Cardiac Magnetic Resonance Imaging: Insights Into Developmental Programming And Its Consequences For Aging Part 2

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CMR studies of the atria have mostly been applied to the left atrium (LA). 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.42 Thus, 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. what is cistanche 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.

Myocardial remodeling is a characteristic of developmental programming, which has been identified using echocardiography in fetuses and infants. I7 The "sphericity index" is used in echocardiography as an indicator of ventricular remodeling. Typically, in echocardiography studies, a sphericity index is approximated by calculation. Since CMR is used to measure the full ventricular volumes, the 3D sphericity index can be used, which is the ratio of the ventricular volume to the volume of a sphere that has the ventricular length as its radius.

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In addition, CMR can be used to assess myocardial deformation. Myofibers in the mid-wall layer encircle the heart while longitudinal fibers in the endocardial and epicardial layers pull the heart from apex to base. The complex motion during contraction includes forces acting along a right-handed helix in the sub-endocardium but in a left-handed helix in the sub-epicardium. The resulting deformation, or "strains" can be resolved into components in three directions: axial, circumferential, and longitudinal. Strain is defined in relation to the original length as a dimensionless percentage. The rate of deformation, "strain rate", is the spatial derivative of velocity and has units of inverse seconds. The initial method used a so-called "tissue tagging" approach, in which a special sequence "spoils"the magnetic nuclei so that lines of a null signal are deposited and tracked throughout the heart cycle.45,46 A recent innovation, CMR feature tracking, evaluates anatomic elements that are different along the margins of the myocardium along the chamber wall/endocardium and epicardial subepicardial boundaries. RV and LV systolic and diastolic function can be characterized using strain and strain rate as well as myocardial torsion and diastolic recoil. Myocardial strain parameters from CMR studies produce more sensitive and earlier markers of contractile dysfunction than ejection fraction.47 Fig.2 displays examples of data obtained from myocardial feature tracking of cine images. Parameters measured include ventricular radial (Fig. 2a, c, e), circumferential, and longitudinal strains (Fig. 2b, d, f), strain rates, velocities, and displacements. Several commercially available image processing packages are available with feature tracking functionality.48Speckle tracking echocardiography has also been used to assess myocardial strain. However, the echo speckle results do not directly correspond to the MRI results. This may be due to the inherent sensitivity of echo speckle to noise and/or the relatively poor lateral resolution of the method.49

cistanche can anti-aging

CMR also can be used to assess the focal or diffuse expansion of the myocardial extracellular space, which may result from prior infarction, infection, or other causes of tissue composition derangement. Hematocrit (hct) should be gathered on the same day as the MRI examination as it can fluctuate. Following administration of intravascular gadolinium contrast agent and a time delay (>10 min), focal scarring/extracellular space expansion can be directly visualized and quantified. For evaluation of diffuse extracellular space expansion, the longitudinal relaxation time(71) of the myocardium and the 71 of blood in the ventricular lumen must be measured (Fig. 3a, b).In a common protocol, myocardial Tl is measured again~10 min after administration of a gadolinium contrast agent. " From these datasets, and the patient's, the extracellular volume(ECV)of the myocardial tissue can be calculated as myocardial ECV=(1-hot)× △ Tlblood)(△ Tlmyocardium).ECVwas found to be directly associated with myocardial fibrosis related to aging in a large human study.51 Diffuse myocardial fibrosis is believed to be one of the conditions associated with impaired ventricular function due to developmental programming. An example of how myocardial Tl is altered ~10 min after Gd infusion in the baboon heart is shown in Fig. A more advanced approach, diffusion tensor CMR (DT-CMR), can be used to evaluate myocyte orientation and sheetlet function, however this a technically challenging method. 52New approaches that combine improved spatial and angular resolution with greater scanning speed and increased coverage may allow DT-CMR to become a routine research tool in the near future. The power of sampling myocardial tissue at necropsy in animal models of developmental programming can be used to correlate features such as fibrosis with in vivo images of the tissue structure.14

MRI is also useful for differentiating between muscle tissue and fat, making it useful for discerning fatty infiltration of the myocardium. Epicardial fat and pericardial adiposity, which are common in patients with insulin resistance, have been associated with a number of cardiovascular conditions. Anti aging cistanche 3 Increased pericardial fat deposition, measured by CMR has been reported in male IUGR baboons, but not females at 5-6 years (human equivalent 20-24 years).54 Volume-localized magnetic resonance spectroscopy(MRS)can be used to determine the amount of fat within the myocardium (Fig. 4a), although the process is more time-consuming and technologically demanding. Fig. 4 depicts an example of a hydrogen-1 CMR spectrum obtained from the interventricular septum of a baboon heart. Note that there are three triglyceride peaks(Fig. 4b). However, due to the complex myofiber orientations in heart muscle, MRS measures total fat and cannot yet distinguish intra- and extracellular lipids, which may have different metabolic origins.

CMR can also be used to measure blood flow, although not with the same temporal resolution afforded by Doppler echocardiography. Phase-contrast MRI can be used to measure the velocity of flowing blood in the great vessels or smaller arteries by relating the change in phase of the MRI signal from blood to the change in position of the blood. Because imaging slices can be positioned flexibly and accurately, CMR can provide precise measures of cardiac output and coronary blood flow.3758 CMR is used to determine aortic compliance and flow across the mitral valve. Aortic distensibility can be calculated from measurements of the cross-sectional area of the distal descending aorta at the level of the heart, taken at ES and ED.57Distensibility is defined as the fractional decrease in an aortic area divided by the difference between systolic and diastolic blood pressure. Pharmaceutical agents, such as dobutamine and adenosine, can be infused during CMR to assess myocardial perfusion during vasodilation and myocardial function during cardiac stress.594D flow MRI combines three-dimensional spatial encoding combined with three-directional velocity-encoded phase-contrast MRI allowing quantitative visualization of complex,three-directional blood flow patterns in vascular structures and entire vascular territories such as the heart, the adjacent aorta, and coronary arteries.60 These approaches allow assessments of cardiac performance under physiological conditions that normally occur with increasing workloads.

The Society for Cardiovascular Magnetic Resonance (SCMR) has developed an expert consensus report that assesses evidence of the accuracy and precision of CMR-derived cardiovascular parameters.FI Although these parameters were considered in the context of diagnosing and evaluating disease severity, the report clarifies the strengths and weaknesses of modern, quantitative CMR. Data presented in the SCMR report have been compiled and summarized in Table 1.

Normative values of CMR parameters

As delineated above, quantitative CMR can provide a multitude of data, not only with regard to chamber sizes and function, but also concerning the regional function of the heart, blood flow, and tissue composition. A recent review of published data lists reference values and influencing factors, such as age and sex, on normative cardiac physiological parameters derived from various CMR techniques and pulse sequences.62

A recent study of 800 adult UK subjects evaluated CMR data from healthy Caucasian British participants in order to establish reference values and abnormal ranges, for LV, RV, LA, and RA structure and function.63 Bland-Altmann analyses of these data found that for LV and RV end-diastolic volume,end-systolic volume, and stroke volume, and LA and RA maximal volume and stroke volume, excellent inter-, and intra-observer agreement was achieved. Another study reported the same cardiovascular parameters from CMR but focused on over 400 healthy Caucasian participants between the ages of 18 and 36 years.64 Using both intra-class correlation coefficients (ICC)and the Bland-Altman method, these investigators showed that LV and RV EDV have biases ≤2.3ml, LA and RA EDV have biases <6.5 ml, and all had ICC values △of 0.92. Two other investigations have aimed to establish normative ranges for RA and LA structural and functional parameters normalized for independent influences such as age, sex, and BSA. One studied 120 asymptomatic medical workers in Great Britain S and the other assessed 115 healthy children and adolescents in Germany.66,67 The latter study found high interobserver and inter-examination agreement by the Bland-Altman method, even for pediatric subjects. BSA-indexed normative cardiac functional data by age group reported from these studies have been compiled in Tables 2-4. The studies cited above, primarily report data from North American and European Caucasian cohorts. A direct comparison between four American ethnicities (Caucasian, Hispanic, African-American, and Asian-American)showed that Asian-American participants, in general, had lower values for mass and volumes than other ethnic groups even when adjusted for BSA. cistanche benefícios 68 A more recent study from the same group found that LA volume also was smaller in Chinese-American subjects even after allometric indexing.69 A comprehensive study of 20-69-year-old Singaporean Chinese subjects(n=180) found smaller cardiac volumes (LV EDV:128±28 vs.146ml;RVEDV:143±35vs.162ml) and lower LV mass(76±22 vs.116 g). These differences remained after normalizing for BSA but, as in Caucasians, negative correlations between ventricular volumes and age were found without associations between LV mass and age. W Further studies are required to understand the normative age-related variability of normal cardiac structure and function across diverse ethnic groups.

MRI tissue parameters also have been measured by CMR. The MRI relaxation times, T1, T2, and T2*can be determined in the myocardium using specialized pulse sequences that measure the changes in the CMR signal with changes in acquisition timing parameters.71 Relaxation measurements require multiple rescans using different timing parameters in order to derive the relaxation times from the signal intensity versus time curves via nonlinear regression as shown in Fig. 3c. Tl increases with the magnetic field strength used for MRI, but also is associated biologically with disease states that lead to fibrosis, edema, and amyloid deposition. TI is reduced by the administration of a gadolinium-based contrast agent (Gd), which briefly is retained in the interstitial space.7 making measurements before and after Gd, the ECV can be determined and used as a biomarker for myocardial fibrosis (Fig. 3). A study conducted at 3 Tesla in a cohort(n=76) of asymptomatic volunteers 20-90 years of age-reported native myocardial 7I and ECV, but not T2, were significantly greater in age-matched women than in men.23 In addition, 71 and ECVincreased with increasing age. However, in children (aged 9-18) 71 did not change with age but was significantly correlated (r=0.448,p-0.005)with body mass index(BMI).4 Although apposite interobserver variability has been reported for myocardial TI measurements with ICC>0.90,75 for multicenter investigations, it is good practice to certify that the Tl mapping method utilizes a standardized acquisition and post-processing approach.76

Studies also have evaluated T2, which increases with water content in myocardial tissues, as in myocardial edema. T2 is reported to decrease significantly with increasing age. R Decreases in the related parameter, myocardial T2*, have been associated with iron deposition which is indicative of thalassemia in children.77 A high-field (7) study of chicken embryos reported that T2 in the heart and other organs decreased during embryonic development. ' In a Polish study of 41 healthy children,9-18 years old, myocardial T2 was found to be significantly higher(44.6±4.2 vs.40.4±3.8p=0.002)in females than in males. 4 Normative values of 71, 72, and T2* for various age groups are listed in Table 5.

The development of the heart in early childhood has also been studied using CMR. Most of these studies have focused on infants with congenital heart diseases such as patent ductus arteriosus (PDA) and preterm infants. In studies of extremely young subjects, cardiac dimension measurements are typically indexed to body weight. Indexed cardiac parameters were significantly greater in a group of 16 PL A infants compared to 29 control infants in a study that showed good intra- and interobserver agreement. " These parameters included LV stroke volume (2.81±0.83 vs.1.82±0.29ml/kg,p<0.001),end-diastolic volume (3.38±1.34 vs.2.47±0.38ml/kg,p=0.001),and LV mass(2.46±0.59 vs.1.39±0.23g/kg,p<0.001).However, there were no significant differences in ejection fraction or fractional thickening between the two groups. Currently, studies of RV function and structure in infants have not demonstrated adequate reproducibility.

CMR was used to measure cardiac output and tricuspid and mitral E/A trans-mitral waveforms with Doppler at median 30.4 weeks gestational age (95% range 28.4-32.7), and then again at a median age of 10.0 years(95% range 9.4-11.7)in 547 subjects.80 These investigators found that higher third-trimester umbilical artery resistance was associated with higher childhood RVEF(p<0.05), but not with other cardiac outcomes. The third-trimester umbilical artery to cerebral artery pulsatility index ratio was not associated with childhood cardiac outcomes. Cistanche Extract Anti Radiation Higher third-trimester fetal LV output was associated with lower childhood LV EF and higher LV mass-to-volume ratios (p<05). Third-trimester fetal RV output was not associated with childhood cardiac outcomes. A higher third-trimester fetal tricuspid valve E/A mitral waveform ratio was associated with higher childhood RV EF(p<0.05).

Through-plane phase-contrast MRI velocity measurements have been used to assess left and right ventricular output in preterm and term newborns in a neonatal unit.81 PA pulse wave velocities, measured in children (ages 9-12-year-old)using velocity-encoded MRI, have been shown to be reproducible and sufficiently sensitive to detect differences in PA compliance between normoxia and hypoxia.82 CMR-derived longitudinal, radial, and circumferential strain measurements also have been characterized recently in children.

CMR developmental programming phenotypes

Quantitative CMR in fetal hearts, including cardiac function, blood flow, and blood oxygenation, is an area of active development. The high resolution demanded in fetal hearts can be confounded by the need to avoid aliasing artifacts from other parts of the mother's body. However, the primary technical challenge is to deal with the various sources of motion artifacts which include the cardiac and respiratory motion of the mother, cardiac motion of the fetus, and fetal body motion. Innovations such as metric-optimized gating,self-gating, and the development of MRI-compatible fetal heart monitoring hardware allow fetal CMR to be more tolerant to motion, thereby allowing high-resolution dynamic imaging of the fetal heart and its associated vessels.84 With adequate control for physiological motion, fetal ventricular volumetry has been shown to be very reliable in the sheep model.85 The development of 4D cine methods, using highly accelerated dynamic MRI with slice-to-volume reconstruction, can capture fetal cardiac motions in real-time.86 The use of 4D flow CMR has been validated for directly measuring flow through fetal vessels of the central circulation and their shunts in an in utero sheep model.87 Also, T2 relaxometry measurements have been used in fetal sheep models to quantitate blood oxygenation with CMR and validate these against blood gas analyzer measurements.88 These methods have been applied to assess cardiac function in a study of late-onset IUGR human fetuses with reported values indexed to estimated fetal weight. Reduced umbilical vein and pulmonary blood flow, along with increased superior vena cava flow, were found in IUGR compared to normal fetuses.89 Also, blood T2 values, oxygen delivery, and oxygen consumption were significantly lower in the IUGR fetuses. The development of reliable CMR methods for assessing fetal hemodynamics and morphometrics will provide more reliable data for understanding the development of IUGR in utero and allow improved classification of IUGR at the early stages of pregnancy.

CMR has shown that small size for gestational age (SGA) at birth was associated with smaller LV and RV end-diastolic volume relative to current BSA, but with a larger LV mass-to-volume ratio(p<0.05). Children in the larger quartile at birth who grow taller and leaner in childhood have larger hearts relative to BSA. In contrast, children in the lower quartile of RV and LV end-diastolic volume and LV mass were smaller at birth and became shorter and heavier in childhood (p<0.05). Both fetal and childhood growth were independently associated with childhood RV and LV end-diastolic volume and LV mass.

In a CMR study of 29 fetuses with IUGR compared to 127 fetuses with various congenital heart diseases, IUGR fetuses were significantly heavier than fetuses with transposition of the great arteries (p=0.03) and coarctation of the aorta(p=0.02), but there were no significant fetal body weight differences between IUGR and other congenital heart diseases. The same group studied 14 IUGR and 26 non-IUGR fetuses at 35 weeks gestation using MRI, reporting that IUGR fetuses had lower umbilical vein (p<004)and pulmonary blood flow (p<0.01) and higher superior vena cava flow(p<0.0001).89The latter change is exemplary of the classical preferential delivery of blood to pre-ductal vascular beds in the presence of intrauterine challenges.92

A recent study of 34 preterm infants and 10 term controls reported greater CMR weight-indexed LV mass and higher weight-indexed end-diastolic volume at term-corrected age (p<0.05 for all preterm gestations).93 Independent associations of increased term-corrected age LV myocardial wall thickness were (false discovery rate <0.05): degree of prematurity, antenatal glucocorticoid administration, and a requirement for>48h postnatal respiratory support. Principal component analysis of volumes, geometry, myocardial mass, and wall thickness revealed statistical differences between all preterm infants at term-corrected age and term controls.93 Intrauterine growth restriction due to reduced maternal nutrition and cardiac health in baboon offspring Investigations of the effects of developmental programming need to consider the species and sex of offspring differences in outcomes. The common experimental model of the laboratory rat is a polytocous, altricial species. Mothers, thus, nurture a much larger nutritional load, and fetuses and neonates have a different trajectory of development from monotocous, precocial mammals such as humans. "4 For this reason, a nonhuman primate, the baboon model has been developed and characterized.95 Molecular techniques were used to evaluate the functional, biochemical, and epigenetic mechanisms and interactions in the heart that result from the challenge of maternal undernutrition and obesity from overnutrition.14,15

CMR has been extensively applied in this IUGR baboon model to study CV changes that arise from developmental programming secondary to moderate (30%)MNR during pregnancy and lactation. Both LV and RV functions were impaired in the offspring, including decreased ejection fractions, ventricular shortening, and increased chamber volumes.38.96 Fig. 5 illustrates differences in the BSA-normalized LV volume-time curves obtained by CMR over the cardiac cycle control and IUGR baboons, differentiated by sex. The results underscored that MNR affected RV function more drastically than the LV function. The severity of the impairment in RV function may be due to increased pulmonary resistance, which would be attributed to decreased fetal pulmonary alveolarization, and pulmonary vessel density, found in a sheep model of IUCGR.97While these data have been interpreted as indicating that growth restriction mimics accelerated aging of the heart, the most essential finding was the interplay and synergistic effect of these changes toward jeopardizing overall cardiovascular health.

Changes in heart morphology and function that are expected to be associated with broader cardiovascular features also can be assessed using CMR. Distal descending indexed aortic cross-section and aortic distensibility were decreased in the same IUGR baboons. Fig.6 depicts how the increased systolic 3D sphericity index (3DSI) was significantly correlated with reduced aortic distensibility(r=0.35,p=0.048). Diastolic 3DSI also was significantly and negatively correlated with aortic distensibility(r=0.36,p=0.044). Complementary changes in carotid, brachial, and iliac artery sizes, distensibility, and blood flow patterns also have been identified in young adult IUGR baboons using ultrasound.99

The biventricular changes signify the core components of the observed findings. In the LV, there is impairment of myocardial contraction. Based on studies from other animal models of poor maternal nutrition, the weakened contraction may be due to diminished cardiomyocyte number,100,101 cardiomyocyte immaturity,102,103 abnormal calcium handling,104 and/or sarcomere dysfunction. 105 With this decrease in contractile force, an increase in end-systolic volume is seen with MRI without significant modification in the end-diastolic volume, resulting in decreases in stroke volume and cardiac output. The decreased wall thickening fraction and trend of reduced rotation together suggest a decline in systolic function. Due to the increased end-systolic volume, there is increased difficulty in LV filling, reflected by a prominent decrease in peak and average filling function.

The struggle to fill the LV may be further compromised by extracellular fibrosis previously seen in the fetal baboon myocardium and as reported in other models.14.106 A study on 36 patients with dilated cardiomyopathy (DCM) examined the degree to which native myocardial 71 could be used to characterize collagen volume fraction measurement from histology.107These investigators found that the native myocardial Tl value was significantly and positively correlated with biopsy-proven collagen volume fraction (r=0.77,p<01). We have measured native myocardial 71 to be significantly greater in IUGR baboons (1033 +93ms)than in controls(905+93ms,p=0.001), Fig.7.

The LV systolic and diastolic function abnormalities as a result of IUGR may originate from cardiomyocyte changes discussed in prior reports. The relationship between RV and LV dysfunction is depicted schematically in Fig.8. The contractile force of the RV was weakened as in the left, supported by decreases in both wall thickening and longitudinal shortening seen on MRI. LV end-systolic volume increased, and RV stroke volume and cardiac output fell. An attempt to increase the ejection function in the form of a mild increase in end-diastolic volume is suspected. Nonetheless, the increased end-systolic volume from inadequate ejection hinders RVfilling, reducing both average and early filling rates. Although decreased sphericity indices are anticipated based on LV sphericity increase, no such difference is seen. This finding likely represents simultaneous RV congestion. Importantly, the impaired LV filling may further deteriorate RV ejection via increasing pulmonary pressure.108 These findings are consistent with impairment of coronary filling and mild hypoxia can be suspected, given the probable rise in diastolic pressure.

On the mechanical level, the weakening of one ventricular chamber's contraction aggravates the other, as normally the cardiac longitudinal shortening force depends on the concurrent pull of both the mitral and tricuspid annuli. The exaggerated septal movement toward the LV during systole, which normally only accounts for~10% RV stroke volume, is interpreted as an attempt to normalize LV ejection, which may hamper RV ejection. Decreased LV systolic function also results in a weakening of the RV output due to ventricular interdependence. cistanche herba The more pronounced decrease in RV function, compared to the LV, indicates a primary component of RV dysfunction is present, which may originate in part from changes in the pulmonary system. However, the status of the RV myocardium and its relationship to pulmonary arterial dysfunction remain to be investigated given the lack of sufficient prior studies.

In the IUGR baboon model, the large systemic arteries demonstrated regional divergent findings. MRI revealed the descending thoracic aorta was decreased in size and distensibility. These decreases diminished the aortic Windkessel function and raised concern for diastolic perfusion of critical organs. In particular, coronary perfusion is likely to be compromised given its predominantly diastolic filling pattern. Additionally, the decreased size and distensibility of the descending aorta, combined with similar changes in the lower extremity arteries uncovered by ultrasound, indicated systemic afterload was likely elevated, contributing to LV dysfunction. Various animal studies have implicated decreased elastin contentl09 as well as changes in extracellular sstructurel10,11 in contributing to the observed changes. In the cranially directed vessels, however, neither difference in size nor distensibility is seen. Instead, the overall carotid blood flow appears preserved, or even increased, due to a mild increase in end-systolic and diastolic flow rates. This constellation of findings is reminiscent of the blood flow redistribution effort known to occur during fetal hypoxia as part of the "brain sparing"effect. Following this analogy, the modification in blood flow in perinatal life would have triggered differential growth of the vasculature via hemodynamic effects, which persist into adulthood. There also may be involvement of additional abdominal and pelvic vessels, which would have implications for other organ systems.

In the baboon model of IUGR, female offspring had increased total cholesterol, low-density lipoprotein, and subcutaneous fat. These changes were absent in male offspring, although MRI in the males did reveal increased pericardial fat depositions.54 Metabolic derangements present in IUGR are detected in the form of a sexually dimorphic increase in pericardial lipid accumulation and serum cholesterol level. These increases were mild, especially when compared to the extent of cardiac changes observed. However, the increased pericardial lipids, if left untreated, may result in local lipotoxic effects later in the life course. The increase in serum cholesterol can contribute to the development of coronary atherosclerosis.

Future applications of CMR in the study of cardiac programming The flexibility of cardiac MRI allows it to interpret the complex interactions of biomarkers related to IUGR pathophysiology, for example, the interplay between IUGR and accelerated aging. Prenatal programming is associated with the development of myocardial fibrosis, which is attributed, in large part, to epigenetic processes.14,15 Physiological trajectories are altered as an adaptive response to maintain the fetus for a successful birth. However, there is strong evidence that these early life adaptations reduce the individual's flexibility to respond to age-associated changes in cardiovascular structure and function in later life. Adverse remodeling is rooted in dysfunctional repair mechanisms that protect the heart from further injury and enhance homeostasis.112

In the baboon IUGR model, we have defined an extensive cardiac functional phenotype at baseline under sedation. Unfortunately, we have yet to study cardiac function under various other challenges. In humans, the resting cardiac functional measurements do not always correlate with those obtained under stress. For instance, aging weakens LV ejection under stress but not at rest, whereas exercise training lowers resting ejection function without affecting stress values. Cardiac MRI evaluations could be performed during pharmacological stress using, for example, dopamine which should help better define the physiologic impact of the observed findings. Biomarkers, such as peak circumferential strain, average diastolic strain rate, contractile reserve, and myocardial blood flow were reported to be robust with good interobserver and intra-observer reproducibility and test-retest reliability during pharmacologically induced stress in healthy males (7-10 years old)macaques.113 Currently, it is unclear what tissue changes contribute to the ventricular dysfunction, Whether the LV extracellular space expansion, previously seen in the fetal heart, persists into adulthood or occurs in the RV has not yet been determined. In addition to measuring the myocardial 71 relaxation time by MRI, cardiac diffusion tensor imaging (DTI) can be used to examine the myocyte architecture and fiber orientation to identify the presence of pathology and/or extracellular space expansion more precisely. Cardiac DTI can also improve our understanding of the mechanisms and structural contributions related to atrial rhythm and pump disorders. II4 Although technically challenging due to heart and respiratory motion, new accelerated DTI pulse sequences and advanced image reconstruction technologies improve the accuracy and efficiency of diffusion CMR. I15

The finding of reduced RV ejection fractions and systemic vascular alteration in offspring of MNR mothers indicates pathophysiology in the pulmonary system that merits investigation, particularly in relation to the rapid changes in pulmonary blood flow that takes place at birth. In fetal sheep, an increase in myocardial fibrosis has been reported in the RV after maternal undernutrition. I'6 Dynamic perfusion MRI can quantitatively analyze regional pulmonary perfusion! land may be helpful in this endeavor. Likewise, the finding of impaired aortic Windkessel function suggests studies such as MRI evaluation of the coronary arterial perfusionll8 and oxygenationl19 also could be beneficial, given the extensive literature on ischemic heart disease risk with IUGR.

MRI also can be used to evaluate related noncardiac conditions that are closely associated with developmental programming. An early and persistent finding has been the increased prevalence of idiopathic hypertension in people with low birth weight. This observation has led to studies in human and animal models that were aimed at discerning the relationships between CVD and kidney disease. IUGR has been linked with a reduction in renal cell size and number that, in turn, has been implicated in renal dysfunction and the occurrence of systemic hypertension. In the baboon IUGR model, it was found that midgestational IUGR fetal kidneys showed down-regulation of genes in pathways related to RNA, DNA, and protein biosynthesis. In addition, upregulation in cell signal transduction, communication, and the transport was reported. I20 Thus, even a challenge of moderate maternal global nutrient restriction causes significant changes in fetal renal gene pathways. Renal perfusion can be evaluated quantitatively using various MRI methods, including dynamic contrast-enhanced MRI, arterial spin labeling, and diffusion-weighted MRI. Moreover, blood oxygen level-dependent (BOLD)MRI, which exploits deoxygenated hemoglobin's paramagnetic influence on the MRI signal, can be used to gain insights into tissue oxygenation.123 Epidemiological evidence also implicates low birth weight as a risk factor for the development of diabetes. The relationship between CVD and metabolic disease is well-established and has been labeled metabolic syndrome. Three of the five hallmarks of metabolic syndrome are related to lipid function: central obesity, high serum triglycerides, and low serum high-density lipoprotein. Maternal obesity during pregnancy has been linked to increasing offspring insulin resistance in humans. 24 In the IUGR baboon model, MNR in pregnancy and lactation were found to program offspring metabolic responses, including insulin resistance and β-cell responsiveness that lay the foundation of an overall phenotype that can predispose to later life type-2 diabetes. I25MRS methods for assessing cardiomyocyte lipidsl26 and phosphorus energeticsl27 have been developed and could be used to help understand the synergistic effects of fetal programming on cardiovascular function and metabolism.

However, the full range of CMR capabilities, which could reveal new information on the IUGR cardio vasculature has not yet been applied on a large scale. Quantitative procedures to assess heart physiology, which is available and clinically validated, have not yet been exploited to better understand the processes underlying normal and divergent development. Current studies have been limited to technologies that have explored only the most basic physiology related to cardiovascular developmental programming.

In conclusion, cardiac MRI encompasses methods that are largely non-invasive and easily translatable from rodents to nonhuman primate models to human studies. Investigations into humans, which parallel those in animal models, are now possible, and given the compelling evidence that prenatal challenges lead to later life CVD and have features of premature cardiac aging, the information obtained will accelerate our understanding of the mechanism of developmental programming and programming- aging interactions in the onset of later life CVD. The MRI biomarkers identified from animal models can be combined with tissue and cellular biomarker information to allow earlier identification of individuals at risk and enable assessment of treatment needs and therapeutic response. Ideally, the knowledge gained will lead to better clinical management of this vulnerable population. The strengths of investigating animal models include having homogeneity of subjects and greater control over environmental and genetic confounds. Animal studies also give us the ability to undertake a greater degree of invasiveness and more frequent repetition across the life course and greater flexibility for therapeutic trials. However, to fully utilize the potential of MRI, the application of standardized protocols must be applied to larger human populations in order to characterize the true nature of CV health and disease. In some areas of biomedicine, particularly in neuroscience, the widespread use of MRI to define normal and abnormal human phenotypes has been undertaken. The Human Connectome Project (https://www.humanconnectome.org), established by the National Institutes of Health in the US, is a multinational and multi-institutional program that utilizes advanced MRI technologies to study over 1200 subjects, focusing on various processes and pathologies involving the human brain, especially those associated a with aging. Other national and international projects of similar scope include the German 1000BRAINS study and the UK Biobank. Recently, the Lifespan Human Connectome Project in Development, a large-scale study of brain connectivity in over 1300 subjects ages 5-21 years, has been establishedl28 and the Lifespan Developing Human Connectome Project at Kings College, UK will perform an MRI of the human brain connectivity in 1500 subjects with post-conceptional ages ranging from 20 to 44 weeks. (https://www.humanconnectome.org/study/lifespandeveloping-human-connectome-project).

The prospect of using MRI to improve understanding of brain changes with early development is important since changes in brain microstructure, microstructure, and hemodynamics have all been documented in human fetuses and infants with late-onset IUGR.89,129,130

However, there is not yet any organized effort to evaluate fetal heart development with CMR. Although CMR has become an important component of the Framingham Heart Study in the USl3I and the Dutch Heart-Brain Study, B2 these megaprojects have focused mostly on adults with various pathologies, without consideration of their early developmental histories. In order to fully appreciate the settings and consequences of developmental programming on CVD in the real world, a larger multinational human study that uses cardiac MRI to investigate CV development, including prenatally, should be undertaken. The results of such an effort, in combination with advanced omics testing, would advance the quest for a clear, clinical definition of IUGR.In addition, the data obtained would produce a wealth of information that would not only inform allopathic medicine but also preventative medicine and public health worldwide.

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