Michele R. Hacker

Cardiac angiogenic imbalance leads to peripartum cardiomyopathy

Peripartum cardiomyopathy (PPCM) is an often fatal disease that affects pregnant women who are near delivery, and it occurs more frequently in women with pre-eclampsia and/or multiple gestation. The aetiology of PPCM, and why it is associated with pre-eclampsia, remain unknown. Here we show that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble FLT1 (sFLT1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by subclinical cardiac dysfunction, the extent of which correlates with circulating levels of sFLT1. Exogenous sFLT1 alone caused diastolic dysfunction in wild-type mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFLT1. These data indicate that PPCM is mainly a vascular disease, caused by excess anti-angiogenic signalling in the peripartum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM.

Cumulative Live-Birth Rates after In Vitro Fertilization

BACKGROUND Outcomes of in vitro fertilization (IVF) treatment are traditionally reported as pregnancies per IVF cycle. However, a couples primary concern is the chance of a live birth over an entire treatment course. METHODS We estimated cumulative live-birth rates among patients undergoing their first fresh-embryo, nondonor IVF cycle between 2000 and 2005 at one large center. Couples were followed until either discontinuation of treatment or delivery of a live-born infant. Analyses were stratified according to maternal age and performed with the use of both optimistic and conservative methods. Optimistic methods assumed that patients who did not return for subsequent IVF cycles would have the same chance of a pregnancy resulting in a live birth as patients who continued treatment; conservative methods assumed no live births among patients who did not return. RESULTS Among 6164 patients undergoing 14,248 cycles, the cumulative live-birth rate after 6 cycles was 72% (95% confidence interval [CI], 70 to 74) with the optimistic analysis and 51% (95% CI, 49 to 52) with the conservative analysis. Among patients who were younger than 35 years of age, the corresponding rates after six cycles were 86% (95% CI, 83 to 88) and 65% (95% CI, 64 to 67). Among patients who were 40 years of age or older, the corresponding rates were 42% (95% CI, 37 to 47) and 23% (95% CI, 21 to 25). The cumulative live-birth rate decreased with increasing age, and the age-stratified curves (< 35 vs. > or = 40 years) were significantly different from one another (P<0.001). CONCLUSIONS Our results indicate that IVF may largely overcome infertility in younger women, but it does not reverse the age-dependent decline in fertility.

Barriers to compliance with prophylaxis therapy in haemophilia

Prophylaxis, or the practice of routine replacement infusions of clotting factor concentrate in persons with severe haemophilia, is a demanding medical regimen. Prophylactic infusions require direct venepuncture or sterile entry into a central venous access device on a regular basis. A telephone survey was conducted to elicit information regarding the barriers to compliance with prophylaxis. The Mountain States Regional Haemophilia and Thrombosis Center has recommended prophylaxis to 52 male patients with haemophilia A or B. The haemophilia nurse attempted to contact all of these patients or their parents, and contact was made with 38 (73.1%) of them. Respondents were asked about the following issues: their decision to initiate prophylaxis; their self‐rated compliance; the challenges, barriers, and facilitators of prophylaxis; and their perceived value of the therapy. Four patients (10.5%) elected not to begin prophylaxis. Of the 34 persons who began prophylaxis, 20 respondents (58.8%) rated their compliance as excellent. Nearly one‐third of the families with excellent compliance (giving 75–100% of prescribed infusions) stated that the time‐consuming nature of prophylaxis was the most significant challenge of the regimen. In addition, 58.3% of the families that gave less than the prescribed number of infusions reported that the time commitment was the primary reason for missing infusions. Knowledge of the benefits of prophylaxis was the primary facilitator of compliance for 44.1% of families. Ninety‐seven percent of respondents rated prophylaxis as very valuable. These data show that despite the known benefits of prophylaxis, it is a demanding medical regimen, and compliance is imperfect. In addition, this study underscores the importance of providing continuing support and education for patients and families who are implementing prophylaxis.

Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.

The Varicella-Autoantibody Syndrome

This cross-sectional study was conducted to determine the incidence of autoantibodies to phospholipids and coagulation proteins in children with acute varicella zoster virus (VZV) infection. Study groups included children with VZV alone or complicated by purpura fulminans and/or thromboembolism. VZV naïve children and children who had VZV >1 y before sample collection formed a control group. Blood was assayed for the following: free protein S (PS), protein C, antithrombin, and prothrombin; antibody binding to these proteins; lupus anticoagulant; anticardiolipin antibody; antiphospholipid antibodies; and prothrombin fragment 1+2. Data regarding coinfections was collected. Forty-three VZV-infected children showed an increased frequency of lupus anticoagulant, anticardiolipin antibody, antiphospholipid antibodies, and autoantibodies to PS, protein C, prothrombin, and antithrombin in comparison to 52 children without acute VZV (p < 0.0001). Seventeen children with VZV and purpura fulminans and/or thromboembolism showed a statistically significant decrease in free PS, significantly increased PS IgG antibody, and significantly increased prothrombin fragment 1+2 (p < 0.0001) compared with the group without acute VZV and the group with uncomplicated VZV. Twenty-six children with uncomplicated VZV showed increased PS IgG antibody (p < 0.001) compared with the children without acute VZV. For all groups combined, elevated PS IgG antibody showed negative correlation with free PS (p < 0.0001) and positive correlation with prothrombin fragment 1+2 (p = 0.0002). Autoantibodies were transient. Transient antiphospholipid and coagulation protein autoantibodies were common with VZV infection, but were not predictive of thrombotic complications.

Elevated Midpregnancy Corticotropin-Releasing Hormone Is Associated with Prenatal, But Not Postpartum, Maternal Depression

CONTEXT Elevated hypothalamic CRH has been implicated in melancholic major depression in nonpregnant individuals, but the role of placental CRH in maternal prenatal and postpartum depression is largely unexplored. OBJECTIVE The objective of the study was to examine the association of maternal midpregnancy plasma CRH levels with prenatal and postpartum depression. PARTICIPANTS The study included 800 participants in Project Viva, a pregnancy and childhood cohort. METHODS CRH levels were analyzed from blood samples obtained at mean 27.9 wk gestation (+/- 1.3 sd; range 24.6-37.4 wk) and were normalized on the logarithmic scale. Depression was assessed with the Edinburgh Postpartum Depression Scale (range 0-30 points) in midpregnancy and at 6 months postpartum. We used logistic regression to estimate the odds of scoring 13 or more points on the Edinburgh Postpartum Depression Scale as indicative of major or minor depression. RESULTS Seventy (8.8%) and 46 (7.5%) women had prenatal and postpartum depression symptoms, respectively. Mean log CRH was 4.93 (+/- 0.62 sd). After adjusting for confounders, an sd increase in log CRH was associated with nearly 50% higher odds of prenatal depression symptoms (odds ratio 1.48, 95% confidence interval 1.14-1.93). Higher CRH levels during pregnancy were unassociated with greater risk of postpartum depressive symptoms. In fact, there was a suggestion that prenatal CRH levels might be inversely associated with risk of postpartum depressive symptoms (odds ratio 0.82, 95% confidence interval 0.58-1.15). CONCLUSIONS Elevated placental CRH levels in midpregnancy are positively associated with risk of prenatal depression symptoms but not postpartum depression symptoms.

Subclinical Left Ventricular Dysfunction in Preeclamptic Women With Preserved Left Ventricular Ejection Fraction A 2D Speckle-Tracking Imaging Study

Background—Patients with preeclampsia are at risk for cardiovascular disease. Changes in cardiac function are subtle in preeclampsia and are difficult to quantify with conventional imaging. Strain measurements using speckle-tracking echocardiography have been used to sensitively quantify abnormalities in other disease settings. Methods and Results—We evaluated the feasibility and sensitivity of strain imaging using speckle-tracking echocardiography in women with preeclampsia. Forty-seven women were enrolled in this pilot study and 39 were analyzed: 11 with preeclampsia, 17 without a hypertensive disorder, and 11 with nonproteinuric hypertension. Echocardiographic ejection fraction and global peak longitudinal, radial, and circumferential strain were measured. Longitudinal strain was significantly worsened in women with preeclampsia compared with women without a hypertensive disorder (P=0.0001). Similar results were observed for radial strain (P=0.006) and circumferential strain (P=0.03). Women with preeclampsia also had significantly worsened longitudinal (P=0.04), radial (P=0.01), and circumferential (P=0.002) strain compared with women with nonproteinuric hypertension. Women with preeclampsia did not have a significantly different ejection fraction compared with women without a hypertensive disorder (P=0.16) and women with nonproteinuric hypertension (P=0.44). Conclusions—Myocardial strain imaging using speckle tracking is more sensitive than left ventricular ejection fraction to detect differences in left ventricular systolic function in women with and without preeclampsia.

Increased platelet Fc receptor expression as a potential contributing cause of platelet hypersensitivity to collagen in diabetes mellitus

Summary. Recent clinical and laboratory observations support a potential role for the platelet FcγRIIA receptor (FcR) in collagen‐mediated platelet activation associated with arterial thrombosis. Stable age‐ and sex‐independent variation in receptor expression exists. Flow cytometry showed that 100 diabetes patients had increased mean platelet FcR expression levels compared with 201 non‐diabetes patients (P < 0·001). Aggregation studies following FcR cross‐linking supported a receptor role in increased activation of diabetes platelets after collagen stimulation (P = 0·018). Immunoprecipitation of collagen‐stimulated and FcR‐crosslinked platelets demonstrated enhanced levels of tyrosine‐phosphorylated Syk in diabetic platelets. Increased platelet FcR‐mediated sensitivity to collagen may contribute to cardiovascular morbidity and mortality in diabetes.

Physicians' Knowledge of Future Vascular Disease in Women with Preeclampsia

Objective. Preeclampsia, a hypertensive disorder of pregnancy, affects 5–8% of women. Large studies demonstrate a strong association between preeclampsia and future cardiovascular disease (CVD). Despite CVD being the leading cause of mortality for women, there has been little education for internal medicine physicians or obstetrician-gynecologists (ob-gyns) about this association; published guidelines do not include preeclampsia as a risk factor for future CVD. Therefore, women with a history of preeclampsia may not receive adequate risk-reduction counseling for CVD. It is unclear whether primary care physicians are aware of the association; thus, we sought to determine whether primary care providers at our institution were aware of preeclampsias association with future CVD and whether they were providing appropriate counseling. Methods. An anonymous online survey was sent to all internists and (ob-gyns) at our hospital. Results. Although most internists (95%) and (ob-gyns) (70%) provide routine cardiovascular risk-reduction counseling, a substantial proportion of them were unaware of any health risk associated with a history of preeclampsia. Many internists were unsure or did not know whether preeclampsia is associated with ischemic heart disease (56%), stroke (48%), and decreased life expectancy (79%). The corresponding proportions for (ob-gyns) were 23, 38, and 77%, respectively. Only 9% of internists and 38% of obstetrician-gynecologists were providing cardiovascular risk-reduction counseling to women with a history of preeclampsia. Conclusion. There is limited knowledge of the association between preeclampsia and future CVD; this deficiency may limit the application of this risk factor to clinical care.

Age-related variations in follicular apolipoproteins may influence human oocyte maturation and fertility potential

OBJECTIVE To investigate involvement of specific apolipoproteins in the process of human oocyte maturation and age-related infertility as molecular constituents of follicular fluid. DESIGN Laboratory-based observational study. SETTING Basic science laboratory at a large academic institution. PATIENT(S) Follicular fluid obtained from healthy women aged 18 to 45 years undergoing in vitro fertilization for unexplained infertility, ovulatory dysfunction, tubal disease, male factor infertility, or oocyte donation. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Specific concentration of apolipoproteins and content of lipoprotein particles in follicular fluid and blood plasma as related to reproductive aging. RESULT(S) We registered a decline of follicular apolipoprotein A1 (Apo A1) and apolipoprotein CII (Apo CII) and an increase of the apolipoprotein E (Apo E) with age, which parallels a lower number of retrieved mature oocytes in older women. Follicular apolipoprotein A1, apolipoprotein B (Apo B), apolipoprotein E, and apolipoprotein C II are present in diverse heterogeneous complexes including very-low-density lipoproteins (VLDL), intermediate-low-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) that vary with patient age and differ from the blood plasma lipoprotein complexes. CONCLUSION(S) Age-related variation in follicular apolipoprotein content and distribution in the cholesterol particles may be associated with the decrease in production of mature oocytes and the age-related decline in fertility potential.