Prevalence of Migraine in Adults with Cyanotic Congenital Heart Disease

Objective. There is an increased prevalence of patent foramen ovale in patients with migraine, leading to the suggestion that migraine is more common in patients with potential right‐to‐left shunts. The aim of this study was to investigate the prevalence of migraine in adults with large right‐to‐left shunts because of cyanotic congenital heart disease. Design and Patients. In total, 29 cyanotic adult patients with congenital heart disease answered a questionnaire to determine the prevalence of migraine with or without aura. A total of 38 matched acyanotic patients with congenital heart disease served as controls. A subgroup of 18 acyanotic patients also underwent bubble contrast echocardiography to look for patent foramen ovale. Results. Twenty (69%) of the cyanotic patients had migraine, the majority 17 (59%) having migraine with aura. Twenty‐two (58%) of the 38 acyanotic patients had migraine, of whom 16 (42%) had migraine with aura. Nine (50%) of the 18 acyanotic patients who consented to an echocardiogram had patent foramen ovale. Of those with patent foramen ovale, 8 (89%) had migraine and 6 (67%) had migraine with aura. Conclusion. There is an increased prevalence of migraine with aura in both cyanotic and acyanotic patients with congenital heart disease. The high prevalence of migraine in acyanotic patients with congenital heart disease may be due to an increased prevalence of patent foramen ovale.     

Haemostatic changes in children with cyanotic and acyanotic congenital heart disease

This study was undertaken to screen children with congenital heart disease for coagulation abnormalities and to compare the groups of cyanotic and acyanotic children with congenital heart disease with respect to abnormalities of the coagulation system. Following investigations were done in all the patients: complete blood count, erythrocyte sedimentation rate, peripheral smear examination, bleeding time, prothrombin time, activated partial thromboplastin time, assay of fibrinogen, D-dimer, factors VII and VIII and antithrombin III. Red cell indices were determined in 12 control, 12 acyanotic and 20 cyanotic children. Twenty-five patients each, with echocardiographically proven cyanotic and acyanotic congenital heart disease under 12 years of age constituted the study group; as many children of the same age group were included as the control group. The results showed isolated abnormalities of laboratory tests with equal frequency (28%) in acyanotic and cyanotic groups but coexisting abnormalities of more than one test were seen in significantly larger number of cyanotic children (5/25 and 16/25, respectively). A significant association was noted between thrombocytopenia and a high haematocrit in cyanotic patients. It is concluded that laboratory abnormalities of tests of haemostasis are more common in cyanotic congenital heart disease patients. The patterns of laboratory abnormalities suggest a chronic compensated disseminated intravascular coagulation at a subclinical level, reduced synthesis of clotting factors and/or deranged platelet aggregation in different subgroups of patients.     

Plasma leptin levels in children with cyanotic and acyanotic congenital heart disease and correlations with growth parameters

BACKGROUND: Leptin has been shown to be an integral component of energy homeostasis and regulation of body weight. Leptin regulates adipose tissue mass and correlates with the fat mass, however the circulating levels are altered by energy intake. Research on the physiological function of leptin has primarily focused on its role in the pathogenesis of obesity. However, its role in the negative energy imbalance is unclear. Increased energy expenditure is a primary factor in the reduced growth in infants with cyanotic congenital heart disease. The objective of this study was to examine the possible role of leptin on growth and nutrition in children with cyanotic and acyanotic congenital heart disease. METHODS AND RESULTS: In this study, plasma leptin levels, nutritional and growth status were evaluated in 28 cyanotic and 20 acyanotic patients with congenital heart disease. Although standard deviation (S.D.) of height (P<0.01), mid arm circumference (MAC) (P<0.001) and body mass index (BMI) (P<0.05) were significantly low in cyanotic group, plasma leptin levels were similar. Energy intake was high in cyanotic group. In both cyanotic and acyanotic group, plasma leptin levels were correlated with BMI (R: 0.388, P<0.05 and R: 0.789, P<0.001, respectively). In addition, leptin levels were significantly correlated with the height (R: 0.415, P<0.05), MAC (R: 0.482, P<0.05) and BMI (R: 0.377, P<0.05) S.D. in cyanotic subjects. CONCLUSIONS: Our results suggest that the leptin regulating axis is intact in cyanotic patients and leptin does not contribute to the cachexia of cyanotic heart disease.     

Serum immunoreactive erythropoietin in children with cyanotic and acyanotic congenital heart disease

Serum immunoreactive erythropoietin (siEp) was measured in 27 cyanotic and 21 acyanotic children with congenital heart disease, age 4 months to 10 years. The geometric mean value was 9 mIU/mL for each group with 95% range from 3 to 26 mIU/mL and 4 to 22 mIU/mL for the cyanotic and acyanotic subjects, respectively. The levels are similar to those found in normal adults using the same assay system. Three cyanotic subjects showed increased siEp values. One was anemic relative to his hypoxemia, and the other two showed signs of increasing hypoxia. There was a significant negative correlation between siEp and arterial oxygen content. However, siEp did not correlate significantly with hemoglobin, hematocrit, PaO2, or SaO2. Despite normal siEp levels, the cyanotic children showed compensatory erythropoiesis with significantly elevated hemoglobin and hematocrit levels, which did correlate inversely with PaO2 and SaO2. Arterial oxygen content was also significantly higher in the cyanotic subjects (p less than 0.02). The cyanotic children seemed to display the same pattern as observed in man and animals exposed to prolonged hypobaric hypoxia, where after an initial rise in erythropoietin values the levels fall to normal, while increased erythropoiesis is sustained.     

Whole blood coagulation measured by modified thrombelastography (ROTEM) is impaired in infants with congenital heart diseases.

Patients with congenital heart disease (CHD) often do have a variety of coagulation abnormalities that results in bleeding diathesis. Our study aimed to determine the impact of cyanosis and CHD on modified thrombelastography parameters, compared with children without CHD. Preoperative blood samples were taken for TEM analyses from a total of 51 infants scheduled for surgery. The following groups were examined: normal patients without CHD, acyanotic patients with acyanotic CHD, and cyanotic patients with CHD and with preoperative hemoglobin values higher than 15 g dl(-1). Mean values of all patient groups as well as all individual values of normal patients were within their normal ranges. Within these limits, however, clots were significantly inferior in cyanotic patients (worse mean values of eight out of 10 measured TEM parameters representing the intrinsic, extrinsic, and plasmatic pathways of coagulation) and in acyanotic patients (two out of 10 TEM parameters). Individually, pathological TEM parameters were found in seven (41%) cyanotic patients (P=0.003; vs. normal patients) and in three (17%) acyanotic patients (P=0.01). More than one abnormal TEM coagulation parameter was found in four patients, all of them cyanotic patients. Hyperfibrinolysis was detected in one patient, a cyanotic patient. The present investigation confirms previous findings that in patients with CHD the heart defect itself compromises coagulation monitored with TEM, but in addition, we demonstrate that cyanosis and/or polycythemia exert the essential negative impact on hemostasis. Preoperative hyperfibrinolysis detected with TEM seems to play no important role.     

Akt信号通路在紫绀型先天性心脏病患儿心肌慢性缺氧适应中的作用

目的:探讨Akt信号通路在紫绀型先天性心脏病患儿心肌慢性缺氧适应中的意义。方法:收集紫绀型和非紫绀型先天性心脏病患儿共50例,其中紫绀型26例(紫绀组),动脉血氧饱和度(SaO2)60%～89%;非紫绀型24例(非紫绀组),SaO2>95%,均不伴肺动脉高压[肺动脉收缩压<30mmHg(1mmHg=0.133kPa)]。心脏外科手术体外循环前留取右心耳组织,应用Western blot方法检测心肌组织蛋白激酶B(总Akt)和磷酸化蛋白激酶B(Ser473P-Akt)表达水平,免疫组织化学技术检测心肌组织总Akt和Ser473 P-Akt蛋白表达部位与水平。结果:与非紫绀组相比,紫绀组患儿心肌组织Ser473P-Akt蛋白表达水平明显增高(P<0.01),而2组患儿总Akt蛋白表达水平差异无统计学意义(P>0.05)。紫绀组患儿心肌组织Ser473P-Akt蛋白大部分表达在心肌细胞的胞质,胞核亦有微弱表达,而非紫绀组心肌细胞则无明显Ser473P-Akt蛋白表达。2组患儿总Akt蛋白绝大部分也表达在心肌细胞的胞质,胞核亦有微弱表达,但表达部位和水平差异无统计学意义。紫绀组患儿心肌组织Ser473 P-Akt蛋白表达水平与患儿术前SaO2呈负相关(r=-0.771,P<0.01)。结论:Akt信号通路激活可能是紫绀型先天性心脏病患儿心肌慢性缺氧适应的重要信号调控机制之一。     

The measurement of serum transferrin receptor.

The concentration of the soluble fragment of transferrin receptor in serum is an important new hematological parameter. Clinical and laboratory studies have shown that this serum form of the receptor reflects the total body mass of cellular transferrin receptor, 80% of which is contained in the erythroid marrow. The two disorders that result in an elevation in the serum transferrin receptor are anemias associated with enhanced erythropoiesis and tissue iron deficiency. The concentration of soluble transferrin receptor provides a useful quantitative measure of the erythroid marrow mass and thereby assists clinically in categorizing the type of anemia. The most important clinical use of the serum transferrin receptor is in determining the cause of iron deficient erythropoiesis (that is, identifying iron deficiency anemia whether it occurs alone or in the presence of the anemia of chronic disease). Present evidence supports the routine use of the serum transferrin receptor in the clinical evaluation of anemic patients.     

Mechanisms of plasma non‐transferrin bound iron generation: insights from comparing transfused diamond blackfan anaemia with sickle cell and thalassaemia patients

In transfusional iron overload, extra‐hepatic iron distribution differs, depending on the underlying condition. Relative mechanisms of plasma non‐transferrin bound iron (NTBI) generation may account for these differences. Markers of iron metabolism (plasma NTBI, labile iron, hepcidin, transferrin, monocyte SLC40A1 [ferroportin]), erythropoiesis (growth differentiation factor 15, soluble transferrin receptor) and tissue hypoxia (erythropoietin) were compared in patients with Thalassaemia Major (TM), Sickle Cell Disease and Diamond‐Blackfan Anaemia (DBA), with matched transfusion histories. The most striking differences between these conditions were relationships of NTBI to erythropoietic markers, leading us to propose three mechanisms of NTBI generation: iron overload (all), ineffective erythropoiesis (predominantly TM) and low transferrin‐iron utilization (DBA).     

Soluble transferrin receptor as a potential determinant of iron loading in congenital anaemias due to ineffective erythropoiesis

Congenital anaemias due to ineffective erythropoiesis may be associated with excessive iron absorption and progressive iron loading. We investigated whether the soluble transferrin receptor (TfR) level was related to the degree of iron overload in 20 patients with thalassaemia intermedia, six patients with congenital dyserythropoietic anaemia type II (CDA II) and four patients with X-linked congenital sideroblastic anaemia (XLSA). All but two patients had increased serum ferritin levels (median 601 microgram/l, range 105-2855 microgram/l). Multiple regression analysis showed that 62% (P < 0.0001) of the variation in serum ferritin was explained by age and by changes in soluble TfR.     

Uncontrolled reoxygenation by initiating cardiopulmonary bypass is associated with higher protein S100 in cyanotic versus acyanotic patients

BACKGROUND: The systemic reoxygenation injury produced by initiating cardiopulmonary bypass (CPB) in infants with cyanotic heart disease may be associated with cerebral dysfunction and injury. Increased protein S100 (S100) serum levels may indicate cerebral and blood brain barrier damage as well as inflammatory changes, therefore serving to quantify these changes. The present clinical study assessed S100 in cyanotic patients undergoing CPB with normoxic versus hyperoxic paO2 in acyanotic cases and in controls without CPB. METHODS: 43 patients with congenital heart disease aged 5 days to 15 years (mean 4.4 years) were enrolled consecutively and divided in four groups: (1) Cyanotic infants undergoing controlled normoxic reoxygenation on CPB (n = 12), (2) cyanotic infants undergoing uncontrolled hyperoxic reoxygenation on CPB (n = 9), (3) acyanotic infants operated with CPB (n = 16) and (4) patients operated without CPB (n = 6). Blood samples were collected after induction of anesthesia (A), up to 4 hours after surgery (B) and at postoperative day one (C). RESULTS: Preoperative S100 serum levels [microg/l] in all groups were below clinical relevance. S100 increased markedly after surgery in groups 1 and 2. Differences in postoperative S100 levels were significant between groups 1 (0.45 +/- 0.13) and 3 (0.35 +/- 0.09; p = 0.018), between groups 2 (1.41 +/- 0.47) and 3 (p = 0.01), and between groups 2 and 4 (0.29 +/- 0.09; p = 0.045). There were no significant differences in postoperative S100 levels (B) between groups 1 and 2 (p = 0.05), groups 1 and 4 (p = 0.05), or groups 3 and 4 (p = 0.93). CONCLUSION: Uncontrolled hyperoxic reoxygenation on CPB for surgical correction of congenital heart defects is associated with higher S100 levels in cyanotic infants as compared to acyanotic patients undergoing comparable operations.     

Serum and pulmonary vascular endothelial growth factor/receptors and haemodynamic measurements in cyanotic congenital heart disease with decreased pulmonary blood flow

Tetralogy of Fallot is the most common cyanotic congenital heart disease with decreased pulmonary blood flow. Right-to-left shunt and infundibular pulmonary stenosis in this disease lead to a decrease in arterial O(2) saturation. Hypoxia is a strong stimulus for angiogenesis; however, the reason for insufficiency in the pulmonary vascular growth in patients despite chronic arterial hypoxia is still not known. This study was planned considering that the impairment in vascular endothelial growth factor-receptor relationship or the vascular endothelial growth factor-receptor deficiency in the pulmonary vascular bed during development may cause insufficiency of pulmonary vascular growth. A total of 24 patients were grouped as cyanotic - including 13 patients with tetralogy of Fallot - and acyanotic - including 11 patients with left-to-right shunt lesions. During cardiac catheterisation, vascular endothelial growth factor measurements were performed; and oxygen saturations, pressures, and haemoglobin levels were measured. Perioperative lung biopsy for vascular endothelial growth factor receptors was performed in the cyanotic group. Vascular endothelial growth factor of the aorta was higher in the acyanotic group. There was a significant negative correlation between vascular endothelial growth factor levels and aortic O(2) saturation in the cyanotic group (p < 0.05). Vascular endothelial growth factor tissue staining was negative in 11 out of 13 (84.6%) patients. KDR/Flk-1 receptor was positive in four out of 13 (30.7%) patients; Flt-1 receptor was positive in six out of 13 (46.1%) patients. Vascular endothelial growth factor values were found to be lower than those of the acyanotic patients in this study. Low serum vascular endothelial growth factor levels of the cyanotic group, in spite of the hypoxia, demonstrated the importance of studying vascular endothelial growth factor tissue levels and vascular endothelial growth factor receptors in these patients.     

Altered erythropoiesis and iron metabolism in carriers of thalassemia

The thalassemia syndromes (α‐ and β‐thalassemia) are the most common and frequent disorders associated with ineffective erythropoiesis. Imbalance of α‐ or β‐globin chain production results in impaired red blood cell synthesis, anemia, and more erythroid progenitors in the blood stream. While patients affected by these disorders show definitive altered parameters related to erythropoiesis, the relationship between the degree of anemia, altered erythropoiesis, and dysfunctional iron metabolism has not been investigated in both α‐thalassemia carriers (ATC) and β‐thalassemia carriers (BTC). Here, we demonstrate that ATC have a significantly reduced hepcidin and increased soluble transferrin receptor levels but relatively normal hematological findings. In contrast, BTC have several hematological parameters significantly different from controls, including increased soluble transferrin receptor and erythropoietin levels. These changes in both groups suggest an altered balance between erythropoiesis and iron metabolism. The index sTfR/log ferritin and (hepcidin/ferritin)/sTfR are, respectively, increased and reduced relative to controls, proportional to the severity of each thalassemia group. In conclusion, we showed in this study, for the first time in the literature, that thalassemia carriers have altered iron metabolism and erythropoiesis.     

The scoliosis of congenital heart disease

Scoliosis occurs with greater frequency in patients with congenital heart disease (CHD) than in the normal population. In a random survey of 121 adolescent and adult patients with CHD, 44 per cent had scoliosis; in 19 per cent of these patients, the scoliosis exceeded 10°. Patients with cyanotic forms of CHD were more commonly affected than acyanotic patients. The severity of the scoliosis was also greater in the cyanotic group, particularly in the male patients.     

紫绀型与非紫绀型先天性心脏病患儿围手术期输血比较

目的：比较紫绀型与非紫绀型先天性心脏病患儿心内直视修补术围手术期输血量。方法：选取北京儿童医院先天性心脏病体外循环下行心脏直视手术的患儿,根据患儿疾病分为2组：紫绀型先天性心脏病组（法洛氏四联征、完全型肺静脉异位引流、完全型大动脉转位、肺动脉闭锁等）和非紫绀型先天性心脏病组（室间隔缺损、房间隔缺损、动脉导管未闭、主肺动脉间隔缺损、心内膜垫缺损等）,分别比较体重7kg以下、10kg以下、20kg以下2组患儿围手术期输注红细胞和血浆的量。结果：紫绀型组患儿平均用红细胞（4.02±2.33）U,非紫绀型组则平均用（3.08±1.07）U,紫绀型组多于非紫绀型组,差异有统计学意义（P〈0.01）。血浆用量紫绀型组平均（445.07±155.64）ml,非紫绀型组平均为（298.77±103.97）ml,前组亦显著多于后组,差异有统计学意义（P〈0.01）。结论：紫绀型先天性心脏病患儿围手术期用血量多于非紫绀型,尤其是血浆用量更是如此。     

Iron requirements in erythropoietin therapy

When erythropoietin (epoetins or darbepoetin) is used to treat the anemias of chronic renal failure, cancer chemotherapy, inflammatory bowel diseases, HIV infection and rheumatoid arthritis, functional iron deficiency rapidly ensues unless individuals are iron-overloaded from prior transfusions. Therefore, iron therapy is essential when using erythropoietin to maximize erythropoiesis by avoiding absolute and functional iron deficiency. Body iron stores (800-1200 mg) are best maintained by providing this much iron intravenously in a year, or more if blood loss is significant (in hemodialysis patients this can be 1-3 g). There is no ideal method for monitoring iron therapy, but serum ferritin and transferrin iron saturation are the most common tests. Iron deficiency is also detected by measuring the percentage of hypochromic red blood cells, content of hemoglobin in reticulocytes, soluble transferrin receptor levels, and free erythrocyte protoporphyrin values, but iron overload is not monitored by these tests. Iron gluconate and iron sucrose are the safest intravenous medications.     

Blunted erythropoietin production and defective iron supply for erythropoiesis as major causes of anaemia in patients with chronic heart failure.

AIMS: Anaemia is often observed in patients with chronic heart failure (CHF), and it may be associated with a worse prognosis. Aim of this study was to identify the individual mechanisms of anaemia in CHF patients. METHODS AND RESULTS: One hundred and forty-eight consecutive patients with haemoglobin concentration <13 g/dL (if males) or <12 g/dL (if females) were enrolled. Factors responsible for anaemia were investigated by evaluating endogenous erythropoietin (Epo) production, serum cytokines levels, body iron status, and iron supply for erythropoiesis. Most patients (57%) presented anaemia of chronic disease and among them, 92% showed evidence of a defective endogenous Epo production. This was indicated by an observed/predicted log(serum Epo) ratio less than 0.8 and/or a defective iron supply for erythropoiesis diagnosed by low transferrin saturation and/or increased value of soluble transferrin receptor. According to regression analysis sex, renal failure, and serum Epo were correlated with anaemia. CONCLUSION: According to our study, about half of anaemic CHF patients showed anaemia of chronic disease with blunted endogenous Epo production and/or a defective iron supply for erythropoiesis. Determination of the individual mechanisms of anaemia in CHF could justify a rational therapeutic approach to anaemia.     

Cessation of intensive treatment with recombinant human erythropoietin is followed by secondary anemia

Little information is available on the evolution of erythropoiesis after interruption of recombinant human erythropoietin (rHuEpo) therapy. Iron-overloaded rats received 20 daily injections of rHuEpo. During treatment, reticulocytes, soluble transferrin receptor (sTfR), and hematocrit increased progressively. This was accompanied by a substantial expansion of spleen erythropoiesis but a decrease in the bone marrow. Five weeks after treatment, rats developed a significant degree of a regenerative anemia. Erythropoietic activity, as assessed by reticulocytes, sTfR, erythroid cellularity, iron incorporation into heme, and the number of erythroid colonies, was severely depressed 3 weeks after cessation of rHuEpo. This was followed by regeneration of erythroblasts and reticulocytes at weeks 6 to 7 post-Epo, but erythroid progenitors recovered only partially by that time. The anemia was definitely corrected 2 months after cessation of rHuEpo treatment. Serum Epo levels remained elevated for several weeks, but the sensitivity of marrow erythroid precursors to Epo was preserved. No rat antibodies to rHuEpo were detected, and serum from post-Epo animals did not exert any inhibitory activity on erythropoiesis. In conclusion, after cessation of intensive rHuEpo therapy, there was a strong inhibition of erythropoietic activity with secondary anemia followed by late recovery. This was not due to antibodies or other soluble inhibitory factors, a defect in endogenous Epo production, or a loss of sensitivity to Epo. This may rather represent intrinsic erythroid marrow exhaustion, mostly at the level of erythroid progenitors but also at later stages of erythropoiesis.     

Blood viscosity and its relationship to iron deficiency, symptoms, and exercise capacity in adults with cyanotic congenital heart disease.

OBJECTIVES: This study sought to determine the relationship between blood viscosity and iron deficiency and their impact on symptoms and exercise function in adults with cyanotic congenital heart disease. BACKGROUND: Iron deficiency is believed to raise whole blood viscosity in cyanotic congenital heart disease, although available data are inconsistent. METHODS: Thirty-nine cyanotic adults were prospectively assessed for iron deficiency (transferrin saturation < or =5%), hyperviscosity symptoms, and exercise capacity. Same-day measurement of whole blood viscosity and hematocrit (Hct) adjusted viscosity (cells resuspended in autologous plasma to Hct of 45%) was performed at shear rates ranging from 0.277 s(-1) to 128.5 s(-1). RESULTS: Viscosity did not differ between patients with iron deficiency (n = 14) and those without (n = 25). Whole blood viscosity correlated with Hct (r = 0.63, p < 0.001 at low shear and r = 0.84, p < 0.001 at high shear) but not with red blood cell size or iron indices. Hyperviscosity symptoms were independent of iron indices but directly correlated with increased Hct-adjusted viscosity (r = 0.41, p = 0.01). Exercise capacity did not differ in iron-deficient patients. However, peak oxygen consumption was higher in those with Hct > or = 65% (12.6 +/- 3.4 ml/kg/m2 vs. 9.8 +/- 2.6 ml/kg/m2, mean +/- SD, p = 0.036) despite higher whole blood viscosity in these same individuals (p < 0.01 for all shear rates). CONCLUSIONS: Iron deficiency is common in cyanotic adults but does not alter viscosity. Hyperviscosity symptoms are associated with a higher Hct-adjusted viscosity independent of cell size or iron stores. Higher Hct is associated with better exercise capacity. Further work to understand the origin of hyperviscosity symptoms is warranted.     

The effects of iron treatment on viscosity in children with cyanotic congenital heart disease

Objective: This study was planned to determine the effects of iron treatment in children with cyanotic congenital heart disease.

Method and Materials: A total of 39 patients with cyanotic congenital heart disease including 20 (51%) females, 19 (49%) males and whose mean age was 9.9?±?6.2 years, average weight was 33?±?18.4?kg were evaluated. Patients were categorized into two groups as having iron deficiency and no iron deficiency with respect to their ferritin levels. 4?mg/kg/day iron treatment with two valences was applied to the groups with iron deficiency for 3 months. Clinical and laboratory findings of both groups were assessed at the outset and 3 months later and viscosity measurements were carried out.

Results: Iron deficiency was identified in 21 (53.8%) out of 39 patients. Average Hb and Hct values following 3-month iron treatment increased from 14.8?±?2.4?g/dl to 16.0?±?2.0 (P?=?0.003) and from %45.8?±?7.5 to %47.6?±?7.2 (P?=?0.052), respectively. Average viscosity value, however, was 5.6?±?1.0?cP, it reduced to 5.5?±?1.0?cP value by demonstrating very little reduction (P?=?0.741). Nevertheless, O₂ sat value increased from 71.7 to 75% and complaints such as headache, visual blurriness, having frequent sinusitis decreased.

Conclusions: It was observed that iron treatment increased Hb and Hct levels in patients with cyanotic congenital heart disease without raising viscosity and it ensured improvement in clinical symptoms.