Intrauterine growth restriction - impact on cardiovascular diseases later in life

In the heart, a number of studies revealed myocardial alterations induced by IUGR, that can be detected long before the onset of metabolic disease and arterial hypertension. IUGR affected cardiac development and significantly reduced the number of cardiomyocytes at the time of birth [13, 14]. Studies in humans revealed early and persistent alterations of myocardial structure and decreased cardiac function detected by echocardiography in fetal, neonatal and juvenile patients with IUGR [15‐17]. These results were supported by findings in an animal model of IUGR exhibiting echocardiographic signs of cardiac dysfunction accompanied by a more distensible myocardium in the absence of arterial hypertension [18]. As a possible underlying mechanism, changes in the expression pattern of Titin (Ttn) after IUGR was observed: The passive elasticity of cardiomyocytes is modulated by alternative splicing of titin, a structural protein of the myocardial sarcomere, resulting in the two isoforms N2BA and N2B. Corresponding to the echocardiographic signs of a more distensible myocardium, relative overexpression of the less rigid isoform N2BA was observed in IUGR animals [18].

Moreover, assessment of inflammatory and profibrotic markers revealed an early induction of the expression of transforming growth factor beta (TGF-ß), connective tissue growth factor (CTGF) and microfibrillar matrix molecules in the myocardium of juvenile IUGR animals without evidence of metabolic syndrome [19]. This supports the notion of early and direct molecular changes in the cardiovascular system (Fig. 1).

IUGR-induced metabolic disease (including dyslipidemia and insulin resistance) may likewise indirectly lead to atherosclerosis [10]. In addition, several studies provided evidence that IUGR is accompanied by early structural alterations in blood vessels [20‐23]. Vascular remodeling favors the development of atherosclerosis [24]. In an animal model of vascular remodeling induced by unilateral ligation of the A. carotis communis significantly increased neointima formation and media thickness was observed in juvenile IUGR rats in the absence of metabolic disease [25]. Moreover, dedifferentiation of vascular smooth muscle cells (VSMC) was more prominent and collagen deposition in the media was increased after IUGR [25].

But even in the absence of experimental vascular disease, primary vascular alterations were detected in normotensive IUGR animals: A significantly increased expression of connective tissue growth factor (CTGF) was observed in aortas of neonatal animals after IUGR. Collagen I and collagen IV deposition in the aorta was more prominent in juvenile IUGR animals [19]. Recent studies examined IUGR-induced molecular mechanisms of endothelial dysfunction that favor the development of atherosclerosis. Oliveira et al. detected lower NO levels and increased eNOS phosphorylation in thoracic aortas of IUGR rats as a sign of endothelial dysfunction [26]. Taken together, these observations indicate that IUGR renders individuals more susceptible to the development of atherosclerotic lesions and vascular dysfunction and thus to cardiovascular-related diseases later in life.