Early and Late Postnatal Myocardial and Vascular Changes in a Protein Restriction Rat Model of Intrauterine Growth Restriction

Intrauterine growth restriction (IUGR) is a risk factor for cardiovascular disease in later life. Early structural and functional changes in the cardiovascular system after IUGR may contribute to its pathogenesis. We tested the hypothesis that IUGR leads to primary myocardial and vascular alterations before the onset of hypertension. A rat IUGR model of maternal protein restriction during gestation was used. Dams were fed low protein (LP; casein 8.4%) or isocaloric normal protein diet (NP; casein 17.2%). The offspring was reduced to six males per litter. Immunohistochemical and real-time PCR analyses were performed in myocardial and vascular tissue of neonates and animals at day 70 of life. In the aortas of newborn IUGR rats expression of connective tissue growth factor (CTGF) was induced 3.2-fold. At day 70 of life, the expression of collagen I was increased 5.6-fold in aortas of IUGR rats. In the hearts of neonate IUGR rats, cell proliferation was more prominent compared to controls. At day 70 the expression of osteopontin was induced 7.2-fold. A 3- to 7-fold increase in the expression of the profibrotic cytokines TGF-β and CTGF as well as of microfibrillar matrix molecules was observed. The myocardial expression and deposition of collagens was more prominent in IUGR animals compared to controls at day 70. In the low-protein diet model, IUGR leads to changes in the expression patterns of profibrotic genes and discrete structural abnormalities of vessels and hearts in adolescence, but, with the exception of CTGF, not as early as at the time of birth. Invasive and non-invasive blood pressure measurements confirmed that IUGR rats were normotensive at the time point investigated and that the changes observed occurred independently of an increased blood pressure. Hence, altered matrix composition of the vascular wall and the myocardium may predispose IUGR animals to cardiovascular disease later in life

Vascular changes after intrauterine growth retardation

Kinder mit intrauteriner Wachstumsretardierung erkranken im späteren Leben häufiger an D.m. II, Hyperlipidämie und Hypertonie. Auch gibt es Hinweise auf eine verstärkte Atheroskleroseneigung. In dieser Arbeit sollte in einem Tiermodell der IUGR untersucht werden, in wie weit die IUGR für die Entwicklung späterer Gefäßschäden prädestiniert und ob sie einen Einfluss auf die Entwicklung atherosklerotischer Gefäßveränderungen hat. Die verstärkte Expression einiger Matrixmoleküle in Gefäßen nach IUGR führt sehr wahrscheinlich zu einer veränderten Zusammensetzung der Gefäßwand, die sich auf die Compliance negativ auswirken könnte und in der Folge die Gefäße anfälliger für Schädigungen macht. Die Tatsache, dass diese Gefäßveränderungen schon früh und vor dem Auftreten von Hypertonie auftreten, lässt darauf schliessen, dass IUGR, unabhängig von anderen Risikofaktoren, direkt Gefäßveränderungen induziert, die eine Atheroskleroseentstehung begünstigen.Children with intrauterine growth retardation more often develop a diabetes, hypertension and hyperlipidemia later in life. Some evidence exists that Children with IUGR also have higher risk to develop atherosclerosis. In this study, we aimed to clarify the contribution of IUGR to the developement of vascular injury in an animal model of IUGR. Furthermore, we studied the effects of IUGR on the developement of atheroclerotic lesions. The increased expression of some matrix components in vessels after IUGR may result in an altered composition of the vascular wall, which could negatively influence vascular compliance. This might render blood vessels more susceptible to injury. The fact that these vascular changes occur early and long befor hypertension can be observed, argue for a direct contribution of IUGR to vascular damage which acts independently from other risk factors for the developement of atherosclerosis

Low homoarginine levels in the prognosis of patients with acute chest pain

Background The endogenous amino acid homoarginine predicts mortality in cerebro‐ and cardiovascular disease. The objective was to explore whether homoarginine is associated with atrial fibrillation (AF) and outcome in patients with acute chest pain. Methods and Results One thousand six hundred forty‐nine patients with acute chest pain were consecutively enrolled in this study, of whom 589 were diagnosed acute coronary syndrome (ACS). On admission, plasma concentrations of homoarginine as well as brain natriuretic peptide (BNP), and high‐sensitivity assayed troponin I (hsTnI) were determined along with electrocardiography (ECG) variables. During a median follow‐up of 183 days, 60 major adverse cardiovascular events (MACEs; 3.8%), including all‐cause death, myocardial infarction, or stroke, were registered in the overall study population and 43 MACEs (7.5%) in the ACS subgroup. Adjusted multivariable Cox regression analyses revealed that an increase of 1 SD of plasma log‐transformed homoarginine (0.37) was associated with a hazard reduction of 26% (hazard ratio [HR], 0.74; 95% CI, 0.57–0.96) for incident MACE and likewise of 35% (HR, 0.65; 95% CI, 0.49–0.88) in ACS patients. In Kaplan–Meier survival curves, homoarginine was predictive for patients with high‐sensitivity assayed troponin I (hsTnI) above 27 ng/L (P<0.05). Last, homoarginine was inversely associated with QTc duration (P<0.001) and prevalent AF (OR, 0.83; 95% CI, 0.71–0.95). Conclusion Low plasma homoarginine was identified as a risk marker for incident MACEs in patients with acute chest pain, in particular, in those with elevated hsTnI. Impaired homoarginine was associated with prevalent AF. Further studies are needed to investigate the link to AF and evaluate homoarginine as a therapeutic option for these patients

Myocardial deposition of collagen IV.

<p>Evaluation of the percentage of positive immunostaining for collagen IV (coll IV) in myocardial tissue of (A) neonatal control rats and neonatal rats with intrauterine growth restriction (neo) with representative photomicrographs; and in myocardial tissue of (B) control rats and rats with intrauterine growth restriction at day 70 of life (d70) with representative photomicrographs. NP, control rats; LP, rats with intrauterine growth restriction. Data are means ± sem.</p

Myocardial deposition of collagen I.

<p>Evaluation of the percentage of positive immunostaining for collagen I (coll I) in myocardial tissue of (A) neonatal control rats and neonatal rats with intrauterine growth restriction (neo) with representative photomicrographs; and in myocardial tissue of (B) control rats and rats with intrauterine growth restriction at day 70 of life (d70) with representative photomicrographs. NP, control rats; LP, rats with intrauterine growth restriction. Data are means ± sem.</p

Markers of inflammation.

<p>Macrophage infiltration and expression of the chemotactic peptides MCP-1 and osteopontin in aortas and hearts of neonatal rats and in rats at day 70 of life with intrauterine growth restriction (LP) or controls (NP).</p>a<p>In aortas, MCP-1 and osteopontin expression were below detection limits.</p><p>*p<0.05 versus NP.</p

Body and relative heart weights.

<p>A: Birth weights, B: body weights at day 70 of life and C: relative heart weights at day 70 of life of rats with intrauterine growth restriction (LP) and their respective controls (NP). Data are means±sem.</p

Examples of myocardial stainings for osteopontin.

<p>Representative photomicrographs of immunostainings for osteopontin (OPN) in myocardial tissue of neonatal control rats and neonatal rats with intrauterine growth restriction (neo); and in myocardial tissue of control rats and rats with intrauterine growth restriction at day 70 of life (d70). NP, control rats; LP, rats with intrauterine growth restriction. Arrow indicates positive immunoreactivity for OPN in the media of myocardial vessels in LP at day 70.</p

Telemetric blood pressure measurements.

<p>Systolic (A), diastolic (B) and mean arterial (C) blood pressure values of two IUGR-rats (LP) and two controls (NP) at the age of 70 days of life obtained by telemetric measurements for one week. Data are means ± sem.</p

Markers of cell growth and differentiation.

<p>Cell proliferation and areas of medial α-smooth muscle actin stain in aortas and hearts of neonatal rats and of rats at day 70 of life with intrauterine growth restriction (LP) or controls (NP).</p><p>*p<0.05 versus NP.</p