Obese and Type 2 Diabetic Youth Have Increased Forward and Backward Wave Reflections.

OBJECTIVE: Pulse wave analysis estimates arterial wave reflections relating to left ventricular dysfunction and cardiovascular event risk in adults. Forward and backward waves (Pf and Pb) may improve risk stratification for cardiovascular events. Data in youth are lacking. We hypothesized that a significant difference in wave reflections would be identified in young subjects with adverse cardiovascular risk factors. Approach and Results: Vital signs and labs were obtained in 551 patients aged 10 to 24 years who were lean (L=199), obese (O=173), or had type 2 diabetes (T=179). Wave separation was performed. Differences in cardiovascular risk factors and wave reflections were assessed using ANOVA. General linear models were constructed to elucidate independent predictors of wave reflections. O and T subjects had an adverse cardiovascular risk profile versus L. O and T subjects had higher Pf and Pb versus L (P≤0.05). When adjusted for adiposity and other cardiovascular risk factors, reflection magnitude increased from L to O to T with higher T versus L values (P≤0.05) and near-significant O versus L values (P=0.06). Adiposity and blood pressure were major determinants of wave reflections. Pb influenced log left ventricular mass index, log E/e', and log composite carotid intima-media thickness. CONCLUSIONS: Adolescents and young adults with obesity and type 2 diabetes have altered forward and backward wave reflections versus lean controls related to adiposity, BP, and insulin levels. These parameters may help risk stratify patients with adverse cardiovascular risk factors.

Markers of cholesterol synthesis are elevated in adolescents and young adults with type 2 diabetes.

BACKGROUND: Changes in cholesterol absorption and cholesterol synthesis may promote dyslipidemia and cardiovascular disease in individuals with type 2 diabetes mellitus (T2DM). OBJECTIVE: To assess cholesterol synthesis and absorption in lean individuals, obese individuals, and individuals with T2DM. METHODS: We measured lathosterol and lanosterol (markers of cholesterol synthesis) as well as campesterol and ß-sitosterol (markers of cholesterol absorption) in the serum of 15 to 26 years old individuals with T2DM (n = 95), as well as their lean (n = 98) and obese (n = 92) controls. RESULTS: Individuals with T2DM showed a 51% increase in lathosterol and a 65% increase in lanosterol compared to lean controls. Similarly, obese individuals showed a 31% increase in lathosterol compared to lean controls. Lathosterol and lanosterol were positively correlated with body mass index, fasting insulin and glucose, serum triglycerides, and C-reactive protein, and negatively correlated with HDL-cholesterol. In contrast, campesterol and ß-sitosterol were not altered in individuals with T2DM. Moreover, campesterol and ß-sitosterol were negatively correlated with body mass index, fasting insulin, and C-reactive protein and were positively correlated with HDL-cholesterol. CONCLUSIONS: Adolescents and young adults with T2DM show evidence of increased cholesterol synthesis compared to non-diabetic lean controls. These findings suggest that T2DM may promote cardiovascular disease by increasing cholesterol synthesis, and provide additional rationale for the use of cholesterol synthesis inhibitors in this group.

Obesity and type 2 diabetes are associated with elevated PCSK9 levels in young women.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein cholesterol and cardiovascular disease risk, and is an emerging therapeutic target. OBJECTIVE: We compared serum PCSK9 levels in young adults, with and without type 2 diabetes. SUBJECTS AND METHODS: Cross-sectional analysis was conducted in a cohort, aged 15 to 26 years, in Cincinnati, OH, from 2005 to 2010. Serum PCSK9 levels were measured in 94 youth with type 2 diabetes, 93 obese control subjects, and 99 lean control subjects. Correlative analyses were conducted to determine significant covariates of PCSK9 by group and sex, and multivariate linear regression models were used to study the independent determinants of PCSK9. RESULTS: In females, PCSK9 levels were significantly increased in the obese and type 2 diabetes subjects relative to the lean controls (P < .01). Moreover, PCSK9 was positively correlated with multiple metabolic parameters in females: body mass index, systolic blood pressure, fasting glucose, fasting insulin, and C-reactive protein levels (P ≤ .02). In males, PCSK9 levels were decreased overall compared with females (P = .03), and did not differ between the lean, obese, or type 2 diabetes groups. CONCLUSIONS: Obesity and type 2 diabetes were associated with significantly higher levels of PCSK9 in young women, but not in young men. These data suggest that sex could modify the effects of obesity and diabetes on PCSK9 in young adults.

Incorrect ventricular lead placement into the systemic right ventricle of a patient with D-transposition of the great vessels after Mustard procedure.

Incorrect pacemaker lead placement into the systemic ventricle is a complication that has rarely been described in patients with D-transposition status after atrial baffle palliation. We present a case of ventricular lead misplacement in the systemic right ventricle of a patient with D-transposition of the great arteries after Mustard procedure. This case demonstrates the challenges with proper imaging of lead placement in patients with atrial baffles and long-term management of a lead in the systemic ventricle.

Echo-Doppler assessment of the biophysical properties of the aorta in children with chronic kidney disease.

Chronic kidney disease (CKD) is known to cause increased arterial stiffness, which is an important independent risk factor for adverse cardiovascular events. The purpose of this study was to assess the vascular properties of the aorta (AO) in a group of children with CKD using a noninvasive echocardiography (echo)-Doppler method. We studied 24 children with stages 2 through 5 CKD and 48 age-matched controls. Detailed echocardiographic assessment and echo-Doppler pulse wave velocity (PWV) was performed. Indices of arterial stiffness, including characteristic (Zc) and input (Zi) impedances, elastic pressure-strain modulus (Ep), and arterial wall stiffness index, were calculated. CKD patients underwent full nephrology assessment, and an iohexol glomerular filtration rate was performed, which allowed for accurate assignment of the CKD stage. CKD patients had greater median systolic blood pressure (114 vs. 110 mmHg; p < 0.04) and pulse pressure (51 vs. 40 mmHg; p < 0.001) compared with controls. PWV was similar between groups (358 vs. 344 cm s(-1); p = 0.759), whereas Zi (182 vs. 131 dyne s cm(-5); p < 0.001), Zc (146 vs. 138 dyne s cm(-5); p = 0.05), and Ep (280 vs. 230 mmHg; p < 0.02) were significantly greater in CKD than in controls. Although load-dependent measures of arterial stiffness were greater in non-dialysis dependent CKD patients, PWV was not increased compared with controls. This suggests that the increased arterial stiffness may not be permanent in these pediatric patients with kidney disease.

Predictors of exaggerated exercise-induced systolic blood pressures in young patients after coarctation repair.

BACKGROUND: In normotensive subjects, an exaggerated blood pressure response to exercise is associated with the development of resting hypertension. We sought to determine the prevalence of elevated blood pressures during exercise in post-operative coarctation patients with normal resting blood pressure, and investigate associations with exercise-induced hypertension in this population. METHODS: A total of 38 patients were enrolled after end-to-end anastomosis repair and resting normotension. All patients underwent anthropometric and blood pressure measurements, echocardiographic evaluation of function, arterial stiffness assessment by pulse wave velocity, and a graded exercise test. An abnormal response was defined as a maximum systolic blood pressure greater than the 95th percentile of published normal values. Correlation analyses and stepwise regression analyses were performed. RESULTS: The mean age was 12.7 years, including 79% male patients. The mean resting systolic blood pressure was 111.3 millimetres of mercury and the mean exercise systolic blood pressure was 178.1 millimetres of mercury. The prevalence of a systolic blood pressure greater than the 95th percentile was 16.7%. In multivariate analysis, the exercise systolic blood pressure index was associated with body mass index, age, aortic valve annulus, shortening fraction, and pulse wave velocity (R2 equal to 0.79, p equal to 0.0009). Estimates of ventricular filling and indexed left ventricular mass were elevated. CONCLUSIONS: There is a risk of elevated systolic blood pressure during exercise in normotensive patients after coarctation repair. Resting blood pressures are useful but not sufficient. Echocardiography demonstrated abnormalities suggestive of a chronic cardiac burden despite resting normotension. Regular imaging may be necessary to improve long-term outcomes. New paradigms for the continued follow-up of these patients are necessary.

Left Juxtaposition of the Right Atrial Appendage: Pitfalls in Diagnosis.

Several congenital anomalies of the right atrial appendage (RAA) have been described including aneurysm, herniation (in association with a pericardial defect), and left juxtaposition. The left juxtaposition of the RAA (LJRAA), first described by Birmingham in 1893 and subsequently introduced by Dixon in 1954, is usually associated with complex cardiac malformations such as obstruction of the left ventricular outflow tract. In this case report, we will describe an unusual variant of LJRAA in the absence of any other cardiac defects, which was initially misinterpreted as an aortic dissection. The correct diagnosis was made after careful reinterpretation and the use of multiple imaging modalities as highlighted.

Nutritional markers accompanying acquired chylothorax in infants: a systematic review.

CONTEXT: Chylothorax is a well-established acquired complication of thoracic surgery in infants. Current data suggest acquired chylothorax may affect infant growth and nutrition because of a loss of essential nutrients via chylous effusion. OBJECTIVE: The 3 objectives for this study were: (1) identify nutritional markers affected by the development of acquired chylothorax in infants; (2) highlight the variability in methods used to assess nutritional status and growth in this patient population; and (3) highlight nutritional deficits that can serve as treatment targets during postoperative feeding protocols. DATA SOURCES: A systematic literature search was conducted between May 31, 2021, and June 21, 2022, using the PubMed, Embase, CINAHL, and Web of Science databases. Search terms included, but were not limited to, "chylothorax," "infants," and "nutrition." DATA EXTRACTION: Inclusion criteria required studies that measured quantitative markers of nutrition in ≥10 participants aged <1 year with acquired chylothorax. A total of 575 studies were screened and all but 4 were eliminated. Nutritional markers were categorized into 4 different groups: total serum protein level, triglyceride levels, growth velocity, and weight for length. DATA ANALYSIS: The variation in methods, time points, interventional groups, and nutritional markers did not facilitate a meta-analysis. Risk of bias was assessed using the Cochrane Risk of Bias in Nonrandomized Studies assessment tool. CONCLUSION: This review highlights the need for reliable quantitative markers of nutrition that will enable providers to assess the nutritional needs of infants with chylothorax. Future studies must focus on measuring markers of nutrition at regular intervals in larger study populations.

Impact of prenatal opioids on cardiac and autonomic development: systematic review and meta-analysis.

Prenatal opioid exposure has recently risen four-fold with limited data on the developmental effects on neonatal physiology. The objective of this systematic review is to develop an association between prenatal opioid exposure and fetal and neonatal cardiac and autonomic development and function. The review was conducted in accordance with PRISMA Guidelines, and searches were conducted using PubMed, Embase, CINAHL, and Web of Science between May 25 and October 27, 2020. Twenty studies fit inclusion criteria, in four categories: (1) fetal cardiac outcomes, (2) neonatal cardiac outcomes, (3) noninvasive autonomic outcomes, and (4) clinical and behavioral measures. For the meta-analysis, three studies (total of 210 subjects) were included. Effect sizes were measured as the mean difference in fetal heart rate between opioid-exposed and non-exposed groups. Mothers with prenatal opioid use had a significantly lower fetal heart rate as compared to mothers without prenatal opioid use, requiring further studies to determine clinical significance.

Racial differences in arterial stiffness among adolescents and young adults with type 2 diabetes.

BACKGROUND: African-American adults demonstrate a higher prevalence of cardiovascular complications including myocardial infarction and stroke. Whether similar racial disparities are present to suggest African-Americans adolescents are at higher risk to develop cardiovascular disease is not known. Thus, we compared arterial stiffness, an early marker of cardiovascular disease, in African-American and Caucasian adolescents and young adults with type 2 diabetes. METHODS: Demographic, anthropometric, laboratory data, and arterial stiffness measures including pulse wave velocity (PWV) and augmentation index (AIx) were collected in a cross-sectional study of 215 adolescents (average age 18 yr) with type 2 diabetes (55% African-American and 65% female). RESULTS: Compared to Caucasians, African-Americans had increased PWV (6.21 ± 0.87 vs. 6.96 ± 1.30, p < .01) and AIx (4.44 ± 11.17 vs. 7.64 ± 12.02, p = 0.05). Regression modeling demonstrated age, lipids, blood pressure, and duration of diabetes were differently associated with arterial stiffness in each race group (p < 0.05). CONCLUSIONS: African-American adolescents and young adults with type 2 diabetes have increased vascular stiffness than age-matched Caucasians. This process is mediated by different cardiovascular risk factors. These results suggest race-specific risk factor modification may be helpful to prevent early cardiovascular disease in this high risk population.

Cardiovascular impact of the pediatric obesity epidemic: higher left ventricular mass is related to higher body mass index.

OBJECTIVE: To compare secular changes in body mass index (BMI) and left ventricular mass (LVM) in today's children versus children of a generation earlier. STUDY DESIGN: All healthy patients aged 2 to 19 years who underwent echocardiography at a single US academic medical center in 1986 to 1989 (prior era) and 2008 (current era) were included in this retrospective cross-sectional study. BMI, BMI z score, LVM indexed to height (LVMI), LVM z score, and relative wall thickness were calculated. Cardiac geometries were assigned based on LVM z score and relative wall thickness and classified as normal, concentric hypertrophy, eccentric hypertrophy, or concentric remodeling. Stepwise regression analysis was performed to identify determinants of LVMI. RESULTS: There were 350 subjects in the prior era and 350 age- and sex-matched subjects in the current era. Mean BMI and LVMI were both significantly higher in the current era than in the prior era (BMI, 19.9 ± 5.6 kg/m(2) vs 18.1 ± 3.8 kg/m(2), P = .0004; LVMI, 32.7 ± 7.8 g/m(2.7) vs 31.5 ± 8.1 g/m(2.7); P = .02). Determinants of LVMI in both eras were BMI z score, younger age, male sex, and African-American race. CONCLUSIONS: Today's children have higher BMI, LVMI, and predicted cardiovascular risk than their counterparts a generation earlier. Reversal of these trends is needed, and intervention is required.

Relationship between elevated arterial stiffness and increased left ventricular mass in adolescents and young adults.

OBJECTIVE: To determine whether arterial stiffness relates to left ventricular mass (LVM) in adolescents and young adults. STUDY DESIGN: Demographic, anthropometric, laboratory, echo, carotid ultrasound and arterial stiffness data were obtained in 670 subjects 10 to 24 years of age (35% male, 62% non-Caucasian). Global stiffness index (GSI) was calculated from five measures of carotid artery stiffness, augmentation index, brachial distensibility, and pulse wave velocity (1 point if ≥95th% for subjects with body mass index <85th%). Stiff arteries (S = 73) were defined as GSI ≥95th%. Differences between flexible (F = 597) and S groups were evaluated by t tests. Models were constructed to determine whether GSI was an independent determinant of LVM index or relative wall thickness (RWT). RESULTS: The S group had more adverse cardiovascular risk factors, higher LVM index and RWT (P ≤ .05) with a trend for abnormal cardiac geometry. Independent determinants of LVM index were higher GSI, age, body mass index, systolic blood pressure, heart rate, glycated hemoglobin A1c, male sex, and sex-by-heart rate interaction (r(2) = 0.52; P ≤ .05). GSI was also an independent determinant of RWT. CONCLUSIONS: Increased arterial stiffness in adolescents and young adults is associated with LVM index independently of traditional cardiovascular risk factors. Screening for arterial stiffness may be useful to identify high risk adolescents and young adults.

Youth with obesity and obesity-related type 2 diabetes mellitus demonstrate abnormalities in carotid structure and function.

BACKGROUND: Adults with obesity or type 2 diabetes mellitus (T2DM) are at higher risk for stroke and myocardial infarction. Increased carotid intima-media thickness (cIMT) and stiffness are associated with these adverse outcomes. We compared carotid arteries in youth who were lean, were obese, or had T2DM. METHODS AND RESULTS: Carotid ultrasound for cIMT measurement was performed, the Young elastic modulus and beta stiffness index were calculated, and anthropometric and laboratory values and blood pressure were measured in 182 lean, 136 obese, and 128 T2DM youth (aged 10 to 24 years). Mean differences were evaluated by ANOVA. Independent determinants of cIMT, Young elastic modulus, and beta stiffness index were determined with general linear models. Cardiovascular risk factors worsened from lean to obese to T2DM groups. T2DM subjects had greater cIMT than that in lean and obese subjects for the common carotid artery and bulb. For the internal carotid artery, cIMT measurements in both obese and T2DM groups were thicker than in the lean group. The carotid arteries were stiffer in obese and T2DM groups than in the lean group. Determinants of cIMT were group, group x age interaction, sex, and systolic blood pressure for the common carotid artery (r2=0.17); age, race, and systolic blood pressure for the bulb (r2=0.16); and age, race, sex, systolic blood pressure, and total cholesterol for the internal carotid artery (r2=0.21). Age, systolic blood pressure, and diastolic blood pressure were determinants of all measures of carotid stiffness, with sex adding to the Young elastic modulus (r2=0.23), and body mass index Z score, group, and group x age interaction contributing to the beta stiffness index (r2=0.31; all P<0.0001). CONCLUSIONS: Youth with obesity and T2DM have abnormalities in carotid thickness and stiffness that are only partially explained by traditional cardiovascular risk factors. These vascular changes should alert healthcare practitioners to address cardiovascular risk factors early to prevent an increase in the incidence of stroke and myocardial infarction.

Accelerated Early Vascular Aging Among Adolescents With Obesity and/or Type 2 Diabetes Mellitus.

Background The normal rate of subclinical vascular aging from adolescence to young adulthood has not been well-characterized. We conducted a 5-year longitudinal study among adolescents with normal-weight, obesity, and/or type 2 diabetes mellitus to examine trajectories of early vascular aging. Methods and Results Adolescents (mean [SD] age 17.6 [3.5]; 35.3% male) had either normal weight (n=141), obesity (n=156), or type 2 diabetes mellitus (n=151) at baseline. Primary metrics used for early vascular aging included measures of vascular structure (carotid intima-media thickness [cIMT]; common, internal, and bulb) and arterial stiffness (carotid-femoral pulse wave velocity, and augmentation index). Longitudinal (5-year) outcomes were examined using generalized estimating equations adjusting for baseline value, sex, race, and age. Compared with participants with normal weight, those with obesity had greater positive change in common cIMT (0.05 mm [0.03, 0.06]; P<0.001), bulb cIMT (0.02 mm [0.00, 0.05]; P=0.033), internal cIMT (0.03 mm [0.01, 0.05]; P<0.001), and pulse wave velocity carotid-femoral (0.38 m/sec [0.14, 0.61]; P=0.001), and those with type 2 diabetes mellitus had greater positive change in common cIMT (0.05 mm [0.04, 0.07]; P<0.001), bulb cIMT (0.06 mm [0.04, 0.09]; P<0.001), internal cIMT (0.04 mm [0.02, 0.07]; P<0.001), augmentation index (4.67% [2.20, 7.13]; P<0.001), and pulse wave velocity carotid-femoral (0.74 m/sec [0.46, 1.02]; P<0.001). Higher baseline systolic blood pressure was associated with greater positive change in common cIMT (0.007 mm [0.003, 0.011]; P<0.001), bulb cIMT (0.009 mm [0.002, 0.016]; P=0.01), internal cIMT (0.008 mm [0.003, 0.013]; P=0.001), and pulse wave velocity carotid-femoral (0.066 m/sec [0.002, 0.130]; P=0.042). Conclusions These longitudinal data support the hypothesis that the presence of obesity, type 2 diabetes mellitus, and elevated baseline systolic blood pressure in early life accelerates the progression of risk factors key in the development of early vascular aging.

Decreased maximal aerobic capacity in pediatric chronic kidney disease.

Adult and pediatric patients with ESRD have impaired maximum oxygen consumption (VO(2) max), a reflection of the cardiopulmonary system's ability to meet increased metabolic demands. We sought to determine factors associated with decreased VO(2) max in pediatric patients with different stages of CKD. VO(2) max was measured using a standardized exercise testing protocol in patients with stage 2 to 4 chronic kidney disease (CKD) (n = 46), in renal transplant recipients (n = 22), in patients treated with maintenance hemodialysis (n = 12), and in age-matched healthy controls (n = 33). VO(2) max was similar between children with stage 2 CKD and controls, whereas lower VO(2) max was observed among children with stage 3 to 4 CKD, those treated with hemodialysis, and transplant recipients. In univariate analysis, VO(2) max was significantly associated with body mass index, resting heart rate, C-reactive protein, serum triglycerides, serum creatinine, and measures of diastolic function; no significant associations with left ventricular structure or systolic function were identified. In multivariate regression analysis, patient category versus control and the presence of diastolic dysfunction were independent predictors of lower VO(2) max. These results suggest that aerobic capacity is decreased in the early stages of CKD in children and that lower VO(2) max can be predicted by the presence of diastolic dysfunction, even if systolic function is normal.

Development of a System to Measure and Improve Outcomes in Congenital Heart Disease: Heart Institute Safety, Quality, and Value Program.

Achieving excellent outcomes for patients with congenital heart disease requires coordinated effort and resources, and a need has developed for a structure that facilitates improvement and measures cardiac centers' progress toward optimal patient care. METHODS: The Heart Institute (HI) at Cincinnati Children's Hospital developed a Safety, Quality and Value (SQV) program to formalize the use of quality improvement (QI) methods with the goal of optimizing patient outcomes, experience, and value. The SQV program adopted a conceptual framework that considers aspects of structure, process, outcome, and value in defining quality metrics, and the program used the Model for Improvement to guide design and implementation of QI interventions. RESULTS: In the first four years since its inception, the SQV program facilitated important improvements in clinical outcomes, cost reductions, and safety. In addition to achieving measurable improvements, the creation of a formal SQV program fostered a culture of transparency and accountability, providing a new structure for how the HI shares clinical data among clinicians, hospital leadership, and the public. CONCLUSION: The creation of an infrastructure to strategically design, implement, and support QI efforts in a clinically busy pediatric acquired and congenital heart institute was successful in meeting its initial aims and is a promising approach and model for other programs.

Comparison of Left Ventricular Mass Calculation Methods via Two-Dimensional Echocardiogram in Children, Adolescents, and Young Adults With Systemic Hypertension.

Left ventricular (LV) mass is a major determining tool for myocardial injury in hypertensive patients. Issues with LV mass calculations exist given that there are multiple methods to assess mass, including from the parasternal long axis (PLA), parasternal short axis (PSA), and 2-dimensional (2D) volumetric methods. The aim of this study was to compare the agreement of LV mass calculations using the PLA, PSA, and 2D volumetric methods. This study retrospectively reviewed 200 consecutive, initial echocardiograms for the indication of hypertension. A single reader calculated the LV mass in each patient via the PLA, PSA, and 2D volumetric methods. Percent differences for each study were calculated. LV mass threshold cutoffs of 51 g/m2.7 (cardiac organ injury) and 38.6 g/m2.7 (elevated LV mass) were used to compare categorical differences between the different measurement methods. Paired comparisons demonstrated an absolute mean percent difference of 8.46% to 9.41% among the different methods. LV mass calculated by the 2D volumetric method was less compared with PLA and PSA methods (31.64 vs 33.90 vs 35.51 g/m2.7; p < 0.0001). Fewer patients were classified as having cardiac target organ injury or elevated LV mass via 2D volumetric calculation, compared with PLA and PSA methods (p = 0.02 and p = 0.03, respectively). In conclusion, there is a small but important difference in LV mass calculations for patients with hypertension. These results emphasize the need for consistency within echocardiography laboratories as surveillance studies are common in this patient population.

Type 1 diabetes is associated with an increase in cholesterol absorption markers but a decrease in cholesterol synthesis markers in a young adult population.

BACKGROUND: To optimize treatment and prevent cardiovascular disease in subjects with type 1 diabetes, it is important to determine how cholesterol metabolism changes with type 1 diabetes. OBJECTIVE: The objective of the study was to compare plasma levels of campesterol and ß-sitosterol, markers of cholesterol absorption, as well as lathosterol, a marker of cholesterol synthesis, in youth with and without type 1 diabetes. METHODS: Serum samples were obtained from adolescent subjects with type 1 diabetes (n = 175, mean age 15.2 years, mean duration of diabetes 8.2 years) and without diabetes (n = 74, mean age 15.4 years). Campesterol, ß-sitosterol, and lathosterol, were measured using targeted liquid chromatography tandem mass spectrometry, compared between groups, and correlated with the available cardiometabolic variables. RESULTS: Campesterol and ß-sitosterol levels were 30% higher in subjects with type 1 diabetes and positively correlated with hemoglobin A1c levels. In contrast, lathosterol levels were 20% lower in subjects with type 1 diabetes and positively correlated with triglycerides, body mass index, and systolic blood pressure. CONCLUSION: Plasma markers suggest that cholesterol absorption is increased, whereas cholesterol synthesis is decreased in adolescent subjects with type 1 diabetes. Further studies to address the impact of these changes on the relative efficacy of cholesterol absorption and synthesis inhibitors in subjects with type 1 diabetes are urgently needed.

GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation.

Here we identified growth-differentiation factor 15 (GDF15) (also known as MIC-1), a secreted member of the transforming growth factor (TGF)-beta superfamily, as a novel antihypertrophic regulatory factor in the heart. GDF15 is not expressed in the normal adult heart but is induced in response to conditions that promote hypertrophy and dilated cardiomyopathy. To elucidate the function of GDF15 in the heart, we generated transgenic mice with cardiac-specific overexpression. GDF15 transgenic mice were normal but were partially resistant to pressure overload-induced hypertrophy. Expression of GDF15 in neonatal cardiomyocyte cultures by adenoviral-mediated gene transfer antagonized agonist-induced hypertrophy in vitro. Transient expression of GDF15 outside the heart by intravenous adenoviral delivery, or by direct injection of recombinant GDF15 protein, attenuated ventricular dilation and heart failure in muscle lim protein gene-targeted mice through an endocrine effect. Conversely, examination of Gdf15 gene-targeted mice showed enhanced cardiac hypertrophic growth following pressure overload stimulation. Gdf15 gene-targeted mice also demonstrated a pronounced loss in ventricular performance following only 2 weeks of pressure overload stimulation, whereas wild-type controls maintained function. Mechanistically, GDF15 stimulation promoted activation of SMAD2/3 in cultured neonatal cardiomyocytes. Overexpression of SMAD2 attenuated cardiomyocyte hypertrophy similar to GDF15 treatment, whereas overexpression of the inhibitory SMAD proteins, SMAD6/7, reversed the antihypertrophic effects of GDF15. These results identify GDF15 as a novel autocrine/endocrine factor that antagonizes the hypertrophic response and loss of ventricular performance, possibly through a mechanism involving SMAD proteins.