Long-term cardiovascular consequences of fetal growth restriction: biology, clinical implications, and opportunities for prevention of adult disease
2018; Elsevier BV; Volume: 218; Issue: 2 Linguagem: Inglês
10.1016/j.ajog.2017.12.012
ISSN1097-6868
AutoresF. Crispi, Jezid Miranda, E. Gratacós,
Tópico(s)Gestational Diabetes Research and Management
ResumoIn the modern world, cardiovascular disease is a leading cause of death for both men and women. Epidemiologic studies consistently have suggested an association between low birthweight and/or fetal growth restriction and increased rate of cardiovascular mortality in adulthood. Furthermore, experimental and clinical studies have demonstrated that sustained nutrient and oxygen restriction that are associated with fetal growth restriction activate adaptive cardiovascular changes that might explain this association. Fetal growth restriction results in metabolic programming that may increase the risk of metabolic syndrome and, consequently, of cardiovascular morbidity in the adult. In addition, fetal growth restriction is strongly associated with fetal cardiac and arterial remodeling and a subclinical state of cardiovascular dysfunction. The cardiovascular effects ocurring in fetal life, includes cardiac morphology changes, subclinical myocardial dysfunction, arterial remodeling, and impaired endothelial function, persist into childhood and adolescence. Importantly, these changes have been described in all clinical presentations of fetal growth restriction, from severe early- to milder late-onset forms. In this review we summarize the current evidence on the cardiovascular effects of fetal growth restriction, from subcellular to organ structure and function as well as from fetal to early postnatal life. Future research needs to elucidate whether and how early life cardiovascular remodeling persists into adulthood and determines the increased cardiovascular mortality rate described in epidemiologic studies. In the modern world, cardiovascular disease is a leading cause of death for both men and women. Epidemiologic studies consistently have suggested an association between low birthweight and/or fetal growth restriction and increased rate of cardiovascular mortality in adulthood. Furthermore, experimental and clinical studies have demonstrated that sustained nutrient and oxygen restriction that are associated with fetal growth restriction activate adaptive cardiovascular changes that might explain this association. Fetal growth restriction results in metabolic programming that may increase the risk of metabolic syndrome and, consequently, of cardiovascular morbidity in the adult. In addition, fetal growth restriction is strongly associated with fetal cardiac and arterial remodeling and a subclinical state of cardiovascular dysfunction. The cardiovascular effects ocurring in fetal life, includes cardiac morphology changes, subclinical myocardial dysfunction, arterial remodeling, and impaired endothelial function, persist into childhood and adolescence. Importantly, these changes have been described in all clinical presentations of fetal growth restriction, from severe early- to milder late-onset forms. In this review we summarize the current evidence on the cardiovascular effects of fetal growth restriction, from subcellular to organ structure and function as well as from fetal to early postnatal life. Future research needs to elucidate whether and how early life cardiovascular remodeling persists into adulthood and determines the increased cardiovascular mortality rate described in epidemiologic studies. Adapt yourself to the environment in which your lot has been cast, and show true love to the fellow-mortals with whom destiny has surrounded you.—Marcus Aurelius, Meditations VI, 39 It is now accepted that the risk of cardiovascular disease (CVD), which is a leading cause of death in the twenty-first century, is influenced by the interaction between our genes and environment. 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In this review, we will focus on the evidence that supports fetal cardiovascular remodeling in FGR; we will discuss potential pathways for its association with clinical CVDs in adults, and the potential implications for preventive public health strategies and treatments that could have a strong impact in the reduction of CVDs. Table 1 is a glossary containing terms used in this review that might be new or uncommon for obstetricians and gynecologists.Table 1Glossary of termsTermExplanation2-Dimensional speckle tracking echocardiographyImaging technique that analyzes the magnitude of myocardial deformation in different directions by the use of the naturally occurring speckle pattern in the myocardium.CardiomyociteColumnar-shaped cells 20 μm in diameter and 60–140 μm in length that make up the cardiac muscle.EpigeneticsThe study of the chemical modification of specific genes or gene-associated proteins of an organism.EpigenomeRecord of the chemical changes to the DNA and histone proteins of an organism.HypertrophyThe enlargement or overgrowth of an organ or part because of an increase in size of its constituent cells.Intima-media thicknessMeasurement of the thickness of tunica intima and tunica media, the innermost two layers of the wall of an artery.M-mode echocardiographyOne-dimensional analysis of the heart in motion. It provides both high spatial and temporal resolution and usually is used to measure the thickness of the ventricular walls and the volumes of the cardiac chambers.Myocardial performance index (Tei index)Doppler-derived index of combined systolic and diastolic function. Defined as the sum of isovolumic contraction time and isovolumic relaxation time divided by the ejection time.Myocardial strainPercentage of change in the length of a myocardial segment during a given period of time.SarcomereFundamental contractile unit within the cardiomyocyte, defined as the segment between 2 neighboring Z-lines (or Z-discs, or Z bodies).Tissue Doppler imagingEchocardiographic technique that uses Doppler effect principles to quantify the myocardial tissue motion.Crispi. Long-term cardiovascular consequences of fetal growth restriction. Am J Obstet Gynecol 2018. Open table in a new tab Crispi. Long-term cardiovascular consequences of fetal growth restriction. Am J Obstet Gynecol 2018. 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First, reduced oxygen and nutrients supply may disrupt cardiomyocyte growth and fiber architecture; and second, villous hypoplasia/thrombosis leads to increased placental resistance and chronic cardiac afterload. Consequently, the developing myocardium develops a variety of changes in cardiac macro and microstructure and function, which is defined as cardiac remodeling, to maintain ventricular output (Figure 1). Initially, the heart develops a more spherical shape that allows maintaining stroke volume with less contraction force, while also reducing wall stress to better tolerate pressure overload.59Tsyvian P. Malkin K. Wladimiroff J.W. Assessment of fetal left cardiac isovolumic relaxation time in appropriate and small-for-gestational-age fetuses.Ultrasound Med Biol. 1995; 21: 739-743Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 60Rodríguez-López M. Cruz-Lemini M. 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Valenzuela-Alcaraz B. et al.Descriptive analysis of the different phenotypes of cardiac remodeling in fetal growth restriction.Ultrasound Obstet Gynecol. 2016; 109: 2079-2088Google Scholar Early-onset FGR is more associated with a hypertrophic response, whereas cardiac phenotypes late-onset FGR usually develops globular or elongated.60Rodríguez-López M. Cruz-Lemini M. Valenzuela-Alcaraz B. et al.Descriptive analysis of the different phenotypes of cardiac remodeling in fetal growth restriction.Ultrasound Obstet Gynecol. 2016; 109: 2079-2088Google Scholar Evaluation of cardiac morphometric parameters, such as the sphericity index, might be more stable and reproducible compared with functional parameters (eg, more susceptible of being affected by heart rate or fetal movements). Alterations in cardiac shape are accompanied by subclinical cardiac dysfunction.59Tsyvian P. Malkin K. Wladimiroff J.W. Assessment of fetal left cardiac isovolumic relaxation time in appropriate and small-for-gestational-age fetuses.Ultrasound Med Biol. 1995; 21: 739-743Abstract Full Text PDF PubMed Scopus (0) Google Scholar Both can be demonstrated with fetal echocardiography.61Crispi F. Gratacos E. Fetal cardiac function: technical considerations and potential research and clinical applications.Fetal Diagn Ther. 2012; 32: 47-64Crossref PubMed Scopus (74) Google Scholar, 62Hernandez-Andrade E. Benavides-Serralde J.A. Cruz-Martinez R. Welsh A. Mancilla-Ramirez J. 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