Patient Engagement in Research: Considerations in Creating a Registry for Adults with Congenital Heart Disease.

PURPOSE OF REVIEW: Patient engagement is defined as the meaningful involvement and active partnership of patients and key partners throughout the entire research project. This article reviews the importance of developing a patient engagement plan to promote better alignment of research with patients' and clinicians' real-world needs and concerns. RECENT FINDINGS: The Congenital Heart Initiative (CHI) launched in 2020 is an entirely web-based longitudinal registry designed in close coordination with the adult congenital heart disease (ACHD) community it is intended to serve. Successful community engagement has resulted in real-world data being collected in large scale in a rare disease population. Establishing patient engagement plans is critical to conducting patient-centered outcomes research. Continued improvement of community engagement strategies is needed to ensure the entire ACHD population is represented to facilitate future research and improved clinical care.

End-stage heart failure in congenitally corrected transposition of the great arteries: a multicentre study.

BACKGROUND AND AIMS: For patients with congenitally corrected transposition of the great arteries (ccTGA), factors associated with progression to end-stage congestive heart failure (CHF) remain largely unclear. METHODS: This multicentre, retrospective cohort study included adults with ccTGA seen at a congenital heart disease centre. Clinical data from initial and most recent visits were obtained. The composite primary outcome was mechanical circulatory support, heart transplantation, or death. RESULTS: From 558 patients (48% female, age at first visit 36 ± 14.2 years, median follow-up 8.7 years), the event rate of the primary outcome was 15.4 per 1000 person-years (11 mechanical circulatory support implantations, 12 transplantations, and 52 deaths). Patients experiencing the primary outcome were older and more likely to have a history of atrial arrhythmia. The primary outcome was highest in those with both moderate/severe right ventricular (RV) dysfunction and tricuspid regurgitation (n = 110, 31 events) and uncommon in those with mild/less RV dysfunction and tricuspid regurgitation (n = 181, 13 events, P < .001). Outcomes were not different based on anatomic complexity and history of tricuspid valve surgery or of subpulmonic obstruction. New CHF admission or ventricular arrhythmia was associated with the primary outcome. Individuals who underwent childhood surgery had more adverse outcomes than age- and sex-matched controls. Multivariable Cox regression analysis identified older age, prior CHF admission, and severe RV dysfunction as independent predictors for the primary outcome. CONCLUSIONS: Patients with ccTGA have variable deterioration to end-stage heart failure or death over time, commonly between their fifth and sixth decades. Predictors include arrhythmic and CHF events and severe RV dysfunction but not anatomy or need for tricuspid valve surgery.

The Fontan Udenafil Exercise Longitudinal Trial: Subgroup Analysis.

The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO2), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO2, work rate at the ventilatory anaerobic threshold (VAT), VO2 at VAT, and ventilatory efficiency (VE/VCO2) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO2, baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation.Trial Registration NCT0274115.

Results of the FUEL Trial.

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Genetic considerations for adults with congenital heart disease.

Congenital heart disease (CHD) remains the most common birth defect, with an estimated incidence of approximately 1% of all births. The population of adults with CHD is growing rapidly with advances in medical care. Overall survival to adulthood in the current era estimated to exceed 90%. Genetic causes of CHD can be classified into several broad categories: (a) chromosomal aneuploidy, (b) large chromosomal deletion or duplication, (c) single gene mutation, and (d) copy number variation. However, only 20-30% of CHD cases have an established etiology characterized by either genetic abnormalities or environmental factors. The role of genetics in the field of adult CHD is only increasing. More adult patients with CHD are seeking genetic counseling to understand the etiology of their underlying CHD and the risks to future offspring. A multidisciplinary approach is essential to provide appropriate counseling to patients regarding indications for genetic testing and interpretations of results. Novel advances with precision medicine may soon enable clinicians to individualize therapies for a comprehensive approach to the care of adult patients with CHD.

Diagnosis and management of the adult patient with a failing Fontan circulation.

Since the original description, the Fontan operation has been widely used for the palliation of children with single ventricle physiology. Although the Fontan operation revolutionized the survival rates of patients with single ventricle physiology, it carries an inevitable risk for long-term morbidity and mortality that impacts clinical outcomes and quality of life. This review will focus on the evaluation and treatment of the patient with the failing Fontan phenotype, with an emphasis on creating an individualized treatment plan.

Appropriate Use of Genetic Testing in Congenital Heart Disease Patients.

PURPOSE OF REVIEW: Congenital heart disease (CHD) remains the most common birth defect, occurring in 1% of all births. Although the exact etiology of CHD is still largely unknown, it is thought to be an interaction of genetic and non-genetic factors. The purposes of this review are to summarize recent advances in CHD genetics and testing and to present a suggested algorithm for appropriate use of genetic testing in patients with CHD. RECENT FINDINGS: Advances in genetic testing technology are rapidly expanding the options for screening and are providing further insights into the genetic and molecular background of non-syndromic CHD. As the field advances, the role of the geneticist and genetic counselor will continue to expand as the testing becomes more complex and interpretation of results becomes increasingly challenging. Coordination of practice between cardiologists and geneticists using a shared clinical structure is essential and will help improve cost utilization and facilitate individualized patient care.

Abnormalities in serum biomarkers correlate with lower cardiac index in the Fontan population.

BACKGROUND: Fontan survivors have depressed cardiac index that worsens over time. Serum biomarker measurement is minimally invasive, rapid, widely available, and may be useful for serial monitoring. The purpose of this study was to identify biomarkers that correlate with lower cardiac index in Fontan patients. Methods and results This study was a multi-centre case series assessing the correlations between biomarkers and cardiac magnetic resonance-derived cardiac index in Fontan patients ⩾6 years of age with biochemical and haematopoietic biomarkers obtained ±12 months from cardiac magnetic resonance. Medical history and biomarker values were obtained by chart review. Spearman's Rank correlation assessed associations between biomarker z-scores and cardiac index. Biomarkers with significant correlations had receiver operating characteristic curves and area under the curve estimated. In total, 97 cardiac magnetic resonances in 87 patients met inclusion criteria: median age at cardiac magnetic resonance was 15 (6-33) years. Significant correlations were found between cardiac index and total alkaline phosphatase (-0.26, p=0.04), estimated creatinine clearance (0.26, p=0.02), and mean corpuscular volume (-0.32, p<0.01). Area under the curve for the three individual biomarkers was 0.63-0.69. Area under the curve for the three-biomarker panel was 0.75. Comparison of cardiac index above and below the receiver operating characteristic curve-identified cut-off points revealed significant differences for each biomarker (p<0.01) and for the composite panel [median cardiac index for higher-risk group=2.17 L/minute/m2 versus lower-risk group=2.96 L/minute/m2, (p<0.01)]. CONCLUSIONS: Higher total alkaline phosphatase and mean corpuscular volume as well as lower estimated creatinine clearance identify Fontan patients with lower cardiac index. Using biomarkers to monitor haemodynamics and organ-specific effects warrants prospective investigation.

Transatrial Endocardial Placement of Epicardial Pacing Lead.

We report a technique wherein an epicardial pacing lead was placed transatrially to achieve optimal pacing in a patient with a complex venous anatomy.

22q11.2 deletion syndrome as a risk factor for aortic root dilation in tetralogy of Fallot.

BACKGROUND: Aortic root dilation has been observed in some patients with tetralogy of Fallot. This study examines whether 22q11.2 deletion is a risk factor for aortic root dilation in tetralogy of Fallot. METHODS: Patients with tetralogy of Fallot, in the age group of 6-18 years, with defined deletion status and echocardiograms (2003-2009) were identified from research databases. The diameter at the aortic annulus, sinus, and sinotubular junction was measured and analysed as Z-scores. Variables were examined in univariate and multivariate regression analysis. RESULTS: Of 171 patients, 66% were male, 16% had 22q11.2 deletion, 40% had an aortic arch anomaly, and 11% had both a 22q11.2 deletion and aortic arch anomaly. Echocardiograms were performed at a mean age of 12 + 3 years. More patients with 22q11.2 deletion had Z-scores >3 at the sinus diameter (45% versus 35%, p = 0.02). In the multivariate analysis, the combination of 22q11.2 deletion and aortic arch anomalies was associated with both aortic annular dilation (p = 0.006) and aortic sinus dilation (p = 0.05). In the subset with pulmonary valve atresia, similar findings were observed at the aortic annulus (Z-score of 4.6 versus 2.2, p = 0.05) and the sinuses (Z-score of 4.4 versus 2.7, p = 0.06). Male sex (p < 0.03) and pulmonary atresia (p < 0.006) were additional risk factors for dilation at the annulus and sinuses. CONCLUSIONS: Children with tetralogy of Fallot with 22q11.2 deletion and aortic arch anomalies have increased aortic annular and aortic sinus dilation. Further longitudinal study is needed to assess whether both features are associated with progressive aortic root dilation.

Anomalous left coronary artery from the right coronary cusp with gene positive apical hypertrophic cardiomyopathy: a case report and literature review.

In the United States, hypertrophic cardiomyopathy and coronary artery anomalies account for the leading two causes of sudden death in athletes. We present a case of a patient with an anomalous origin of the left main from the right coronary sinus with associated gene-confirmed hypertrophic cardiomyopathy. The patient underwent surgical repair with unroofing of the intramural portion of the left main coronary artery with a good result. We also review the reported cases in the medical literature describing this uncommon association between anomalous coronary artery origin and hypertrophic cardiomyopathy.

Meta-analysis: Incidence of cirrhosis and hepatocellular carcinoma in patients with Fontan palliation.

BACKGROUND AND AIMS: The Fontan palliation is the final stage of surgery for many children born with univentricular physiology. Almost all Fontan patients develop liver fibrosis which may eventually lead to cirrhosis and hepatocellular carcinoma (HCC). These are important causes of morbidity and mortality in these patients. We performed a systematic review and meta-analysis to assess the incidence of cirrhosis and HCC in Fontan patients and stratify it based on time since surgery. METHODS: A literature search of seven databases identified 1158 records. Studies reporting the number of cirrhosis and HCC cases in Fontan patients and time since Fontan surgery were included. In the cirrhosis cohort, we included only those studies where all patients underwent liver biopsy. RESULTS: A total of 23 studies were included: 12 and 13 studies in the cirrhosis and HCC cohorts, respectively, with two studies included in both cohorts. The incidence of cirrhosis was 0.97 per 100 patient-years (95% CI 0.57-1.63), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 1.61 per 100 patient-years (95% CI 1.24-2.08) and 32.2% (95% CI 25.8%-39.4%), respectively. The incidence of HCC was 0.12 per 100 patient-years (95% CI 0.07-0.21), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 0.20 per 100 patient-years (95% CI 0.12-0.35) and 3.9% (95% CI 2.2%-6.8%), respectively. Only about 70% of patients with HCC (20/28) had underlying cirrhosis. CONCLUSION: The incidence of cirrhosis and HCC increases over time, especially at ≥20 years post Fontan surgery. Studies are needed to further identify at-risk patients in order to streamline surveillance for these highly morbid conditions.

COVID-19-Related Thrombotic and Bleeding Events in Adults With Congenital Heart Disease.

Background: Altered coagulation is a striking feature of COVID-19. Adult patients with congenital heart disease (ACHD) are prone to thromboembolic (TE) and bleeding complications. Objectives: The purpose of this study was to investigate the prevalence and risk factors for COVID-19 TE/bleeding complications in ACHD patients. Methods: COVID-19-positive ACHD patients were included between May 2020 and November 2021. TE events included ischemic cerebrovascular accident, systemic and pulmonary embolism, deep venous thrombosis, myocardial infarction, and intracardiac thrombosis. Major bleeding included cases with hemoglobin drop >2 g/dl, involvement of critical sites, or fatal bleeding. Severe infection was defined as need for intensive care unit, endotracheal intubation, renal replacement therapy, extracorporeal membrane oxygenation, or death. Patients with TE/bleeding were compared to those without events. Factors associated with TE/bleeding were determined using logistic regression. Results: Of 1,988 patients (age 32 [IQR: 25-42] years, 47% male, 59 ACHD centers), 30 (1.5%) had significant TE/bleeding: 12 TE events, 12 major bleeds, and 6 with both TE and bleeding. Patients with TE/bleeding had higher in-hospital mortality compared to the remainder cohort (33% vs 1.7%; P < 0.0001) and were in more advanced physiological stage (P = 0.032) and NYHA functional class (P = 0.01), had lower baseline oxygen saturation (P = 0.0001), and more frequently had a history of atrial arrhythmia (P < 0.0001), previous hospitalization for heart failure (P < 0.0007), and were more likely hospitalized for COVID-19 (P < 0.0001). By multivariable logistic regression, prior anticoagulation (OR: 4.92; 95% CI: 2-11.76; P = 0.0003), cardiac injury (OR: 5.34; 95% CI: 1.98-14.76; P = 0.0009), and severe COVID-19 (OR: 17.39; 95% CI: 6.67-45.32; P < 0.0001) were independently associated with increased risk of TE/bleeding complications. Conclusions: ACHD patients with TE/bleeding during COVID-19 infection have a higher in-hospital mortality from the illness. Risk of coagulation disorders is related to severe COVID-19, cardiac injury during infection, and use of anticoagulants.

Advances in Managing Transition to Adulthood for Adolescents With Congenital Heart Disease: A Practical Approach to Transition Program Design: A Scientific Statement From the American Heart Association.

It is now expected that most individuals with congenital heart disease will survive to adulthood, including those with complex heart conditions. Maintaining lifelong medical care requires those with congenital heart disease to eventually transfer from pediatric to adult-oriented health care systems. Developing health care transition skills and gaining independence in managing one's own health care is imperative to this process and to ongoing medical and psychosocial success. This scientific statement reviews the recent evidence regarding transition and provides resources, components, and suggestions for development of congenital heart disease transition programs with the goals of improving patient knowledge, self-management, and self-efficacy skills to the level they are capable to eventually integrate smoothly into adult-oriented health care. Specifically, the scientific statement updates 3 sections relevant to transition programming. First, there is a review of specific factors to consider, including social determinants of health, psychosocial well-being, and neurocognitive status. The second section reviews costs of inadequate transition including the public health burden and the impairment in individual quality of life. Finally, the last section discusses considerations and suggestions for transition program design including communication platforms, a family-centered approach, and individual models. Although this scientific statement reviews recent literature surrounding transitions of care for individuals with congenital heart disease there remain significant knowledge gaps. As a field, we have yet to determine ideal timing and methods of transition, and barriers to transition and transfer remain, particularly for the underserved populations. The consequences of poor health care transition are great and garnering outcomes and information through organized, multifaceted, collaborative approaches to transition is critical to improving the lifelong care of individuals with congenital heart disease.

Long-Term Outcomes After Atrial Switch Operation for Transposition of the Great Arteries.

BACKGROUND: For patients with d-loop transposition of the great arteries (d-TGA) with a systemic right ventricle after an atrial switch operation, there is a need to identify risks for end-stage heart failure outcomes. OBJECTIVES: The authors aimed to determine factors associated with survival in a large cohort of such individuals. METHODS: This multicenter, retrospective cohort study included adults with d-TGA and prior atrial switch surgery seen at a congenital heart center. Clinical data from initial and most recent visits were obtained. The composite primary outcome was death, transplantation, or mechanical circulatory support (MCS). RESULTS: From 1,168 patients (38% female, age at first visit 29 ± 7.2 years) during a median 9.2 years of follow-up, 91 (8.8% per 10 person-years) met the outcome (66 deaths, 19 transplantations, 6 MCS). Patients experiencing sudden/arrhythmic death were younger than those dying of other causes (32.6 ± 6.4 years vs 42.4 ± 6.8 years; P < 0.001). There was a long duration between sentinel clinical events and end-stage heart failure. Age, atrial arrhythmia, pacemaker, biventricular enlargement, systolic dysfunction, and tricuspid regurgitation were all associated with the primary outcome. Independent 5-year predictors of primary outcome were prior ventricular arrhythmia, heart failure admission, complex anatomy, QRS duration >120 ms, and severe right ventricle dysfunction based on echocardiography. CONCLUSIONS: For most adults with d-TGA after atrial switch, progress to end-stage heart failure or death is slow. A simplified prediction score for 5-year adverse outcome is derived to help identify those at greatest risk.

COVID-19 in Adults With Congenital Heart Disease.

BACKGROUND: Adults with congenital heart disease (CHD) have been considered potentially high risk for novel coronavirus disease-19 (COVID-19) mortality or other complications. OBJECTIVES: This study sought to define the impact of COVID-19 in adults with CHD and to identify risk factors associated with adverse outcomes. METHODS: Adults (age 18 years or older) with CHD and with confirmed or clinically suspected COVID-19 were included from CHD centers worldwide. Data collection included anatomic diagnosis and subsequent interventions, comorbidities, medications, echocardiographic findings, presenting symptoms, course of illness, and outcomes. Predictors of death or severe infection were determined. RESULTS: From 58 adult CHD centers, the study included 1,044 infected patients (age: 35.1 ± 13.0 years; range 18 to 86 years; 51% women), 87% of whom had laboratory-confirmed coronavirus infection. The cohort included 118 (11%) patients with single ventricle and/or Fontan physiology, 87 (8%) patients with cyanosis, and 73 (7%) patients with pulmonary hypertension. There were 24 COVID-related deaths (case/fatality: 2.3%; 95% confidence interval: 1.4% to 3.2%). Factors associated with death included male sex, diabetes, cyanosis, pulmonary hypertension, renal insufficiency, and previous hospital admission for heart failure. Worse physiological stage was associated with mortality (p = 0.001), whereas anatomic complexity or defect group were not. CONCLUSIONS: COVID-19 mortality in adults with CHD is commensurate with the general population. The most vulnerable patients are those with worse physiological stage, such as cyanosis and pulmonary hypertension, whereas anatomic complexity does not appear to predict infection severity.

Development of a Novel Adult Congenital Heart Disease-Specific Patient-Reported Outcome Metric.

Background Patient-reported outcome metrics (PROs) quantify important outcomes in clinical trials and can be sensitive measures of patient experience in clinical practice. Currently, there is no validated disease-specific PRO for adults with congenital heart disease (ACHD). Methods and Results We conducted a preliminary psychometric validation of a novel ACHD PRO. ACHD patients were recruited prospectively from 2 institutions and completed a series of questionnaires, a physician health assessment, and a 6-minute walk test. Participants returned to complete the same questionnaires and assessment 3 months±2 weeks later. We tested the internal consistency and test-retest reliability by comparing responses among clinically stable patients at the 2 study visits. We assessed convergent and divergent validity by comparison of ACHD PRO responses to existing validated questionnaires. We assessed responsiveness by comparison with patient-reported clinical change. One hundred three patients completed 1 study visit and 81 completed both. The ACHD PRO demonstrated good internal consistency in each of its 5 domains (Cronbach's α: 0.87; 0.74; 0.74; 0.90; and 0.89, respectively) and in the overall summary score (0.92). Test-retest reliability was good with an intraclass correlation ≥0.73 for all domains and 0.78 for the Summary Score. The ACHD PRO accurately assessed domain concepts based on comparison with validated standards. Preliminary estimates of responsiveness suggest sensitivity to clinical status. Conclusions These studies provide initial support for the validity and reliability of the ACHD PRO. Further studies are needed to assess its sensitivity to changes in clinical status.

Aortic root dilation in patients with 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome is characterized by a highly variable phenotype including a range of cardiac malformations. The most common cardiovascular features include a subset of conotruncal defects, perimembranous ventricular septal defects and aortic arch anomalies. This report describes a series of patients with 22q11.2 deletion syndrome with the novel cardiac finding of mild aortic root dilation. A chart review was performed on 93 patients with documented 22q11.2 deletion without significant congenital heart disease to determine the number of patients with aortic root dilation. Patients ranged in age from 1 to 13 years of age. Of these 93 patients, 10 patients were found to have aortic root dilation on a screening echocardiogram. Seven of these patients did not have any additional risk factors while three patients had a bicuspid aortic valve (BAV). Four of 10 patients had additional minor cardiac anomalies including repaired ventricular septal defect (1), patent ductus arteriosus(1), arch anomalies (1), and left pulmonary artery stenosis (1). Three patients had isolated cases of aortic root dilation. Interestingly, several of these patients did not have aortic root dilation on their initial echocardiograms. The purpose of this study is to draw attention to a novel cardiac finding in patients with 22q11.2 deletion that may be of clinical importance. Further long-term study is warranted to assess the need for echocardiographic screening in the 22q11.2 deleted population for aortic root dilation into adolescence and adulthood.

Thrombospondin-1 (TSP-1) up-regulates tissue inhibitor of metalloproteinase-1 (TIMP-1) production in human tumor cells: exploring the functional significance in tumor cell invasion.

Thrombospondin-1 (TSP-1), a matrix-bound adhesive glycoprotein, has been shown to modulate tumor progression. We previously demonstrated that TSP-1 up-regulates matrix metalloproteinases MMP-2 and MMP-9. Our studies suggested that the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs) is a key determinant in tumor cell invasion. We now report that TSP-1 up-regulates TIMP-1 expression in both human breast and prostate cancer cell lines. The effect of TSP-1 on TIMP-1 expression was examined in human breast adenocarcinoma cell lines (MDA-MB-231) and human prostate cancer cell lines (PC3-NI and PC3-ML) treated with exogenous TSP-1. TIMP-1 expression was also examined in TSP-1 stably transfected breast cancer cell line (MDA-MB-435). Northern and western blot analysis revealed TIMP-1 mRNA and TIMP-1 protein expression increased with increasing concentrations of TSP-1. This effect was inhibited by antibodies against the type I repeat domain of TSP-1 further suggesting that TSP-1 mediates TIMP-1 secretion. Inhibition of TSP-1 induced TIMP-1 levels increased tumor cell invasion. We conclude that TSP-1 is involved in influencing the critical balance between MMPs and their inhibitors, maintaining the controlled degradation of the extracellular matrix needed to support metastasis and our results may provide an explanation for the divergent activities reported for TSP-1 in tumor progression.

Ovulation Suppression to Prevent Hemoperitoneum and Surgical Menopause in Anticoagulated Women.

Premenopausal women taking anticoagulation therapy are at risk of developing hemorrhagic ovarian cysts. This paper presents 3 cases of acute hemoperitoneum, with resultant surgical menopause, secondary to cystic hemorrhage in premenopausal women with repaired congenital heart disease (CHD). Adults with CHD taking long-term anticoagulation should be considered candidates for ovulation suppression with hormone-based contraception. (Level of Difficulty: Intermediate.).