Remodelado ventricular izquierdo en pacientes con infarto agudo de miocardio evaluados mediante estudios de perfusión miocárdica SPECT gatillados

Introducción: Las terapias de reperfusión redujeron la mortalidad y mejoraron el pronóstico de los pacientes (p) que han sufrido un IAM. La importancia clínica de evaluar geometría ventricular/función sistólica post-IAM se debe a que el desarrollo de remodelado ventricular (RV) triplica la mortalidad a 5 años y ésta, aumenta unas diez veces si se asocia con ICC. Objetivos: 1-Evaluar el remodelado ventricular izquierdo con estudios de perfusión miocárdica (EPM) Spect gatillado en p con IAM reperfundidos. 2-Evaluar la relación entre el tiempo de la AP y el comienzo de los síntomas con el remodelado y la recuperación de la FVI. Métodos: Se incluyeron p con IAM CEST y AP dentro de las 12 hs de inicio del dolor precordial, clasificándose en 2 grupos según el tiempo de dolor : Grupo 1 < 4hs/ Grupo 2: > 4hs . Se les realizo EPM Spect gatillado en reposo dentro de las 24 hs de la AP y EPM Spect gatillado Reposo/Esfuerzo a los 6 meses del evento. Resultados: los p reperfundidos en forma precoz presentan mejores parámetros RV y FVI que los reperfundidos en forma tardía: VFS 103,5 ± 30,1 ml (ingreso) vs 53± 16 ml (6 meses) (P 0,005); VFD 160,6 ± 34,1 ml (ingreso) vs 103 ± 9,5 ml (6 meses) (P 0,005), FE 34 ±6% vs 53,5 ± 5,3% (P 0,0001), Mientras que en el grupo 2 no hubo diferencias significativas en los volúmenes ventriculares; promedio de diferencia de FE al ingreso y a los 6 meses de 19.66 % en G1 y 12,3% σFE en G2. Conclusiones: Los EPM gatillados son una técnica válida para evaluar el RV en pacientes con IAM reperfundidos. El tiempo de reperfusión seria un predictor de remodelado VI y de compromiso de la función ventricular izquierda.Facultad de Ciencias Médica

The Anrep effect requires transactivation of the epidermal growth factor receptor

Myocardial stretch elicits a biphasic contractile response: the Frank-Starling mechanism followed by the slow force response (SFR) or Anrep effect. In this study we hypothesized that the SFR depends on epidermal growth factor receptor (EGFR) transactivation after the myocardial stretch-induced angiotensin II (Ang II)/endothelin (ET) release. Experiments were performed in isolated cat papillary muscles stretched from 92 to 98% of the length at which maximal twitch force was developed (Lmax). The SFR was 123 ± 1% of the immediate rapid phase (n = 6, P < 0.05) and was blunted by preventing EGFR transactivation with the Src-kinase inhibitor PP1 (99 ± 2%, n = 4), matrix metalloproteinase inhibitor MMPI (108 ± 4%, n = 11), the EGFR blocker AG1478 (98 ± 2%, n = 6) or the mitochondrial transition pore blocker clyclosporine (99 ± 3%, n = 6). Stretch increased ERK1/2 phosphorylation by 196 ± 17% of control (n = 7, P < 0.05), an effect that was prevented by PP1 (124 ± 22%, n = 7) and AG1478 (131 ± 17%, n = 4). In myocardial slices, Ang II (which enhances ET mRNA) or endothelin-1 (ET-1)-induced increase in O2- production (146 ± 14%, n = 9, and 191 ± 17%, n = 13, of control, respectively, P < 0.05) was cancelled by AG1478 (94 ± 5%, n = 12, and 98 ± 15%, n = 8, respectively) or PP1 (100 ± 4%, n = 6, and 99 ± 8%, n = 3, respectively). EGF increased O2- production by 149 ± 4% of control (n = 9, P < 0.05), an effect cancelled by inhibiting NADPH oxidase with apocynin (110 ± 6% n = 7), mKATP channels with 5-hydroxydecanoic acid (5-HD; 105 ± 5%, n = 8), the respiratory chain with rotenone (110 ± 7%, n = 7) or the mitochondrial permeability transition pore with cyclosporine (111 ± 10%, n = 6). EGF increased ERK1/2 phosphorylation (136 ± 8% of control, n = 9, P < 0.05), which was blunted by 5-HD (97 ± 5%, n = 4), suggesting that ERK1/2 activation is downstream of mitochondrial oxidative stress. Finally, stretch increased Ser703 Na+/H+ exchanger-1 (NHE-1) phosphorylation by 172 ± 24% of control (n = 4, P < 0.05), an effect that was cancelled by AG1478 (94 ± 17%, n = 4). In conclusion, our data show for the first time that EGFR transactivation is crucial in the chain of events leading to the Anrep effect.Facultad de Ciencias Médica

Blood pressure control is not enough to normalize endothelial repair by progenitor cells

Patients presenting with classical cardiovascular risk factors within acceptable or average value ranges often develop cardiovascular disease, suggesting that other risk factors need to be considered. Considering that endothelial progenitor cells (EPCs) contribute to endothelial repair, we investigated whether EPCs might be such a factor. We compared the ability of peripheral blood EPCs to attach to extracellular matrix proteins and to grow and function in culture, between controlled hypertensive patients exhibiting a Framingham score (FS) of < 10% while showing severe vascular impairment (intima-media thickness/diameter, carotid-femoral pulse wave velocity, brachial artery flow-mediated dilation, carotid and femoral atherosclerotic plaque presence; vulnerable group, N = 30) and those with an FS of ≥ 10% and scarce vascular changes (protected group, N = 30). When compared with vulnerable patients, protected patients had significantly higher early and late-EPC and early and latetunneling nanotube (TNT) numbers. Significant negative associations were found between vascular damage severity and early EPC, lateEPC, or late-TNT numbers, whereas EPC or TNT numbers and patient characteristics or cardiovascular risk factors were not associated. Except for protected patients, in all controlled hypertensive patients, early and late-EPC and early and late-TNT counts were significantly lower than those in the normotensive subjects studied (N = 30). We found that the disparity in vascular status between patients presenting with both an FS of ≥10% and scarce vascular changes and those presenting with both an FS of < 10% and severe vascular impairment is related to differences in peripheral blood EPC and TNT numbers. These observations support the role of EPCs as contributors to vascular injury repair and suggest that EPC numbers may be a potential cardiovascular risk factor to be included in the FS calculation. New & Noteworthy: As individuals who present with risk factors within acceptable or average value ranges often develop cardiovascular (CV) disease, it has been suggested that other CV risk factors need to be considered in addition to those that are commonly combined in the Framingham score (FS) to estimate the risk of general CV disease. We investigated whether peripheral endothelial progenitor cells (EPCs) and tunneling nanotubes (TNTs) deserve to be considered. Here we report that EPCs and TNTs are significantly lower in controlled hypertensive patients versus normotensive subjects and that the disparity in vascular status between patients presenting with an FS of ≥ 10% with scarce vascular changes and those presenting with an FS of < 10% with severe vascular impairment is related to differences in EPC and TNT numbers. These data point to EPC and TNT numbers as potential CV risk factors to be included in the FS calculation.Fil: De Cavanagh, Elena M. V.. No especifíca;Fil: González, Sergio Alejandro. Universidad Austral. Hospital Universitario Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Inserra, Felipe. Universidad Maimónides; ArgentinaFil: Forcada, Pedro. No especifíca;Fil: Castellaro, Carlos. Universidad Austral; Argentina. Centro de Educación Medica E Invest.clinicas; ArgentinaFil: Chiabaut Svane, Jorge. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Obregón, Sebastián. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Casarini, María Jesús. No especifíca;Fil: Kempny, Pablo. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Kotliar, Carol Virginia. Universidad Austral. Hospital Universitario Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

El efecto Anrep post-estiramiento del miocardio requiere transactivación del receptor del factor de crecimiento epidérmico (RFCE)

En trabajos anteriores demostramos que la segunda fase de fuerza (SFF) post-estiramiento (efecto Anrep) es la manifestación mecánica de un mecanismo autocrino/paracrino que se inicia con la liberación secuencial de angiotensina II (Ang II) y endotelina (ET) y promueve la fosforilación y consecuente activación del intercambiador Na+ /H+ cardíaco (NHE1). Las quinasas mas frecuentemente involucradas en la fosforilación y activación del NHE1 son ERK 1/2-p90 RSK . Existen evidencias experimentales que demuestran que al menos ciertos efectos de Ang II/ET son mediados por transactivación del RFCE, mecanismo que requiere activación de la tirosina quinasa citosólica SRC.Facultad de Ciencias Médica

The Anrep effect requires transactivation of the epidermal growth factor receptor

Myocardial stretch elicits a biphasic contractile response: the Frank-Starling mechanism followed by the slow force response (SFR) or Anrep effect. In this study we hypothesized that the SFR depends on epidermal growth factor receptor (EGFR) transactivation after the myocardial stretch-induced angiotensin II (Ang II)/endothelin (ET) release. Experiments were performed in isolated cat papillary muscles stretched from 92 to 98% of the length at which maximal twitch force was developed (Lmax). The SFR was 123 ± 1% of the immediate rapid phase (n = 6, P < 0.05) and was blunted by preventing EGFR transactivation with the Src-kinase inhibitor PP1 (99 ± 2%, n = 4), matrix metalloproteinase inhibitor MMPI (108 ± 4%, n = 11), the EGFR blocker AG1478 (98 ± 2%, n = 6) or the mitochondrial transition pore blocker clyclosporine (99 ± 3%, n = 6). Stretch increased ERK1/2 phosphorylation by 196 ± 17% of control (n = 7, P < 0.05), an effect that was prevented by PP1 (124 ± 22%, n = 7) and AG1478 (131 ± 17%, n = 4). In myocardial slices, Ang II (which enhances ET mRNA) or endothelin-1 (ET-1)-induced increase in O2- production (146 ± 14%, n = 9, and 191 ± 17%, n = 13, of control, respectively, P < 0.05) was cancelled by AG1478 (94 ± 5%, n = 12, and 98 ± 15%, n = 8, respectively) or PP1 (100 ± 4%, n = 6, and 99 ± 8%, n = 3, respectively). EGF increased O2- production by 149 ± 4% of control (n = 9, P < 0.05), an effect cancelled by inhibiting NADPH oxidase with apocynin (110 ± 6% n = 7), mKATP channels with 5-hydroxydecanoic acid (5-HD; 105 ± 5%, n = 8), the respiratory chain with rotenone (110 ± 7%, n = 7) or the mitochondrial permeability transition pore with cyclosporine (111 ± 10%, n = 6). EGF increased ERK1/2 phosphorylation (136 ± 8% of control, n = 9, P < 0.05), which was blunted by 5-HD (97 ± 5%, n = 4), suggesting that ERK1/2 activation is downstream of mitochondrial oxidative stress. Finally, stretch increased Ser703 Na+/H+ exchanger-1 (NHE-1) phosphorylation by 172 ± 24% of control (n = 4, P < 0.05), an effect that was cancelled by AG1478 (94 ± 17%, n = 4). In conclusion, our data show for the first time that EGFR transactivation is crucial in the chain of events leading to the Anrep effect.Facultad de Ciencias Médica

La inhibición de la fosfodiesterasa 5A (FDE5A) disminuye la actividad del intercambiador Na<SUB>+</SUB>/h<SUB>+</SUB> miocárdico (NHE1) por activación de la fosfatasa PP2A

Hallazgos previos de nuestro laboratorio sugieren que los inhibidores de la FDE5A disminuyen la actividad del NHE1. Objetivo: Nuestro objetivo fue profundizar la caracterización de dicha vía de señalización.Facultad de Ciencias Médica

La inhibición de la fosfodiesterasa 5A (FDE5A) disminuye la actividad del intercambiador Na<SUB>+</SUB>/h<SUB>+</SUB> miocárdico (NHE1) por activación de la fosfatasa PP2A

Hallazgos previos de nuestro laboratorio sugieren que los inhibidores de la FDE5A disminuyen la actividad del NHE1. Objetivo: Nuestro objetivo fue profundizar la caracterización de dicha vía de señalización.Facultad de Ciencias Médica

Phosphodiesterase 5A inhibition decreases NHE-1 activity without altering steady state pH<SUB>i</SUB>: Role of phosphatases

Background/Aims: This study aimed to identify the signaling pathway for the proposed link between phosphodiesterase-5A (PDE5A) inhibition and decreased cardiac Na + /H + exchanger (NHE-1) activity. Methods: NHE-1 activity was assessed in rat isolated papillary muscles by the Na + -dependent initial pH i recovery from a sustained acidosis (ammonium prepulse). ERK1/2, p90RSK and NHE-1 phosphorylation state during acidosis was determined. Results: PDE5A inhibition (1 μmol/L sildenafil, SIL) did not modify basal pH i but significantly blunted pH i recovery after sustained acidosis. Although preventing ERK1/2- p90RSK signaling pathway (10 μmol/L U0126) mimicked SIL effect, SIL did not blunt the acidosis-mediated increase in kinases activation. SIL+U0126 did not show additive effect on NHE-1 activity. Then, we hypothesized that SIL could be activating phophasatases (PP1 and/or PP2A) to directly dephosphorylate NHE-1 despite preserved ERK1/2-p90RSK activation. Non-specific phosphatases inhibition (1 μmol/L okadaic acid) canceled SIL effect on pH i recovery from acidosis. Same result was observed by inhibiting PP2A either with a lower dose of okadaic acid (1 nmol/L) or, more specifically, with 100 μmol/L endothall. Consistently, NHE-1 phosphorylation at Ser703 increased after acidosis, SIL prevented this effect and PP2A inhibition (endothall) reverted SIL effect. Conclusion: We suggest that PDE5A inhibitors decrease NHE-1 phosphorylation and activity through a mechanism that involves PP2A activation.Facultad de Ciencias Médica