Elisa Di Pietro

β1-Adrenergic Receptor and Sphingosine-1-Phosphate Receptor 1 (S1PR1) Reciprocal Downregulation Influences Cardiac Hypertrophic Response and Progression to Heart Failure Protective Role of S1PR1 Cardiac Gene Therapy

Background— The sphingosine-1-phosphate receptor 1 (S1PR1) and &bgr;1-adrenergic receptor (&bgr;1AR) are G-protein–coupled receptors expressed in the heart. These 2 receptors have opposing actions on adenylyl cyclase because of differential G-protein coupling. Importantly, both of these receptors can be regulated by the actions of G-protein–coupled receptor kinase-2, which triggers desensitization and downregulation processes. Although classic signaling paradigms suggest that simultaneous activation of &bgr;1ARs and S1PR1s in a myocyte would simply result in opposing action on cAMP production, in this report we have uncovered a direct interaction between these 2 receptors, with regulatory involvement of G-protein–coupled receptor kinase-2. Methods and Results— In HEK (human embryonic kidney) 293 cells overexpressing both &bgr;1AR and S1PR1, we demonstrated that &bgr;1AR downregulation can occur after stimulation with sphingosine-1-phosphate (an S1PR1 agonist), whereas S1PR1 downregulation can be triggered by isoproterenol (a &bgr;-adrenergic receptor agonist) treatment. This cross talk between these 2 distinct G-protein–coupled receptors appears to have physiological significance, because they interact and show reciprocal regulation in mouse hearts undergoing chronic &bgr;-adrenergic receptor stimulation and in a rat model of postischemic heart failure. Conclusions— We demonstrate that restoration of cardiac plasma membrane levels of S1PR1 produces beneficial effects that counterbalance the deleterious &bgr;1AR overstimulation in heart failure.

Induction of Mitogen-Activated Protein Kinases Is Proportional to the Amount of Pressure Overload

Pressure overload has been shown to induce mitogen activated protein kinases (MAPKs) and reactivate the atrial natriuretic factor in the heart. To test the sensitivity of these signals to pressure overload, we assayed the activity of MAPKs extracellular signal–regulated kinase, c-Jun N-terminal kinase 1, and p38 in protein lysates from the left ventricle (LV) or white blood cells (WBC) isolated from aortic banded mice with varying levels of pressure overload. In separated mice we measured atrial natriuretic factor mRNA levels by Northern blotting. As expected, a significant induction of atrial natriuretic factor mRNA levels was observed after aortic banding, and it significantly correlated with the trans-stenotic systolic pressure gradient but not with the LV weight:body weight ratio. In contrast, a significant correlation with systolic pressure gradient or LV weight:body weight ratio was observed for all of the MAPK activity detected in LV samples or WBCs. Importantly, LV activation of MAPKs significantly correlated with their activation in WBCs from the same animal. To test whether MAPK activation in WBCs might reflect uncontrolled blood pressure levels in humans, we assayed extracellular signal–regulated kinase, c-Jun N-terminal kinase 1, and p38 activation in WBCs isolated from normotensive volunteers, hypertensive patients with controlled blood pressure values, or hypertensive patients with uncontrolled blood pressure values. Interestingly, in hypertensive patients with controlled blood pressure values, LV mass and extracellular signal–regulated kinase phosphorylation were significantly reduced compared with those in hypertensive patients with uncontrolled blood pressure values. These results suggest that MAPKs are sensors of pressure overload and that extracellular signal–regulated kinase activation in WBCs might be used as a novel surrogate biomarker of uncontrolled human hypertension.

Percutaneous treatment of a aorto-caval fistula in a old high risk patient

BackgroundTo remark the feasibility of endovascular treatment of an aorto-caval fistula in a old high risk patient with “hostile” abdomen for previous surgeries.MethodsIn September 2009 a 81-years-old patient was admitted in emergency at our department because of abdominal pain and massive oedema of the lower extremities associated to dyspnoea (New York Heart Association (NYHA) functional class III). A CT scan showed an aorto-caval fistula involving the abdominal aorta below the renal arteries. This abnormal communication was likely due to the previous abdominal surgeries, was complicated by occlusion of the inferior vena cava at the diaphragm and was responsible for the massive oedema of the lower extremities. Because of unstable conditions and hostile abdomen the patient was considered unfit for conventional surgery and an endovascular approach was planned. After unsuccessful attempt by positioning of an Amplatzer vascular ring into the fistula, a Medtronic covered stent-grafts were implanted from the renal arteries to the both common iliac arteries. The patient had an impressive improvement characterized by a 18 Kg weight loss and a complete restoration of the functional capacity (from NYHA class III to NYHA class I) associated to a complete resolution of the lower extremities oedema as confirmed at the a month-CT-scan.ConclusionEndovascular surgery of aorto-caval fistula represents a good option in alternative to conventional surgery mostly in old high risk patient.

Infantile facial haemangioma and subclinical left ventricular dysfunction: the importance of z score in the diagnostic and therapeutic process.

Large facial haemangiomas have a high rate of complications and can be associated with neurological, ophthalmological and cardiac abnormalities (PHACE syndrome; Posterior fossa malformations, Haemangiomas, Arterial anomalies, Coarctation of the aorta and cardiac defects, and Eye abnormalities). However, a thorough clinical examination is absolutely necessary. In fact, even in the absence of a PHACE syndrome, large haemangiomas can induce important complications. In the present brief report we describe a case of left ventricular dilatation in a 6-month-old girl due to a giant facial haemangioma. Left ventricular dilatation has been evaluated by two-dimensional echocardiography. Studies to identify other major arteriovenous malformations were negative. Medical therapy with diuretics, angiotensin-converting enzyme (ACE) inhibitors and steroids was able to halt the progression towards left ventricular dysfunction, avoiding an early surgical approach for a disease that very often is self-limiting.

Growth hormone improves cardiopulmonary capacity and body composition in children with growth hormone deficiency.

Context: Growth hormone deficiency (GHD) in children may be associated with early cardiovascular risk factors and alterations in left ventricular (LV) structure and function; data on cardiopulmonary functional capacity are lacking. Objectives: Aim of the study was to evaluate the effect of GHD and growth hormone (GH) therapy on cardiopulmonary functional capacity, left and right cardiac structure and function, and body composition in children and adolescents. Design: Prospective, case‐control study. Patients and Methods: Twenty‐one untrained GHD children (11.3 ± 0.8 years) underwent cardiopulmonary exercise testing, echocardiography and dual‐energy x‐ray absorptiometry, before and after 12 months of GH therapy. Twenty‐one controls matched for sex, pubertal status, body mass index, and physical activity (PA) were evaluated at baseline and after 1 year. Results: At baseline, GHD patients showed reduced LV mass (LVM; 63.32 ± 7.80 vs 80.44 ± 26.29 g/m2, P = 0.006), peak oxygen consumption (VO2peak; 22.92 ± 4.80 vs 27.48 ± 6.71 mL/Kg/min, P = 0.02), peak workload (80.62 ± 29.32 vs 103.76 ± 36.20 W, P = 0.02), and O2 pulse (4.93 ± 1.30 vs 7.67 ± 2.93 mL/beat, P = 0.0003), compared with controls. GHD patients also exhibited lower lean body mass (LBM 65.36 ± 7.84% vs 76.13 ± 8.23%, P < 0.001), and higher fat mass (FM 30.84 ± 7.92% vs 22.19 ± 8.18%, P = 0.001) than controls. GH therapy resulted in a significant increase of LVM (72.01 ± 15.88, P = 0.03), VO2peak (26.80 ± 4.97; P = 0.01), peak workload (103.67 ± 32.24, P = 0.001), O2 pulse (6.64 ± 1.68, P = 0.0007), and LBM (75.36 ± 7.59%, P = 0.0001), with a reduction in FM (22.62 ± 7.73%, P = 0.001). No difference was found in either left or right ventricular function. Conclusion: Our results suggest that cardiac structure, body composition and cardiopulmonary functional capacity are impaired in children with untreated GHD and can be restored after short‐term GH replacement therapy.

An imbalance between protective and detrimental molecular pathways is associated with right ventricular dysfunction in congenital heart diseases with outflow obstruction

An imbalance between protective and detrimentalmolecular pathways is associatedwith right ventricular dysfunction in congenital heart diseases with outflow obstruction Elisa di Pietro , Maria Carmen De Angelis , Francesca Esposito , Gennaro Maresca , Alessia Agresta , Annunziata Cerrone , Ovidio De Filippo , Philip J. Kilner , Gaetano Palma , Gennaro Galasso , Dario Leosco , Carlo Vosa , Bruno Trimarco , Antonio Rapacciuolo a,⁎

Multiple MGuard stent implantation to treat massive right coronary artery dissection during primary coronary angioplasty.

Here we report a case of a 79-year-old woman with inferior myocardial infarction, transferred to our cath lab to perform a primary percutaneous coronary intervention (PPCI). During the procedure, a massive dissection complicated the thrombotic lesion of the right coronary artery (RCA). In this case, we decided to use the MGuard stent to treat both the large dissection and the thrombotic lesion. MGuard stent is a combination of a coronary stent merged with an embolic protection device. After multiple MGuard stent implantation we obtained a complete resolution of the coronary dissection obtaining a patent RCA with normal antegrade flow.

Late onset of hypoxemia due to a pulmonary arteriovenous malformation during selective estrogen receptor modulator therapy.

![Figure][1] [![Graphic][3] ][3][![Graphic][4] ][4][![Graphic][5] ][5] A 76-year-old woman with unexplained hypoxemia and severe exertional dyspnea was admitted to our department. The symptoms had appeared during tamoxifen therapy after resection of breast carcinoma; history

β1-Adrenergic Receptor and Sphingosine-1-Phosphate Receptor 1 (S1PR1) Reciprocal Downregulation Influences Cardiac Hypertrophic Response and Progression to Heart Failure

Background— The sphingosine-1-phosphate receptor 1 (S1PR1) and &bgr;1-adrenergic receptor (&bgr;1AR) are G-protein–coupled receptors expressed in the heart. These 2 receptors have opposing actions on adenylyl cyclase because of differential G-protein coupling. Importantly, both of these receptors can be regulated by the actions of G-protein–coupled receptor kinase-2, which triggers desensitization and downregulation processes. Although classic signaling paradigms suggest that simultaneous activation of &bgr;1ARs and S1PR1s in a myocyte would simply result in opposing action on cAMP production, in this report we have uncovered a direct interaction between these 2 receptors, with regulatory involvement of G-protein–coupled receptor kinase-2. Methods and Results— In HEK (human embryonic kidney) 293 cells overexpressing both &bgr;1AR and S1PR1, we demonstrated that &bgr;1AR downregulation can occur after stimulation with sphingosine-1-phosphate (an S1PR1 agonist), whereas S1PR1 downregulation can be triggered by isoproterenol (a &bgr;-adrenergic receptor agonist) treatment. This cross talk between these 2 distinct G-protein–coupled receptors appears to have physiological significance, because they interact and show reciprocal regulation in mouse hearts undergoing chronic &bgr;-adrenergic receptor stimulation and in a rat model of postischemic heart failure. Conclusions— We demonstrate that restoration of cardiac plasma membrane levels of S1PR1 produces beneficial effects that counterbalance the deleterious &bgr;1AR overstimulation in heart failure.

Recurrent pulmonary and cerebral thromboembolism in an adult patients following incomplete removal of ventriculoatrial shunt for congenital hydrocephalus.

A 34-year-old man was admitted to our hospital’s department of neurology because he had experienced a cryptogenic stroke followed by a transient ischaemic attack. The patient suffered from congenital hydrocephalus which was treated by ventriculoatrial shunt at 8 months of age. Twelve months later, because of recurrent infections, the catheter was partially removed and the distal segment was left in place. At admission, the transoesophageal echocardiogram showed severe pulmonary hypertension (80 mm Hg confirmed by invasive measurement). The distal tip of the catheter had migrated into the left atrium through a patent foramen ovale inducing a massive right-to-left shunt. We surgically removed the catheter and closed the interatrial defect. At 1 and 6 months follow-up the patient was asymptomatic with a reduced pulmonary hypertension (50 mm Hg). Since there was no other clinical finding responsible for the recurrent thromboembolic events, both at the pulmonary and cerebral level, the catheter was removed to prevent further complications.