Eduardo M. Escudero

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na+/H+ Exchanger Inhibition

Abstract— Cardiac hypertrophy is often associated with an increased sympathetic drive, and both in vitro and in vivo studies have demonstrated the development of cardiomyocyte hypertrophy in response to either [alpha]‐ or [beta]‐adrenergic stimulation. Because an association between the Na+/H+ exchanger and cellular growth has been proposed, this study aimed to analyze the possible role of the antiporter in isoproterenol‐induced cardiac hypertrophy. Isoproterenol alone (5 mg/kg IP once daily) or combined with a selective inhibitor of the Na+/H+ exchanger activity (3 mg · kg‐1 · d‐1 BIIB723) was given to male Wistar rats for 30 days. Sex‐ and age‐matched rats that received 0.9% saline IP daily served as controls. Echocardiographic follow‐up showed a 33% increase in left ventricular mass in the isoproterenol‐treated group, whereas it did not increase in the isoproterenol+BIIB723‐treated group. Heart weight–to–body weight ratio at necropsy was 2.44±0.11 in controls and increased to 3.35±0.10 (P <0.05) with isoproterenol, an effect that was markedly attenuated by BIIB723 (2.82±0.07). Intense cardiomyocyte enlargement and severe subendocardial fibrosis were found in isoproterenol‐treated rats, and both effects were attenuated by BIIB723. Myocardial Na+/H+ exchanger activity and protein expression significantly increased in isoproterenol‐treated rats compared with the control group (1.45±0.11 vs 0.91±0.05 arbitrary units, P <0.05). This effect was significantly reduced by BIIB723 (1.17±0.02, P <0.05). In conclusion, our results show that Na+/H+ exchanger inhibition prevented the development of isoproterenol‐induced hypertrophy and fibrosis, providing strong evidence in favor of a key role played by the antiporter in this model of cardiac hypertrophy.

Endurance Training in the Spontaneously Hypertensive Rat: Conversion of Pathological into Physiological Cardiac Hypertrophy

The effect of endurance training (swimming 90 min/d for 5 days a week for 60 days) on cardiac hypertrophy was investigated in the spontaneously hypertensive rat (SHR). Sedentary SHRs (SHR-Cs) and normotensive Wistar rats were used as controls. Exercise training enhanced myocardial hypertrophy assessed by left ventricular weight/tibial length (228±7 versus 251±5 mg/cm in SHR-Cs and exercised SHRs [SHR-Es], respectively). Myocyte cross-sectional area increased ≈40%, collagen volume fraction decreased ≈50%, and capillary density increased ≈45% in SHR-Es compared with SHR-Cs. The mRNA abundance of atrial natriuretic factor and myosin light chain 2 was decreased by the swimming routine (100±19% versus 41±10% and 100±8% versus 61±9% for atrial natriuretic factor and myosin light chain 2 in SHR-Cs and SHR-Es, respectively). The expression of sarcoplasmic reticulum Ca2+ pump was significantly augmented, whereas that of Na+/Ca2+ exchanger was unchanged (93±7% versus 167±8% and 158±13% versus 157±7%, sarcoplasmic reticulum Ca2+ pump and Na+/Ca2+ exchanger in SHR-Cs and SHR-Es, respectively; P<0.05). Endurance training inhibited apoptosis, as reflected by a decrease in caspase 3 activation and poly(ADP-ribose) polymerase-1 cleavage, and normalized calcineurin activity without inducing significant changes in the phosphatidylinositol 3-kinase/Akt pathway. The swimming routine improved midventricular shortening determined by echocardiography (32.4±0.9% versus 36.9±1.1% in SHR-Cs and SHR-Es, respectively; P<0.05) and decreased the left ventricular free wall thickness/left ventricular cavity radius toward an eccentric model of cardiac hypertrophy (0.59±0.02 versus 0.53±0.01 in SHR-Cs and SHR-Es, respectively; P<0.05). In conclusion, we present data demonstrating the effectiveness of endurance training to convert pathological into physiological hypertrophy improving cardiac performance. The reduction of myocardial fibrosis and calcineurin activity plus the increase in capillary density represent factors to be considered in determining this beneficial effect.

Phosphodiesterase 5A Inhibition Induces Na/H Exchanger Blockade and Protection Against Myocardial Infarction

Acute phosphodiesterase 5A inhibition by sildenafil or EMD360527/5 promoted profound inhibition of the cardiac Na+/H+ exchanger (NHE-1), detected by the almost null intracellular pH recovery from an acute acid load (ammonium prepulse) in isolated papillary muscles from Wistar rats. Inhibition of phosphoglycerate kinase-1 (KT5823) restored normal NHE-1 activity, suggesting a causal link between phosphoglycerate kinase-1 increase and NHE-1 inhibition. We then tested whether the beneficial effects of NHE-1 inhibitors against the deleterious postmyocardial infarction (MI) remodeling can be detected after sildenafil-mediated NHE-1 inhibition. MI was induced by left anterior descending coronary artery ligation in Wistar rats, which were randomized to placebo or sildenafil (100 mg kg−1 day−1) for 6 weeks. Sildenafil significantly increased left ventricular phosphoglycerate kinase-1 activity in the post-MI group without affecting its expression. MI increased heart weight/body weight ratio, left ventricular myocyte cross-sectional area, interstitial fibrosis, and brain natriuretic peptide and NHE-1 expression. Sildenafil blunted these effects. Neither a significant change in infarct size nor a change in arterial or left ventricular systolic pressure was detected after sildenafil. MI decreased fractional shortening and the ratio of the maximum rate of rise of LVP divided by the pressure at the moment such maximum occurs, effects that were prevented by sildenafil. Intracellular pH recovery after an acid load was faster in papillary muscles from post-MI hearts (versus sham), whereas sildenafil significantly inhibited NHE-1 activity in both post-MI and sildenafil-treated sham groups. We conclude that increased phosphoglycerate kinase-1 activity after acute phosphodiesterase 5A inhibition blunts NHE-1 activity and protects the heart against post-MI remodeling and dysfunction.

Diagnostic role of new Doppler index in assessment of renal artery stenosis

BackgroundRenal artery stenosis (RAS) is one of the main causes of secondary systemic arterial hypertension. Several non-invasive diagnostic methods for RAS have been used in hypertensive patients, such as color Doppler ultrasound (US). The aim of this study was to assess the sensitivity and specificity of a new renal Doppler US direct-method parameter: the renal-renal ratio (RRR), and compare with the sensitivity and specificity of direct-method conventional parameters: renal peak systolic velocity (RPSV) and renal aortic ratio (RAR), for the diagnosis of severe RAS.MethodsOur study group included 34 patients with severe arterial hypertension (21 males and 13 females), mean age 54 (± 8.92) years old consecutively evaluated by renal color Doppler ultrasound (US) for significant RAS diagnosis. All of them underwent digital subtraction arteriography (DSA). RAS was significant if a diameter reduction > 50% was found. The parameters measured were: RPSV, RAR and RRR. The RRR was defined as the ratio between RPSV at the proximal or mid segment of the renal artery and RPSV measured at the distal segment of the renal artery. The sensitivity and specificity cutoff for the new RRR was calculated and compared with the sensitivity and specificity of RPSV and RAR.ResultsThe accuracy of the direct method parameters for significant RAS were: RPSV >200 cm/s with 97% sensitivity, 72% specificity, 81% positive predictive value and 95% negative predictive value; RAR >3 with 77% sensitivity, 90% specificity, 90% positive predictive value and 76% negative predictive value. The optimal sensitivity and specificity cutoff for the new RRR was >2.7 with 97% sensitivity (p < 0.004) and 96% specificity (p < 0.02), with 97% positive predictive value and 97% negative predictive value.ConclusionThe new RRR has improved specificity compared with the direct method conventional parameters (RPSV >200cm/s and RAR >3). Both RRR and RPSV show better sensitivity than RAR for the RAS diagnosis.

Sex-Related Difference in Left Ventricular Mass in Nonhypertensive Young Adults: Role of Arterial Pressure

BACKGROUND Blood pressure (BP) is higher in men than in women at similar ages through adult life. Interestingly, a similar pattern is detected in left ventricular mass (LVM), classically attributed to differences in body size. However, the existing difference in BP between sexes might be relevant in determining LVM and it has been not fully investigated. Therefore, we set out to determine the impact of nonhypertensive levels of BP on the sex-associated LVM difference. METHODS We conducted population-based study including 283 young students (52% male; age 20.62 ± 1.31 years). BP was determined twice using standard mercury sphygmomanometers in 2 occasions. LVM was determined with M-mode echocardiography. To dissect the relative contribution of BP, volume load, and body size to the sex-related difference in LVM, an analysis of covariance was performed. RESULTS Mean systolic and diastolic BP were 10.00 ± 0.96 and 4.59 ± 0.78 mm Hg higher and LVM was 34.87 ± 3.12 g larger in men than in women, respectively (P < 0.01, t test). When LVM was adjusted to mean BP, the sex difference was reduced by 16%. When LVM was adjusted to body size and hemodynamic load, this difference was reduced by 68.5%. CONCLUSIONS We report in a sample of young nonhypertensive students a difference in LVM between women and men that is partially explained (16%) by sex differences in BP, supporting an early effect of BP on cardiac mass even in the absence of hypertension. A more relevant effect could be expected as the population ages.

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.

Atrial Mass and Antiphospholipid Syndrome

Antiphospholipid Syndrome (APS) is found in 20% to 35% of patients with systemic lupus erythematosus (SLE); it is known as secondary APS1 and produces both venous and arterial thrombosis. Another feature is the cardiovascular affection, especially valvular, being the mitral valve the most affected. This may be asymptomatic or may cause regurgitation. In some cases, the presence of intracardiac thrombi mimicking atrial myxoma is described.2,3 We report the case of a patient with diagnosis of SLE and secondary APS who had a mass in the right atrium.

Left Ventricular Mass and Diastolic Function in Young Individuals With a First Elevated “Casual” Blood Pressure

Blood pressure (BP) measurement induces an alerting reaction that causes an increase of BP above the “basal” when it is measured in the clinic. The intensity of this elevation is function of many factors and decreases in subsequent measurements. Thus some individuals who have elevated BP values at a first “casual” determination have normal values at subsequent examinations. The present study was undertaken to investigate left ventricular (LV) function and structure in young individuals with a first elevated “casual” BP. In order to study this we separated two groups of young male individuals (average age 21 ± 0.6) from a previous screening in which BP had been measured at two different examinations separated by 1 week. Group A (n =12) had diastolic blood pressure (DBP) <70mmHg at both screenings (63 ± 2 and 62 ± 2mmHg, respectively), and group B (n = 9) had DBP 3≥90 mmHg at the first screening (94 ± 1 mmHg) but below these values at the second screening (76 ± 3 mmHg). Average age and body mass index were similar in both groups. Left ventricular function and structure were evaluated with echocardiographic and Doppler studies. None of the parameters measured was significantly different in any of the groups. The results provide evidence that young individuals who could be classified as hypertensives on a first screening and lose their condition at latter screenings do not present with LV dysfunction and consequently they should be considered normotensives according to the JNC-IV criteria.