Early myocardial changes in normotensive children of hypertensive parents: a tissue Doppler study.

The aim of this study was to examine early left ventricular systolic and diastolic changes using tissue Doppler imaging (TDI) in normotensive children of hypertensive parents (NCHP), a risk group for cardiovascular diseases. Ninety-two children characterized as NCHP (age range: 6-18 years) and 90 age-, gender-, height-, weight-, and body mass index-matched children characterized as normotensive children of normotensive parents (NCNP) were included in the study. Left ventricular diastolic parameters were assessed using transmitral flow pulse wave Doppler echocardiography and mitral septal and lateral annular TDI. Left ventricular systolic and diastolic function was evaluated globally using the TDI-derived myocardial performance index (MPI'). Mean systolic, diastolic, and average blood pressure values were found to be higher in the NCHP group than in the NCNP group. Echocardiographic parameters in the NCHP group showed statistically significant differences, including increased interventricular septum end-diastolic wall thickness (p = 0.039), left ventricular end-diastolic posterior wall thickness (p = 0.011), relative wall thickness (p = 0.013), and transmitral flow A velocity (p = 0.003); parameters determined by TDI included a prolonged isovolumetric relaxation time (p < 0.001) and isovolumetric contraction time (p = 0.002), shortened ejection time (p = 0.001), and increased MPI' (p < 0.001) in the NCHP group. Early alterations in myocardial function, indicated by increased MPI' values, had a positive correlation with systolic blood pressure and myocardial thickness. Conversely, they were negatively correlated with the ejection fraction and E/A ratio, which decreases with diastolic dysfunction. The MPI' is considered a repeatable, non-invasive, and low-cost assessment method that can surpass conventional methods in the detection of early left ventricular systolic and diastolic functional changes in the subclinical period of hypertension in children with familial risk.

Evaluation of cardiac autonomic function using heart rate variability in children with acute carbon monoxide poisoning.

Introduction Carbon monoxide poisoning may cause myocardial toxicity and cardiac autonomic dysfunction, which may contribute to the development of life-threatening arrhythmias. We investigated the potential association between acute carbon monoxide exposure and cardiac autonomic function measured by heart rate variability. METHOD: The present study included 40 children aged 1-17 years who were admitted to the Pediatric Intensive Care Unit with acute carbon monoxide poisoning and 40 healthy age- and sex-matched controls. Carboxyhaemoglobin and cardiac enzymes were measured at admission. Electrocardiography was performed on admission and discharge, and 24-hour Holter electrocardiography was digitally recorded. Heart rate variability was analysed at both time points - 24-hour recordings - and frequency domains - from the first 5 minutes of intensive care unit admission. RESULTS: Time domain and frequency indices such as high-frequency spectral power and low-frequency spectral power were similar between patient and control groups (p>0.05). The ratio of low-frequency spectral power to high-frequency spectral power was significantly lower in the carbon monoxide poisoning group (p<0.001) and was negatively correlated with carboxyhaemoglobin levels (r=-0.351, p<0.05). The mean heart rate, QT dispersion, corrected QT dispersion, and P dispersion values were higher in the carbon monoxide poisoning group (p<0.05) on admission. The QT dispersion and corrected QT dispersion remained longer in the carbon monoxide poisoning group compared with controls on discharge (p<0.05). CONCLUSION: The frequency domain indices, especially the ratio of low-frequency spectral power to high-frequency spectral power, are useful for the evaluation of the cardiac autonomic function. The decreased low-frequency spectral power-to-high-frequency spectral power ratio reflects a balance of the autonomic nervous system, which shifted to parasympathetic components.

Echocardiographic Follow-Up of Patent Foramen Ovale and the Factors Affecting Spontaneous Closure.

BACKGROUND: The aim of the present study was to evaluate the echocardiographic follow-up of patent foramen ovale, which is considered a potential etiological factor in various diseases, and to determine the factors affecting spontaneous closure. METHODS: Between January 2000 and June 2012, records of 918 patients with patent foramen ovale were retrospectively reviewed. Patency of less than 3 mm around the fossa ovalis is called patent foramen ovale. Patients with cyanotic congenital heart diseases, severe heart valve disorders and severe hemodynamic left to right shunts were excluded from the study. The patients were divided into three groups based on age; 1 day-1 month in group 1, 1 month-12 months in group 2, and more than 12 months in group 3. RESULTS: Of the 918 patients, 564 (61.4%) had spontaneous closure, 328 (35.8%) had patent foramen ovale continued, 15 (1.6%) patients had patent foramen ovale enlarged to 3-5 mm, 6 patients were enlarged to 5-8 mm, and in one patient patent foramen ovale reached to more than 8 mm size. Defect was spontaneously closed in 65.9% of the patients in group 1, 66.7% of the patients in group 2, and 52.3% of the patients in group 3. There was a negative correlation between the age of diagnosis and spontaneous closure (p < 0.05). Gender, prematurity and coexisting malformations such as patent ductus arteriosus and atrial septal aneurysm did not have any effect on spontaneous closure of patent foramen ovale (p > 0.05). However, ventricular septal defect and spontaneous closure of patent foramen ovale had a positive correlation (p < 0.01). No correlation was noted between the existence of atrial septal aneurysm, prematurity, and maturity of the patients. CONCLUSIONS: The present study demonstrated that spontaneous closure rate of patent foramen ovale is high. Furthermore, a positive correlation was found between spontaneous closure of patent foramen ovale with early diagnosis and small defect size.

The Diagnostic Value of Troponin T Level in the Determination of Cardiac Damage in Perinatal Asphyxia Newborns.

Perinatal asphyxia is a clinical condition which results from oxygen deprivation of the fetus or newborn and the breakdown of perfusion in various organs. The aim of this study was to evaluate and compare troponin T levels over time as a marker of cardiac injury in cases of perinatal asphyxia and healthy newborns. The study included a total of 30 newborns diagnosed with perinatal asphyxia with a gestational age of 32-41 weeks, based on the last menstruation date, and 30 healthy newborns with a gestational age of 34-40 weeks, as the control group. Levels of troponin T and creatinin kinase MB were recorded for all participants. No difference was determined between the groups in terms of gestational age, manner of birth, electrocardiographic findings, and PaO2 and PaCO2 values. The umbilical artery pH levels and bicarbonate levels in the study group were found to be statistically lower than those in the control group (p < 0.001). The troponin T and creatinin kinase MB levels in the patients in the study group were higher than those within the control group, at all times. The periods when specificity and sensitivity were highest together for troponin T were the 12th and 24th h. Specificity for troponin T reached the highest value at the 24th h and sensitivity reached the highest value in the cord blood. A positive correlation was found between the troponin T and creatinin kinase MB values at the 6th and 12th h. However, no correlation could be found in the blood between the serum troponin T and creatinin kinase MB levels at the 3rd and 24th h. The troponin T level is a useful test for showing cardiac damage in hypoxic patients in the neonatal period. The sensitivity and specificity of cardiac specific troponin T levels in detecting cardiac damage are much higher according to telecardiography and electrocardiography, while the implementation of the method is simple.

Acute rheumatic fever: a single center experience with 193 clinical cases.

BACKGROUND: Acute rheumatic fever is an inflammatory disease that develops via an auto-immune mechanism following group A beta hemolytic streptococcal tonsillopharyngitis. The aim of this study was to describe the clinical presentation of and cardiac involvement in acute rheumatic fever. METHODS: The medical records of acute rheumatic fever patients admitted to the Pediatric Cardiology Unit between January 2001 and January 2013 were reviewed. The patients were divided into two groups: 53 patients admitted during January 2001-January 2007 were designated as group 1, and 140 patients admitted during January 2007-January 2013 were designated as group 2. RESULTS: A total of 193 patients were evaluated, including 53 in group 1 and 140 in group 2. There was no statistically significant difference in age, gender and latent period between the two groups. There was, however, a statistically significant difference between the annual number of cases (P=0.001). Moreover, 35 (66%) patients in group 1 and 89 (64%) patients in group 2 were admitted during the spring or winter. The most common finding, as the major criteria in the current study, was concurrent carditis and arthritis. The most common minor finding was the presence of increased acute-phase reactants. We noted a statistically significant difference between the two groups in terms of valvular involvement. Group 2 had significantly higher frequencies of isolated aortic and mitral regurgitation than group 1, but the composite frequency of these was lower. CONCLUSIONS: Acute rheumatic fever continues to be prevalent in Turkey despite the country's socioeconomic improvements. We conclude that echocardiography should be performed on all of the patients with suspected acute rheumatic fever because it markedly increases the detection of carditis.

Uric Acid Levels in Normotensive Children of Hypertensive Parents.

This study evaluated uric acid concentrations in normotensive children of parents with hypertension. Eighty normotensive children from families with and without a history of essential hypertension were included. Concentrations of lipid parameters and uric acid were compared. Demographic and anthropometric characteristics were similar in the groups. Systolic and diastolic blood pressure were higher in the normotensive children of parents with hypertension without statistically significant difference (P > 0.05). Uric acid concentrations were higher in the normotensive children of parents with hypertension (4.61 versus 3.57 mg/dL, P < 0.01). Total cholesterol and triglyceride concentrations were similar in the two groups. Systolic and diastolic blood pressure were significantly higher in control children aged >10 years (P < 0.01). Uric acid levels were significantly higher in all children with more pronounced difference after age 10 of years (P < 0.001). Positive correlations were found between the level of serum uric acid and age, body weight, body mass index, and systolic and diastolic blood pressure in the normotensive children of parents. The higher uric acid levels in the normotensive children of hypertensive parents suggest that uric acid may be a predeterminant of hypertension. Monitoring of uric acid levels in these children may allow for prevention or earlier treatment of future hypertension.

Growth hormone and the risk of atherosclerosis in growth hormone-deficient children.

OBJECTIVE: Growth hormone-deficient (GHD) children have been found to have higher cardiovascular mortality rates and an increased carotid intima-media thickness (CIMT). This study investigated the risk of atherosclerosis and the effect of recombinant growth hormone (rhGH) replacement therapy on the lipid profile and CIMT in GHD children. DESIGN: A total of 40 GHD children (mean age: 12.3±2.04 years) were investigated before and after 1 year of rhGH therapy at a dosage of 0.03 mg/kg/day and 40 age- and sex-matched healthy children (mean age: 12.1±2.23 years) were enrolled as a control group, in the same pubertal stage. Fasting blood samples were obtained for lipid profile, IGF-1, and IGFBP-3 analyses. The patients and controls underwent CIMT measurements before and after 1 year of rhGH treatment. RESULTS: The growth velocity and height standard deviation scores increased significantly over 1 year of treatment in all patients. The total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, and atherogenic index (Ai) values were increased while the high-density lipoprotein (HDL) cholesterol value was decreased in the GHD children, as compared to the controls; however, the triglyceride (TG) level was comparable. After 1 year of treatment, a significant decrease in the TC, LDL cholesterol, and Ai values as well as a significant increase in the HDL value were observed in the GHD patients, with the values becoming similar to those in the control group. The mean CIMT was significantly greater in the GHD subjects than in the controls. After 1 year of therapy, the CIMT in the GHD subjects had decreased significantly; however, it was still greater than that in the control group. IGF-1 was negatively correlated with TC, LDL cholesterol, Ai, right CIMT, and left CIMT. CONCLUSIONS: GHD is associated with increased atherosclerotic risk in children. An improved lipid profile and CIMT were detected after 1 year of hormone replacement therapy.

Carotid intima-media thickness and elastic properties of aortas in normotensive children of hypertensive parents.

A significant correlation between hypertension history and high blood pressure has been observed with regard to age, race and gender. Investigating carotid intima-media thickness and aortic stiffness prior to the development of hypertension in children of hypertensive parents enabled us to evaluate these patients for subclinical atherosclerosis. We compared carotid intima-media thickness, aortic strain, distensibility, stiffness indices and elastic modulus in 67 normotensive children whose parents had a diagnosis of essential hypertension and 39 normotensive children with no parental history of hypertension. Although there were no significant differences between the two groups in terms of systolic blood pressure, diastolic blood pressure, average blood pressure and pulse pressure (P>0.05), systolic blood pressures were higher among patients 15 years and older in the study group. No significant differences were noted between the control and study groups regarding interventricular septal thickness, left-ventricular posterior wall thickness, left-ventricular systolic and diastolic diameter and aortic annulus diameter (P>0.05). The left atrium diameter was larger in the study group compared with that in the control group, mainly because of the values of the 15-year-old and older children (P=0.01). The mean, maximum and minimum values of carotid intima-media thickness were significantly different in the study group compared with the control group among all age groups (P<0.001, P<0.001, P=0.006, respectively). Aortic systolic and diastolic diameters were larger in normotensive children of hypertensive parents compared with the control group (P=0.014, P=0.001, respectively). Although there were no differences between the study and control groups regarding aortic strain, aortic distensibility, elastic modulus and stiffness indices (P>0.05), aortic distensibility was lower, and aortic stiffness indices were higher among children 15 years and older in the study group. An increase in the carotid intima-media thickness in all age groups and a decrease in aortic elastic properties in 15-year-old and older children of hypertensive parents may indicate subclinical atherosclerosis in these apparently healthy children.

Homocysteine levels in normotensive children of hypertensive parents.

OBJECTIVE: There are several studies showing an association between an increase in the plasma levels of homocysteine and the pathogenesis of hypertension. In this study, we assessed normotensive children of hypertensive adult parents to determine whether there is any change in homocysteine levels prior to the onset of hypertension. METHODS: A total of 79 normotensive children of essential hypertensive parents who were followed-up at the cardiology department and 72 healthy children of normotensive parents who presented to the department of pediatrics at our clinic with complaints such as nonspecific chest pain and innocent murmur were included in the study. The participants' complete blood count and low-density lipoprotein, high-density lipoprotein, triglyceride, total cholesterol, folic acid, vitamin B12, and homocysteine levels were noted. RESULTS: No statistically significant differences were noted between the two groups in terms of age, gender, height, weight, body mass index, or levels of fasting lipids, folic acid, and vitamin B12 (p>0.05). Although the mean systolic and diastolic blood pressures were within the normal limits in both groups, they were significantly higher in children with a family history of hypertension than in controls (p<0.05). Similarly, homocysteine levels of children with a family history of hypertension were significantly higher than those of controls (p<0.01). CONCLUSION: Homocysteine levels of normotensive children of hypertensive parents are elevated before they develop hypertension. Homocysteine levels may be predictive of the subsequent development of hypertension in normotensive children of hypertensive parents.

Circadian blood pressure rhythm in normotensive offspring of hypertensive parents.

BACKGROUND: The aim of this study was to explore the circadian blood pressure (BP) rhythm using ambulatory BP monitoring (ABPM) in normotensive children with a family history of essential hypertension. METHODS: Group 1 consisted of children with hypertensive mothers and/or fathers (n = 20), Group 2 consisted of children with hypertensive grandparents (n = 20), and Group 3 consisted of children with normotensive parents (n = 20). All participating children underwent a 24-h ABPM and echocardiography. RESULTS: Significantly higher systolic burden was found in children with hypertensive parents (p < 0.05) and grandparents (p < 0.05) compared to controls. Ambulatory BP measurements had a higher daytime systolic BP in Group 1 compared to controls (p < 0.05). While left ventricular (LV) posterior wall thickness was similar in Group 1 and Group 2, it was significantly higher in both of these groups compared to the controls. The LV mass index (LVMI) was significantly higher in Group 1 than in controls (p < 0.05). However, diastolic BP was significantly higher in dippers compared to non-dippers (p < 0.05). LV posterior wall thickness, interventricular septum thickness and LVMI were significantly higher among non-dippers compared to dippers (p < 0.05). In children with a family history of hypertension, a positive correlation between nocturnal systolic BP and LVMI was found, and increasing nocturnal BP values were associated with increasing LVMI (p < 0.01). CONCLUSIONS: In children with a family history of hypertension, target-organ damage may precede the clinical detection of hypertension, and in those with a nocturnal non-dipper status, a more marked effect on LVMI may occur.

Plasma adiponectin levels and relations with cytokines in children with acute rheumatic fever.

AIM: We aimed to investigate the role of adiponectin in acute rheumatic fever by evaluating correlations with cytokines and acute-phase reactants. METHODS: Patients were divided into three groups by clinical findings. Group 1 included 8 patients with only chorea, Group 2 included 13 patients with arthritis and carditis, and Group 3 included 12 patients with only carditis. A total of 54 age- and gender-matched children were enrolled in the control group. Blood samples were drawn for analysing acute-phase reactants, adiponectin, tumour necrosis factor-α, interleukin-6, and interleukin-8 levels at baseline on Days 2, 5, 10, and 15, and at 8 weeks. RESULTS: There was no statistically significant difference between baseline age, gender, body mass index, serum triglyceride, total cholesterol, and low-density lipoprotein levels of the study and control groups (p>0.05). No correlation was found between baseline plasma adiponectin levels, age, body mass index, follicle-stimulating hormone, luteinising hormone, oestradiol, total testosterone, and blood lipid levels of the study and control groups (p>0.05). We found that adiponectin and interleukin-6 levels increased, tumour necrosis factor-α levels decreased, and interleukin-8 levels remained unchanged in acute rheumatic fever, which is an inflammatory disease. Moreover, adiponectin level was higher and tumour necrosis factor-α level was lower in the improvement period in comparison with the acute period, particularly in the carditis group. CONCLUSION: It was considered that, increasing throughout the treatment period, adiponectin may have anti-inflammatory effects in acute rheumatic fever. In addition, adiponectin levels are associated with a decline in inflammatory mediators in rheumatic fever.

Circulating matrix metalloproteinases and tissue inhibitors of metalloproteinases levels in pediatric patients with congenital heart disease: Relationship to cardiac functions.

OBJECTIVE: The pathological effects of matrix metalloproteinases and their tissue inhibitors in cardiovascular diseases are of considerable interest. In our study, we aimed to determine and evaluate the potential significance of circulating matrix metalloproteinases-2 and 9, tissue inhibitors of matrix metalloproteinases-1 and 2 levels in four patient subgroup of pediatric cardiology field and expose pathophysiologic differences between these groups. METHODS: Eighty-seven patients with the diagnosis of congenital heart disease and 47 healthy controls were enrolled in the study. The study group was stratified to 4 subgroups; 14 patients with right ventricular volume overload, 30 patients with left ventricular volume overload, 19 patients with left to right shunt who developed pulmonary hypertension and 24 patients with cyanotic congenital heart disease. For evaluation of the relationships between serum matrix metalloproteinases and their tissue inhibitors levels with cardiac structures and functions; complete blood count, arterial oxygen saturation, detailed echocardiographic measurements (including tissue Doppler) in all patients and hemodynamic parameters of the patients who went to cardiac catheterization were recorded. Serum matrix metalloproteinase levels were determined by ELISA test. Statistical evaluations were performed with SPSS 16.0. For parameters showing normal distribution, comparisons were made with t-test and ANOVA test. However, for parameters without normal distribution, groups were compared with Mann-Whitney U test and Kruskal-Wallis test. RESULTS: We demonstrated that serum tissue inhibitors of matrix metalloproteinases-1 levels of patients with pulmonary hypertension secondary to congenital heart diseases were significantly higher than the patients with left to right shunt without pulmonary hypertension and controls (p<0.01). Although serum matrix metalloproteinases and their tissue inhibitors levels in patients with cyanotic congenital heart diseases and patients with right or left ventricular volume overload were found to be altered when compared with controls but not significant. CONCLUSION: Our data may suggest the possible role of matrix metalloproteinases and their tissue inhibitors on myocardial remodeling in congenital heart defects and especially in patients who developed pulmonary hypertension.

Total anomalous systemic venous drainage with heterotaxia syndrome: a rare case.

Total anomalous systemic venous return is a very rare anomaly, where vena cava inferior, vena cava superior, and coronary sinus drain into left atrium. Two-day-old male baby was admitted with cyanosis and tachypnea after the birth. Left atrial isomerism with anomalous systemic venous drainage was found on echocardiographic examination. We present an unusual case of total anomalous systemic venous drainage in to the left atrium.

Heart rate variability in children with tricyclic antidepressant intoxication.

The aim of this study was to evaluate HRV in children requiring intensive care unit stays due to TCA poisoning between March 2009 and July 2010. In the time-domain nonspectral evaluation, the SDNN (P < 0.001), SDNNi (P < 0.05), RMSDD (P < 0.01), and pNN50 (P < 0.01) were found to be significantly lower in the TCA intoxication group. The spectral analysis of the data recorded during the first 5 minutes after intensive care unit admission showed that the values of the nLF (P < 0.05) and the LF/HF ratio (P = 0.001) were significantly higher in the TCA intoxication group, while the nHF (P = 0.001) values were significantly lower. The frequency-domain spectral analysis of the data recorded during the last 5 minutes showed a lower nHF (P = 0.001) in the TCA intoxication group than in the controls, and the LF/HF ratio was significantly higher (P < 0.05) in the intoxication group. The LF/HF ratio was higher in the seven children with seizures (P < 0.001). These findings provided us with a starting point for the value of HRV analysis in determining the risk of arrhythmia and convulsion in TCA poisoning patients. HRV can be used as a noninvasive testing method in determining the treatment and prognosis of TCA poisoning patients.

The value of serum N-terminal pro-brain natriuretic peptide levels in the differential diagnosis and follow-up of congestive cardiac failure and respiratory distress due to pulmonary aetiologies in infants and children.

OBJECTIVE: We aimed to determine whether N-terminal pro-brain natriuretic peptide can differentiate between cardiac and pulmonary aetiologies of dyspnoea, if N-terminal pro-brain natriuretic peptide can be used for evaluating the effect of treatment in cardiac failure, and for predicting severe pulmonary diseases that are complicated by cardiac failure. METHODS: In all, 76 children with dyspnoea were enrolled; 41 of them suffered cardiac failure - 25 caused by cardiac disease, 16 caused by pulmonary disease - and 35 had dyspnoea due to pulmonary disease. The control group consisted of 32 children. We calculated Ross scores, analysed N-terminal pro-brain natriuretic peptide levels, and evaluated left ventricular systolic functions by echocardiography. RESULTS: N-terminal pro-brain natriuretic peptide levels were significantly higher in children with cardiac failure than in those with pulmonary disease and in controls (medians 7321, 241, 87.71 picograms per millilitre, respectively), were higher in children with cardiac failure due to pulmonary disease than in those with only pulmonary disease (medians 2728, 241 picograms per millilitre, respectively), and were higher in children who died from cardiac failure than in survivors (p < 0.05). After treatment of cardiac failure, N-terminal pro-brain natriuretic peptide levels decreased significantly (p < 0.001). The cut-off level of N-terminal pro-brain natriuretic peptide for differentiating cardiac failure from pulmonary disease was 726.8 picograms per millilitre, sensitivity 100%, specificity 94.3%. CONCLUSIONS: N-terminal pro-brain natriuretic peptide levels can differentiate dyspnoea due to cardiac failure from pulmonary diseases. It can also be used to monitor the effects of treatment of cardiac failure and to estimate the prognosis, as well as to predict pulmonary diseases that are complicated with cardiac failure.

Atrioventricular thrombus in a 14-year-old patient: a case report.

Right atrioventricular thrombus was diagnosed by echocardiography in a 14-year-old boy. Thrombus was reached through the right ventricle to the pulmonary artery and it was caused to tricuspit valve insufficiency. Surgical thrombectomy was performed and, he was treated with oral anticoagulation in postoperative period.

Angiotensin-converting enzyme gene insertion/deletion polymorphism frequency in normotensive children with a positive family history of essential hypertension.

AIM: To evaluate the possible relationship between blood pressure (BP) and angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in normotensive children with a positive family history of essential hypertension (EHT). MATERIAL AND METHODS: Three hundred seventy-six randomly selected normotensive schoolchildren (147 boys, 229 girls) between the ages of seven and 17 years were enrolled. Children were subdivided into a 'first-degree relative group' and a 'second-degree relative group' according to the presence of EHT in parents or grandparents, respectively. BP was measured twice from the right arm and the systolic BP, diastolic BP and mean BP were recorded. ACE gene I/D polymorphism was performed from all studied children and frequency od DD, ID and ID allele were analysed in each study group. RESULTS: Allelic frequencies of the DD genotype of the ACE gene were higher in children with a positive history in the first- (36.2%) and second-degree (38.3%) relatives for EHT than the controls (30.7%) (P < 0.05 for both). Children with a positive family history of EHT and a DD genotype, had significantly higher SBP, DBP and MBP levels (P < 0.05) than the children with ID or II genotypes. CONCLUSION: We found that the ACE gene DD genotype was common and that BP levels were higher in Turkish children with a positive family history of EHT and DD genotype. Because the presence of DD allele might be the one of the potential contributor of EHT pathogenesis, further studies needed in large cohort for long term follow-up for EHT in children with DD allele.