Active and passive contractile changes in spontaneously beating hearts of Fabry mice

ROZENFELD P,; FRITZ M,; BRADY R,; CARLOS ALBERTO FOSSATI; RINALDI G,

Estocolmo

Congreso; 6th. International Symposium on Lysosomal Storage Diseases; 2006

Introduction: Heart failure in Fabry disease is one of the major complications, leading to early death. Cardiac involvement is due to structural and functional changes of the myocardium, conduction system and the valves. We propose to use the Fabry disease murine model to study the pathophysiology of the heart in Fabry disease. The aim of this work was to study contractile behaviour of hearts from Fabry mice (F), in comparison with the wild type mice (WT). Methods: passive myocardial properties were studied in hearts excised from 8 F and 12 WT. After cardiac arrest with KCl 15% a needle with a small balloon at its tip was introduced through the left ventricular (LV) apex. Saline solution was infused at 10 µl/sec with an infusion pump, and the pressure was recorded through a side tubing with a P23Gb Gould transducer. Pressure-volume curves were generated up to a pressure of » 60 mmHg. Active contraction was recorded in the hearts of 8 F and 11 WT anesthetized with sodium pentobarbital 90 mg/kg I.P. and ventilated with a Harvard small rodent ventilator. After opening the chest a short cannula connected to a P23Gb Gould transducer was introduced through the LV apex. LV pressure (LVP), its first derivative (DP/DT) and heart rate (HR) were measured. Results: Body weight did not differ between both strains (WT: 29 ± 1 g, F: 30 ± 2 g, NS). In KCl-arrested hearts passively distended, at any given volume between 4 and 20 µl the pressure was higher in the WT ventricles, reaching significance after 8 µl (at 20 µl: WT 68 ± 6 mmHg, F 35 ± 3 mmHg, P<0.05). In spontaneously beating hearts, the F strain exhibited reductions in LVP (F: 79 ± 1 mmHg, WT: 93 ± 3 mmHg, P< 0.05) and in DP/DT(+) (F: 2832 ± 85 mmHg/sec, WT: 3179 ± 119 mmHg/sec, P<0.05), with no changes in DP/DT(-) (F: -2397 ± 119 mmHg/sec, WT: -2513 ± 122 mmHg/sec, NS) or in HR (F: 479 ± 25 bpm, WT: 485 ± 40 bpm, NS). Conclusions: the hearts of F mice were more distensible and had their contractility slightly but significantly depressed with respect to their WT controls. The progressive deposition of glycosphingolipids could result in detriment of the contractile machinery, producing functional changes compatible with our hemodynamic findings.