Cardiac disease in mucopolysaccharidosis type I attributed to catecholaminergic and hemodynamic deficiencies

Abstract

Cardiac dysfunction is a common cause of death among pediatric patients with mutations in the lysosomal hydrolase α-l-iduronidase (IDUA) gene, which causes mucopolysaccharidosis type I (MPS-I). The purpose of this study was to analyze adrenergic regulation of cardiac hemodynamic function in MPS-I. An analysis of murine heart function was performed using conductance micromanometry to assess in vivo cardiac hemodynamics. Although MPS-I (IDUA(-/-)) mice were able to maintain normal cardiac output and ejection fraction at baseline, this cohort had significantly compromised systolic and diastolic function compared with IDUA(+/-) control mice. During dobutamine infusion MPS-I mice did not significantly increase cardiac output from baseline, indicative of blunted cardiac reserve. Autonomic tone, measured functionally by β-blockade, indicated that MPS-I mice required catecholaminergic stimulation to maintain baseline hemodynamics. Survival analysis showed mortality only among MPS-I mice. Linear regression analysis revealed that heightened end-systolic volume in the resting heart is significantly correlated with susceptibility to mortality in MPS-I hearts. This study reveals that cardiac remodeling in the pathology of MPS-I involves heightened adrenergic tone at the expense of cardiac reserve with cardiac decompensation predicted on the basis of increased baseline systolic volumes.

Carotid intima-media thickness is increased in patients with mucopolysaccharidoses

“…The mechanism for persistence of vascular GAG storage despite treatment is unexpected, as removal of storage material from the intima and media should be facilitated by the close proximity to circulating treatment-derived lysosomal hydrolase. Cardiovascular disease is becoming more prevalent as treatments for MPS are increasing the longevity of affected individuals but unable to mitigate ongoing vascular storage and other abnormal hemodynamic compensatory mechanisms [24]. While the paucity of MPS long-term survivor data has not yet allowed for direct correlation between the intima-medial storage and cardiovascular events, prior experience with pediatric carotid intima-media thickness as a risk marker for other conditions indicates C-IMT may be useful as a non-invasive predictor of cardiovascular disease for MPS patients.…”

Experimental Impact of Mucopolysaccharidosis on Right Atrial Contractile Capacity of Skinned Fibers

“…This could explain the significant lower forces and calcium sensitivity in these patients and might be the histologic correlation to the echocardiographic findings of left atrial/ventricular volume overload and dilatation resulting in systolic as well as diastolic dysfunction [7]. Palpant showed in his study on MPS mice that differences in venous return is one of the fundamental deficiency of cardiac disease in MPS mice and that systolic and diastolic dysfunction might be decreased because of reduced preload [9]. He concludes that based on the Frank-Starling mechanism (increasing preload enhances contractility) reduced preload leads to reduced end diastolic volume and left ventricular pressure.…”

“…But as mentioned studies are missing and these conclusions remain assumptions. Experimental examinations concerning cardiac contractile capacity in MPS-mice revealed significant contractile deficiencies indicated by decreases in end-systolic pressures when dobutamine was infused in MPS-mice [9]. Palpant concludes that cardiac remodeling in animals with MPS leads to heightened adrenergic tone at the expense of cardiac reserve.…”

“…The fibers started at a pCa of 6.5 (lowest calcium concentration) until the final calcium concentration of 4.0 (highest concentration) was achieved. The rising calcium concentration and force development were simultaneously (GAGs) accumulate in the enlarged lysosomes and are stored in several tissues, like the myocardium or the heart valves, but of course affect multiple organ systems [9]. Cardiac involvement is described in all MPS syndromes, but is highly associated with the dermatan sulfate storing types of MPS, i.e.…”

Carotid Intima-Media thickness is increased in patients with mucopolysaccharidoses

“…The mechanism for persistence of vascular GAG storage despite treatment is unexpected, as removal of storage material from the intima and media should be facilitated by the close proximity to circulating treatment-derived lysosomal hydrolase. Cardiovascular disease is becoming more prevalent as treatments for MPS are increasing the longevity of affected individuals but unable to mitigate ongoing vascular storage and other abnormal hemodynamic compensatory mechanisms [24]. While the paucity of MPS longterm survivor data has not yet allowed for direct correlation between the intima-medial storage and cardiovascular events, prior experience with pediatric carotid intima-media thickness as a risk marker for other conditions indicates C-IMT may be useful as a noninvasive predictor of cardiovascular disease for MPS patients.…”