is characterized by a compensatory increase in subchondral bone synthesis in response to increased collagen breakdown.Conclusions: The results suggest that arthropathy in patients with type 1 and type 2 diabetes is characterized by an increase in the cartilage degradation marker in direct proportion to the severity and number of affected joints.

Transmural variation in microvascular remodeling following percutaneous revascularization of a chronic coronary stenosis in swine

Remodeling of the coronary microcirculation is known to occur distal to a chronic coronary stenosis, but the reversibility of these changes and their functional significance on maximum myocardial perfusion before and after revascularization is unknown. Accordingly, swine instrumented with a chronic silastic stenosis on the left anterior descending coronary artery to produce hibernating myocardium underwent percutaneous coronary intervention (PCI; n = 8) and were compared with animals with a persistent stenosis ( n = 8), as well as sham controls ( n = 6). Stenotic animals demonstrated an increased subendocardial arteriolar wall thickness-to-lumen ratio (37.8 ± 3.3 vs. 28.3 ± 1.3% in sham, P = 0.04), reduced lumen area per arteriole (597 ± 88 vs. 927 ± 113 μm2, P = 0.04), and a compensatory increase in arteriolar density (9.4 ± 1.0 vs. 5.3 ± 0.4 arterioles/mm2, P < 0.01). As a result, vasodilated flow immediately after PCI was similar to normally perfused remote regions (5.1 ± 1.0 vs. 4.8 ± 0.9 ml·min−1·g−1, P = 0.87). When assessed 1-mo after PCI, increases in wall thickness-to-lumen diameter (42.2 ± 3.3%) and reductions in lumen area per arteriole (638 ± 59 μm2) remained unchanged, but arteriolar density returned to normal (5.2 ± 0.5 arterioles/mm2). As a result, maximum subendocardial flow during adenosine declined and was lower than remote regions (2.6 ± 0.3 vs. 5.9 ± 1.1 ml·min−1·g−1, P = 0.01). There was no microvascular remodeling in subepicardial arterioles, and maximum perfusion remained unchanged. These data demonstrate that subendocardial microvascular remodeling occurs distal to a chronic epicardial stenosis. The regression of arteriolar density without increases in luminal area may precipitate stress-induced subendocardial ischemia in the absence of a physiologically significant stenosis. NEW & NOTEWORTHY Swine with a chronic coronary stenosis exhibit subendocardial microvascular remodeling distal to a critical stenosis characterized by an increase in arteriolar wall thickness and reduction in lumen area with a compensatory increase in arteriolar density. The present study is the first to demonstrate that subendocardial arteriolar density normalizes 1-mo after revascularization, but the lumen area of individual arterioles remains reduced. This leads to a reduction in maximal subendocardial perfusion at this time point despite initial normalization of vasodilator reserve after revascularization. This pattern of chronic microvascular structural remodeling could contribute to recurrent subendocardial ischemia in the absence of coronary restenosis during tachycardia and increases in myocardial oxygen demand.

The Markedly Increased PAI1 in Obesity Induces a Compensatory Increase of Hepatocyte Tpa Expression By Activating a LRP1-CREB1 Pathway

Tissue-type plasminogen activator (tPA) initiates fibrinolysis, the primary mechanism that dissolves a thrombus. We have shown that in lean mice the hepatocytes maintain a basal level of circulating tPA that influences fibrinolysis in the occurrence of a vessel injury. As a serine protease, tPA is inhibited by the serpin plasminogen activator inhibitor 1 (PAI1). Both PAI1 and tPA which can be produced by hepatocytes, which is important for regulating energy metabolism and is sensitive to metabolic stress. In obesity, despite an increase in plasma tPA, blood tPA activity and fibrinolysis are reduced primarily due to a larger increase in PAI1. However, the source and regulatory mechanism of this phenomena are unknown. Palmitate treatment of human primary hepatocytes causes an increase in tPA mRNA/protein, reflecting the situation in the obese liver. This increase, however, is overcompensated by a larger increase in PAI1 mRNA, resulting in decreased net tPA activity in the cell culture medium. Silencing PAI1 mRNA with si-SERPINE1 in these cells increased tPA activity in the culture medium. Surprisingly, silencing PAI1 also prevented the increase of tPA mRNA induced by palmitate. Building on this observation, we further treated the cells with active recombinant PAI1 (rPAI1), which induced tPA expression. Next, we fed PAI1fl/flmice with a diet-induced obesity (DIO) diet for three months and silenced their hepatic PAI1 using AAV8-TBG-Cre, which inactivates ~95% floxed gene expression in hepatocytes but not in other cell types of the liver or other tissues. We found that while plasma tPA activity was increased in hepatocyte-PAI1 knockout mice, plasma tPA protein concentration was reduced. In other words, reducing hepatocyte PAI1 in obesity stopped the compensatory increase in liver tPA mRNA and protein. Thus, PAI1 induces tPA, which is likely a compensatory response. To explore the mechanism whereby rPAI1 induces tPA, we considered CREB1, as it is a transcription activator of tPA expression in endothelial cells and is expressed in hepatocytes. We found that CREB1 was activated (phosphorylated) by rPAI1 in human primary hepatocytes and that silencing CREB1 prevented the elevated tPA expression induced by rPAI1. Next, we silenced hepatic CREB1 in obese mice by treating DIO diet-fed CREB1fl/flmice with AAV8-TBG-Cre, which blocked the compensatory increase in tPA and thus worsened the impaired fibrinolysis in obesity. LDL receptor-related protein 1 (LRP1), the major cellular receptor of PAI1, can stimulate CREB1 transcription activity in neurons and adipocytes. As LRP1 is expressed on the surface of hepatocytes, we hypothesized that PAI1 activates CREB1 through LRP1-mediated signaling to increase tPA expression in obesity. Indeed, silencing LRP1 with si-LRP1 stopped the increase of tPA expression induced by rPAI1 in human primary hepatocytes. Interestingly, treating the cells with a mutant rPAI1 lacking the LRP1-interacting heparin-binding domain was unable to induce tPA expression. In summary, hepatocyte tPA mRNA/protein is increased in obesity, but this increase is ultimately overcompensated by a larger increase in PAI1, resulting in decreased plasma tPA activity and fibrinolysis. The markedly increased PAI1, through activating LRP1-CREB1 signaling pathway, drives an increase in hepatic tPA expression as a "compensatory" pathway in obesity. Preventing this compensatory pathway in obesity resulted in the worsening of fibrinolysis. Therapeutic boosting of this compensatory pathway may provide novel strategies to restore effective fibrinolysis in obesity. Disclosures No relevant conflicts of interest to declare.

Utjecaj semantičkih i sintaktičkih faktora na razumijevanje rečenica kod broca-afazičara

Yugoslav agrammatic aphasics and normal control subjects were tested for comprehension of agent-object relations in a series of simple Serbo-Croatian sentences consisting of two nouns and a transactive action verb. The availability of nominative and accusative case inflections and a semantic contrast was systematically varied across sentences. Sentences were also varied with respect to the two sequences NVN and VNN. An analysis of subjects’ agent-object assignments yielded the following results: While Broca’s aphasics showed some sensitivity to case inflections, their ability to process such cues was greatly impaired relative to normal subjects, for whom morphological cues were almost completely deterministic. Broca’s aphasics were impaired to a lesser degree in their ability to employ a strategy of »choose the first noun as agent« when case inflections and semantic contrasts were not available. While Broca’s aphasics showed no impairment in their ability to exploit semantic contrasts for agent-object assignment, there was no absolute compensatory increase in the degree to which they relied on semantic cues. Differences in word sequence had no effect on agent-object assignment in Broca’s aphasics. Finally, Broca’s aphasics frequently responded unsystematically when cues to agent-object relations occurred in isolation or in competition with one another, but when there was a convergence of cues, their performance approached that of normal subjects. This result was interpreted in terms of the accessing hypothesis.