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PubMed2006

A comprehensive review and analysis of 25 years of data from an in vivo canine model of sudden cardiac death: implications for future anti-arrhythmic drug development.

Sudden cardiac death resulting from ventricular tachyarrhythmias remains the leading cause of death in industrially developed countries, accounting for between 300,000 and 500,000 deaths each year in the United States. Yet, despite the enormity of this problem, the development of safe and effective anti-arrhythmic agents remains elusive. The identification of effective anti-arrhythmic agents is critically dependent upon the use of appropriate animal models of human disease. During the last 25 years, a canine model of sudden cardiac death has proven to be useful in both the identification of factors contributing to ventricular fibrillation (VF) and the evaluation of potential anti-arrhythmic therapies. The present review provides a detailed retrospective analysis of the data obtained with this model. Briefly, VF was reliably and reproducibly induced by the combination of acute myocardial ischemia at site distant from a previous myocardial infarction during submaximal exercise (to activate the autonomic nervous system). This exercise plus ischemia test identified 2 stable populations of dogs: those that development malignant arrhythmias (susceptible, n=303) and those that rarely developed even single premature ventricular activation (resistant, n=209). The susceptible animals exhibited an elevated sympathetic activation (due to an enhanced beta2-adrenoceptor responsiveness) and a subnormal parasympathetic regulation. Several interventions have proven to be particularly effective in preventing VF in the susceptible dogs; including calcium channel antagonists, left stellate ganglion disruption, ATP-sensitive potassium channel antagonists, beta-adrenoceptor antagonists, and non-pharmacological interventions (endurance exercise training and dietary omega-3 fatty acids).

Animals↗
PubMed2002

Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy.

FK506 binding proteins 12 and 12.6 (FKBP12 and FKBP12.6) are intracellular receptors for the immunosuppressant drug FK506 (ref. 1). The skeletal muscle ryanodine receptor (RyR1) is isolated as a hetero-oligomer with FKBP12 (ref. 2), whereas the cardiac ryanodine receptor (RyR2) more selectively associates with FKBP12.6 (refs 3, 4, 5). FKBP12 modulates Ca2+ release from the sarcoplasmic reticulum in skeletal muscle and developmental cardiac defects have been reported in FKBP12-deficient mice, but the role of FKBP12.6 in cardiac excitation-contraction coupling remains unclear. Here we show that disruption of the FKBP12.6 gene in mice results in cardiac hypertrophy in male mice, but not in females. Female hearts are normal, despite the fact that male and female knockout mice display similar dysregulation of Ca2+ release, seen as increases in the amplitude and duration of Ca2+ sparks and calcium-induced calcium release gain. Female FKBP12.6-null mice treated with tamoxifen, an oestrogen receptor antagonist, develop cardiac hypertrophy similar to that of male mice. We conclude that FKBP12.6 modulates cardiac excitation-contraction coupling and that oestrogen plays a protective role in the hypertrophic response of the heart to Ca2+ dysregulation.

Animals↗
PubMed2003

Cardiac resynchronization therapy in heart failure: recent advances and new insights.

Newer non-pharmacological therapies for heart failure are being evaluated for patients of congestive heart failure (CHF). Mechanical support with left ventricular assist devices and heart transplantation are reserved for the minority of patients who have severely decompensated heart failure. Despite these therapeutic advances, it is generally accepted that current therapies do not adequately address the clinical need of patients with heart failure, and additional strategies are being developed. Cardiac resynchronization therapy (CRT) is a new modality that involves synchronization of ventricular contraction and has shown a lot of promise in managing symptomatic patients of CHF who are on optimal medical therapy and have interventricular conduction delay (IVCD). It has improved exercise tolerance and NYHA functional class in such patients in sinus rhythm and a recent meta-analysis has also shown mortality benefits in CHF. Recently benefits of CRT have also been observed in CHF patients who do not have wide QRS complexes on electrocardiogram (EKG). It has also been shown to benefit drug refractory angina in CHF. Recent studies have also focused on the combined use of CRT and implantable cardioverter defibrillator (ICD) and it has shown encouraging results. Our aim in this descriptive review is to define practice guidelines and to improve clinicians' knowledge of the available published clinical evidence, concentrating on few randomized controlled trials.

Journal Article↗
PubMed1998

Regulation of beta-adrenoceptors in a rat model of cardiac failure: effect of perindopril.

This study investigated the effects of myocardial infarction (MI)-induced cardiac failure and treatment with an angiotensin-converting enzyme (ACE) inhibitor perindopril (2 mg/kg/day) on rat beta-adrenoceptor (beta-ar) subtypes in anatomically defined regions of infarcted left ventricular (LV) free wall and noninfarcted tissue from right ventricle (RV) by using autoradiography. After 5 weeks of MI, rats with large MI size (>42%) had developed cardiac failure and beta1-ars were significantly decreased (-59%; p < 0.01) in the border region of the infarcted LV and almost abolished in the infarcted area (-90%; p < 0.005) compared with normal LV from sham-operated controls. The beta-ar changes were not found in the noninfarcted area of the same LV or in RV. MI did not significantly alter the number of beta2-ar subtypes in any region of the ventricles. Perindopril treatment for 4 weeks reduced mean cardiac region weights but did not affect beta-ar density in any cardiac region in either sham-operated or MI rats. These results indicate that cardiac failure due to MI causes significant downregulation of beta1-ars only in border and infarcted regions of rat LV and no change in beta2-ar in any area. It also suggests that the improved response of the infarcted rat heart to isoprenaline stimulation after ACE inhibitors does not result from changes in the numbers of cardiac beta-ars.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

[Implantable automatic defibrillator. Evaluation after 8 years of use].

The thirty nine patients (30 men and 9 women, mean age 49 +/- 14 years) who were implanted with an automatic cardioverter defibrillator (AICD) between October 1982 and April 1990 were reviewed retrospectively. This group included 22 patients with ischaemic cardiomyopathy (55%), 9 primary cardiomyopathies (23%) 5 ventricular tachycardias in patients with normal hearts (13%), 1 case of arrhythmogenic right ventricular dysplasia and two of mitral valve prolapse. The mean ejection fraction for the whole group was 38 +/- 14%. The indication for implantation of the AICD was life-threatening ventricular arrhythmias for which other forms of treatment were either ineffective (29 patients), impossible to assess (9 patients) or poorly tolerated (1 patient). Two patients died during the perioperative period and the follow-up is too short in two other cases. Therefore, 35 patients were studied over an average of 23.7 +/- 16 months. During follow-up, 5 patients died, 3 of progressive cardiac failure and 2 suddenly, one of whom was waiting for a replacement of an exhausted generator. The AICD never functioned in 40% of patients. In addition, it was impossible to determine for the majority of shocks delivered if they had been triggered by a sustained ventricular arrhythmia. Long term tolerance was generally good but two patients developed cardiac constriction induced by the epicardial patch electrodes. The results of this review confirm the efficacy of AICD in preventing sudden death at the expense of a low operative mortality and with good long term tolerance. Quite a large proportion of AICDs never functioned and the interpretation of the delivered shocks remains questionable.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

Correlation between cardiac hypertrophy and plasma levels of atrial natriuretic factor in non-spontaneous models of hypertension in the rat.

We have compared atrial and plasma concentration of atrial natriuretic factor (ANF) in 4 models of non spontaneous experimental hypertension with different pathogenic mechanisms in the rat: two-kidney, one-clip (2-K, 1-C), one-kidney, one-clip (1-K, 1-C), DOCA-NaCl and adrenal regeneration hypertension (ARH) and their respective normotensive controls. All hypertensive groups developed cardiac hypertrophy. In all hypertensive groups plasma ANF was higher than in controls. Atrial ANF concentration was lower in the right and left atrium of 1-K, 1-C rats and in the left atrium of ARH. A good correlation was found between systolic BP and plasma ANF in 2-K, 1-C (r = 0.82; p less than 0.01) and 1-K, 1-C animals (r = 0.70; p less than 0.01). This correlation was less good in DOCA-NaCl (r = 0.41; p less than 0.05) and non existent in ARH (r = 0.28; NS). A negative correlation between plasma ANF and atrial ANF concentrations was found only in the 1-K, 1-C group (r = 0.41; p less than 0.05). A good correlation between plasma ANF levels and cardiac weight was found in all groups: 2-K, 1-C (r = 0.83; p less than 0.01), 1-K, 1-C (r = 0.73; p less than 0.01), DOCA-NaCl (r = 0.69; p less than 0.01) and ARH (r = 0.71; p less than 0.01). We suggest that the release of ANF in experimental hypertension depends of the pathogenesis and could be related either to the level of BP (hence the magnitude of the left ventricular end-diastolic pressure) or to the existence of an expanded blood volume. The correlation between plasma ANF levels and cardiac hypertrophy suggests that ANF could be partially released by the ventricles.

Adrenal Glands↗
PubMed1992

Orthostatic reactions in the 85-year olds.

Testing of the orthostatic reaction is recommended in the examination of elderly fallers. This test usually includes blood pressure and instantaneous heart rate measurement but is difficult to perform in very elderly people according to the guidelines suggested for younger subjects. One reason for this is that old people often stand up slowly. The use of a tilt table, which enables a rapid change in posture from recumbent to erect position, is tempting as it could provide a method for a better standardized test. To study the usefulness of the tilt table as well as the degree of orthostatic reaction in the very elderly, we examined a sample of 85-year olds who did not suffer from falls. All were tested both with the tilt table and with active rising. The drop in blood pressure was equal in the two test types, but the increase in heart rate was significantly larger in active rising. Many test subjects were afraid of the tilt table, and two developed cardiac arrhythmia, i.e., atrial fibrillation, during the test. In our opinion, active rising is the method of choice in old persons. While the test subjects were in unusually good health for their age and thus could provide a suitable reference group for this test, the systolic blood pressure dropped considerably in several during the test. Criteria and indexes developed for younger subjects are not useful, and different evaluation criteria should be developed for the very elderly.

Adult↗
PubMed1976

[Mechanism of inhibition of the glycolytic activity of the myocardium during the early postnatal period].

Reduction of the activity of glycolysis and glycogenolysis regularly observed in the developing cardiac muscle was not associated with reduction of the glycolytic system, but was due to the regulatory inhibition of the phosphofructokinase link in the glycolytic link. This was indicated by a 4.5-fold increase in the rat heart of the ratio of the active masses of the phosphofructokinase reaction in the course of 2 weeks of the postnatal development.

Animals↗
PubMed1992

Relationship between cardiac cycle length and ventricular relaxation rate in the chick embryo.

We hypothesized that during chick embryo cardiac development, cycle length decrease (heart rate increase) may be associated with developmental changes in the ventricular relaxation rate constant, tau, which can be estimated from ventricular pressure decrease by the function P(t) = P0e-t/tau, where P0 = pressure at the time of minimum time derivative of ventricular pressure and t = time. Natural logarithm conversion results in a linear relation between In P(t) and t with slope of -1/tau. We determined tau in Hamburger-Hamilton stage 17-27 (d 3-5) embryos (n = 35) at intrinsic cycle length and in stage 24 embryos (n = 5) during cardiac cycle length perturbations with the hot-cold probe technique. Regression analysis of In P(t) from the minimum dP/dt until t = 30 ms was used to estimate tau. Intrinsic cycle length decreased during development from stage 17 to 27 and tau decreased linearly as cycle length decreased (r = 0.39, p less than 0.005). Thus, during early development, both tau and cycle length decrease (relaxation rate and heart rate increase). In stage 24 embryos, cycle length perturbation yielded a nonlinear cycle length-dependent relation with tau, with a plateau at cycle lengths less than intrinsic, i.e. tau decreased with cycle length decrease to intrinsic cycle length, then tau plateaued with further cycle length decrease. These findings demonstrate that ventricular relaxation rate is both maturation and cycle length dependent. The plateau effect of the tau-cycle length relationship may be due to developmental limitations of the calcium transport system.

Animals↗
PubMed2005

Gene expression profiling of exercise-induced cardiac hypertrophy in rats.

AIMS: Exercise training causes physiological cardiac hypertrophy, which acts to enhance cardiac function during exercise. However, the underlying molecular mechanisms are unclear. We investigated gene expression profile of exercise training-induced cardiac hypertrophy using left ventricle (LV) excised from exercise-trained and sedentary control rats (12-week old). METHOD: Rats in the training group exercised on a treadmill for 8-week. RESULTS: Left ventricular mass index and wall thickness in the exercise-trained group were significantly greater than that in the control group, indicating that the trained rats developed cardiac hypertrophy. Of the 3800 genes analysed in the microarray analyses, a total of 75 relevant genes (upregulation of 33 genes and downregulation of 42 genes) displayed alterations with exercise training. Among these genes, we focused on glycogen synthase kinase (GSK)-3beta, calcineurin-inhibitor (Cain), and endothelin (ET)-1 for their implicated roles in pathological cardiac hypertrophy, and confirmed the results of microarray analysis at mRNA and protein/peptide levels using quantitative PCR, Western blot, and EIA analyses. The gene expression of GSK-3beta decreased significantly and those of Cain and ET-1 increased significantly with exercise training. Furthermore, LV mass index was significantly correlated with GSK-3beta protein activity (r = -0.70, P < 0.01) and tissue ET-1 concentration (r = 0.52, P < 0.05). There were no changes in gene expressions in brain natriuretic peptide (BNP), angiotensin-correcting enzyme (ACE), interleukin-6, and vascular cell adhesion molecule (VCAM)-1. CONCLUSION: These findings suggest that physiological and pathological LV hypertrophy may share some of the same molecular mechanisms in inducing LV hypertrophy (e.g. GSK-3beta, Cain, and ET-1) and that other genes (e.g. BNP, ACE) may differentiate physiological from pathological LV hypertrophy.

Adaptation, Physiological↗
PubMed1998

Ischemia/reperfusion-induced arrhythmias in the isolated rat heart: prevention by melatonin.

Cardiac arrhythmias during ischemia/reperfusion are believed to be related to free radicals generated in the heart especially during the period of reperfusion. Since melatonin functions as a free radical scavenger and antioxidant, the ability of this molecule to influence cardiac arrhythmias was investigated. The pineal secretory product, melatonin, reduced the incidence and severity of arrhythmias induced by ischemia/reperfusion due to ligation of the anterior descending coronary artery in the isolated rat heart. Melatonin was either infused during both the ischemia and reperfusion periods or only late in the ischemia period and throughout reperfusion. The percentage of hearts that developed cardiac arrhythmias during reperfusion as indicated by the incidence of premature ventricular contraction (PVC) and ventricular fibrillation (VF) were recorded. Melatonin either infused during both the ischemia and reperfusion periods or during essentially the period of reperfusion greatly reduced PVC and VF due to occlusion and reopening the anterior descending coronary artery. Presumably melatonin's beneficial effect in reducing cardiac arrhythmias was due in part to its free radical scavenging activity, which is greatly assisted by the rapidity with which it is taken up into cells. Previous studies have shown that vitamin C is effective in reducing the severity of cardiac arrhythmias induced by ischemia/reperfusion; thus, we also compared the efficacy of melatonin with this well-known antioxidant. Melatonin was more potent than vitamin C in protecting against arrhythmias induced by ischemia/reperfusion. Besides melatonin's function as a broad spectrum free radical scavenger, melatonin may have also reduced cardiac arrhythmias due to its regulation of intracellular calcium levels, i.e., by preventing calcium overloading, or due to its ability to suppress sympathetic nerve function and reduce adrenergic receptor function in the myocardium. Additional studies into the mechanisms of melatonin's action in reducing cardiac arrhythmias due to ischemia/reperfusion or other causes are warranted because of the possible application of this information to humans with heart disease.

Animals↗
PubMed2003

Chronic cholestasis and cardiac mitochondrial function in Wistar rats: a model for cardiovascular alterations in chronic liver disease?

OBJECTIVES: A growing number of reports in the literature have been correlating cardiovascular alterations with the presence of chronic liver disease, such as cirrhosis and cholestasis. The objective of this work was to compare mitochondrial bioenergetics and calcium loading capacity in the hearts of rats injected with alpha-naphthylisothiocyanate (ANIT), a compound used to induce cholestasis in animal models. METHODS: Female Wistar rats (n = 12) were randomly divided into two groups. One of the groups was injected with six weekly doses of ANIT. Each group was evaluated in terms of mitochondrial bioenergetic capacity and susceptibility to the mitochondrial permeability transition (MPT), a deleterious phenomenon associated with oxidative stress and excessive mitochondrial calcium accumulation. RESULTS: Our data showed unequivocally that cardiac mitochondria of rats chronically injected with ANIT lost their ability to accumulate calcium, in a cyclosporin A sensitive manner. This was reflected in a higher calcium-dependent swelling rate and amplitude (p < 0.01). The RCI value, an index of mitochondrial integrity, was also lower in the ANIT-treated group (p < 0.05). CONCLUSIONS: This suggests that during cholestasis development, cardiac mitochondria lose their normal ability to control cytosolic calcium due to increased susceptibility to the MPT. Our results may suggest an explanation for the occurrence of cardiomyopathies associated with cholestatic disease, which may persist even in the absence of serum markers for liver disease.

1-Naphthylisothiocyanate↗
PubMed2006

Model systems for the study of heart development and disease. Cardiac neural crest and conotruncal malformations.

Neural crest cells are multipotential cells that delaminate from the dorsal neural tube and migrate widely throughout the body. A subregion of the cranial neural crest originating between the otocyst and somite 3 has been called "cardiac neural crest" because of the importance of these cells in heart development. Much of what we know about the contribution and function of the cardiac neural crest in cardiovascular development has been learned in the chick embryo using quail-chick chimeras to study neural crest migration and derivatives as well as using ablation of premigratory neural crest cells to study their function. These studies show that cardiac neural crest cells are absolutely required to form the aorticopulmonary septum dividing the cardiac arterial pole into systemic and pulmonary circulations. They support the normal development and patterning of derivatives of the caudal pharyngeal arches and pouches, including the great arteries and the thymus, thyroid and parathyroids. Recently, cardiac neural crest cells have been shown to modulate signaling in the pharynx during the lengthening of the outflow tract by the secondary heart field. Most of the genes associated with cardiac neural crest function have been identified using mouse models. These studies show that the neural crest cells may not be the direct cause of abnormal cardiovascular development but they are a major component in the complex tissue interactions in the caudal pharynx and outflow tract. Since, cardiac neural crest cells span from the caudal pharynx into the outflow tract, they are especially susceptible to any perturbation in or by other cells in these regions. Thus, understanding congenital cardiac outflow malformations in human sequences of malformations as represented by the DiGeorge syndrome will necessarily require understanding development of the cardiac neural crest.

Animals↗
PubMed1993

[Angiotensin receptors in the rat myocardium during pre- and postnatal development].

Angiotensin II exerts positive inotropic and chronotropic effects on mammalian heart by binding to specific membrane receptors. Recently, 2 subtypes of angiotensin II receptors (AT1 and AT2) have been distinguished using the nonpeptide antagonists losartan and PD123177. Because angiotensin II has been reported to have growth potentiating effects in several tissues, we examined angiotensin II receptors in fetal (embryonic day 16 and 19), neonatal (1, 2, 3 and 10 days), and adult (10 and 16 weeks) rats. We performed an 125I-[Sar1,Ile8]-angiotensin II in situ binding assay on tissue sections obtained from Sprague-Dawley rats. Binding specificity was verified by competition with unlabeled [Sar1]-angiotensin II. Distribution of AT1 and AT2 receptors was determined by competition with losartan and PD123177, respectively, and the density of receptors quantitated by emulsion autoradiography. Angiotensin II receptors were widely distributed throughout the heart, with each receptor subtype accounting for approximately 50% of the specific binding. Binding density was comparable in right and left ventricles, and interventricular septum. Throughout cardiac development a significant increase (p < 0.005) in the density of both receptor subtypes was found immediately after birth, reaching a maximum on day 2, and decreasing toward prenatal values thereafter. No variation in the proportion of the 2 receptor subtypes was observed during development. Thus, in rat heart, AT1 and AT2 receptors are equally distributed over the myocardium. The density of these angiotensin II receptors is developmentally regulated, suggesting a possible role of the cardiac renin-angiotensin system in heart growth and in the adaptation of the heart to postnatal circulatory conditions.

Analysis of Variance↗
PubMed1996

Regulation of DNA synthesis of myocardial and epicardial cells in developing rat heart by [Met5]enkephalin.

Endogenous opioids serve as negative growth factors in neural and nonneural tissues in addition to being neuromodulators. This study investigated the hypothesis that native opioid peptides are inhibitory growth factors in heart development. DNA synthesis of ventricular myocardial and epicardial cells in 1-day-old rats was examined. Administration of a variety of opioids and peptides revealed that [Met5]enkephalin had the greatest inhibitory effect on DNA synthesis; peptides related to mu-, delta-, kappa-, epsilon-, and sigma-receptors had no influence on cell proliferation, even at concentrations as high as 10 mg/kg. [Met5]enkephalin, also termed opioid growth factor (OGF), depressed DNA synthesis at 1 and 10 mg/kg but not at 0.01 or 0.1 mg/kg. The effects of OGF were noted within 1 h of treatment, persisted for as long as 22 h after drug administration, and could depress DNA synthesis in myocardial and epicardial cells to 43 and 36%, respectively, of control values. The effect of OGF on DNA synthesis of heart cells was opioid receptor-mediated. Organ culture experiments revealed that opioids acted directly on developing cardiac cells. Both OGF and its receptor, zeta, were detected in heart cells of 1-day-old rats by immunocytochemistry. mRNA for preproenkephalin, the precursor to OGF, was observed in 1-day-old rat heart. These results indicate that an autocrine- or paracrine-produced endogenous opioid peptide (i.e., OGF) and its receptor (i.e., zeta) are present in the developing heart and govern DNA synthesis, with OGF acting directly as a tonic negative regulator of cell generation.

Aging↗
PubMed2007

Tissue engineering of vascularized cardiac muscle from human embryonic stem cells.

Transplantation of a tissue-engineered heart muscle represents a novel experimental therapeutic paradigm for myocardial diseases. However, this strategy has been hampered by the lack of sources for human cardiomyocytes and by the scarce vasculature in the ischemic area limiting the engraftment and survival of the transplanted muscle. Beyond the necessity of endothelial capillaries for the delivery of oxygen and nutrients to the grafted muscle tissue, interactions between endothelial and cardiomyocyte cells may also play a key role in promoting cell survival and proliferation. In the present study, we describe the formation of synchronously contracting engineered human cardiac tissue derived from human embryonic stem cells containing endothelial vessel networks. The 3D muscle consisted of cardiomyocytes, endothelial cells (ECs), and embryonic fibroblasts (EmFs). The formed vessels were further stabilized by the presence of mural cells originating from the EmFs. The presence of EmFs decreased EC death and increased EC proliferation. Moreover, the presence of endothelial capillaries augmented cardiomyocyte proliferation and did not hamper cardiomyocyte orientation and alignment. Immunostaining, ultrastructural analysis (using transmission electron microscopy), RT-PCR, pharmacological, and confocal laser calcium imaging studies demonstrated the presence of cardiac-specific molecular, ultrastructural, and functional properties of the generated tissue constructs with synchronous activity mediated by action potential propagation through gap junctions. In summary, this is the first report of the construction of 3D vascularized human cardiac tissue that may have unique applications for studies of cardiac development, function, and tissue replacement therapy.

Cell Culture Techniques↗
PubMed2003

Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure.

Aldosterone classically promotes unidirectional transepithelial sodium transport, thereby regulating blood volume and blood pressure. Recently, both clinical and experimental studies have suggested additional, direct roles for aldosterone in the cardiovascular system. To evaluate aldosterone activation of cardiomyocyte mineralocorticoid receptors, transgenic mice overexpressing 11beta-hydroxysteroid dehydrogenase type 2 in cardiomyocytes were generated using the mouse alpha-myosin heavy chain promoter. This enzyme converts glucocorticoids to receptor-inactive metabolites, allowing aldosterone occupancy of cardiomyocyte mineralocorticoid receptors. Transgenic mice were normotensive but spontaneously developed cardiac hypertrophy, fibrosis, and heart failure and died prematurely on a normal salt diet. Eplerenone, a selective aldosterone blocker, ameliorated this phenotype. These studies confirm the deleterious consequences of inappropriate activation of cardiomyocyte mineralocorticoid receptors by aldosterone and reveal a tonic inhibitory role of glucocorticoids in preventing such outcomes under physiological conditions. In addition, these data support the hypothesis that aldosterone blockade may provide additional therapeutic benefit in the treatment of heart failure.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2003

Anaemia stimulates aquaporin 1 expression in the fetal sheep heart.

Interstitial fluid fluxes are much greater in the fetus than in the adult, and filtration rates are increased over control in most tissues of the anaemic fetus. Increased capillary filtration may lead to cardiac oedema which, in turn, severely impacts cardiac function. Mechanisms that underlie these differences in flux are incompletely understood. One possible mechanism is an increase in capillary water permeability. Therefore, the goal of our study was to determine the level of expression of the water channel aquaporin 1 (AQP1) during cardiac development and in the anaemic fetal sheep heart. Hearts from chronically instrumented anaemic sheep fetuses and hearts from normal early fetal, late fetal, neonatal and adult sheep were used for Northern and Western analyses and immunohistochemistry. We found that AQP1 mRNA levels were lower in the young fetal left ventricle than in the adult left ventricle (P < 0.05). We also found that cardiac AQP1 expression was increased in anaemic fetuses compared to age-matched controls (P < 0.05). Expression of AQP1 in all groups was greatest in the microvascular endothelium. These data suggest that AQP1 plays an important role in the physiological accommodation to fetal anaemia.

Adaptation, Physiological↗