Gender differences in cardiac left ventricular mass and function: clinical and experimental observations

Background: The aim of this study was to evaluate gender-associated impact on left ventricular mass (LVM) and on left ventricular function (LVF) in humans and rats with aging. Methods: Myocyte area and collagen volume fraction (CVF) were studied in rats. LVM and LVF were evaluated in animals and humans by echocardiography and LVM index (LVMI) was obtained. Results: LVMI, myocyte area and CVF were similar in males and females of 1-month-old rats. LVMI in children was similar in both genders. In contrast, in 6-month-old rats (5 males and 5 females), LVMI (17.7 ± 0.7 mg/mm vs. 10.1 ± 0.2 mg/mm; p < 0.01), and myocyte area (4572.5 ± 72.6 μm2 vs. 3293.85 ± 57.8 μm2 , p < 0.01) were higher in male animals without differences in CVF. Men (n = 25) exhibited greater LVMI than women (n = 25) (77.4 ± 3.2 g/m2 vs. 63.3 ± 1.8 g/m2 , p < 0.01), whereas the LVF was higher in women (105.9 ± 2.9% vs. 95.3 ± 3.5%, p < 0.01). Conclusions: There is a clear gender-associated impact on LVM with aging in humans and rats. Similar CVF and LVF associated to greater myocyte size and LVM in male rats suggest a process of physiological response. However, the increase in cardiac mass without an associated improved cardiac function in men in comparison to women could likely represent a potential disadvantage in the adaptive response during growth. (Cardiol J 2014; 21, 1: x–x)Fil: Escudero, Eduardo Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Orlowski, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Diaz, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Pinilla, Oscar Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Ennis, Irene Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Aiello, Ernesto Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - la Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentin

Transport and release of calcium by sarcoplasmic reticulum in chemically skinned ventricular muscle of the rat

Strips of rat ventricle were treated with EGTA (5 mM) for 24 h at 4°C and used to perform isotopical measurements of transport and release of Ca2+ in the SR in situ.45Ca accumulated by these preparations showed dependence on time of incubation until it reached saturation after 30 min. Rate and capacity of Ca2+ accumulation were calculated in 0.075 nmol mg ww−1 min−1 and 0.402 nmol mg ww−1, respectively. These values were increased by a factor of 2.6 and 8.6 when K oxalate was present in the incubation media as could be expected for Ca2+ transported by SR. Ca2+ release was assayed on45Ca desaturation curves at three free Ca2+ concentrations: 0.3, 1 and 10 μM. Significant increases in the velocity of Ca2+ efflux and net release of Ca2+ were induced only by 1 μM free Ca2+, and the Ca2+ release could be inhibited by 75% when 50 μM of ruthenium red was included in the washout solution. These results are in agreement with those obtained in assessing the SR function by mechanical measurements in skinned cardiac cells or by biochemical determinations in isolated cardiac SR vesicles. In spite of the fact that the resolution time is not as high as that required for the physiological handling of Ca2+ by SR, this methodology looks promising for approaching the SR function in cardiac pathologies as well as the effects of drugs on transport and release of Ca2+ by cardiac SR.Centro de Investigaciones Cardiovasculare

Calcium-induced calcium release in EGTA-skinned aortic strips from genetically hypertensive and normotensive rats

The release of 45Ca induced by Ca2+ was studied in genetically hypertensive (SHR) and normotensive (WKY) rats using EGTA-skinned aortic strips. Strips preloaded with 45Ca (pCa 6.6) were desaturated at 5mM of EGTA. A slow component of the washout in aorta from SHRs exhibited higher Ca content and a lower rate of Ca leak than that in aorta from WKY rats. This slow component was stimulated during washing with 0.03, 0.3, 1 or 10μM free Ca2+. The release of 45Ca induced by Ca2+ proceeded at similar rates in preparations of the two strains. Compared to WKY aortic strips the stimulated efflux of 45Ca was greater in SHR aortic strips due to the higher Ca content. About half of the release of 45Ca induced by 1μM free Ca2+ during the first 6 minutes of stimulation was blocked by 0.6mM of ryanodine or 50μM of ruthenium red, thus identifying the sarcoplasmic reticulum as a source of Ca release. The results suggest that this intracellular storage of Ca in aorta from genetically hypertensive rats is relevant for the generation of high levels of cytosolic Ca2+.Centro de Investigaciones Cardiovasculare

Modulation of the cardiac sodium/bicarbonate cotransporter by the renin angiotensin aldosterone system: pathophysiological consequences

The sodium/bicarbonate cotransporter (NBC) is one of the major alkalinizing mechanisms in the cardiomyocytes. It has been demonstrated the existence of at least two functional isoforms, one that promotes the co-influx of 1 molecule of Na+ per 1 molecule of HCO¯3 (electroneutral isoform; NBCn1) and the other one that generates the co-influx of 1 molecule of Na+ per 2 molecules of HCO¯3 (electrogenic isoform; NBCe1). Both isoforms are important to maintain intracellular pH (pHi) and sodium concentration ([Na+]i). In addition, NBCe1 generates an anionic repolarizing current that modulates the action potential duration (APD). The renin-angiotensin-aldosterone system (RAAS) is implicated in the modulation of almost all physiological cardiac functions and is also involved in the development and progression of cardiac diseases. It was reported that angiotensin II (Ang II) exhibits an opposite effect on NBC isoforms: it activates NBCn1 and inhibits NBCe1. The activation of NBCn1 leads to an increase in pHi and [Na+]i, which indirectly, due to the stimulation of reverse mode of the Na+/Ca2+ exchanger (NCX), conduces to an increase in the intracellular Ca2+ concentration. On the other hand, the inhibition of NBCe1 generates an APD prolongation, potentially representing a risk of arrhythmias. In the last years, the potentially altered NBC function in pathological scenarios, as cardiac hypertrophy and ischemia-reperfusion, has raised increasing interest among investigators. This review attempts to draw the attention on the relevant regulation of NBC activity by RAAS, since it modulates pHi and [Na+]i, which are involved in the development of cardiac hypertrophy, the damage produced by ischemia-reperfusion and the generation of arrhythmic events, suggesting a potential role of NBC in cardiac diseases.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Autocrine stimulation of cardiac Na+-Ca2+ exchanger currents by endogenous endothelin released by angiotensin II

The goal of the present study was to evaluate the effects of Ang II on the current produced by the Na+-Ca2+ exchanger (INCX) working in the reverse mode and the possible autocrine role played by the release of endothelin (ET) in these actions. INCX was studied in isolation in cat cardiac myocytes. Angiotensin II (Ang II) (100 nmol/L) increased INCX at potentials higher than 0 mV (at +60 mV: 2.07±0.22 pA/pF in control versus 2.73±0.22 pA/pF in Ang II, n = 9; P NCX induced by Ang II was prevented by the treatment of the cells with the unspecific blocker of the ET receptors, TAK 044 (1 μmol/L) (at +60 mV: 2.15±0.27 pA/pF in control versus 2.01±0.26 pA/pF in Ang II, n=5, NS). These results show, for the first time, that the effect of Ang II on INCX is the result of the autocrine actions of ET released by the octapeptide.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Autocrine stimulation of cardiac Na+-Ca2+ exchanger currents by endogenous endothelin released by angiotensin II

The goal of the present study was to evaluate the effects of Ang II on the current produced by the Na+-Ca2+ exchanger (INCX) working in the reverse mode and the possible autocrine role played by the release of endothelin (ET) in these actions. INCX was studied in isolation in cat cardiac myocytes. Angiotensin II (Ang II) (100 nmol/L) increased INCX at potentials higher than 0 mV (at +60 mV: 2.07±0.22 pA/pF in control versus 2.73±0.22 pA/pF in Ang II, n = 9; P NCX induced by Ang II was prevented by the treatment of the cells with the unspecific blocker of the ET receptors, TAK 044 (1 μmol/L) (at +60 mV: 2.15±0.27 pA/pF in control versus 2.01±0.26 pA/pF in Ang II, n=5, NS). These results show, for the first time, that the effect of Ang II on INCX is the result of the autocrine actions of ET released by the octapeptide.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Physical and functional interaction of carbonic anhydrases and nbce1 Na+/HCO3- cotransporter in the heart : The metabolon revisited

To allow the control of their intracellular pH (pHi) and bicarbonate (HCO3 - ) levels, cells express HCO3 - transport proteins (NBC) that rapidly and selectively move HCO3 - across the plasma membrane. In the heart electroneutral NBCn1 and electrogenic NBCe1 Na+ /HCO3 - cotransporters facilitate the transmembrane movement of HCO3 - ions into cardiomyocytes, as a response to acid loading. NBCe1 associates with carbonic anhydrases (CA), the enzymes that catalyze the reversible conversion of CO2 to HCO3 - , to form a transport metabolon, a weakly associated complex of sequential metabolic enzymes. NBCe1 physically/functionally interact with the isoforms II, IV, and IX of CA, to increase the HCO3 - flux through cell membranes. NBCe1 and CAs interaction occurs in different cellular compartments in the heart muscle. Physiologically, the NBCe1/CA complex could contribute to the removal of H+ ions accumulated as the result of the contractile activity of the cardiac muscle cell, and this process may occur at the surface sarcolemma (CAII-NBCe1-CAIV complex) or at the ttubule (CAII-NBCe1-CAIX complex) of the cardiomyocyte. Pathologically, upregulation of the NBCe1/CA metabolon system upon ischemic/hypoxic conditions of the heart would favor the hypertrophic growth of the cardiac cells.Centro de Investigaciones Cardiovasculare

Gender differences in cardiac left ventricular mass and function: Clinical and experimental observations

Background: The aim of this study was to evaluate gender-associated impact on left ventricular mass (LVM) and on left ventricular function (LVF) in humans and rats with aging.Methods: Myocyte area and collagen volume fraction (CVF) were studied in rats. LVM and LVF were evaluated in animals and humans by echocardiography and LVM index (LVMI) was obtained.Results: LVMI, myocyte area and CVF were similar in males and females of 1-month-oldrats. LVMI in children was similar in both genders. In contrast, in 6-month-old rats (5 malesand 5 females), LVMI (17.7 ± 0.7 mg/mm vs. 10.1 ± 0.2 mg/mm; p &lt; 0.01), and myocyte area (4572.5 ± 72.6 μm2 vs. 3293.85 ± 57.8 μm2, p &lt; 0.01) were higher in male animals without differences in CVF. Men (n = 25) exhibited greater LVMI than women (n = 25) (77.4 ± 3.2 g/m2 vs. 63.3 ± 1.8 g/m2, p &lt; 0.01), whereas the LVF was higher in women (105.9 ± 2.9% vs. 95.3 ± 3.5%, p &lt; 0.01).Conclusions: There is a clear gender-associated impact on LVM with aging in humans and rats. Similar CVF and LVF associated to greater myocyte size and LVM in male rats suggest a process of physiological response. However, the increase in cardiac mass without an associated improved cardiac function in men in comparison to women could likely represent a potential disadvantage in the adaptive response during growth

Gender differences in cardiac left ventricular mass and function: clinical and experimental observations

Background: The aim of this study was to evaluate gender-associated impact on left ventricular mass (LVM) and on left ventricular function (LVF) in humans and rats with aging. Methods: Myocyte area and collagen volume fraction (CVF) were studied in rats. LVM and LVF were evaluated in animals and humans by echocardiography and LVM index (LVMI) was obtained. Results: LVMI, myocyte area and CVF were similar in males and females of 1-month-old rats. LVMI in children was similar in both genders. In contrast, in 6-month-old rats (5 males and 5 females), LVMI (17.7 ± 0.7 mg/mm vs. 10.1 ± 0.2 mg/mm; p < 0.01), and myocyte area (4572.5 ± 72.6 μm2 vs. 3293.85 ± 57.8 μm2, p < 0.01) were higher in male animals without differences in CVF. Men (n = 25) exhibited greater LVMI than women (n = 25) (77.4 ± 3.2 g/m2 vs. 63.3 ± 1.8 g/m2, p < 0.01), whereas the LVF was higher in women (105.9 ± 2.9% vs. 95.3 ± 3.5%, p < 0.01). Conclusions: There is a clear gender-associated impact on LVM with aging in humans and rats. Similar CVF and LVF associated to greater myocyte size and LVM in male rats suggest a process of physiological response. However, the increase in cardiac mass without an associated improved cardiac function in men in comparison to women could likely represent a potential disadvantage in the adaptive response during growth.Facultad de Ciencias Médica

Generación de anticuerpos inhibitorios de la función del cotransportador sodio/bicarbonato cardíaco : Una posible futura herramienta terapéutica

El cotransportador Na+/HCO3- (NBC) cardíaco es un importante mecanismo alcalinizante encargado de regular el pH intracelular (pHi) en las células cardíacas. En el corazón se han identificado al menos 3 isoformas del NBC: 1 electroneutra (NBC3), con estequiometría 1 Na+ 1 HCO3-, y 2 electrogénicas (NBC1 y NBC4), las cuales introducen 2 moléculas de HCO3- por cada 1 de Na+. Dado que este último mecanismo genera una corriente aniónica repolarizante, su correcto funcionamiento es relevante en el control de la forma y duración del potencial de acción (PA).Centro de Investigaciones Cardiovasculare