Cardiac Weight Index Research Articles

Reinitiation of compensatory lung growth after subsequent lung resection

In experimental animals, pneumonectomy results in rapid, hyperplastic compensatory growth of the remaining lung. The limits of this induced growth are unknown. We tested the hypothesis that compensatory growth can be reinitiated in the same lung after subsequent lung resection. A left thoracotomy (Sham group) or left pneumonectomy (PNX group) was performed in Sprague-Dawley rats. A third group underwent left pneumonectomy followed 4 weeks later by a bilobectomy of the right upper and middle lobes (PNX+LBX group). Four weeks after bilobectomy in the PNX+LBX group (8 weeks in the Sham and PNX groups), right ventricular pressures were measured by using the open chest technique, and total lung weight and lower plus cardiac lobe weight indices were measured. Lungs were inflation fixed at 25 cm H2O to measure lobe volume index and to perform morphometric measurements on lung sections. Right ventricle/left ventricle plus septum weight index was measured as another index of pulmonary hypertension. Total lung weight index was similar in all groups. Pneumonectomy resulted in increased lower plus cardiac lobe weight and volume indices, which were significantly augmented in the PNX+LBX group. The PNX+LBX group underwent a significant increase in total volume of respiratory region, airspace, and tissue and a decrease in alveolar surface density versus the PNX group. The PNX+LBX group also had significantly increased right ventricular systolic pressure and right ventricle/left ventricle plus septum index. These results demonstrate that compensatory growth can be reinitiated in lungs that had previously undergone postpneumonectomy compensatory growth. This subsequent growth, however, is more hypertrophic, and pulmonary hypertension develops despite subsequent compensatory growth.

Ovariectomy exacerbates the hypertrophic response in a mouse model of primary cardiac hypertrophy

There is evidence for sex-based differences in the development of cardiac hypertrophy that cannot be explained by differences in blood pressure. As functional oestrogen and testosterone receptors have been identified in the heart it is likely that sex-steroids may be responsible for such male-female differences. A transgenic mouse model, in which cardiac hypertrophy is driven by cardiac-specific overexpression of angiotensinogen, independent of changes in blood pressure (TG 1306), was used to investigate sex differences and the roles of the sex hormones in heart growth. We hypothesised that absence of oestrogen and presence of testosterone both exert pro-growth influences in the heart and, where there is genetic predisposition for cardiac hypertrophy, these effects are more pronounced. Male and female wild type (WT) and transgenic (TG) mice underwent gonadectomy (GDX) at 12 weeks of age. 4 weeks post surgery body weight and blood pressure were recorded and the hearts collected for determination of cardiac and ventricular weight indices (CWI and VWI mg/g). GDX had no effect on heart weight in WT or TG male mice compared to sham-operated males. In females GDX had no effect on heart weight in WT mice, however, tended to increase heart weight in TG mice (n=5) compared to sham-operated TG controls (n=7) (CWI 6.4±0.62 GDX vs 5.66±0.19 sham and VWI 6.05±0.59 GDX vs 5.32±0.17 sham). These results suggest that the absence of oestrogen exacerbates heart growth where there is genetic predisposition for cardiac hypertrophy.

Post-natal cardiac development in an experimental model of normotensive cardiac hypertrophy

Background:The mechanisms underlying neonatal programming of adult diseases remain elusive, but considerable attention has recently focussed on apoptosis as an antecedent of cellular hypertrophy. At maturity, the Hypertrophic Heart Rat (HHR) displays cardiomyocyte hypertrophy in association with an apparent reduction in myocyte number.Aim:The aim of this study was to establish a link between neonatal myocardial apoptosis and the developmental onset of cardiac hypertrophy in the HHR.Methods: Hearts were freshly isolated from male HHR, and control strain Normal Heart Rats (NHR), at different stages of post-natal development (p2, 4 wk, 6 wk, 8 wk, 12 wk; n = 8−11). Total cardiac weights were measured and divided by body mass to give a cardiac weight index (mg/g). Tissue bax-1 and bcl-2 mRNA expression levels were quantified in neonates by real-time RT-PCR to give a bax-1/bcl-2 ratio which was used as a ‘cell death index’.Results: At post-natal day 2, HHR hearts were considerably smaller than NHR (4.33 ± 0.19 vs 5.01 ± 0.08 mg/g, P < 0.05). This growth-restricted phenotype was associated with a high bax-1/bcl-2 mRNA expression ratio in the heart (50% higher than NHR, P < 0.05). HHR hearts ‘caught-up’ to NHR by 4 weeks (5.10 ± 0.15 vs 5.16 ± 0.11 mg/g) and were 11% larger than NHR by 8 weeks of age. This was followed by a rapid period of growth, and by 12 weeks of age HHR CWIs were 27% larger than NHR (P(strain) < 0.01).Conclusion: Neonatal cardiac growth restriction, in association with increased expression of pro-apoptotic (or anti-survival) genes, is a prelude to cardiac hypertrophy at maturity in the HHR.

Chronic Administration of Aqueous Extract of Hibiscus sabdariffa. Enhances Na+-K+-ATPase and Ca2+-Mg2+-ATPase Activities of Rat Heart

The effect of oral administration of an aqueous extract of Hibiscus sabdariffa. Linn petals on Na+-K+-ATPase and Ca2+-Mg2+-ATPase activities of rat heart have been investigated in Sprague-Dawley rats. The extract was administered orally in doses of 25.0 and 50.0 mg/kg body weight for 28 days. Results showed that Hibiscus sabdariffa. treatment led to significant increases (p < 0.001) of Na+-K+-ATPase and Ca2+-Mg2+-ATPase at both doses. Cardiac weight index of rats treated with H. sabdariffa. at a dose of 50 mg/kg body weight was significantly reduced (p < 0.01) compared with those of the control and rats treated with H. sabdariffa. at a lower dose. Administration of the extract at both doses did not show any signs of cardiotoxicity and hepatotoxicity as judged by biochemical “marker” enzymes (alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase) activities in plasma, heart, and liver of rats. These results demonstrate that aqueous extract of H. sabdariffa. enhances cardiac Na+-K+-ATPase and Ca2+-Mg2+-ATPase activities and supports the public belief that H. sabdariffa. may be a safe cardioprotective agent.

Elevated dietary sodium intake exacerbates myocardial hypertrophy associated with cardiac-specific overproduction of angiotensin II

Cardiac hypertrophy is an independent risk factor predictive of cardiovascular disease and is significantly associated with morbidity and mortality. The mechanism by which angiotensin II (Ang II) and dietary sodium exert additive effects on the development of cardiac hypertrophy is unclear. The goal of this study was to evaluate the hypothesis that, where there is a genetic predisposition to Ang II-dependent hypertrophy, there is also an increased susceptibility to sodium-induced hypertrophy mediated by AT1-receptor expression. Diets of low sodium (LS, 0.3% w:w) and high sodium (HS, 4.0% w:w) content were fed to adult (age 25 weeks) control wild-type mice (WT) and to transgenic mice exhibiting cardiac-specific overexpression of angiotensinogen (TG). At the conclusion of a 40-day treatment period, cardiac tissue weights were compared and the relative expression levels of Ang II receptor subtypes (AT(1A) and AT(2)) were evaluated using RT-PCR. WT and TG mice fed HS and LS diets maintained comparable weight gains during the treatment period. The normalised heart weights of TG mice were elevated compared to WT, and the extent of the increase was greater for mice maintained on the HS diet treatments (WT 12% vs TG 41% increase in cardiac weight index). While a similar pattern of growth was observed for ventricular tissues, the atrial weight parameters demonstrated an additional significant effect of dietary sodium on tissue weight, independent of animal generic type. No differences in the relative (GAPDH normalised) expression levels of AT(1A)- and AT(2)-receptor mRNA were observed between diet or animal generic groups. This study demonstrates that, where there is a pre-existing genetic condition of Ang II-dependent cardiac hypertrophy, the pro-growth effect of elevated dietary sodium is selectively augmented. In TG and WT mice, this effect was evident with a relatively short dietary treatment intervention (40 days). Evaluation of the levels of Ang II receptor mRNA further demonstrated that this differential growth response was not associated with an altered relative expression of either AT(1A)- or AT(2)-receptor subtypes. The cellular mechanistic bases for this specific ANG II-dietary sodium interaction remain to be elucidated.

Renal endothelin receptor type B upregulation in rats with low or high renin hypertension.

To evaluate the role of endothelin-1 (ET-1) in hypertension, we investigated density and distribution of ETA and ETB receptors in hearts and kidneys of deoxycorticosterone acetate (DOCA)-salt and 1 kidney -- 1 clip (1K1C) hypertensive rats. Five groups of uninephrectomized Wistar rats were put on a low salt diet. Three groups of rats drank tap water and two groups received saline. One group of each regimen received DOCA subcutaneously and two corresponding groups without DOCA served as controls. The fifth group of rats had the renal artery clipped to induce 1K1C hypertension. At 6 weeks, mean arterial pressure (MAP) was recorded and membrane binding assays using 125I-ET-1 were carried out. MAP was increased from control 122 +/- 3 to 155 +/- 6 and 218 +/- 11 mmHg in DOCA-salt and 1K1C rats, respectively, and cardiac weight index was increased. ETA receptors were predominantly expressed in the heart, whereas ETB receptors were predominant in the kidney. In the kidneys, the density of the ETB receptor subtype was upregulated in DOCA-salt and 1K1C rats from 160 +/- 8 to 217 +/- 12 and 190 +/- 2 fmol/mg (P < 0.05), respectively, and ETA tended to be downregulated (P = 0.057). Plasma renin activity was decreased in DOCA-salt rats from 17 +/- 3 to 0.17 +/- 0.01 ng/ml per h and increased in 1K1C rats on low salt diet to 30 +/- 5 ng/ml per h. Since ETB is the predominant endothelin receptor in the kidneys, upregulation of the ETB receptor mediating vasodilation and downregulation of the ETA receptor mediating vasoconstriction would be compatible with a mainly renal counter-regulatory effect of endothelin-1 to hypertension. Both low and high renin models of hypertension may be affected.

Blood pressure, cardiac, and renal responses to salt and deoxycorticosterone acetate in mice: role of Renin genes.

Several studies have demonstrated that mice are polymorphic for the number of renin genes, with some inbred strains harboring one gene (Ren-1(c)) and other strains containing two genes (Ren-1(d) and Ren-2). In this study, the effects of 1% salt and deoxycorticosterone acetate (DOCA)/salt were investigated in one- and two-renin gene mice, for elucidation of the role of renin in the modulation of BP, cardiac, and renal responses to salt and DOCA. The results demonstrated that, under baseline conditions, mice with two renin genes exhibited 10-fold higher plasma renin activity, 100-fold higher plasma renin concentrations, elevated BP (which was angiotensin II-dependent), and an increased cardiac weight index, compared with one-renin gene mice (all P < 0.01). The presence of two renin genes markedly increased the BP, cardiac, and renal responses to salt. The number of renin genes also modulated the responses to DOCA/salt. In one-renin gene mice, DOCA/salt induced significant renal and cardiac hypertrophy (P < 0.01) even in the absence of any increase in BP. Treatment with losartan, an angiotensin II AT(1) receptor antagonist, decreased BP in two-renin gene mice but not in one-renin gene mice. However, losartan prevented the development of cardiac hypertrophy in both groups of mice. In conclusion, these data demonstrate that renin genes are important determinants of BP and of the responses to salt and DOCA in mice. The results confirm that the Ren-2 gene, which controls renin production mainly in the submaxillary gland, is physiologically active in mice and is not subject to the usual negative feedback control. Finally, these data provide further evidence that mineralocorticoids promote cardiac hypertrophy even in the absence of BP changes. This hypertrophic process is mediated in part by the activation of angiotensin II AT(1) receptors.

Exacerbation of chronic renovascular hypertension and acute renal failure in heme oxygenase-1-deficient mice.

Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO and its products, we hypothesized that HO would be important for the regulation of blood pressure and ischemic injury. We studied chronic renovascular hypertension in mice deficient in the inducible isoform of HO (HO-1) using a one kidney-one clip (1K1C) model of disease. Systolic blood pressure was not different between wild-type (HO-1(+/+)), heterozygous (HO-1(+/-)), and homozygous null (HO-1(-/-)) mice at baseline. After 1K1C surgery, HO-1(+/+) mice developed hypertension (140+/-2 mm Hg) and cardiac hypertrophy (cardiac weight index of 5.0+/-0.2 mg/g) compared with sham-operated HO-1(+/+) mice (108+/-5 mm Hg and 4.1+/-0.1 mg/g, respectively). However, 1K1C produced more severe hypertension (164+/-2 mm Hg) and cardiac hypertrophy (6.9+/-0.6 mg/g) in HO-1(-/-) mice. HO-1(-/-) mice also experienced a high rate of death (56%) within 72 hours after 1K1C surgery compared with HO-1(+/+) (25%) and HO-1(+/-) (28%) mice. Assessment of renal function showed a significantly higher plasma creatinine in HO-1(-/-) mice compared with HO-1(+/-) mice. Histological analysis of kidneys from 1K1C HO-1(-/-) mice revealed extensive ischemic injury at the corticomedullary junction, whereas kidneys from sham HO-1(-/-) and 1K1C HO-1(+/-) mice appeared normal. Taken together, these data suggest that chronic deficiency of HO-1 does not alter basal blood pressure; however, in the 1K1C model an absence of HO-1 leads to more severe renovascular hypertension and cardiac hypertrophy. Moreover, renal artery clipping leads to an acute increase in ischemic damage and death in the absence of HO-1.

Cardiac and Kidney Weight Indices following Dietary Salt Loading and/or Chronic Nitric Oxide Synthase Inhibition in the Hooded (Aguti) Rat

This study was designed to investigate if dietary salt-loading and/or chronic Nitric Oxide Synthase (NOS) inhibition are associated with cardiac hypertrophy and changes in renal mass in the hooded (Aguti) rat. Hooded rats 8-10 weeks old were divided into 4 groups viz: control, salt, L-NAME (N?-L-Arginine Methyl Ester) and salt + L-NAME. Control rats were given a normal rat diet and water. Hypertension was induced in hooded rats by giving the following treatments: rats in the salt group were given an 8% NaCl diet and water for 6 weeks; rats in the L-NAME group were fed the normal rat diet and given water containing L-NAME at a dose of 100mg/Kg/day for 4 weeks; rats in the salt + L-NAME group were given both treatments. The rats (n = 8 per group) were anaesthetized and the hearts and kidneys excised. The cardiac weight indices and the kidney weights were measured. The cardiac weight, cardiac weight index, left and right ventricular weight indices and kidney weight showed no significant difference in the test groups compared to control. Kidney weight/body weight (g/100g body weight) increased significantly (P<0.05) in salt+L-NAME rats (0.35 +/- 0.015) compared to control (0.31 +/- 0.013), salt-loaded (0.29 +/- 0.013) and L-NAME rats (0.20 +/- 0.010). Six weeks of dietary salt-loading and /or four weeks of L-NAME-loading were not associated with cardiac hypertrophy in the hooded rat. However a combination of both manoeuvres resulted in renal hypertrophy.