PFO closure in high-risk patient with paradoxical arterial embolism, deep vein thrombosis, pulmonary embolism and factor V Leiden genetic mutation.

Occurrence of paradoxical arterial embolism may cause the first symptoms in patients with a coexisting hypercoagulable state and patent foramen ovale (PFO). This can result in significant morbidity and mortality depending on the location of the embolism. The risks and benefits of closure of small PFOs have not been well elucidated in prior studies. We describe a patient with a history of Factor V Leiden heterozygosity who presented with left arm pain secondary to arterial embolism. The patient was a 51-year-old male who initially presented to the emergency department after awaking from sleep with progressive, severe, burning left arm pain. He had also noted intermittent shortness of breath over the 2 weeks prior to admission. Temperature was 97.4 F, pulse 86, respiratory rate 20 and blood pressure 121/87. Oxygen saturation was 94% on supplemental oxygen. He had a cool left upper extremity and the patient described subjective paresthesias in this extremity. Left radial pulse was difficult to palpate. Physical exam was otherwise unremarkable. Troponin I was mildly elevated at 0.217 ng/l. White blood cell count was 11.8 and INR 1.1. EKG showed sinus tachycardia with non-specific T abnormalities in the anterior leads. His past medical history was notable for only hypertension and hyperlipidemia. Current recommendation is for antiplatelet or anticoagulation for those with hypercoaguable states who suffer a stroke; there is currently no absolute indication for closure device. We describe the case of a 51-year-old male who had presented with left arm pain and shortness of breath. The computed tomography (CT) angiography of chest showed pulmonary emboli with heavy clot burden bilaterally. Heparin was started, but patient was found to have occlusion along large arteries of the left arm. Emergent left axillary, brachial, radial and ulnar embolectomy for acute critical arm ischemia were performed. The transthoracic echocardiogram done the next day with bubble study was positive for patent foramen ovale. Hypercoaguability showed factor V Leiden heterozygosity. Decision was made for the patient to initiate long-term anticoagulation with rivaroxaban and closure was performed. Patient was advised that closure is off label but opted to proceed with closure in light of hypercoaguable state.

TIMP-2 mutant decreases MMP-2 activity and augments pressure overload induced LV dysfunction and heart failure.

Pressure overload induces cardiac extracellular matrix (ECM) remodelling and results in heart failure. ECM remodelling by matrix metalloproteinases (MMPs) is primarily regulated by their target inhibitors, tissue inhibitor of matrix metalloproteinases (TIMPs). It is known that TIMP-2 is highly expressed in myocardium and is required for cell surface activation of pro-MMP-2. We and others have reported that imbalance between angiogenic growth factors and anti-angiogenic factors results in transition from compensatory cardiac hypertrophy to heart failure. We previously reported the pro-angiogenic role of MMP-2 in cardiac compensation, however, the specific role of TIMP-2 during pressure overload is yet unclear. We hypothesize that genetic ablation of TIMP-2 exacerbates the adverse cardiac matrix remodelling due to lack of pro-angiogenic MMP-2 and increase in anti-angiogenic factors during pressure overload stress and results in severe heart failure. To verify this, ascending aortic banding (AB) was created to mimic pressure overload, in wild type C57BL6/J and TIMP-2-/- (model of MMP-2 deficiency) mice. Left ventricular (LV) function assessed by echocardiography and pressure-volume loop studies showed severe LV dysfunction in TIMP-2-/- AB mice compared to controls. Expression of MMP-2, vascular endothelial growth factor (VEGF) was decreased and expression of MMP-9, anti-angiogenic factors endostatin and angiostatin was increased in TIMP-2-/- AB mice compared with wild type AB mice. Connexins (Cx) are the gap junction proteins that are widely present in the myocardium and play an important role in endothelial-myocyte coupling. Our results showed that expression of Cx 37 and 43 was decreased in TIMP-2-/- AB mice compared with corresponding wild type controls. These results suggest that genetic ablation of TIMP-2 decrease the expression of pro-angiogenic MMP-2, VEGF and increases anti-angiogenic factors that results in exacerbated abnormal ventricular remodelling leading to severe heart failure.

Homocysteine effects classical pathway of GPCR down regulation: Galpha(q/11), Galpha(12/13), G(i/o).

G protein-coupled receptors (GPCRs) are known to modulate intracellular effectors involved in cardiac function. We recently reported homocysteine (Hcy)-induced ERK-phosphorylation was suppressed by pertussis toxin (PTX), which suggested the involvement of GPCRs in initiating signal transduction. An activated GPCR undergoes down regulation via a known mechanism involving ERK, GRK2, beta-arrestin1: ERK activity increases; GRK2 activity increases; beta-arrestin1 is degraded. We hypothesized that Hcy treatment leads to GPCR activation and down regulation. Microvascular endothelial cells were treated with Hcy. Expression of phospho-ERK1 and phospho-GRK2 was determined using Western blot, standardized to ERK1, GRK2, and beta-actin. Hcy was shown to dephosphorylate GRK2, thereby enhancing the activity. The results provided further evidence that Hcy acts as an agonist to activate GPCRs, followed by their down regulation. Hcy was also shown to decrease the content of the following G proteins and other proteins: beta-arrestin1, Galpha(q/11), Galpha(12/13), G(i/o).