Person:

Hess, Philip

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-(1\alpha), 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-(1\alpha). 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.

Objective: Adequate control of postoperative pain directly improves patient satisfaction and outcomes, and timely identification of patients with poorly controlled pain is essential. Pain management protocols are best studied in patients recovering from the same operation. In our institution, the postoperative pain regimen for patients undergoing deep inferior epigastric perforator (DIEP) flap breast reconstruction is standardized using patient-controlled analgesia (PCA) followed by conversion to oral narcotics. From this uniform population, we were able to identify a subgroup of patients with poor pain control. Methods: Over a 44-month period, 179 consecutive patients underwent DIEP flap breast reconstruction with 242 flaps performed. A retrospective chart review recorded PCA usage, visual analog scale pain scores, and length of stay. Results: Pain management with PCA after DIEP flap breast reconstruction was uniformly controlled. Most patients (74.9%) required PCA usage in the first 2 days with conversion to oral analgesics. A subgroup of patients (25.1%) continued to require PCA usage on the third postoperative day. These “nonresponder” patients had a higher visual analog scale score on the first postoperative day, higher total intravenous morphine use, and a longer length of stay (all, P less than .05). A multivariate analysis revealed more nonresponders among patients undergoing immediate breast reconstruction (P less than .05); however, all other factors analyzed had no correlation. Conclusion: We report a subgroup of patients with poor pain control after DIEP flap breast reconstruction. This group of patients required a longer course of pain management and subsequently a longer hospital stay. Pain management protocols that identify these patients promptly can allow for appropriate modifications.

Background

During an epidural blood patch, we inject blood until the patient describes mild back pressure, often leading to injection of more than 20 mL of blood. We undertook this study to measure the epidural pressures generated during an epidural blood patch and to identify the impact of volume on epidural elastance in obstetric patients.

Methods

This study was performed in postpartum patients who presented for an epidural blood patch with symptoms consistent with a postdural puncture headache. After identification of the epidural space using loss of resistance to air or saline, we measured static epidural pressure after each 5-mL injection of blood. Models were then fitted to the data and the epidural elastance and compliance calculated.

Results

Eighteen blood patches were performed on 17 patients. The mean final volume injected was 18.9 ± 7.8 mL [range 6 to 38 mL]. The mean final pressure generated was 13.1 ± 13.4 mmHg [range 2 to 56 mmHg]. A curvilinear relationship existed between volume injected and pressure, which was described by two models: (1) pressure = 0.0254 × (mL injected)2 + 0.0297 × mL, or (2) pressure = 0.0679 × mL1.742. The value for r2 was approximately 0.57 for both models. We found no correlation between the final pressure generated and the success of the EBP.

Conclusions

We found a curvilinear relationship between the volume of blood injected during an epidural blood patch and the pressure generated in the epidural space. However, there was a large variation in both the volume of blood and the epidural pressure generated. The clinical importance of this finding is not known. A larger study would be required to demonstrate whether pressure is a predictor of success.

An incomplete understanding of the molecular mechanisms responsible for myometrial activation from the quiescent pregnant state to the active contractile state during labor has hindered the development of effective therapies for preterm labor. Myometrial stretch has been implicated clinically in the initiation of labor and the etiology of preterm labor, but the molecular mechanisms involved in the human have not been determined. We investigated the mechanisms by which gestation-dependent stretch contributes to myometrial activation, by using human uterine samples from gynecologic hysterectomies and Cesarean sections. Here we demonstrate that the Ca requirement for activation of the contractile filaments in human myometrium increases with caldesmon protein content during gestation and that an increase in caldesmon phosphorylation can reverse this inhibitory effect during labor. By using phosphotyrosine screening and mass spectrometry of stretched human myometrial samples, we identify 3 stretch-activated focal adhesion proteins, FAK, p130Cas, and alpha actinin. FAK-Y397, which signals integrin engagement, is constitutively phosphorylated in term human myometrium whereas FAK-Y925, which signals downstream ERK activation, is phosphorylated during stretch. We have recently identified smooth muscle Archvillin (SmAV) as an ERK regulator. A newly produced SmAV-specific antibody demonstrates gestation-specific increases in SmAV protein levels and stretch-specific increases in SmAV association with focal adhesion proteins. Thus, whereas increases in caldesmon levels suppress human myometrium contractility during pregnancy, stretch-dependent focal adhesion signaling, facilitated by the ERK activator SmAV, can contribute to myometrial activation. These results suggest that focal adhesion proteins may present new targets for drug discovery programs aimed at regulation of uterine contractility.

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.

Objective We investigated the role of neuropeptide Y (NPY), abundant in the myocardial sympathetic nervous system and endothelial cells, in angiogenesis during chronic myocardial ischemia.

Methods Adult male Yorkshire swine underwent ameroid constrictor placement on the proximal left circumflex coronary artery. After three weeks, an osmotic pump was placed to deliver either placebo (control, n=8) or NPY3-36 (NPY, n=8) to the collateral dependent region. Five weeks after pump placement, after cardiac catheterization and hemodynamic assessment, the heart was harvested for analysis.

Results NPY treated animals demonstrated increased mean arterial pressures and improved left ventricular function (+dP/dt). Cardiac catheterization demonstrated a significant increase in the blush score in the NPY group (p<0.001). Blood flow to the ischemic myocardium was not different between groups at rest or during ventricular pacing. Immunohistochemical double staining for CD-31 and smooth muscle actin demonstrated an increase in capillary and arteriole formation in NPY treated animals (p=0.02 and p<0.001). Immunoblotting showed a significant upregulation of DPPIV (p=0.009) and NPY receptors 1 (p=0.008), 2 (p=0.02) and 5 (p=0.03) in the NPY treated group. Additionally, there was significant upregulation of VEGF (p=0.04), eNOS (p=0.014), phospho-eNOS(ser1177)(p=0.02), and PDGF (p<0.001) in NPY treated group. The anti-angiogenic factors endostatin and angiostatin were significantly decreased in NPY treated animals (endostatin, p=0.03, angiostatin p=0.04).

Conclusion Exogenous NPY3-36 resulted in improved myocardial function and increased angiogenesis and arteriogenesis by stimulating growth factor, pro-angiogenic receptor upregulation, and decreasing anti-angiogenic expression, but did not increase blood flow to the ischemic myocardium. NPY may act as a good adjunct to primary agents of therapeutic angiogenesis.

Background: Mitral valve (MV) annular dynamics have been well described in animal models of functional mitral regurgitation (FMR). Despite this little, if any, data exists regarding the dynamic MV annular geometry in humans with FMR. In the current study we hypothesized that three-dimensional (3D) echocardiography, in conjunction with commercially available software, could be used to quantify the dynamic changes in MV annular geometry associated with FMR. Methods: Intraoperative 3D transesophageal echocardiographic data obtained from 34 patients with FMR and 15 controls undergoing cardiac surgery were dynamically analyzed for differences in mitral annular geometry with TomTec© 4D MV Assessment 2.0 software. Results: In patients with FMR, the mean mitral annular area (14.6cm2 vs. 9.6cm2), circumference (14.1cm vs. 11.4 cm), anteroposterior (4.0cm vs. 3.0cm) and anterolateral-posteromedial (4.3cm vs. 3.6cm) diameters, tenting volume (6.2mm3 vs. 3.5mm3) and nonplanarity angle (154° ± 15 vs. 136° ± 11) were greater at all points during systole compared to controls (p<0.01). Vertical mitral annular displacement (5.8mm vs. 8.3mm) was reduced in FMR compared to controls (p<0.01). Conclusions: There are significant differences in dynamic mitral annular geometry between patients with and without FMR. We were able to analyze these changes in a clinically feasible fashion. Ready availability of this information has the potential to aid comprehensive quantification of mitral annular function and possibly assist in both clinical decision-making and annuloplasty ring selection.

Background: Proficiency in transthoracic echocardiography (TTE) requires an integration of cognitive knowledge and psychomotor skills. Whereas cognitive knowledge can be quantified, psychomotor skills are implied after repetitive task performance. We applied motion analyses to evaluate psychomotor skill acquisition during simulator-based TTE training.

Methods and Results: During the first month of their fellowship training, 16 cardiology fellows underwent a multimodal TTE training program for 4 weeks (8 sessions). The program consisted of online and live didactics as well as simulator training. Kinematic metrics (path length, time, probe accelerations) were obtained at the start and end of the course for 8 standard TTE views using a simulator. At the end of the course TTE image acquisition skills were tested on human models. After completion of the training program the trainees reported improved self-perceived comfort with TTE imaging. There was also an increase of 8.7% in post-test knowledge scores. There was a reduction in the number of probe accelerations [median decrease 49.5, 95% CI = 29-73, adjusted P < 0.01], total time [median decrease 10.6 s, 95% CI = 6.6-15.5, adjusted P < 0.01] and path length [median decrease 8.8 cm, 95% CI = 2.2-17.7, adjusted P < 0.01] from the start to the end of the course. During evaluation on human models, the trainees were able to obtain all the required TTE views without instructor assistance.

Conclusion: Simulator-derived motion analyses can be used to objectively quantify acquisition of psychomotor skills during TTE training. Such an approach could be used to assess readiness for clinical practice of TTE.