Pablo I. Altieri

Massive pulmonary embolism associated with a right ventricular myxoma.

A 12 year old boy had a massive pulmonary embolism associated with a right ventricular myxoma. This caused complete occlusion of the main trunk of the left pulmonary artery and of a branch of the right pulmonary artery supplying the basal area of the lower lobe of the right lung. The patient died despite two surgical attempts to remove the tumor clots. To our knowledge this constitutes the first report of a massive pulmonary artery embolism associated with a right ventricular myxoma.

Altered vascular function in early stages of heart failure in hamsters

BACKGROUND Congestive heart failure is a clinical condition associated with alterations in the normal balance of neurohumoral agents and factors acting on the vascular wall. The etiology of this condition, however, remains largely undefined. To help elucidate the pathophysiology of this disease, vascular function and angiotensin-converting enzyme activity were evaluated in 2-month-old Syrian cardiomyopathic hamsters (SCHs) that had not yet developed heart failure. Age-matched normal hamsters were used as control hamsters. METHODS AND RESULTS Vascular function studies included determinations of contractile responses of aortic rings to 0.1 microM angiotensin II and 0.1 microM norepinephrine. In addition, endothelial function was evaluated by the vasorelaxant action of acetylcholine on norepinephrine-precontracted aortic rings. The results indicate that the pressor effect of angiotensin II (0.1 microM) was 35% greater in aortic rings from SCRs than that observed in control animals. This effect is specific for angiotensin II because the contraction induced by NE (0.1 microM) was similar in both of these strains. Angiotensin-converting enzyme activity was three-fold higher in aorta homogenates from SCHs but normal in plasma and heart tissue when compared with control hamsters. Aortic ring preparations from SCHs also exhibited endothelial dysfunction because the maximal relaxation elicited by 10 microM acetylcholine was reduced 53%. Concentration-response curves with acetylcholine yielded EC50 values that were threefold lower in SCHs (97.2 +/- 0.1 nM) than in control animals (286 +/- 7 nM). Indomethacin (1 microM) increased the vasorelaxant effect of acetylcholine 28% in SCHs and shifted to the left the concentration-response curve of this agonist, suggesting an increased relaxation with the cyclooxygenase inhibitor. No effect of indomethacin on acetylcholine-induced relaxation was observed in control animals. Sodium nitroprusside induced similar relaxations in both control animals and SCHs, suggesting that the vascular smooth muscle response is normal in SCR. CONCLUSIONS Altogether these results point to a state of enhanced vascular contractility in young SCHs that could predispose these animals to develop heart failure, the enhanced vascular contractility could result from increased activity of the local renin-angiotensin system, augmented vascular response to angiotensin II, reduced nitric oxide synthesis, and enhanced production of prostaglandins.

Simvastatin releases Ca2+ from a thapsigargin-sensitive pool and inhibits InsP3-dependent Ca2+ mobilization in vascular smooth muscle cells.

Simvastatin (SV), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity inhibits migration and proliferation of vascular smooth muscle cells (SMC). To investigate whether these effects of SV are related to inhibition of cell calcium mobilization, cultured SMC obtained from rat aorta were loaded with Fura-2 to determine the basal cytosolic free calcium levels ([Ca2+]i) and the agonist-stimulated Ca2+ mobilization. SV (20 mu M) transiently increased cytosolic free calcium, an effect that depends mainly on intracellular calcium release (68%). This effect of SV was markedly reduced (75%) by thapsigargin, an inhibitor of the Ca2+ ATPase of inositol 1,4,5-triphosphate (InsP3)-sensitive calcium pools. Incubation of cells with SV (15 min) inhibited the mobilization of Ca2+ by angiotensin II, platelet-derived growth factor, and vasopressin (IC50 = 5 mu M). SV did not affect inositol trisphosphate (InsP3) levels or modify its generation by angiotensin II (Ang II) and vasopressin. Furthermore, in saponin-permeabilized cells, SV abolished the release of calcium by 2,3-dideoxy-InsP3. SV reduced the effect of thapsigargin on InsP3-sensitive stores by 67%, suggesting that SV depletes these calcium pools. The inhibitory effect of SV on calcium mobilization was prevented by coincubation of cultured cells (24 h) with 1 mM mevalonic acid, the product of HMG-CoA reductase activity. These results support the notion that SV inhibits [corrected] the migration and proliferation of SMC by directly affecting cell Ca2+.

Enalapril and Losartan Are More Effective Than Carvedilol in Preventing Dilated Cardiomyopathy in the Syrian Cardiomyopathic Hamster

To assess the role of the renin—angiotensin (RAS) and adrenergic systems in the development and progression of dilated cardiomyopathy in the Syrian cardiomyopathic hamster (SCH), echocardiographic parameters were evaluated in 6-month-old animals after 5 months of treatment with enalapril (25 mg/kg/day) plus losartan (10 mg/kg/day), or with carvedilol (1 mg/kg/day). Cardiac output indexes (COI) increased by 53% after RAS blockade and by 20% after β-blockade in SCH. Moreover, LVEDV and LVESV decreased 30% and 62%, respectively (P < .05) during RAS blockade, whereas ejection fraction (EF) increased by 48%. By contrast, carvedilol reduced LVESV by only 28% (P < .05) and increased EF by only 15% (P < .05). These results suggest that RAS activation plays a critical role in the development of cardiac dysfunction in SCH and that suppression of RAS may be more effective than β-blockade in retarding the development of cardiomyopathy in SCH. Owing to timing (pre—heart failure stage) and to the single dose protocol, the implications of this study for human subjects remain to be clarified.

Concentraciones totales de homocisteína plasmática en pacientes puertorriqueños con cardiopatía isquémica

Introduccion y objetivos En Puerto Rico se ha comprobado que, a pesar de que la enfermedad coronaria es la principal causa de muerte, la poblacion tiene una incidencia menor de estas enfermedades que en los EE.UU. y posee una incidencia menor de taquicardia ventricular y muerte subita. Un factor que puede contribuir a la menor incidencia de enfermedades coronarias en Puerto Rico es que las concentraciones totales de homocisteina plasmatica (tHcys) en nuestra poblacion sean menores que en la poblacion de los EE.UU. Nuestro objetivo era medir tHcys en la poblacion puertorriquena con cardiopatia isquemica. Metodos Se midio aleatoriamente la tHcys en 70 pacientes puertorriquenos hospitalizados en el Centro Cardiovascular de Puerto Rico y el Caribe (Division UPR). Resultados La concentracion promedio de tHcys en estos pacientes resulto similar a la comunicada por el estudio de Framingham cuando es ajustada por edad (11,2 frente a 11,8 mmol/l). En la poblacion puertorriquena, los varones tenian una concentracion mayor de tHcys que las mujeres (11,7 frente a 9,5 mmol/l; p = 0,07). Ademas, no observamos un aumento en la concentracion de tHcys en pacientes diabeticos cuando se compararon con los pacientes no diabeticos (10,1 frente a 11,2 mmol/l; p = 0,74). Tampoco observamos una correlacion directa entre la concentracion de tHcys y las condiciones cardiacas medidas por angiografia coronaria (normal = 11,1 mmol/l; leve = 10,5 mmol/l; moderado = 10,9 mmol/l; severo = 10,5 mmol/l; Kruskal-Wallis = 0,45). Conclusion Estos resultados sugieren que la concentracion de tHcys no predice fiablemente la gravedad de las lesiones de cardiopatia isquemica en la poblacion puertorriquena.

Enalapril increases cardiac refractoriness.

Summary: The influence of enalapril—an angiotensin converting enzyme inhibitor—on cardiac refractoriness was investigated. Strength-interval curves were initially obtained under control conditions and after exposing the muscles to Tyrode solution containing 50 µg/ml of enalapril. The results indicate that enalapril displaced the strength-curves to the right. The minimal current intensity required to elicit a propagated response was clearly increased by enalapril at all the intervals used. No change in action potential duration was found with enalapril but the action potential amplitude and the resting potential were both increased. The rise in cardiac refractoriness caused by enalapril might indicate that the drug has antiarrhythmic properties

Parallel regulation of arginine transport and nitric oxide synthesis by angiotensin II in vascular smooth muscle cells role of protein kinase C

SummaryExperiments were performed to characterize arginine transport in vascular smooth muscle cells (SMCs) and the effect of angiotensin II (Ang II) on this process. In addition, the role of arginine transport in the cytokineinduced nitric oxide (NO) production was assessed. Arginine transport takes place through Na+-independent (≈60%) and Na+-dependent pathways (≈40%). The Na+-independent arginine uptake appears to be mediated by system y+ because of its sensitivity to cationic amino acids such as lysine, ornithine and homoarginine. The transport system was relatively insensitive to acidification of the extracellular medium. By contrast, the Na+-dependent pathway is consistent with system B0,+ since it was inhibited by both cationic and neutral amino acids (i.e., glutamine, phenylalanine, and asparagine), and did not accept Li+ as a Na+ replacement. Treatment of SMCs with 100nM Ang II significantly inhibited the Na+-dependent arginine transport without affecting systems y+, A, and L. This effect occurred in a dose-dependent manner (IC50 of 8.9 ± 0.9nM) and is mediated by the AT-1 receptor subtype because it was blocked by DUP 753, a non-peptide antagonist of this receptor. The inhibition of system B0,+ by Ang II is mediated by protein kinase C (PKC) because it was mimicked by phorbol esters (phorbol 12-myristate 13-acetate) and was inhibited by staurosporine. Ang II also inhibited the IL-1β induced nitrite accumulation by SMCs. This action was also inhibited by staurosporine and reproduced with phorbol esters, suggesting a coupling between arginine uptake and NO synthesis through a PKC-dependent mechanism. However, arginine supplementation in the medium (10mM) failed to prevent the inhibitory action of Ang II on NO synthesis. These findings suggest that although Ang II inhibits concomitantly arginine transport and NO synthesis in SMCs, the reduction of NO synthesis is not associated with alterations in the cellular transport of arginine.

Effect of enalapril on intracellular resistance and conduction velocity in rat ventricular muscle.

Summary: The effect of enalapril on the intracellular resistance (ri) and conduction velocity was investigated in isolated rat trabeculae. The results indicated a decline in the internal resistance of 35.5% (SE ± 3.3) and an increase in conduction velocity of 58.7% (SE ± 6.6). The action potential duration was not altered, but the resting potential was increased by 10.5 mV (SE ± 4.4). Enalaprilat had no effect on ri probably because the molecule is a diacid and does not cross the cell membrane. These findings indicate that the renin-angiotensin system is involved in the modulation of cell communication in cardiac muscle and that the beneficial effect of the drug in patients with congestive heart failure is, in part, related to an improvement of electrical synchronization of heart cells.

Chronic Treatment With N-acetylcysteine Improves Cardiac Function but Does Not Prevent Progression of Cardiomyopathy in Syrian Cardiomyopathic Hamsters

Oxidative stress has been postulated to contribute to the onset and development of heart failure (HF). The efficacy of antioxidant therapy in HF, however, remains controversial. This study evaluates the effect of the antioxidant N-acetylcysteine (NAC, 1 g/kg per day) on cardiovascular function in 2- and 6-month-old Bio-TO2 Syrian cardiomyopathic hamsters (SCH) after treatment for 1 month and 5 months with this drug. Endothelial function, systolic blood pressure (SBP), and echocardiographic parameters were evaluated. Age-matched F1-B golden hamsters were used as controls. One month of NAC administration significantly decreased SBP in 2-month-old SCH (n = 5, P < 0.001) without modifying echocardiographic values. Five-month treatment of cardiomyopathic animals with the antioxidant improved the acetylcholine-induced relaxation in aortic rings by 24% (E Max value from 45.8% ± 4% to 55.3% ± 2% n = 7, P < .05) but did not modify EC50 values for the acetylcholine concentration-response curve. In addition, 5-month administration of NAC to SCH increased ejection fraction from 39% ± 4% to 57% ± 4% (n = 11, P < .001) and decreased left ventricular end-diastolic and end-systolic volumes (from 0.38 ± 0.04 mL/100 g body weight (BW) and 0.22 ± 0.03 mL/100 g BW, before, to 0.24 ± 0.04 mL/100 g BW and 0.12 ± 0.03 mL/100 g BW after treatment, P < .01). Cardiac output index also improved after 5 months of treatment, although it did not reach statistical significance. These results suggest that antioxidant therapy alone decreases ventricular dilatation and improves cardiovascular function in this animal model of dilated cardiomyopathy, but it does not prevent the appearance of HF.

Aliskiren improves left ventricular dysfunction and reduces cardiac dilation in Syrian cardiomyopathic hamsters.

Objective: Chronic activation of the renin–angiotensin–aldosterone system is a major contributing factor to the pathogenesis and progression of cardiovascular and renal diseases. Methods: To evaluate the role of renin–angiotensin–aldosterone system blockade with aliskiren, a direct renin inhibitor, in the development and progression of dilated cardiomyopathy in the Syrian cardiomyopathic hamster (SCH) model, we treated 1-month-old SCH with aliskiren (10 mg·kg−1·d−1) over a 4-month period. For comparative purposes, we also evaluated the effects of the angiotensin receptor blocker valsartan (10 mg·kg−1·d−1) and the combination of both drugs. Age-matched golden hamsters were used as controls. Left ventricular end-diastolic volume and end-systolic volume, ejection fraction, and diastolic function were determined by echocardiography. Systolic blood pressure (SBP) was also measured in the left femoral artery by sphygmomanometry. Results: Results indicate that at 2 months of age, SBP is higher in SCH than in controls, and administration for 1 month of aliskiren, valsartan, or the combination of these drugs normalized SBP in SCH to a similar extent. In 5-month-old SCH, aliskiren improved ejection fraction (from 48.6% ± 5.8% to 69.4% ± 3.2%, n = 5, P < 0.05), left ventricular end-systolic volume (from 0.28 ± 0.06 to 0.10 ± 0.01 mL/100 g body weight), left ventricular end-diastolic volume (from 0.61 ± 0.05 to 0.34 ± 0.02 mL/100 g body weight), and normalized diastolic function (E:A ratio increases from 0.93 ± 0.13 to 1.70 ± 0.03, n = 5, P < 0.05). Similar results were observed with valsartan or the combination of aliskiren and valsartan. Conclusions: Our results indicate that in this animal model, aliskiren is as effective as valsartan, or the combination of both drugs, in improving diastolic function and in preventing the development of dilated cardiomyopathy. These findings suggest that aliskiren may be used as a monotherapy in heart failure management. Clinical studies, however, are needed to assess the effectiveness of this drug in patients with heart failure.