Adam J. Lewandowski

Cardiovascular Risk Factors in Children and Young Adults Born to Preeclamptic Pregnancies: A Systematic Review

BACKGROUND AND OBJECTIVE: Preeclampsia is an independent cardiovascular risk factor for the mother, and recent studies reveal that offspring of affected pregnancies also may have an increased cardiovascular risk. Our objective was to examine evidence for increased cardiovascular risk factors in children exposed to preeclampsia in utero. METHODS: We performed a systematic review and meta-analysis on studies reporting traditional cardiovascular risk factors in those exposed to preeclampsia compared to controls. Information was extracted on the classic cardiovascular risk factors, including blood pressure, lipid profile, glucose metabolism, and BMI from articles published between 1948 and August 2011 in Medline and Embase. RESULTS: Eighteen studies provided cumulated data on 45 249 individuals. In utero exposure to preeclampsia was associated with a 2.39 mm Hg (95% confidence interval: 1.74–3.05; P < .0001) higher systolic and a 1.35 mm Hg (95% confidence interval: 0.90–1.80; P < .00001) higher diastolic blood pressure during childhood and young adulthood. BMI was increased by 0.62 kg/m2 (P < .00001). Associations were similar in children and adolescents, for different genders, and with variation in birth weight. There was insufficient evidence to identify consistent variation in lipid profile or glucose metabolism. CONCLUSIONS: Young offspring of pregnancies complicated by preeclampsia already have increased blood pressure and BMI, a finding that may need to be considered in future primary prevention strategies for cardiovascular disease.

Preterm heart in adult life: cardiovascular magnetic resonance reveals distinct differences in left ventricular mass, geometry, and function.

Background— Preterm birth leads to an early switch from fetal to postnatal circulation before completion of left ventricular in utero development. In animal studies, this results in an adversely remodeled left ventricle. We determined whether preterm birth is associated with a distinct left ventricular structure and function in humans. Methods and Results— A total of 234 individuals 20 to 39 years of age underwent cardiovascular magnetic resonance. One hundred two had been followed prospectively since preterm birth (gestational age=30.3±2.5 week; birth weight=1.3±0.3 kg), and 132 were born at term to uncomplicated pregnancies. Longitudinal and short-axis cine images were used to quantify left ventricular mass, 3-dimensional geometric variation by creation of a unique computational cardiac atlas, and myocardial function. We then determined whether perinatal factors modify these left ventricular parameters. Individuals born preterm had increased left ventricular mass (66.5±10.9 versus 55.4±11.4 g/m2; P<0.001) with greater prematurity associated with greater mass (r = −0.22, P=0.03). Preterm-born individuals had short left ventricles with small internal diameters and a displaced apex. Ejection fraction was preserved (P>0.99), but both longitudinal systolic (peak strain, strain rate, and velocity, P<0.001) and diastolic (peak strain rate and velocity, P<0.001) function and rotational (apical and basal peak systolic rotation rate, P =0.05 and P =0.006; net twist angle, P=0.02) movement were significantly reduced. A diagnosis of preeclampsia during the pregnancy was associated with further reductions in longitudinal peak systolic strain in the offspring (P=0.02, n=29). Conclusions— Individuals born preterm have increased left ventricular mass in adult life. Furthermore, they exhibit a unique 3-dimensional left ventricular geometry and significant reductions in systolic and diastolic functional parameters. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01487824.Background— Preterm birth leads to an early switch from fetal to postnatal circulation before completion of left ventricular in utero development. In animal studies, this results in an adversely remodeled left ventricle. We determined whether preterm birth is associated with a distinct left ventricular structure and function in humans. Methods and Results— A total of 234 individuals 20 to 39 years of age underwent cardiovascular magnetic resonance. One hundred two had been followed prospectively since preterm birth (gestational age=30.3±2.5 week; birth weight=1.3±0.3 kg), and 132 were born at term to uncomplicated pregnancies. Longitudinal and short-axis cine images were used to quantify left ventricular mass, 3-dimensional geometric variation by creation of a unique computational cardiac atlas, and myocardial function. We then determined whether perinatal factors modify these left ventricular parameters. Individuals born preterm had increased left ventricular mass (66.5±10.9 versus 55.4±11.4 g/m2; P 0.99), but both longitudinal systolic (peak strain, strain rate, and velocity, P <0.001) and diastolic (peak strain rate and velocity, P <0.001) function and rotational (apical and basal peak systolic rotation rate, P =0.05 and P =0.006; net twist angle, P =0.02) movement were significantly reduced. A diagnosis of preeclampsia during the pregnancy was associated with further reductions in longitudinal peak systolic strain in the offspring ( P =0.02, n=29). Conclusions— Individuals born preterm have increased left ventricular mass in adult life. Furthermore, they exhibit a unique 3-dimensional left ventricular geometry and significant reductions in systolic and diastolic functional parameters. Clinical Trial Registration— URL: . Unique identifier: [NCT01487824][1]. # Clinical Perspective {#article-title-37} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01487824&atom=%2Fcirculationaha%2F127%2F2%2F197.atom

Normal variation of magnetic resonance T1 relaxation times in the human population at 1.5 T using ShMOLLI

BackgroundQuantitative T1-mapping is rapidly becoming a clinical tool in cardiovascular magnetic resonance (CMR) to objectively distinguish normal from diseased myocardium. The usefulness of any quantitative technique to identify disease lies in its ability to detect significant differences from an established range of normal values. We aimed to assess the variability of myocardial T1 relaxation times in the normal human population estimated with recently proposed Shortened Modified Look-Locker Inversion recovery (ShMOLLI) T1 mapping technique.MethodsA large cohort of healthy volunteers (n = 342, 50% females, age 11–69 years) from 3 clinical centres across two countries underwent CMR at 1.5T. Each examination provided a single average myocardial ShMOLLI T1 estimate using manually drawn myocardial contours on typically 3 short axis slices (average 3.4 ± 1.4), taking care not to include any blood pool in the myocardial contours. We established the normal reference range of myocardial and blood T1 values, and assessed the effect of potential confounding factors, including artefacts, partial volume, repeated measurements, age, gender, body size, hematocrit and heart rate.ResultsNative myocardial ShMOLLI T1 was 962 ± 25 ms. We identify the partial volume as primary source of potential error in the analysis of respective T1 maps and use 1 pixel erosion to represent “midwall myocardial” T1, resulting in a 0.9% decrease to 953 ± 23 ms. Midwall myocardial ShMOLLI T1 was reproducible with an intra-individual, intra- and inter-scanner variability of ≤2%. The principle biological parameter influencing myocardial ShMOLLI T1 was the female gender, with female T1 longer by 24 ms up to the age of 45 years, after which there was no significant difference from males. After correction for age and gender dependencies, heart rate was the only other physiologic factor with a small effect on myocardial ShMOLLI T1 (6ms/10bpm). Left and right ventricular blood ShMOLLI T1 correlated strongly with each other and also with myocardial T1 with the slope of 0.1 that is justifiable by the resting partition of blood volume in myocardial tissue. Overall, the effect of all variables on myocardial ShMOLLI T1 was within 2% of relative changes from the average.ConclusionNative T1-mapping using ShMOLLI generates reproducible and consistent results in normal individuals within 2% of relative changes from the average, well below the effects of most acute forms of myocardial disease. The main potential confounder is the partial volume effect arising from over-inclusion of neighbouring tissue at the manual stages of image analysis. In the study of cardiac conditions such as diffuse fibrosis or small focal changes, the use of “myocardial midwall” T1, age and gender matching, and compensation for heart rate differences may all help to improve the method sensitivity in detecting subtle changes. As the accuracy of current T1 measurement methods remains to be established, this study does not claim to report an accurate measure of T1, but that ShMOLLI is a stable and reproducible method for T1-mapping.

Pre-eclampsia and offspring cardiovascular health: mechanistic insights from experimental studies.

Pre-eclampsia is increasingly recognized as more than an isolated disease of pregnancy. Women who have had a pregnancy complicated by pre-eclampsia have a 4-fold increased risk of later cardiovascular disease. Intriguingly, the offspring of affected pregnancies also have an increased risk of higher blood pressure and almost double the risk of stroke in later life. Experimental approaches to identify the key features of pre-eclampsia responsible for this programming of offspring cardiovascular health, or the key biological pathways modified in the offspring, have the potential to highlight novel targets for early primary prevention strategies. As pre-eclampsia occurs in 2–5% of all pregnancies, the findings are relevant to the current healthcare of up to 3 million people in the U.K. and 15 million people in the U.S.A. In the present paper, we review the current literature that concerns potential mechanisms for adverse cardiovascular programming in offspring exposed to pre-eclampsia, considering two major areas of investigation: first, experimental models that mimic features of the in utero environment characteristic of pre-eclampsia, and secondly, how, in humans, offspring cardiovascular phenotype is altered after exposure to pre-eclampsia. We compare and contrast the findings from these two bodies of work to develop insights into the likely key pathways of relevance. The present review and analysis highlights the pivotal role of long-term changes in vascular function and identifies areas of growing interest, specifically, response to hypoxia, immune modification, epigenetics and the anti-angiogenic in utero milieu.

Right Ventricular Systolic Dysfunction in Young Adults Born Preterm

Background— Young adults born preterm have distinct differences in left ventricular mass, function, and geometry. Animal studies suggest that cardiomyocyte changes are evident in both ventricles after preterm birth; therefore, we investigated whether these young adults also have differences in their right ventricular structure and function. Methods and Results— We studied 102 preterm-born young adults followed up prospectively since birth and 132 term-born control subjects born to uncomplicated pregnancies. We quantified right ventricular structure and function by cardiovascular magnetic resonance on a 1.5-T Siemens scanner using Argus and TomTec postprocessing software. Preterm birth was associated with a small right ventricle (end diastolic volume, 79.8±13.2 versus 88.5±11.8 mL/m2; P<0.001) but greater right ventricular mass (24.5±3.5 versus 20.4±3.4 g/m2; P<0.001) compared with term-born controls, with the severity of differences proportional to gestational age (r=−0.47, P<0.001). Differences in right ventricular mass and function were proportionally greater than previously reported for the left ventricle. This was most apparent for systolic function; young adults born preterm had significantly lower right ventricular ejection fraction (57±8% versus 60±5%; P=0.006). Indeed, 21% had values below the lower limit observed in the term-born adults and 6% had mild systolic dysfunction (<45%). Postnatal ventilation accounted for some of the variation in mass but not function. Conclusions— Preterm birth is associated with global myocardial structural and functional differences in adult life, including smaller right ventricular size and greater mass. The changes are greater in the right ventricle than previously observed in the left ventricle, with potentially clinically significant impairment in right ventricular systolic function.

Antenatal Glucocorticoid Exposure and Long-Term Alterations in Aortic Function and Glucose Metabolism

OBJECTIVE: Animal studies have demonstrated long-term effects of in utero glucocortcoid exposure on vascular development and glucose metabolism. We hypothesized that there would be a similar impact in humans. METHODS: One hundred and two young adults born preterm aged 23 to 28 years, with prospective data collection from birth, and 95 adults born term after uncomplicated pregnancies underwent cardiovascular MRI. We compared cardiac and aortic structure and function, as well as cardiovascular risk profile, in a nested case-control study of 16 participants exposed to antenatal steroids and 32 who were not, but with otherwise similar perinatal care. Outcomes were compared with normal ranges in those born term. RESULTS: Adults whose mothers had received antenatal steroids had decreased ascending aortic distensibility (9.88 ± 3.21 vs 13.62 ± 3.88 mm Hg−1 × 103, P = .002) and increased aortic arch pulse wave velocity (5.45 ± 1.41 vs 4.47 ± 0.91 m/s, P = .006). The increase in stiffness was equivalent to that of term adults a decade older. Those who had in utero exposure to antenatal steroids also had significant differences in homeostatic model assessments for β-cell function (P = .010), but in multiple regression analysis this did not explain the impact of steroids on aortic function. CONCLUSIONS: Antenatal glucocorticoid exposure in preterm infants is associated with increased aortic arch stiffness and altered glucose metabolism in early adulthood.

Gender-specific differences in left ventricular remodelling in obesity: insights from cardiovascular magnetic resonance imaging

AIMS As obesity-related cardiovascular mortality, although elevated when compared with normal weight, is lower in females than in males at every body mass index (BMI) level, we aimed to investigate gender-specific differences in left ventricular (LV) hypertrophy in obesity, which themselves have been shown to have varying prognostic value. METHOD AND RESULTS In total, 741 subjects (female, n = 399) without identifiable cardiovascular risk factors (BMI 15.7-59.2 kg/m(2)) underwent cardiovascular magnetic resonance (1.5 T) to determine LV mass, end-diastolic volume (EDV, mL), and LV mass/volume ratio (LVM/VR). Across both sexes, there was a strong positive correlation between BMI and LV mass (male r = 0.44, female r = 0.57, both P < 0.001), with males showing a greater LV hypertrophic response (male +2.3 vs. female +1.6 g per BMI point increase, P = 0.001). Concentric hypertrophy was present in both sexes and LVM/VR positively correlated to BMI (male r = 0.45, female r = 0.29, both P < 0.001) on linear regression analysis. However, the degree of concentric hypertrophy was greater in males (male +0.13 vs. female +0.06 LVM/VR increase per BMI point increase, P = 0.001). On the other hand, females showed a greater LV cavity dilatory response (female +1.1 vs. male +0.3 mL per BMI point increase, P < 0.001). Indeed, in contrast to females, where BMI and LV-EDV were positively correlated (r = 0.38, P < 0.001), BMI did not correlate with EDV in men (r = 0.03, P = 0.62). CONCLUSION In the absence of traditional cardiovascular risk factors, obese men show predominantly concentric hypertrophy, whereas obese women exhibit both eccentric and concentric hypertrophy. As concentric hypertrophy is more strongly related to cardiovascular mortality than eccentric hypertrophy, our observations may explain the observed gender difference in obesity-related mortality.

Unique blood pressure characteristics in mother and offspring after early onset preeclampsia.

Risk of hypertension in mother and offspring after preeclampsia is greater if preeclampsia develops early in pregnancy. We investigated whether those who develop early onset disease have unique adverse blood pressure characteristics. One hundred forty women were studied 6 to 13 years either after a pregnancy complicated by preeclampsia (45 women with early onset preeclampsia before 34 weeks gestation and 45 women with late-onset preeclampsia) or after a normotensive pregnancy (50 women). Forty-seven offspring from these pregnancies also participated. Data on maternal antenatal and postnatal blood pressures were extracted from maternity records and related to peripheral, central, and ambulatory blood pressure measurements in later life. Compared with late-onset preeclampsia, early onset preeclampsia was associated with higher diastolic blood pressure 6 weeks postnatally (86.25±13.46 versus 75.00±5.00 mm Hg, P<0.05), a greater increase in blood pressure relative to booking blood pressure over the subsequent 6 to 13 years, and higher nocturnal systolic and diastolic blood pressures in later life (111.07±13.18 versus 101.13±11.50 mm Hg, P=0.04, and 67.00±7.25 versus 58.60±5.79 mm Hg, P=0.002). Furthermore, at age 6 to 13 years their offspring had higher systolic blood pressure compared with those born to late-onset preeclampsia (96.27±7.30 versus 88.39±7.57 mm Hg, P=0.005). Mothers who developed early onset preeclampsia, and the offspring of that pregnancy display specific adverse blood pressure characteristics later in life. These are not evident in mothers and offspring after late-onset preeclampsia or normotensive pregnancy.

Short-Term Exposure to Exogenous Lipids in Premature Infants and Long-Term Changes in Aortic and Cardiac Function

Objective— Intravenous lipid use is associated with an acute hyperlipidemia, but long-term consequences have not been studied. We investigated whether elevated lipids in humans during the critical period of preterm neonatal life have a long-term impact on aortic and myocardial function relevant to adult disease. Methods and Results— We followed up 102 subjects born prematurely and now aged 23 to 28 years. Eighteen received intravenous lipids as neonates and were matched to controls with equivalent perinatal characteristics. Global and regional aortic stiffness and left ventricular function were assessed by cardiovascular magnetic resonance. Those who received intravenous lipids had greater aortic stiffness in early adulthood (P=0.0002), with greater stiffness in the abdominal aorta (P=0.012). The relationship was graded according to the elevation in neonatal cholesterol induced by intravenous lipids (P<0.0001) but not other metabolic parameters altered by the infusion. Peak systolic circumferential strain was also reduced in the lipid group (P=0.006), which, again, was proportional to neonatal cholesterol level (P<0.01). Conclusion— Aortic and myocardial function in young adulthood is associated with intralipid exposure during neonatal life for preterm infants, in a graded manner related to the rise in cholesterol. Circulating cholesterol during critical developmental periods may have long-term impacts on the human cardiovascular system.

Dynamic Release and Clearance of Circulating Microparticles During Cardiac Stress

Rationale: Microparticles are cell-derived membrane vesicles, relevant to a range of biological responses and known to be elevated in cardiovascular disease. Objective: To investigate microparticle release during cardiac stress and how this response differs in those with vascular disease. Methods and Results: We measured a comprehensive panel of circulating cell-derived microparticles by a standardized flow cytometric protocol in 119 patients referred for stress echocardiography. Procoagulant, platelet, erythrocyte, and endothelial but not leukocyte, granulocyte, or monocyte-derived microparticles were elevated immediately after a standardized dobutamine stress echocardiogram and decreased after 1 hour. Twenty-five patients developed stress-induced wall motion abnormalities suggestive of myocardial ischemia. They had similar baseline microparticle levels to those who did not develop ischemia, but, interestingly, their microparticle levels did not change during stress. Furthermore, no stress-induced increase was observed in those without inducible ischemia but with a history of vascular disease. Fourteen patients subsequently underwent coronary angiography. A microparticle rise during stress echocardiography had occurred only in those with normal coronary arteries. Conclusions: Procoagulant, platelet, erythrocyte, and endothelial microparticles are released during cardiac stress and then clear from the circulation during the next hour. This stress-induced rise seems to be a normal physiological response that is diminished in those with vascular disease.