Cardiac Magnetic Resonance Imaging: Insights Into Developmental Programming And Its Consequences For Aging

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Abstract: Cardiovascular diseases(CVD) are important consequences of adverse perinatal conditions such as fetal hypoxia and maternal malnutrition. Cardiac magnetic resonance imaging(CMR) can produce a wealth of physiological information related to the development of the heart. This review outlines the current state of CMR technologies and describes the physiological biomarkers that can be measured. These phenotypes include impaired ventricular and atrial function, maladaptive ventricular remodeling, and the proliferation of myocardial steatosis and fibrosis. The discussion outlines the applications of CMR to understanding the developmental pathways leading to impaired cardiac function. The use of CMR, both in animal models of developmental programming and human studies is described. lost empire cistanche Specific examples are given in a baboon model of intrauterine growth restriction (IUGR).CMFR offers great potential as a tool for understanding the sequence of dysfunctional adaptations of developmental origin that can affect the human cardiovascular system.

Keywords: Heart disease; cardiac MRI; ventricular remodeling; developmental programming

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Cardiovascular disease (CVD) plays a major role in the genesis of human morbidity and mortality. Some of the earliest clues that early life stresses can predispose to severe health consequences in later life were the links found between perinatal dietary challenges imposed by war and famine and the increased risk for chronic later life CVD. Further human epidemiological studies and carefully controlled animal experiments established that both maternal nutrient restriction (MNR) and overnutrition predispose offspring to an increased prevalence of obesity, glucose intolerance, insulin resistance, endocrine, and renal dysfunction, hypertension, and vascular dysfunction as well as heart disease that varies with the precise timing of the nutritional challenge2 These same insights have been reported in a variety of studies conducted in multiple countries over the last two decades.3,4 The study of the developmental origins of health and disease focuses on the process of "developmental programming", which aims to discover mechanisms that underlie adaptations to a poor nutritional environment and other challenges occurring during development. The premise is that responses to developmental challenges can enhance short-term survival outcomes, but in so doing alter the trajectory of development in many physiological systems (metabolic, cardiac, renal, neural, and reproductive). Consequently, programming predisposes an individual to be more susceptible to chronic diseases later in life.

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During development, a series of epigenetic processes are central to normal fetal development. In utero challenges to the fetus such as nutrient restriction, fetal hypoxia due to placental insufficiency, anemia, maternal obesity, overnutrition, respiratory disease, and/or preeclampsia elicit physiological adaptations aimed at overcoming nutrient deficiencies in order to maintain fetal viability.5,6 These challenges begin a process that includes other epigenetic changes that can predispose the offspring to CVD in later life.7 Key myocardial biomarkers resulting from these processes are ventricular remodeling and cardiac fibrosis.8 More recently, the life course consequences of exposure to perinatal environmental toxins due to maternal smoking, pollution, alcohol, and consumption of drug abuse have increased the scope of intensive programming investigations.9.10

Epidemiological studies typically employ public medical databases and focus on diagnostic end points. This approach provides powerful distribution patterns but lacks the ability to determine causative mechanisms by which malnutrition and other early challenges alter the physiology of maturation, life course disease pathology, and aging. Mechanistic pathways are best obtained in carefully controlled experiments studying appropriate animal models of fetal programming.

The application of classical physiological and molecular biological methods has improved a specific understanding of the potential mechanisms involved in the developmental programming of CVD. For example, the expressions of cardiac-specific transcription factors have been shown to be disrupted during fetal development affecting the renin-angiotensin system (RAS). I Altered expressions of angiotensin Ⅱ type 1 and type 2 occur with perinatal hypoxia in many species, which result in impaired kidney development and lead to hypertension in adult life. I2 Histone deacetylases have been shown to play complicated roles in cardiomyocyte development and are implicated in the programming of endothelial dysfunction. B Also, sex-dependent accumulation of fibrotic tissue, activation of cardiac autophagy, and myocardial miRNAs were found in fetuses of baboons with calorie-restricted diets during pregnancy. " Changes in cardiac miRNA also have been demonstrated in the response to maternal obesity and high-fat diets. The degree to which each of these factors, and many others affecting multiple systems, combine to determine the phenotype of the programmed heart is still incompletely understood despite abundant knowledge of individual mechanisms.

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In this review, we discuss the use of noninvasive cardiac magnetic resonance imaging (CMR) to evaluate developmental programming in both human cohorts and animal models with a spotlight on its ability to assess cardiovascular physiology. Although ultrasound has been widely used in obstetrical research, here we focus on CMR as an imaging modality that has unique and powerful capabilities to evaluate cardiovascular morphology, physiology, tissue microstructure, and biochemistry. We describe the technical capabilities of CMR, review the research reported to date, and discuss additional applications for potential exploitation of CMR in future studies on the developmental origins of CVD. The following discussion also will explain how CMR can not only produce information on physiological consequences but also may provide insights into which cell types are susceptible to epigenetic modifications and other alterations relevant to developmental programming.

CVD imaging phenotypes in developmental programming

Until recently, technological limitations did rot allow for a detailed understanding of the overall effect of disease progression in complex mammalian organisms. Now, advances in noninvasive quantitative imaging methods applied to whole organisms provide tools and methods for gaining new insights into underlying physiological and pathophysiological processes. For example, the details of atherosclerotic plaque progression were not appreciated until intravascular ultrasound became available in the 190s, allowing physicians to discern the differences between vulnerable and stable coronary plaques and to appreciate the role of atheromatous plaque remodeling on coronary restenosis.16 However, intravascular ultrasound is invasive and requires placement under fluoroscopy guidance, which can produce a significant radiation dose.

Ultrasound is a well-established and extensively used tool for obstetric evaluations of fetal and placental health, which can also be used to assess early life course adaptations to fetal stress exposures in humans. In studying developmental programming, echocardiographic investigations of late-onset small fetuses have reported relative increases in left ventricle (LV)sphericity(globular phenotype), LV length(elongated phenotype), and LV myocardial wall thickness (hypertrophic phenotype).17,18 The hypertrophic phenotype has been attributed to early-onset intrauterine growth restriction (IUGR)while the elongated and spherical phenotypes represent degrees of remodeling in late-onset IUGR.19Further, fetal M-mode and Doppler echocardiography studies have revealed deficits in both systolic and diastolic function associated with IUGR. I9

Echocardiography can also reveal CVD progression after birth. A study conducted in neonates deemed small for gestational age(SGA), both prenatally and at 6 months, showed a more globular cardiac shape prenatally and as infants compared to controls.20 In addition, there were signs of systolic longitudinal dysfunction, both prenatally and postnatally, tricuspid annular plane systolic excursion, and diastolic dysfunction. In a separate study, Ponderal index was significantly lower, blood pressure was significantly higher, diastolic dysfunction was greater, and aortic intima-media thickness was significantly greater in term-born SGA infants compared to controls. 21

Echocardiography also has been used in small animal models to study the mechanisms of CVD in the setting of fetal programming. micronized purified flavonoid fraction 1000 mg uses High-resolution echocardiography has been used to evaluate the effect of a prenatal hypoxic insult on cardiovascular function in a rat model of IUGR.22 This study revealed an increased susceptibility to additional stresses, such as myocardial ischemia, for offspring with hypoxia-induced IUGR. The same group studied a placental hypoxia rat model, using echocardiography to demonstrate improved diastolic function in 7-month-old female rat offspring, whose mothers had been treated prenatally with the antioxidant, MitoQ.23 Administration of a low-protein diet during pregnancy and lactation to Wistar-Kyoto dams was found to reduce aortic peak systolic velocity measured by echocardiography in 18-week-old offspring.24

Transthoracic echocardiography is widely employed to assess cardiovascularly

hemodynamics, yielding physical parameters that are used to characterize blood flow. The success of studies that have used echocardiography to identify CVD imaging phenotypes of developmental programming, in both humans and rodents, implies that there may be applications for other noninvasive imaging technologies with greater levels of sensitivity that can discern additional characteristics related to heart structure and function.

Echocardiography is convenient due to its availability, relatively low expense, portability of the equipment, and high temporal resolution. However, the ultrasonic imaging process relies on a sound beam entering and leaving the body through the standard “acoustic windows”, which often necessitates visualizing deep structures from limited perspectives. In addition, studies may have inadequate image quality due to the inability to compensate for respiratory variation and lack of operator skill. Echocardiography also suffers from numerous artifacts that are associated with the physics of sound reflection and refraction in the body, ultrasound beam properties, and/or transceiver electronics.

CMR is equally noninvasive and can generate extensive physiological information about subclinical functional and structural abnormalities of the heart. Like ultrasound, CMR can be used multiple times across the life span of a subject to follow the trajectory of the cardiovascular changes without dangers such as repeated ionizing radiation exposure. However, some patients may not be able to tolerate CMR well, being anxious at confinement in a tube for up to an hour or unable to hold their breath during data acquisition. Patients with arrhythmias or who present challenges in detecting ECG vectors make it difficult to obtain static images at specific times in the cardiac cycle. In conventional cine CMR, magnetic field inhomogeneities can produce black lines that have to be avoided. Also, signal voids in the anterior LV wall can appear due to sternal wires in patients who have had thoracic surgery. Other artifacts that appear include chemical shift artifacts that present as the signal from pericardial fat overlapping the myocardium and ghosting artifacts due to the pulsatile flow of blood in the pulmonary arteries and aorta. This article explains the particular advantages of using CMR to evaluate the interrelationships of fetal programming and life course and aging cardiovascular changes.

Cardiac MRI evaluations of heart anatomy, physiology, and biochemistry

Almost four decades after its establishment as an effective clinical diagnostic modality, CMR also is becoming recognized as a research tool that can produce quantitative imaging biomarkers to understand both normal and subtly dysregulated biological processes. CMR is a specialized application of MRI that includes a group of tools that have been developed to assess cardiac function and structure. In particular, CMR can be used to evaluate both rest and stress left ventricular (LV) and right ventricular (RV) function and anatomy, atrial function/anatomy, ventricular stresses and strains, tissue composition, the biochemical environment, pericardial fat deposition, and blood flow within vessels and chambers. Since the clinical introduction of MRI in the early 1980s, CMR has exhibited the capability to measure important cardiological parameters with great flexibility and high precision. These assessments all are performed in vivo, requiring only that the subject stay immobile during scanning, probably having to perform a breath hold during each scan. A few CMR measurements also utilize exogenous contrast agents, which are injected intravenously. In spite of its general acceptance, the scope of utilization of CMR largely has been limited because of instrumentation cost, availability, and the technical skill required to successfully perform quantitative CMR studies and analyses.

It was soon recognized that CMR could produce accurate measurements of volume and myocardial mass.2> However, these early studies covered limited portions of the heart and were not time or cost-efficient. The acquisition of lines of CMR image data is triggered by an ECG signal and is acquired during a series of heartbeats to create an image. The development of breath-hold segmented gradient-echo CMR techniques allowed reduced data acquisition which lowered scan time to 15-20 heartbeats, allowing accurate assessments of LV function. oteflavonoid 20 Initially, the motion of a single myocardial slice could be imaged as a cine loop across the R-R interval. With modern hardware and image reconstruction methods, multiple slices, and currently, the entire beating heart can be imaged in a single breath hold. Although they are readily visualized on CMR, the papillary muscles and trabecular tissues typically are routinely ignored in measurements of ventricular volume, in order for CMR results to be comparable to those obtained from modalities in which these structures cannot be identified. Being able to measure ventricular volumes at end-diastole (ED) and end-systole (ES) allows for the direct calculation of ejection fraction, stroke volume, and cardiac output (Fig. la-f).27 The ability to measure L\J and RV volumes at ~30 ms intervals during a cardiac cycle enables measurements of ventricular ejection rates and ventricular filling rates. Further, the disordered backflow due to regurgitation can be visualized in these cine images as black jets (signal voids) that are a sign of valvular insufficiency.28 Today, a typical whole-heart cine CMR study typically is 25-30 cardiac phases and 20-25 slices of the heart, comprising a total of 500 or more images.

Determining the functional phenotypes from these image datasets requires delineation of the cardiac boundaries. Performed manually, this is a very time-consuming process, so state-of-the-art techniques incorporating machine learning have been developed for the automatic and semi-automatic segmentation of cardiac structures and calculation of physiological parameters.2" Several cardiac image analysis software products are available, both commercial and freely available packages.30,31 Most MRI system manufacturers also offer cardiac post-processing modules. Fig. 1 shows the steps performed for a typical baboon heart segmentation of the RV and LV using the cmr42TM cardiac image analysis software (Circle Cardiovascular Imaging Inc., Alberta, Canada).

One reason for the limited use of CMR is that many clinically important measures can be obtained using other, more established, imaging modalities. Biplanar fluoroscopic X-ray angiography and multi-detector X-ray computed tomography (CT) can both visualize the ventricular lumens and provide model-based estimations of ejection fraction and cardiac output. However, these modalities come with risks to the patient from iodinated contrast agents and ionizing radiation exposures. Radiation risks also may be greater in pediatric patients. Single-photon emission computed tomography (SPECT) can also produce ejection fraction estimates, but also imposes a radiation burden and has inherently poor spatial resolution compared to CMR. Echocardiography can be used to evaluate LV function with high temporal resolution and essentially no biological risk. puritans vitamin c However, the application of echocardiography may be impaired by the depth of tissue penetration of the ultrasound beam and the limited availability of adequate acoustic windows. Echocardiography is highly operator-dependent, requiring the manipulation of the ultrasound transducer by a skillful sonographer. Also, echo measurements of RV and LV volumes rely on geometrical assumptions based on a limited number of views, while CMR measures each ventricle in its entirety, slice-by-slice.

Although the absolute size of heart structures can be determined by CMR with high accuracy and reproducibility, it is well-established that the absolute sizes, volumes, and rates of cardiac parameters are strongly associated with body size.33 Thus, a method to assess relative differences, independent of body size is desirable. The most common method to address this variability is by indexing to body surface area(BSA), though in some situations myocardial mass is referenced. Estimation of BSA itself is no trivial matter, often relying on approximations using formulas based on height/length, weight, or both. Allometric indexing of intracardiac areas to BSA during normal growth has also been validated, although linear dimensions should be indexed by the square root of BSA and volumes should be indexed by BSA to the 1.5 power.34 Despite this limitation, normalization to BSA has proved useful for various measurements of the LV, RV, aortic root, and pulmonary vein.34,35 Thus, normalization to BSA is the preferred approach when comparing cardiac structure and function parameters between sexes and during natural growth periods.

CMR is particularly useful for evaluating function. RV functional parameters are similar to those measured in the LV, including RV systolic and diastolic volumes, RV ejection fraction and stroke volume, and RV cardiac output. The combination of soft-tissue contrast and spatial resolution available with CMR makes it a useful tool for studying the changes in RV structure and function, mitigating the fact that the RV has a more complex geometry than the LV and a myocardial wall thickness that is often one-fifth that of the LV wall.36 CMR has been used to measure RV functions in mice effectively.37CMR can produce reliable measurements of RV myocardial mass, which can inform our understanding of perinatal programming on cardiac development.38 MRI-derived assessments of RV pressure-volume loops can be constructed and used to evaluate RV contractility.39The CMR-derived ventricular mass index affords an accurate and practical method to noninvasively assess pulmonary artery (PA)pressure and may produce a more accurate estimate than Doppler echocardiography in pulmonary hypertension.40

CMR studies of the atria have mostly been applied to the left atrium (LA). sistanche The LA acts as a volume sensor, which through atrial stretching inhibits the secretion of vasopressin thus altering the RAS. Vasopressin's effects are mediated through several physiological mechanisms including escalation of arterial blood pressure, central blood volume, central venous pressure, and altering the sympathetic baroreflex set point.41 Concurrently, left atrial stretching triggers the release of natriuretic peptides that decrease systemic vascular resistance, reduce central venous pressure, and increase the excretion of sodium by the kidneys.42Thus, it is not surprising that changes in LA size can be a biomarker for sustained elevations of LV filling pressures, especially in patients with heart failure with preserved ejection fraction complicated by hypertension.43Measures obtained by CMR include maximum/minimum LA volumes, total LA emptying volume and fraction, passive LA emptying volume and fraction, active LA emptying volume and fraction, and conduit volume. Changes in LA volume, indexed to myocardial mass, have been shown to be generally related to diastolic function in the normal population, although it may be predictive for more specific issues depending on the population being studied.44 Right atrial (RA) volumes also have been investigated with CMR with regards to chronic heart failure and pulmonary hypertension. The utility of atrial imaging measurements in the setting of cardiac physiology altered by developmental programming in animal models has not yet been studied and is an emerging area of investigation.

This article is extracted from J Dev Orig Health Dis. Author manuscript; available in PMC 2021 October 01.