Debora Robba

Multiorgan paradoxical embolism consequent to acute pulmonary thromboembolism with patent foramen ovale: a case report

Paradoxical embolism is defined as a systemic arterial embolism requiring the passage of a venous thrombus into the arterial circulatory system through a right-to-left shunt. It is a relatively rare phenomenon, representing about 2% of all cases of arterial embolism. We report a case of a 79-years-old woman admitted to hospital because of dyspnea and lower left limb pain. CT scan revealed multiple thrombi to kidney, lower limb and superior mesenteric artery during acute pulmonary embolism. Echocardiogram documented a patent foramen ovale with a right-to-left shunt. The patient was treated with thrombolytic therapy and heparin with progressive improvement of symptoms and resolution of pulmonary embolism and peripheral thrombosis. Patent foramen ovale closure was not performed because a life-long anticoagulation therapy was necessary, a tunnel-type patent foramen ovale may increases difficulty in realizing device implantation and there are no clear evidence-based guidelines to date addressing treatment in presence of a patent foramen ovale.

Nitric oxide and cardiovascular risk factors

The endothelium is a dynamic organ with many properties that takes part in the regulation of the principal mechanisms of vascular physiology. Its principal functions include the control of blood-tissue exchange and permeability, the vascular tonus, and the modulation of inflammatory or coagulatory mechanisms. Many vasoactive molecules, produced by the endothelium, are involved in the control of these functions. The most important is nitric oxide (NO), a gaseous molecule electrically neutral with an odd number of electrons that gives the molecule chemically reactive radical properties. Already known in the twentieth century, NO, sometimes considered as a dangerous molecule, recently valued as an important endogenous vasodilator factor. Recently, it was discovered that it is involved in several physiological mechanisms of endothelial protection (Tab. I). In 1992, Science elected it as “molecule of the year”; 6 yrs later three American researchers (Louis Ignarro, Robert Furchgott and Fried Murad) obtained a Nobel Prize for Medicine and Physiology “for their discoveries about NO as signal in the cardiovascular system”. TABLE I EFFECTS OF ENDOTHELIAL NITRIC OXIDE ON THE CARDIOVASCULAR SYSTEM NO is synthesized by endothelial cells from L-argynine and oxygen (Fig. 1). Blood flow and laminar shear stress induce the activation through phosphorilation of NO synthase (NOS), that catalyzes the conversion reaction from L-arginine to citrullin and NO, through two cofactors: calmodulin and pteridin-thetraidrobiopterine (BH4) (Fig. 2). There are at least three isoforms of constitutive NOS: the endothelial form (eNOS), the neuronal form (nNOS) and the inducible form (iNOS); eNOS, the calcium-dependent form of the enzyme, is in many cellular types and it is responsible for NO production in healthy blood vessels. nNOS is a special type of eNOS, expressed in the central nervous system. iNOS, a form induced by immunological stimuli (1), is expressed in the myocytes, in the macrophages and in the endothelial cells. NOS are formed by two distinct catalytic subunits, as terminal C-reductase and terminal N-oxygenase domain. In the presence of sufficient amounts of BH4, these domains work together and synthesize NO. Otherwise in case of increased oxidative stress they cause the production of peroxynitrites. The NO produced induces guanilate cyclase to the synthesis of cGMP from cGTP. The last molecule causes cellular hyperpolarization due to the activation of the potassium canals. These reactions cause the inhibition of the entrance of calcium and, in this way, the vasodilatation in the cardiovascular system (Tab. I). Fig. 1 Fig. 2 1 ENDOTHELIAL DYSFUNCTION AND NO Normal vascular tonus depends on the equilibrium between the vasoconstrictor and vasodilator molecules released from the endothelium. In healthy endothelium, the balance is shifted towards vasodilatation due to NO (Tab. II). Endothelial dysfunction is synonymous with the insufficiency of endothelium dependent vasodilatation and results in the failure of vasoactive, anticoagulant and anti-inflammatory effects of healthy endothelium. The most important mechanism for endothelial dysfunction is the reduction in NO availability. The substrate insufficiency such as the reduction in L-arginine in endothelial cells or any defect in the transport of L-arginine into the cell, the existence of NOS inhibitors such as asymmetrical dimethylarginine (ADMA) and G-monomethyl-L-arginine (L-NM-MA), increase in the reactive oxygen molecules, reduction in the diffusion of NO due to intimal thickening, the mutations in the eNOS gene expression, increase in the catabolism of NO, cofactor insufficiency and increase in the vasoconstrictor molecules released from the endothelium are the other mechanisms that must be considered in endothelial dysfunction. Endothelial dysfunction coexists with many disease states in the cardiovascular system and is known as the first stage of atherosclerosis, which is probably the most important disease of the modern age. In the cardiovascular system, other clinical conditions, which are related with endothelial dysfunction are hypertension, are hyperglycemia-insulin resistance, dyslipidemia, menopause, heart failure, variant angina, cardiac syndrome X and hyperhomocysteinemia. TABLE II EFFECTS OF ENDOTHELIAL NITRIC OXIDE ON THE CARDIOVASCULAR SYSTEM NO oppose the atherogenical stimuli preventing vascular structural modifications; it can inhibit the adhesion of platelets and monocytes, the migration of the smooth muscular cells and the endothelial apoptosys. It was demonstrated that NO, for example, inhibits, through S-nytrosation, key-enzymes of the apoptotic chart (Caspases 6, 7, 8) (2). I. Aging Data obtained in humans and in animal experiments indicate that aging alters the endothelial dependent vasodilatation in the big arteries and in the resistance vessels (3). Moreover, aging is associated with a progressive remodeling of the vascular wall, which includes the thickening of the tunica intima and of the tunica media and the increase in its rigidity (4). With advancing old age, smooth muscular cells migrate progressively from the tunica media and accumulate in the intima (5). This fact is associated with a progressive decline in endothelial functionality, which causes a reduced response to the vasodilating factors, consequent to the alteration of the expression and/or the activity of NOS and with an increased formation of free radicals. Aging is associated with an alteration in the equilibrium between vasoconstrictor and vasodilating factors released by the endothelium, or rather with a progressive reduction in NO and endothelial derived hyperpolarizing factor (EDHF) associated with an increase in oxygen free radicals and prostanoids derived from cycle-oxygenase. In addition, it was recently demonstrated that, with aging, there is an inferior proliferation and migration of the endothelial cells from the sites near the atherosclerotic lesion, preventing the preservation of intimal integrity, which is normally favored by a healthy endothelium (6).

Tako-tsubo cardiomyopathy in two sisters: a chance finding or familial predisposition?

A 54-year-old woman was admitted to our coronary care unit for prolonged chest pain and dizziness that began while she was performing allergological tests. She had a family history of myocardial infarction and no other additional cardiovascular risk factors. She was undergoing skin prick test for allergic asthma, which resulted positive for oat grass (Poaceae family). The physical examination was unremarkable. Her blood pressure was 120/80 mmHg and the heart rate was 114 bpm. The electrocardiogram (ECG) showed sinus tachycardia and ST elevation in the anterior and inferior leads with a QS wave in the anterior leads. Echocardiography showed a dilatation of left ventricle due to a dyskinesia of all distal segments. Basal segments were hypercontractile and no left ventricular dynamic obstruction was described. Laboratory tests showed a significant increase in cardiac enzymes, reaching a peak approximately 10 h after the beginning of symptoms (troponin I 9.91 ng/ml, upper reference limit 0.03 ng/ ml; CK-MB 23.06 ng/ml, upper reference limit 5.00 ng/ ml). In the suspect of an acute coronary syndrome, the patient was treated with low weight molecular heparin, dual antiplatelet therapy and nitroglycerin. Coronary angiography excluded the presence of obstructive coronary artery disease. Left ventriculography showed an extensive apical akinesis with a moderately reduced left ventricular systolic function (LVEF 42 %). Atrial fibrillation occurred during hospitalization, which resolved with infusion of amiodarone after 48 h. Because of a history of asthma, a calcium channel blocker was preferred to beta-blocker therapy. The presence of underlying disorders predisposing to a coronary thrombosis or myocarditis was excluded. In addition, screening for cardiotropic viral agents was negative as well as the urinary catecholamine metabolites amount. Cardiac biomarkers showed progressive normalization in the next days, with a curve consistent with an acute cardiac injury at the time of admission. Our diagnosis was tako-tsubo cardiomyopathy (TTC) and the patient was discharged after 5 days with oral anticoagulant therapy and a calcium channel blocker. An echocardiogram performed 10 days after discharge showed a normalization of the left ventricular systolic function (Fig. 1a, b). One year later, a 44-year-old female presented to our department with a 1-week history of mild dyspnoea on exertion, atypical chest pain, fatigue, and lightheadedness. She had prior diagnosis of mild mitral valve prolapse and cigarette smoking as unique cardiovascular risk factor. She reported an emotional stress event (a dispute with a close person) 1 week before. This woman was the sister of the patient we previously described. The ECG showed sinus rhythm with negative T waves in the anterior, lateral and inferior leads. Transthoracic echocardiography demonstrated akinesis of all the mid-ventricular and apical segments, and hyperkinesia of the basal portions. The left ventricular systolic function was significantly reduced (LVEF 38 %). Serial cardiac markers showed an elevated troponin I at the admission (0.97 ng/ml, upper reference limit 0.03 ng/ml) and slightly elevated CK-MB (7.14 ng/ ml, upper normal limit 5.0 ng/ml). The patient was treated with an antiplatelet drug, low molecular weight heparin and ACE inhibitor. Cardiac catheterization revealed G. Caretta (&) D. Robba Department of Cardiology, A.O. ‘‘Istituti Ospitalieri’’ di Cremona, Cremona, Italy e-mail: giorgio.caretta@gmail.com

Diagnostic value of the head-up tilt test and the R-test in patients with syncope

The diagnostic value of the head-up tilt test (HUTT) in discovering vasovagal syndrome depends on the pre-test probability. An accurate anamnesis and clinical examination screens the patients indicated for the HUTT. In patients with unexplained syncope, the R-test is an alternative procedure to discover its cause. In our study, we evaluated the diagnostic significance of the HUTT in a group of 211 patients and of the R-test in a subgroup of 45 patients with negative HUTT results and with negative traditional Holter ECG monitoring (24 hr).