Aims Diabetic cardiomyopathy is a multifactorial disease characterized by an early onset of diastolic dysfunction (DD) that precedes the development of systolic impairment. Mechanisms that can restore cardiac relaxation improving intracellular Ca2+ dynamics represent a promising therapeutic approach for cardiovascular diseases associated to DD. Istaroxime has the dual properties to accelerate Ca2+ uptake into sarcoplasmic reticulum (SR) through the SR Ca2+ pump (SERCA2a) stimulation and to inhibit Na+/K+ ATPase (NKA). This project aims to characterize istaroxime effects at a concentration (100 nmol/L) marginally affecting NKA, in order to highlight its effects dependent on the stimulation of SERCA2a in an animal model of mild diabetes. Methods and Results Streptozotocin (STZ) treated diabetic rats were studied at 9 weeks after STZ injection in comparison to controls (CTR). Istaroxime effects were evaluated in vivo and in left ventricular (LV) preparations. STZ animals showed 1) marked DD not associated to cardiac fibrosis, 2) LV mass reduction associated to reduced LV cell dimension and T-tubules loss, 3) reduced LV SERCA2 protein level and activity and 4) slower SR Ca2+ uptake rate, 5) LV action potential (AP) prolongation and increased short-term variability (STV) of AP duration, 6) increased diastolic Ca2+, and 7) unaltered SR Ca2+ content and stability in intact cells. Acute istaroxime infusion (0.11 mg/kg/min for 15 min) reduced DD in STZ rats. Accordingly, in STZ myocytes istaroxime (100 nmol/L) stimulated SERCA2a activity and blunted STZ-induced abnormalities in LV Ca2+ dynamics. In CTR myocytes, istaroxime increased diastolic Ca2+ level due to NKA blockade albeit minimal, while its effects on SERCA2a were almost absent. Conclusions SERCA2a stimulation by istaroxime improved STZ-induced DD and intracellular Ca2+ handling anomalies. Thus, SERCA2a stimulation can be considered a promising therapeutic approach for DD treatment. Translational perspective Deficient sarcoplasmic reticulum (SR) Ca2+ uptake has been identified in cardiomyocytes from failing human hearts with impaired diastolic relaxation (e.g. diabetic hearts) and has been associated with a decreased SERCA2a expression and activity and/or with a higher SERCA2a inhibition by phospholamban. Thus, SERCA2a may represent a pharmacological target for interventions aimed at improving cytosolic Ca2+ compartmentalization into the SR to limit diastolic dysfunction pathologies. In this context, istaroxime is the first-in-class luso-inotropic agent targeting SERCA2a that has already demonstrated its efficacy in clinical trials and may be useful to clarify the relevance of SERCA2a stimulation in controlling cytosolic Ca2+ level.

Objectives: To evaluate and illustrate complications of cardiac catheterisation and the associated risk factors of the most common cardiac intervention procedures. Materials and MethOds: Retrospective study of clinical records of client-owned dogs presented to a cardiology referral centre between January 2006 and December 2017. results: Five hundred and twenty-four dogs were included, 62 of which had complications. Complications were divided into technical complications and those due to unexpected additional anatomical abnormalities. Seven procedures (1.33%) were interrupted; five dogs (0.95%) subsequently underwent surgery, and four dogs died during the interventional procedure, indicating a mortality rate of 0.76% clinical significance: There is a low risk of complications following closure of patent ductus arteriosus or pulmonary balloon valvuloplasty when carried out by a trained team using standardised procedures in a referral centre. 613 FIG 4. Longitudinal cross-section of a patent ductus arteriosus (PDA) with unusual morphology studied with three-dimensional transoesophageal echocardiography (on the left); angiography that highlights the PDA in the same patient (on the right)

One hundred and twenty dogs were enrolled to value the effect of loading condition changes on left ventricular volumes before and 24-hours after the patent ductus arteriosus (PDA) occlusion by Amplatzer Canine Duct Occluder (ACDO) using standard echocardiography. The animals were divided in pure breed (n. 94) and mixed breed (n. 26); subsequently, the pure breed dogs were divided on the basis of the size of the breed of belonging in 3 groups (small size n. 36; medium size n. 8; large size n. 50). Moreover, the animals were divided in three classes based on their age: until 6 months; 6–12 months; over 12 months. A significant reduction of all the examined parameters (left ventricle internal diameter at end-diastole—LVIDd; left ventricle internal diameter at end-systole—LVIDs; end-diastolic volume—EDV; end-systolic volume—ESV; end-diastolic volume index—EDVI; end-systolic volume index—ESVI; fractional shortening—FS) was observed after ductal closure. Twenty-four hours after the closure, the evaluation of the relative percentage difference (RPD) of the echocardiographic parameters showed a significant reduction, higher in small size breed than in large size breed dogs. No significant difference related to breed size was observed only for RPD_FS variable. A significant interaction effect, between breed size and age classes, was observed only for RPD_EDVI (F = 3.39; p = 0.039). Until six months of age there was no significant difference in RPD_EDVI reduction, but over 6 months a significant reduction between small size and large size breed dogs at 24-hours from the occlusion was observed. In conclusion, our data seem to indicate that small breed dogs show a greater tolerance to congenital volume overload than large breed dogs, and this finding could be justify a delay of PDA closure in order to simplify the interventional procedure.

No abstract

No abstract