Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice

Fabry disease is an X-linked metabolic disorder caused by a deficiency of α-galactosidase A (α-Gal A). The enzyme defect leads to the systemic accumulation of glycosphingolipids with α-galactosyl moieties consisting predominantly of globotriaosylceramide (Gb3). In patients with this disorder, glycolipid deposition in endothelial cells leads to renal failure and cardiac and cerebrovascular disease. Recently, we generated α-Gal A gene knockout mouse lines and described the phenotype of 10-week-old mice. In the present study, we characterize the progression of the disease with aging and explore the effects of bone marrow transplantation (BMT) on the phenotype. Histopathological analysis of α-Gal A −/0 mice revealed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Gb3 accumulation and pathological lesions in the affected organs increased with age. Treatment with BMT from the wild-type mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of α-Gal A activity. These findings suggest that BMT may have a potential role in the management of patients with Fabry disease.

Myocardial signaling defects and impaired cardiac function of a human beta 2-adrenergic receptor polymorphism expressed in transgenic mice.

A threonine to isoleucine polymorphism at amino acid 164 in the fourth transmembrane spanning domain of the beta 2-adrenergic receptor (beta 2AR) is known to occur in the human population. The functional consequences of this polymorphism to catecholamine signaling in relevant cells or to end-organ responsiveness, however, are not known. To explore potential differences between the two receptors, site-directed mutagenesis was carried out to mimic the polymorphism. Transgenic FVB/N mice were then created overexpressing wild-type (wt) beta 2AR or the mutant Ile-164 receptor in a targeted manner in the heart using a murine alpha myosin heavy chain promoter. The functional properties of the two receptors were then assessed at the level of in vitro cardiac myocyte signaling and in vivo cardiac responses in intact animals. The expression levels of these receptors in the two lines chosen for study were approximately 1200 fmol/mg protein in cardiac membranes, which represents a approximately 45-fold increase in expression over endogenous beta AR. Myocyte membrane adenylyl cyclase activity in the basal state was significantly lower in the Ile-164 mice (19.5 +/- 2.7 pmol/min/mg) compared with wt beta 2AR mice (35.0 +/- 4.1 pmol/min/mg), as was the maximal isoproterenol-stimulated activity (49.8 +/- 7.8 versus 77.1 +/ 7.3 pmol/min/mg). In intact animals, resting heart rate (441 +/- 21 versus 534 +/- 17 bpm) and dP/dtmax (10,923 +/- 730 versus 15,308 +/- 471 mmHg/sec) were less in the Ile-164 mice as compared with wt beta 2AR mice. Similarly, the physiologic responses to infused isoproterenol were notably less in the mutant expressing mice. Indeed, these values, as well as other contractile parameters, were indistinguishable between Ile-164 mice and nontransgenic littermates. Taken together, these results demonstrate that the Ile-164 polymorphism is substantially dysfunctional in a relevant target tissue, as indicated by depressed receptor coupling to adenylyl cyclase in myocardial membranes and impaired receptor mediated cardiac function in vivo. Under normal homeostatic conditions or in circumstances where sympathetic responses are compromised due to diseased states, such as heart failure, this impairment may have important pathophysiologic consequences.

Electro-mechanical coupling in the aging heart: role of the Late Na+ current

The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. However, the difficulty in defining myocardial aging and the mechanisms involved complicates the recognition of the cellular processes underlying impaired diastolic relaxation. We raised the possibility that, in a mouse model of physiological aging, defects in the electromechanical properties of cardiomyocytes are important determinants of the diastolic properties of the myocardium, independently from changes in the structural composition of the muscle and collagen framework. Here we show that an increase in the late Na+ current (INaL) in aging cardiomyocytes prolongs the action potential (AP) and influences the temporal kinetics of Ca2+ cycling and cell shortening. These alterations increase force development and passive tension. Inhibition of INaL shortens the AP and corrects the dynamics of Ca2+ transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. INaL offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the etiology of the defective cardiac performance in the elderly.

Contributors to and impact of residual shunting after device closure of atrial septal defects.

BACKGROUND: The prevalence of residual shunt in patients after device closure of atrial septal defect and its impact on long-term outcome has not been previously defined. METHODS: From a prospective, single-institution registry of 408 patients, we selected individuals with agitated saline studies performed 1 year after closure. Baseline echocardiographic, invasive hemodynamic, and comorbidity data were compared to identify contributors to residual shunt. Survival was determined by review of the medical records and the Social Security Death Index. Survival analysis according to shunt included construction of Kaplan-Meier curves and Cox proportional hazards modeling. RESULTS: Among 213 analyzed patients, 27% were men and age at repair was 47 ± 17 years. Thirty patients (14%) had residual shunt at 1 year. Residual shunt was more common with Helex (22%) and CardioSEAL/STARFlex (40%) occluder devices than Amplatzer devices (9%; P = .005). Residual shunts were more common in whites (79% vs 46%, P = .004). At 7.3 ± 3.3 years of follow-up, 13 (6%) of patients had died, including 8 (5%) with Amplatzer, 5 (25%) with CardioSEAL/STARFlex, and 0 with Helex devices. Patients with residual shunting had a higher hazard of death (20% vs 4%, P = .001; hazard ratio 4.95 [1.59-14.90]). In an exploratory multivariable analysis, residual shunting, age, hypertension, coronary artery disease, and diastolic dysfunction were associated with death. CONCLUSIONS: Residual shunt after atrial septal defect device closure is common and adversely impacts long-term survival.

A systematic review of trends and patterns of congenital heart disease in children in Nigeria from 1964-2015.

Background: Congenital heart diseases cause significant childhood morbidity and mortality. Several restricted studies have been conducted on the epidemiology in Nigeria. No truly nationwide data on patterns of congenital heart disease exists. Objectives: To determine the patterns of congenital heart disease in children in Nigeria and examine trends in the occurrence of individual defects across 5 decades. Method: We searched PubMed database, Google scholar, TRIP database, World Health Organisation libraries and reference lists of selected articles for studies on patterns of congenital heart disease among children in Nigeria between 1964 and 2015. Two researchers reviewed the papers independently and extracted the data. Seventeen studies were selected that included 2,953 children with congenital heart disease. Results: The commonest congenital heart diseases in Nigeria are ventricular septal defect (40.6%), patent ductus arteriosus (18.4%), atrial septal defect (11.3%) and tetralogy of Fallot (11.8%). There has been a 6% increase in the burden of VSD in every decade for the 5 decades studied and a decline in the occurrence of pulmonary stenosis. Studies conducted in Northern Nigeria demonstrated higher proportions of atrial septal defects than patent ductus arteriosus. Conclusions: Ventricular septal defects are the commonest congenital heart diseases in Nigeria with a rising burden.

Transcatheter Closure of Atrial Septal Defects in a Center With Limited Resources: Outcomes and Short Term Follow-Up

Background: Transcatheter closure of atrial septal defects (ASD) has been accepted world-wide as an alternative to surgical closure with excellent results. This interventional, non-surgical technique plays an important role in the treatment of ASD mostly in the developing world where resources are limited. Objectives: To report the outcomes and short term follow-up of transcatheter closure of ASD over a 12-year period at our institution with limited resources. Patients and Methods: This retrospective study included all patients with the diagnosis of secundum ASD and significant shunting (Qp/Qs > 1.5:1) as well as dilated right atrium and right ventricle who had transcatheter closure at Integrated Cardiovascular Center (PJT), Dr. Cipto Mangunkusumo Hospital between October 2002 and October 2014. One hundred fifty-two patients enrolled in this study were candidates for device closure. Right and left heart cardiac catheterization was performed before the procedure. All patients underwent physical examination, ECG, chest X-ray and transthoracal echocardiography (TTE) prior to device implantation. Results: A total of 152 patients with significant ASD underwent device implantation. Subjects’ age ranged from 0.63 to 69.6 years, with median 9.36 years and mean 16.30 years. They consisted of 33 (21.7%) males and 119 (78.3%) females, with mean body weight of 29.9 kg (range 8 to 75; SD 18.2). The device was successfully implanted in 150 patients where the majority of cases received the Amplatzer septal occluder (147/150; 98%) and the others received the Heart Lifetech ASD occluder (3/150, 2%), whereas two other cases were not suitable for device closure and we decided for surgical closure. The mean ASD size was 19.75 (range 14 - 25) mm. During the procedure, 5 (4.9%) patients had bradycardia and 3 (2.9%) patients had supraventricular tachycardia (SVT), all of which resolved. Conclusions: In our center with limited facilities and manpower, transcatheter closure of atrial septal defect was effective and safe as an alternative treatment to surgery. The outcome and short-term follow-up revealed excellent results, but long-term follow-up is needed.