Design and Synthesis of Three Tetracyclic-Dione Derivatives and their Biological Activity on Perfusion Pressure Using an Isolated Rat Heart Model

Several tetracyclic derivatives have been prepared with different biological activity; however, there are few reports on the effects exerted by the tetracyclic derivatives on the cardiovascular system. The objective of this investigation was to prepare three tetracyclic-dione derivatives (compounds 3 to 5) to evaluate their biological activity on perfusion pressure and coronary resistance. The first stage was achieved by the synthesis of three tetracyclic‐dione analogs using some chemical strategies. The second stage involves evaluating biological activity from tetracyclic‐derivatives on perfusion pressure and coronary resistance using an isolated rat heart model. The results showed that only compound 5 increases perfusion pressure and coronary resistance compared with the control conditions. In conclusion, the biological activity of compound 5 exerted against perfusion pressure and coronary resistance depends on the functional groups involved in their chemical structure.

Long-term exercise results in morphological and biomechanical changes in coronary resistance arterioles in male and female rats

Background Biomechanical remodeling of coronary resistance arteries in physiological left ventricular hypertrophy has not yet been analyzed, and the possible sex differences are unknown. Methods Wistar rats were divided into four groups: male and female sedentary controls (MSe and FSe) and male and female animals undergoing a 12-week intensive swim training program (MEx and FEx). On the last day, the in vitro contractility, endothelium-dependent dilatation, and biomechanical properties of the intramural coronary resistance arteries were investigated by pressure microarteriography. Elastica and collagen remodeling were studied in histological sections. Results A similar outer radius and reduced inner radius resulted in an elevated wall to lumen ratio in the MEx and FEx animals compared to that in the sedentary controls. The wall elastic moduli increased in the MEx and FEx rats. Spontaneous and TxA2 agonist-induced tone was increased in the FEx animals, whereas endothelium-dependent relaxation became more effective in MEx rats. Arteries of FEx rats had stronger contraction, while arteries of MEx animals had improved dilation. Conclusions According to our results, the coronary arterioles adapted to an elevated load during long-term exercise, and this adaptation depended on sex. It is important to emphasize that in addition to differences, we also found many similarities between the sexes in the adaptive response to exercise. The observed sport adaptation in the coronary resistance arteries of rats may contribute to a better understanding of the physiological and pathological function of these arteries in active and retired athletes of different sexes.

P855Evaluation of epicardial coronary resistance using computed tomography angiography

Background A Fractional flow reserve (FFR) pullback allows assessing the distribution of pressure loss along the vessel. FFR derived from CT (FFRCT) provides a virtual pullback curve that may also aid in the assessment of epicardial coronary resistance in the non-invasive setting. Purpose The present study aims to determine the accuracy of the virtual FFRCT pullback curve using a motorized invasive FFR pullback as reference in patients with stable coronary artery disease. Methods This is a single centre, prospective study of patients with stable coronary artery disease in whom FFRCT was performed as standard of care for non-invasive assessment. Patients referred to coronary angiography with clinically indicated invasive FFR measurement were included. FFRCT and invasive FFR values were extracted from coronary vessels every 1 mm to generate pullback curves. Invasive FFR pullbacks were acquired using a dedicated device at a speed of 1 mm/s. The area under the pullback curve (AUPC), defined as the sum of areas under the FFR pullback curve, was compared between FFRCT and invasive FFR pullbacks. Lesions were defined based on invasive angiography. FFR gradients in lesions and non-obstructive segments were defined as the difference between FFR values at the proximal and distal edge of the segments. FFR vessel gradient was defined as the difference between the most distal FFR value and the FFR at the ostium of the vessel. Mixed effect model was used to account for the correlation of FFR values within vessels. The agreement between FFRCT and FFR gradients was assessed using the Passing Bablok regression analysis and Bland-Altman methods at the vessel, lesion and non-obstructive level. Results A total of 3172 matched FFRCT and FFR values were obtained in 24 vessels. The correlation coefficient between FFRCT and FFR was 0.76 (95% CI 0.75 to 0.78; p<0.001). The mean difference between the FFRCT and invasive FFR pullback values was 0.07 (LOA −0.11 to 0.24). AUPC was similar between FFRCT and invasive FFR (79.0±16.1 vs. 85.3±16.4, p=0.097); the mean slope of FFRCT pullback curve was steeper compared to invasive FFR (p<0.001). The mean difference in lesion gradient was −0.07 (LOA −0.26 to 0.13) and −0.01 (LOA −0.06 to 0.05) in non-obstructive segments. There were no systematic or proportional differences between FFRCT and FFR gradients either in lesion or non-obstructive segments); however, vessel gradients were overestimated by FFRCT with a bias of −0.12 (LOA −0.35 to 0.12) driven by a higher mean difference in lesion gradients (−0.07; 95% CI −0.26 to 0.13). Conclusions The evaluation of epicardial coronary resistance using coronary CT angiography with FFRCT was feasible. FFRCT pullbacks were accurate in the assessment of lesion and non-obstructive gradients. FFRCT can identify the physiological pattern of coronary artery disease in the non-invasive setting.

Insulin resistance in an animal model of polycystic ovary disease is aggravated by vitamin D deficiency: Vascular consequences

Hyperandrogenic state in females is accompanied with metabolic syndrome, insulin resistance and vascular pathologies. A total of 67%–85% of hyperandrogenic women suffer also from vitamin D deficiency. We aimed to check a potential interplay between hyperandrogenism and vitamin D deficiency in producing insulin resistance and effects on coronary resistance arteries. Adolescent female rats were divided into four groups, 11–12 animals in each. Transdermal testosterone-treated and vehicle-treated animals were kept either on vitamin D-deficient or on vitamin D-supplemented diet for 8 weeks. Plasma sexual steroid, insulin, leptin and vitamin D plasma levels were measured, and oral glucose tolerance test was performed. In coronary arterioles, insulin receptor and vitamin D receptor expressions were tested by immunohistochemistry, and insulin-induced relaxation was measured in vitro on isolated coronary resistance artery segments. Testosterone impaired glucose tolerance, and it diminished insulin relaxation but did not affect the expression of insulin and vitamin D receptors in vascular tissue. Vitamin D deficiency elevated postprandial insulin levels and homeostatic model assessment insulin resistance. It also diminished insulin-induced coronary arteriole relaxation, while it raised the expression of vitamin D and insulin receptors in the endothelial and medial layers. Our conclusion is that both hyperandrogenism and vitamin D deficiency reduce sensitivity of coronary vascular tissue to insulin, but they do it with different mechanisms.