Vascular function in adults with cyanotic congenital heart disease.

BACKGROUND: Patients with cyanotic congenital heart disease (CCHD) may have a low burden of atherosclerosis. Endothelial dysfunction is an early stage of atherosclerosis and endothelial function is previously studied in smaller CCHD groups with different techniques and variable results. We aimed to examine endothelial function and carotid atherosclerosis in a larger group of CCHD patients. METHODS: This multicentre study assessed endothelial function in adults with CCHD and controls by measuring the dilatory response of the brachial artery to post-ischemic hyperaemia (endothelium-dependent flow-mediated-vasodilatation (FMD)), and to nitroglycerin (endothelium-independent nitroglycerin-induced dilatation (NID)). Flow was measured at baseline and after ischaemia (reactive hyperaemia). Carotid-intima-media-thickness (CIMT), prevalence of carotid plaque and plaque thickness (cPT-max) were evaluated ultrasonographically. Lipoproteins, inflammatory and vascular markers, including sphingosine-1-phosphate (S1P) were measured. RESULTS: Forty-five patients with CCHD (median age 50 years) and 45 matched controls (median age 52 years) were included. The patients presented with lower reactive hyperaemia (409 ± 114% vs. 611 ± 248%, p < 0.0001), however preserved FMD response compared to controls (106.5 ± 8.3% vs. 106.4 ± 6.1%, p = 0.95). In contrast, NID was lower in the patients (110.5 ± 6.1% vs. 115.1 ± 7.4%, p = 0.053). There was no difference in CIMT, carotid plaque or cPT-max. The patients presented with lower high-density-lipoprotein cholesterol, and higher level of inflammatory markers and S1P. CONCLUSION: Adults with CCHD had preserved FMD in the brachial artery, but impaired NID response and lower reactive hyperaemia than controls. The preserved FMD and the comparable prevalence of carotid atherosclerosis indicate that CCHD patients have the same risk of atherosclerosis as controls.

Intravascular assessment of coronary arteries in patients with cyanotic congenital heart disease.

AIMS: Patients with cyanotic congenital heart disease (CCHD) have been suggested to develop less atherosclerosis than the general population. This study aimed to evaluate the extent of coronary atherosclerosis in patients with CCHD using intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS). METHODS AND RESULTS: Fifteen patients with CCHD (women, 9; median age, 53 years) and 14 acyanotic controls (women, 6; median age, 53 years) were examined with IVUS-NIRS of the right coronary artery (RCA). The patients with CCHD presented with a larger RCA diameter than the controls (external elastic membrane diameter, 6.1 [4.8-6.7] vs. 4.7 [4.1-5.1] mm, respectively; p=0.01). No difference in area stenosis was found between the patients and the controls (15.8% [12.3-19.7] vs. 15.2% [9.5-18.8]; p=0.87). The presence of lipid by NIRS was noted in 43% of patients with CCHD and in 92% of the controls; however, no differences in total or max 4 mm lipid core burden index (LCBI) or in plasma lipid profile were found. CONCLUSIONS: Patients with CCHD presented with larger coronary arteries than acyanotic controls. No difference in the degree of area stenosis in the coronary arteries was found between the cyanotic and acyanotic patients; however, a lower proportion of patients with CCHD showed a positive LCBI.

Past and current cause-specific mortality in Eisenmenger syndrome.

AIMS: Eisenmenger syndrome (ES) is associated with considerable morbidity and mortality. Therapeutic strategies have changed during the 2000s in conjunction with an emphasis on specialist follow-up. The aim of this study was to determine the cause-specific mortality in ES and evaluate any relevant changes between 1977 and 2015. METHODS AND RESULTS: This is a retrospective, descriptive multicentre study. A total of 1546 patients (mean age 38.7 ± 15.4 years; 36% male) from 13 countries were included. Cause-specific mortality was examined before and after July 2006, 'early' and 'late', respectively. Over a median follow-up of 6.1 years (interquartile range 2.1-21.5 years) 558 deaths were recorded; cause-specific mortality was identified in 411 (74%) cases. Leading causes of death were heart failure (34%), infection (26%), sudden cardiac death (10%), thromboembolism (8%), haemorrhage (7%), and peri-procedural (7%). Heart failure deaths increased in the 'late' relative to the 'early' era (P = 0.032), whereas death from thromboembolic events and death in relation to cardiac and non-cardiac procedures decreased (P = 0.014, P = 0.014, P = 0.004, respectively). There was an increase in longevity in the 'late' vs. 'early' era (median survival 52.3 vs. 35.2 years, P < 0.001). CONCLUSION: The study shows that despite changes in therapy, care, and follow-up of ES in tertiary care centres, all-cause mortality including cardiac remains high. Patients from the 'late' era, however, die later and from chronic rather than acute cardiac causes, primarily heart failure, whereas peri-procedural and deaths due to haemoptysis have become less common. Lifelong vigilance in tertiary centres and further research for ES are clearly needed.

Epidemiological changes in Eisenmenger syndrome in the Nordic region in 1977-2012.

OBJECTIVE: Improved diagnostic tools, timely closure of the shunt and a better understanding of the complexity of Eisenmenger syndrome (ES) have led to improved care and treatment in tertiary centres. These may have decreased the incidence of ES and improved survival of patients with ES, although evidence is still lacking. The aim of this study was to investigate temporal changes in incidence, prevalence and mortality in patients with ES for 35 years in the Nordic region. METHODS: This was a retrospective population-based study including 714 patients with ES. Survival analysis was performed based on all-cause mortality and accounting for immortal time bias. RESULTS: The incidence of ES decreased from 2.5/million inhabitants/year in 1977 to 0.2/million inhabitants/year in 2012. Correspondingly, prevalence decreased from 24.6 to 11.9/million inhabitants. The median survival was 38.4 years, with 20-year, 40-year and 60-year survival of 72.5%, 48.4%, and 21.3%, respectively. Complex lesions and Down syndrome were independently associated with worse survival (HR 2.2, p<0.001 and HR 1.8, p<0.001, respectively). Age at death increased from 27.7 years in the period from 1977 to 1992, to 46.3 years from July 2006 to 2012 (p<0.001). CONCLUSIONS: The incidence and prevalence of ES in the Nordic region have decreased markedly during the last decades. Furthermore, the median age at death increased throughout the study period, indicating prolonged life expectancy in the ES population. However, increasing age represents decreased incidence, rather than improved survival. Nonetheless, longevity with ES is still shorter than in the background population.

A mutation in the glutamate-rich region of RNA-binding motif protein 20 causes dilated cardiomyopathy through missplicing of titin and impaired Frank-Starling mechanism.

AIM: Mutations in the RS-domain of RNA-binding motif protein 20 (RBM20) have recently been identified to segregate with aggressive forms of familial dilated cardiomyopathy (DCM). Loss of RBM20 in rats results in missplicing of the sarcomeric gene titin (TTN). The functional and physiological consequences of RBM20 mutations outside the mutational hotspot of RBM20 have not been explored to date. In this study, we investigated the pathomechanism of DCM caused by a novel RBM20 mutation in human cardiomyocytes. METHODS AND RESULTS: We identified a family with DCM carrying a mutation (RBM20(E913K/+)) in a glutamate-rich region of RBM20. Western blot analysis of endogenous RBM20 protein revealed strongly reduced protein levels in the heart of an RBM20(E913K/+ )carrier. RNA deep-sequencing demonstrated massive inclusion of exons coding for the spring region of titin in the RBM20(E913K/+ )carrier. Titin isoform analysis revealed a dramatic shift from the less compliant N2B towards the highly compliant N2BA isoforms in RBM20(E913K/+ )heart. Moreover, an increased sarcomere resting-length was observed in single cardiomyocytes and isometric force measurements revealed an attenuated Frank-Starling mechanism (FSM), which was rescued by protein kinase A treatment. CONCLUSION: A mutation outside the mutational hotspot of RBM20 results in haploinsufficiency of RBM20. This leads to disturbed alternative splicing of TTN, resulting in a dramatic shift to highly compliant titin isoforms and an impaired FSM. These effects may contribute to the early onset, and malignant course of DCM caused by RBM20 mutations. Altogether, our results demonstrate that heterozygous loss of RBM20 suffices to profoundly impair myocyte biomechanics by its disturbance of TTN splicing.

Long-Term Outcome of Mustard/Senning Correction for Transposition of the Great Arteries in Sweden and Denmark.

BACKGROUND: The atrial switch operation, the Mustard or Senning operation, for the transposition of the great arteries (TGA) was introduced in the late 1950s and was the preferred surgery for TGA until the early 1990s. The Mustard and Senning operation involves extensive surgery in the atria and leaves the right ventricle as the systemic ventricle. The Mustard and Senning cohort is now well into adulthood and we begin to see the long-term outcome. METHODS AND RESULTS: All the 6 surgical centers that performed Mustard and Senning operations in Sweden and Denmark identified all operated TGA patients. Information about death was obtained in late 2007 and early 2008 from the Danish and Swedish Centralised Civil Register by using the patients' unique national Civil Registration Numbers. Four hundred sixty-eight patients undergoing the atrial switch operation were identified. Perioperative 30-day mortality was 20%, and 60% were alive after 30 years of follow-up. Perioperative mortality was significantly increased by the presence of a ventricular septal defect, left ventricular outflow obstruction, surgery early in the Mustard and Senning era. However, only pacemaker implantation is predictive of long-term outcome (hazard ratio, 1.90; 95% confidence interval, 1.05-3.46, P=0.04), once the TGA patient has survived the perioperative period. The risk of reoperation was correlated to the presence of associated defects and where the first Mustard/Senning operation was performed. CONCLUSIONS: The long-term survival of patients with Mustard and Senning correction for TGA appears to be primarily determined by factors in the right ventricle and tricuspid valve and not the timing of or the type of surgery in childhood. Cardiac function necessitating the implantation of a pacemaker is associated with an increase in mortality.

Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study.

BACKGROUND: The Fontan procedure has improved survival in children with functionally univentricular hearts. With time, however, complications such as reduced exercise capacity are seen more frequently. Exercise intolerance is multifactorial, but pulmonary vascular resistance probably plays a crucial role. Elevated pulmonary vascular resistance has been associated with raised levels of endothelin-1, which are common both before and after Fontan operations. Treatment with endothelin-1 receptor antagonists could theoretically improve cardiopulmonary hemodynamics and exercise capacity. The aim of this study was therefore to examine the efficacy and safety of bosentan in Fontan patients. METHODS AND RESULTS: Seventy-five adolescents and adults were randomized 1:1 to 14 weeks of treatment with bosentan or placebo. Cardiopulmonary exercise test, functional class, blood samples, and quality-of-life questionnaires were evaluated at baseline and at the end of treatment. Sixty-nine patients (92%) completed the study. Peak oxygen consumption increased 2.0 mL·kg(-1)·min(-1) (from 28.7 to 30.7 mL·kg(-1)·min(-1)) in the bosentan group compared with 0.6 mL·kg(-1)·min(-1) (from 28.4 to 29.0 mL·kg(-1)·min(-1)) in the placebo group (P=0.02). Cardiopulmonary exercise test time increased by 0.48 minute (from 6.79 to 7.27 minutes) versus 0.08 minute (from 6.94 to 7.02 minutes; P=0.04). Nine bosentan-treated patients improved 1 functional class, whereas none improved in the placebo group (P=0.0085). Side effects were mild and occurred equally in both groups. No serious adverse effects were seen, and no patients had liver enzyme levels above the 3-fold upper limit. CONCLUSIONS: Bosentan improves exercise capacity, exercise time, and functional class in Fontan patients without serious adverse events or hepatotoxicity. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01292551.

[Two uncomplicated pregnancies with a univentricular heart]. / To vellykkede graviditeter med et univentrikulært hjerte.

Fontan type operations provide long-term palliation for patients with functionally univentricular hearts. The haemodynamics of these patients were previously considered inhibitory for contemplating pregnancy. We describe the first Danish woman, who gave birth to two healthy children after relatively uncomplicated pregnancies.

Hemodynamic causes of exercise intolerance in Fontan patients.

BACKGROUND: Exercise intolerance is frequent among Fontan patients and an important determinant for quality of life. This study investigated the hemodynamic causes of impaired exercise capacity in Fontan patients with particular focus on the influence of stroke volume index (SVI) and heart rate (HR). METHODS AND RESULTS: In 38 Fontan patients, peak oxygen consumption (VO2), SVI and HR were recorded during incremental load exercise test and compared with 19 age and gender matched controls. SVI (ml/m(2)) was lower in patients than controls during warm-up (28[26-31] vs. 35[30-39], p=0.0093), at submaximal (40[37-43] vs. 55[51-59], p<0.0001) and at maximal exercise (38[35-40] vs. 54[51-58], p<0.0001). Similarly, HR (% of expected maximum) was lower in patients at warm-up (45[43-48]% vs. 64[57-64]%, p<0.0001), submaximal (71[68-75]% vs 85[82-88]%, p<0.0001) and maximal exercise (84[80-88]% vs. 97[95-99]%, p<0.0001). Furthermore, SVI dropped 14% (from 44[41-48] to 38[35-40] ml/m(2)) in Fontan patients from the peak plateau to maximal exercise vs. 5% (from 57[53-61] to 54[51-58] ml/m(2)) in controls, p<0.0001. The low SVI and HR explained 67% and 20% of the difference in peak VO2 between Fontan patients and controls respectively. CONCLUSION: SVI decreased significantly in Fontan patients near the end of maximal effort exercise. The low SVI at maximal exercise was the most important hemodynamic factor limiting exercise capacity in Fontan patients, whereas chronotropic impairment had a smaller impact. The low SVI and HR at maximal exercise accounted for the difference in peak VO2 between Fontan patients and controls in this study. CLINICAL TRIAL REGISTRATION: http://www.cvk.sum.dk/CVK/Home/English.aspx (protocol nr: H-3-2010-045).

Remote ischemic preconditioning with--but not without--metabolic support protects the neonatal porcine heart against ischemia-reperfusion injury.

BACKGROUND: While remote ischemic preconditioning (rIPC) protects the mature heart against ischemia-reperfusion (IR) injury, the effect on the neonatal heart is not known. The neonatal heart relies almost solely on carbohydrate metabolism, which is modified by rIPC in the mature heart. We hypothesized that rIPC combined with metabolic support with glucose-insulin (GI) infusion improves cardiac function and reduces infarct size after IR injury in neonatal piglets in-vivo. METHODS AND RESULTS: 32 newborn piglets were randomized into 4 groups: control, GI, GI+rIPC and rIPC. GI and GI+rIPC groups received GI infusion continuously from 40 min prior to ischemia. rIPC and GI+rIPC groups underwent four cycles of 5 min limb ischemia. Myocardial IR injury was induced by 40 min occlusion of the left anterior descending artery followed by 2 h reperfusion. Myocardial lactate concentrations were assessed in microdialysis samples analyzed by mass spectrometry. Infarct size was measured using triphenyltetrazolium chloride staining. Systolic recovery (dP/dt(max) as % of baseline) after 2 h reperfusion was 68.5±13.8% in control, 53.7±11.2% in rIPC (p<0.05), and improved in GI (83.6±18.8%, p<0.05) and GI+rIPC (87.0±15.7%, p<0.01). CONCLUSION: rIPC+GI protects the neonatal porcine heart against IR injury in-vivo. rIPC alone has detrimental metabolic and functional effects that are abrogated by simultaneous GI infusion.

Remote ischemic preconditioning impairs ventricular function and increases infarct size after prolonged ischemia in the isolated neonatal rabbit heart.

OBJECTIVES: Remote ischemic preconditioning (rIPC) reduces myocardial injury in adults and children undergoing cardiac surgery. We compared the effect of rIPC in adult and neonatal rabbits to investigate whether protection against ischemia-reperfusion injury can be achieved in the newborn heart by (1) in vivo rIPC and (2) dialysate from adult rabbits undergoing rIPC. METHODS: Isolated hearts from newborn and adult rabbits were randomized into 3 subgroups (control, in vivo rIPC, and dialysate obtained from adult, remotely preconditioned rabbits). Remote preconditioning was induced by four 5-minute cycles of lower limb ischemia. Left ventricular (LV) function was assessed using a balloon-tipped catheter, glycolytic flux by tracer kinetics, and infarct size by tetrazolium staining. Isolated hearts underwent stabilization while perfused with standard Krebs-Henseleit buffer (control and in vivo rIPC) or Krebs-Henseleit buffer with added dialysate, followed by global no-flow ischemia and reperfusion. RESULTS: Within the age groups, the baseline LV function was similar in all subgroups. In the adult rabbit hearts, rIPC and rIPC dialysate attenuated glycolytic flux and protected against ischemia-reperfusion injury, with better-preserved LV function compared with that of the controls. In contrast, in the neonatal hearts, the glycolytic flux was lower and LV function was better preserved in the controls than in the rIPC and dialysate groups. In the adult hearts, the infarct size was reduced in the rIPC and dialysate groups compared with that in the controls. In the neonatal hearts, the infarct size was smaller in the controls than in the rIPC and dialysate groups. CONCLUSIONS: Remote ischemic preconditioning does not protect against ischemia-reperfusion injury in isolated newborn rabbit hearts and might even cause deleterious effects. Similar adverse effects were induced by dialysate from remotely preconditioned adult rabbits.

The effect of bosentan on exercise capacity in Fontan patients; rationale and design for the TEMPO study.

BACKGROUND: Palliative treatment with the Fontan procedure has greatly improved survival for children with functionally univentricular heart. Since Fontan performed the first successful operation, the procedure has evolved and is now performed as Total Cavo-Pulmonary Connection (TCPC).An increasing prevalence and longer life expectancy of TCPC patients have raised new challenges. The survivors are often suffering complications such as arrhythmias, myocardial dysfunction, thromboembolic events, neuropsychological deficit, protein-losing enteropathy and reduced exercise capacity. Several causes for the reduced exercise capacity may be present e.g. impaired function of the single ventricle, valve dysfunction and chronotropic impairment, and perhaps also increased pulmonary vascular resistance. Thus, plasma endothelin-1 has been shown to correlate with increased pulmonary vascular resistance and the risk of failing Fontan circulation. This has raised the question of the role for pulmonary vasodilation therapy, especially endothelin receptor antagonist in the management of TCPC patients. METHODS/DESIGN: The TEMPO trial aims to investigate whether Bosentan, an endothelin receptor antagonist, can be administered safely and improve exercise capacity in TCPC patients. The trial design is randomized, double-blind and placebo-controlled. Bosentan/placebo is administered for 14 weeks with control visits every four weeks. The primary endpoint is change in maximal oxygen consumption as assessed on bicycle ergometer test. Secondary endpoints include changes in pulmonary blood flow during exercise test, pro brain natriuretic peptide and quality of life. DISCUSSION: We hypothesize that treatment with Bosentan, an endothelin receptor antagonist, can be administered safely and improve exercise capacity in TCPC patients.

Quality of life and cognitive function in Fontan patients, a population-based study.

BACKGROUND: After the Fontan procedure patients are at risk for reduced quality of life (QoL) and cognitive function. We aimed to assess these important factors in Danish Fontan patients and to compare the results with a group of healthy controls. METHODS: All Fontan patients living in Denmark were identified and invited to participate. QoL was evaluated using the Pediatric Quality of Life Inventory (PedsQL) version 4.0 generic core module in patients <16 years and the Short Form 36 questionnaire (SF-36) in patients ≥16 years. Cognitive function was evaluated in all patients ≥6 years using the Quick Test of Cognitive Speed. To evaluate if QoL correlated with exercise capacity, patients performed a symptom-limited bicycle test. RESULTS: 158 of 179 eligible patients (88%) consented to participate. Median age was 13.9 years (IQR: 10.2-19.3). PedsQL scores increased with age but were significantly lower among patients than among controls. SF-36 physical scores were significantly lower in patients compared to controls while psychosocial scores were similar. Cognitive speed was significantly reduced in patients at all ages compared to controls. No significant difference in PedsQL-/SF-36 scores or cognitive speed was found between hypoplastic left heart syndrome (HLHS) and non-HLHS Fontan patient. PedsQL-/SF-36 scores in patients ≥10 years correlated significantly to cognitive speed but not to peak exercise capacity. CONCLUSION: QoL is reduced in Fontan children compared to their healthy counterparts whereas in patients ≥16 years only physical, but not psychosocial QoL is reduced. Cognitive speed was significantly lower in patients at all ages compared to controls.

Heart defects and other features of the 22q11 distal deletion syndrome.

22q11.2 distal deletion syndrome is distinct from the common 22q11.2 deletion syndrome and caused by microdeletions localized adjacent to the common 22q11 deletion at its telomeric end. Most distal deletions of 22q11 extend from LCR22-4 to an LCR in the range LCR22-5 to LCR22-8. We present three patients with 22q11 distal deletions, of whom two have complex congenital heart malformation, thus broadening the phenotypic spectrum. We compare cardiac malformations reported in 22q11 distal deletion to those reported in the common 22q11 deletion syndrome. We also review the literature for patients with 22q11 distal deletions, and discuss the possible roles of haploinsufficiency of the MAPK1 gene. We find the most frequent features in 22q11 distal deletion to be developmental delay or learning disability, short stature, microcephalus, premature birth with low birth weight, and congenital heart malformation ranging from minor anomalies to complex malformations. Behavioral problems are also seen in a substantial portion of patients. The following dysmorphic features are relatively common: smooth philtrum, abnormally structured ears, cleft palate/bifid uvula, micro-/retrognathia, upslanting palpebral fissures, thin upper lip, and ear tags. Very distal deletions including region LCR22-6 to LCR22-7 encompassing the SMARCB1-gene are associated with an increased risk of malignant rhabdoid tumors.

Individualized miRNA assay panels using optically encoded beads.

This chapter describes how to create a multiplexed miRNA profiling assay using readily available technology and reagents for midplex miRNA profiles (midplex used to denote mutliplexing up to about 100 miRNAs per well). The assay described is a direct hybridization assay, i.e., it involves no amplification. Further, the reagents are simple and an assay can be assembled in a few hours with simple design rules and very simple execution. The assay execution takes less than 5 h and involves only liquid addition, which makes it possible to create a multiplexed assay for a large number of miRNAs and run the entire profile for hundreds of samples in a matter of a couple of days. In addition, the profiles can be created for any short RNAs, i.e., they are not tied to human or any other species database for miRNAs, and the described assay works for both animal and plant miRNAs.

Dilation of the ascending aorta in Turner syndrome - a prospective cardiovascular magnetic resonance study.

BACKGROUND: The risk of aortic dissection is 100-fold increased in Turner syndrome (TS). Unfortunately, risk stratification is inadequate due to a lack of insight into the natural course of the syndrome-associated aortopathy. Therefore, this study aimed to prospectively assess aortic dimensions in TS. METHODS: Eighty adult TS patients were examined twice with a mean follow-up of 2.4 ± 0.4 years, and 67 healthy age and gender-matched controls were examined once. Aortic dimensions were measured at nine predefined positions using 3D, non-contrast and free-breathing cardiovascular magnetic resonance. Transthoracic echocardiography and 24-hour ambulatory blood pressure were also performed. RESULTS: At baseline, aortic diameters (body surface area indexed) were larger at all positions in TS. Aortic dilation was more prevalent at all positions excluding the distal transverse aortic arch. Aortic diameter increased in the aortic sinus, at the sinotubular junction and in the mid-ascending aorta with growth rates of 0.1 - 0.4 mm/year. Aortic diameters at all other positions were unchanged. The bicuspid aortic valve conferred higher aortic sinus growth rates (p < 0.05). No other predictors of aortic growth were identified. CONCLUSION: A general aortopathy is present in TS with enlargement of the ascending aorta, which is accelerated in the presence of a bicuspid aortic valve.

Pregnancy with prosthetic heart valves - 30 years' nationwide experience in Denmark.

OBJECTIVE: Pregnancy in women with prosthetic heart valves remains a risk factor for both mother and fetus, but unselected and unbiased outcome and complication data remain scarce. We analyzed nationwide outcome data from 1977 to 2007 for all pregnancies in women with prosthetic valves. METHODS: Cardiac, obstetric, and neonatal data were obtained from obligatory databases and compared with general female population data. Questionnaires were used to corroborate important information. Outcome data were analyzed according to type of anticoagulation used. The data were compared between the two first and the last decades of the study period. In the last decade, patients were compared to an age-adjusted selected population of healthy, pregnant women. RESULTS: Of 356 women between 15 and 40 years of age, 79 women had 155 pregnancies after valve replacement. Two women died during pregnancy, one from heart failure and one from post-partum bleeding. There were four thrombo-embolic episodes in the early study period in women with mitral prosthesis on unfractionated heparin. Important cardiac complications were otherwise almost absent. There were significantly more early miscarriages and terminations in patients compared with controls (last decade 34%, vs 20% (p=0.0036) and 26% vs 13% (p=0.000019)). Post-partum bleeding was more common in the patient group (p=0.0021). Two late fetal losses (one from intracerebral bleeding) were seen. The remaining pregnancies resulted in 60 live births. Cesarean section was the predominant method of delivery in patients as opposed to controls (55% vs 16%, p=0.000000000097). Premature births were more frequent in patients (49% vs 5.5%, p=0.00000000039) as were congenital malformations (14% vs 5.7%, p=0.044). Two of the six malformations were warfarin embryopathy (8% of all first-trimester warfarin exposures), both seen in high-risk patients on high warfarin dosing. Small for gestational age did not differ significantly from the general population (9.3% vs 6.0%, p=0.39). CONCLUSION: Data acquired over 30 years confirm that women with prosthetic heart valves, especially aortic prostheses for congenital lesions, generally tolerate pregnancy well, although cardiac mortality, mortality related to anticoagulation and thrombo-embolic risks are raised. Our data provide further documentation on the significance and importance of the risks associated with predominantly warfarin-based treatment regimens, which still remains optional for a number of patients. Finally, the data also serve as a comparison for recently published series based on low-molecular-weight heparin (LMWH) regimens.

Abnormalities of the major intrathoracic arteries in Turner syndrome as revealed by magnetic resonance imaging.

BACKGROUND: Ectatic aortopathy and arterial abnormalities cause excess morbidity and mortality in Turner syndrome, where a state of vasculopathy seemingly extends into the major head and neck branch arteries. OBJECTIVE: We investigated the prevalence of abnormalities of the major intrathoracic arteries, their interaction with arterial dimensions, and their association with karyotype. DESIGN: Magnetic resonance imaging scans determined the arterial abnormalities as well as head and neck branch artery and aortic dimensions in 99 adult women with Turner syndrome compared with 33 healthy female controls. Echocardiography determined aortic valve morphology. RESULTS: In Turner syndrome, the relative risk of any congenital abnormality was 7.7 (p = 0.003) and 6.7 of ascending aortic dilation (p = 0.02). A bovine aortic arch was seen in both Turner syndrome and controls. Other abnormalities were only encountered in Turner syndrome: elongated transverse aortic arch (47%), bicuspid aortic valve (27%), aortic coarctation (13%), aberrant right subclavian artery (8%), and aortic arch hypoplasia (2%). The innominate and left common carotid arteries were enlarged in Turner syndrome (p < 0.001). Significant associations were first, bicuspid aortic valve with aortic coarctation, elongated transverse aortic arch, and ascending aortic dilation; second, aortic coarctation with elongated aortic arch and descending aortic dilation; third, 45,X with aortic coarctation, elongated transverse aortic arch and ascending aortic dilation; and fourth, branch artery dilation with bicuspid aortic valve, aortic coarctation, elongated transverse aortic arch and 45,X. CONCLUSION: An increased risk of arterial abnormalities, aortic dilation, and enlargement of the branch arteries was found in Turner syndrome without distinct patterns of co-segregation.

Thoracic aortopathy in Turner syndrome and the influence of bicuspid aortic valves and blood pressure: a CMR study.

BACKGROUND: To investigate aortic dimensions in women with Turner syndrome (TS) in relation to aortic valve morphology, blood pressure, karyotype, and clinical characteristics. METHODS AND RESULTS: A cross sectional study of 102 women with TS (mean age 37.7; 18-62 years) examined by cardiovascular magnetic resonance (CMR- successful in 95), echocardiography, and 24-hour ambulatory blood pressure. Aortic diameters were measured by CMR at 8 positions along the thoracic aorta. Twenty-four healthy females were recruited as controls. In TS, aortic dilatation was present at one or more positions in 22 (23%). Aortic diameter in women with TS and bicuspid aortic valve was significantly larger than in TS with tricuspid valves in both the ascending (32.4 +/- 6.7 vs. 26.0 +/- 4.4 mm; p < 0.001) and descending (21.4 +/- 3.5 vs. 18.8 +/- 2.4 mm; p < 0.001) aorta. Aortic diameter correlated to age (R = 0.2 - 0.5; p < 0.01), blood pressure (R = 0.4; p < 0.05), a history of coarctation (R = 0.3; p = 0.01) and bicuspid aortic valve (R = 0.2-0.5; p < 0.05). Body surface area only correlated with descending aortic diameter (R = 0.23; p = 0.024). CONCLUSIONS: Aortic dilatation was present in 23% of adult TS women, where aortic valve morphology, age and blood pressure were major determinants of the aortic diameter.