Philip E. Hess

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.

An association between severe labor pain and cesarean delivery.

The relationship between epidural analgesia and cesarean delivery remains controversial. Several studies have documented an association, although others have not. This inconsistency may result from an association between severe labor pain and dystocia. We hypothesized that dystocia causes severe labor pain, such that more epidural medication is required to maintain comfort. We examined the relationship between labor outcome and severe pain, defined by the number of supplemental epidural boluses. We retrospectively reviewed the anesthesia records of 4493 parturients who received small-dose labor epidural analgesia. An independent association was found between operative delivery and maternal age, body mass index, nulliparity, fetal weight, induction of labor, and the number of boluses required during labor. By using multivariate analysis, the odds ratio of cesarean delivery among women who required at least three boluses was 2.3 compared with those who required two boluses or less. No association was found between the concentration of bupivacaine in the epidural infusion and operative delivery. Because women with cesarean deliveries appeared to have more pain, degree of labor pain may be a confounding factor in studies examining epidural analgesia and outcome. Implications: This is a retrospective observational study demonstrating an association between labor pain and cesarean delivery. Our results provide an alternative explanation of why epidural analgesia is associated with cesarean delivery.

Evaluation of cranberry tablets for the prevention of urinary tract infections in spinal cord injured patients with neurogenic bladder.

Study Design:Randomized, double blind, placebo-controlled trial with a crossover design.Objective:To evaluate cranberry tablets for the prevention of urinary tract infection (UTI) in spinal cord injured (SCI) patients.Setting:Spinal Cord Injury Unit of a Veterans Administration Hospital, MA, USA.Methods:Subjects with spinal cord injury and documentation of neurogenic bladder were randomized to receive 6 months of cranberry extract tablet or placebo, followed by the alternate preparation for an additional 6 months. The primary outcome was the incidence of UTI.Results:Forty-seven subjects completed the trial. We found a reduction in the likelihood of UTI and symptoms for any month while receiving the cranberry tablet (P<0.05 for all). During the cranberry period, 6 subjects had 7 UTI, compared with 16 subjects and 21 UTI in the placebo period (P<0.05 for both number of subjects and incidence). The frequency of UTI was reduced to 0.3 UTI per year vs 1.0 UTI per year while receiving placebo. Subjects with a glomerular filtration rate (GFR) greater than 75 ml min−1 received the most benefit.Conclusion:Cranberry extract tablets should be considered for the prevention of UTI in SCI patients with neurogenic bladder. Patients with a high GFR may receive the most benefit.Sponsorship:Spinal Cord Research Foundation, sponsored by the Paralyzed Veterans of America

Perioperative diastolic dysfunction during vascular surgery and its association with postoperative outcome

OBJECTIVE To assess the association of perioperative cardiac dysfunction during elective vascular surgery with postoperative outcome. BACKGROUND Patients with normal systolic function can have isolated diastolic dysfunction. Routine preoperative evaluation of left ventricular (LV) function does not include an assessment of diastolic function for risk stratification. We hypothesized that perioperative assessment of both diastolic and systolic function with transesophageal echo (TEE) may improve our ability to predict postoperative outcome. METHODS Perioperative TEE examinations were carried out on patients undergoing elective vascular surgery under general anesthesia. Abnormal systolic function was defined as LV ejection fraction (LVEF) <40%. Left ventricular diastolic function was assessed using transmitral flow propagation velocity (Vp); Vp <45 cm/sec was considered abnormal. We determined the association between LV function and the primary outcome of postoperative adverse outcome, defined as one or more adverse events: myocardial infarction (MI), congestive heart failure (CHF), significant arrhythmia, prolonged intubation, renal failure, and death. RESULTS Three hundred thirteen patients undergoing vascular surgery were studied. We found that 8% (n = 24) of patients had isolated systolic dysfunction, 43% (n = 134) had isolated diastolic dysfunction, and 24% (n = 75) both systolic and diastolic dysfunction. The most common postoperative adverse outcome was CHF 20% (n = 62). By multivariate logistic regression, we found that patient age, Vp, type of surgery, female gender, and renal failure were predictive of postoperative adverse outcome. CONCLUSION The presence of perioperative diastolic dysfunction as assessed with Vp is an independent predictor of postoperative CHF and prolonged length of stay after major vascular surgery. Patient age, gender, type of surgery, and renal failure were also predictors of outcome. Perioperative systolic function was not a predictor of postoperative outcome in our patients.

Dynamic 3-Dimensional Echocardiographic Assessment of Mitral Annular Geometry in Patients With Functional Mitral Regurgitation

BACKGROUND Mitral valve (MV) annular dynamics have been well described in animal models of functional mitral regurgitation (FMR). Despite this, little if any data exist regarding the dynamic MV annular geometry in humans with FMR. In the current study we hypothesized that 3-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 operations were dynamically analyzed for differences in mitral annular geometry with TomTec 4D MV Assessment 2.0 software (TomTec Imaging Systems GmbH, Munich, Germany). RESULTS In patients with FMR, the mean mitral annular area (14.6 cm(2) versus 9.6 cm(2)), circumference (14.1 cm versus 11.4 cm), anteroposterior (4.0 cm versus 3.0 cm) and anterolateral-posteromedial (4.3 cm versus 3.6 cm) diameters, tenting volume (6.2 mm(3) versus 3.5 mm(3)) and nonplanarity angle (NPA) (154 degrees ± 15 versus 136 degrees ± 11) were greater at all points during systole compared with controls (p < 0.01). Vertical mitral annular displacement (5.8 mm versus 8.3 mm) was reduced in FMR compared with controls (p < 0.01). CONCLUSIONS There are significant differences in dynamic mitral annular geometry between patients with FMR and those without. 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.

Stretch Activates Human Myometrium via ERK, Caldesmon and Focal Adhesion Signaling

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.

Simulator-based Transesophageal Echocardiographic Training with Motion Analysis: A Curriculum-based Approach

Background:Transesophageal echocardiography (TEE) is a complex endeavor involving both motor and cognitive skills. Current training requires extended time in the clinical setting. Application of an integrated approach for TEE training including simulation could facilitate acquisition of skills and knowledge. Methods:Echo-naive nonattending anesthesia physicians were offered Web-based echo didactics and biweekly hands-on sessions with a TEE simulator for 4 weeks. Manual skills were assessed weekly with kinematic analysis of TEE probe motion and compared with that of experts. Simulator-acquired skills were assessed clinically with the performance of intraoperative TEE examinations after training. Data were presented as median (interquartile range). Results:The manual skills of 18 trainees were evaluated with kinematic analysis. Peak movements and path length were found to be independent predictors of proficiency (P < 0.01) by multiple regression analysis. Week 1 trainees had longer path length (637 mm [312 to 1,210]) than that of experts (349 mm [179 to 516]); P < 0.01. Week 1 trainees also had more peak movements (17 [9 to 29]) than that of experts (8 [2 to 12]); P < 0.01. Skills acquired from simulator training were assessed clinically with eight additional trainees during intraoperative TEE examinations. Compared with the experts, novice trainees required more time (199 s [193 to 208] vs. 87 s [83 to 16]; P = 0.002) and performed more transitions throughout the examination (43 [36 to 53] vs. 21 [20 to 23]; P = 0.004). Conclusions:A simulation-based TEE curriculum can teach knowledge and technical skills to echo-naive learners. Kinematic measures can objectively evaluate the progression of manual TEE skills.

Low dose intrathecal ropivacaine with or without sufentanil provides effective analgesia and does not impair motor strength during labour: a pilot study.

PurposeAlthough ropivacaine has been used to provide spinal anesthesia in the surgical population, its intrathecal administration for labour analgesia has only recently been described. We evaluated the effects of low dose intrathecal ropivacaine with or without sufentanil for labour analgesia.MethodsThirty-six term parturients in active labour were randomly assigned to receive 3 mg of intrathecal ropivacaine (group R) or 3 mg ropivacaine with 10 μg of sufentanil (group RS). Patients were evaluated by a blinded observer for hypotension, linear analogue score (VAS 0–100) for labour pain, motor power in the lower limbs, onset of analgesia, sensation to cold and pin prick, duration of analgesia, and neonatal Apgar scores. The following day patients were assessed for satisfaction, headache and neurologic deficit.ResultsThe mean duration of analgesia in the R group was 41.4 ± 4.9 min and 95.0 ± 6.1 min in the RS group (mean ± SEM, P=0.0001). All subjects had satisfactory analgesia at five minutes, although analgesia from the ropivacaine-sufentanil combination was superior to that provided by ropivacaine alone. Total duration of labour was no different between the groups (R-306 ± 34, RS-384 ± 44 min, P=0.17). No patient showed evidence of motor block. All patients were satisfied with the labour analgesia. No neurological complications were observed.ConclusionsLow dose ropivacaine provides effective analgesia during labour via the intrathecal route. It can be mixed with sufentanil in the above-mentioned concentrations to improve both the quality and duration of analgesia. Fetal outcome remains favourable. It may provide minimal or no motor block, to facilitate ambulation.RésuméObjectifMême si la ropivacaïne a été utilisée pour la rachianesthésie chirurgicale, son administration intrathêcale comme analgésie pendant le travail n’a été étudiée que récemment. Nous avons évalué les effets d’une faible dose de ropivacaïne intrathêcale avec ou sans sufentanil comme analgésie pendant le travail.MéthodeTrente-six parturientes à terme, en travail actif, ont été réparties au hasard et ont reçu 3 mg de ropivacaïne intrathêcale (groupe R) ou 3 mg de ropivacaïne avec 10 mg de sufentanil (groupe RS). Un observateur objectif a évalué l’hypotension, la douleur du travail selon une échelle visuelle analogique (EVA, 0–100), la force motrice des membres inférieurs, le début de l’analgésie, la sensation de froid, la sensibilité à la piqûre, la durée de l’analgésie chez la mère et l’indice d’Apgar chez le nouveau-né. Le jour suivant l’accouchement, on a noté la satisfaction des patientes, la présence de céphalées et de déficit neurologique.RésultatsLa durée moyenne de l’analgésie a été, dans le groupe R, de 41,4 ± 4,9 min et, dans le groupe RS, de 95,0 ± 6,1 min (moyenne ± erreur type), P = 0,0001). Toutes les patientes étaient satisfaites de l’analgésie à cinq minutes, quoique l’analgésie fournie par la combinaison de ropivacaïne-sufentanil ait été supérieure à l’analgésie fournie par la ropivacaïne seule. La durée totale du travail n’a pas présenté de différence intergroupe (R-306 ± 34, RS- 384 ± 44 min, P = 0,17). Aucune patiente n’a présenté d’évidence de bloc moteur. Toutes les patientes ont été satisfaites de l’analgésie pendant le travail. Aucune complication neurologique n’est survenue.ConclusionL’administration intrathécale d’une faible dose de ropivacaïne fournit une analgésie efficace pendant le travail. Elle peut être combinée au sufentanil selon les concentrations susmentionnées afin d’améliorer la qualité et la durée de l’analgésie. L’évolution du bébé demeure favorable. La ropivacaïne peut entraîner un blocage moteur minimal, ou l’absence de bloc, ce qui permet à la patiente de déambuler.

Increased glycemic variability in patients with elevated preoperative HbA1C predicts adverse outcomes following coronary artery bypass grafting surgery.

BACKGROUND:In the setting of protocolized glycemic control, the relationship between postoperative glycemic variability on major adverse events (MAEs) after cardiac surgery is unknown for patients with increased preoperative hemoglobin A1C (HbA1C >6.5%). In this study, we sought to establish (a) whether postoperative glycemic variability is associated with MAEs after CABG surgery and (b) whether preoperative HbA1C could identify patients at increased risk of postoperative glycemic variability. METHODS:Patients undergoing coronary artery bypass grafting with or without valvular surgery from January 2008 to May 2011 were enrolled in this prospective, single-center, observational cohort study. Demographic, intraoperative, and postoperative outcome data were obtained from institutional data collected for the Society of Thoracic Surgery (STS) database. The primary outcome, MAE was a composite of in-hospital death, myocardial infarction (MI), reoperations, sternal infection, cardiac tamponade, pneumonia, stroke, or renal failure. Glycemic variability in the postoperative period was assessed by the coefficient of variation (CV). CV was used as quartiles for the multivariate logistic regression. Variable selection in multivariable modeling was based on clinical and statistical significance and was performed in a hierarchical fashion. RESULTS:Of the 1461 patients enrolled, 9.8% had an MAE. Based on the established target of HbA1C <6.5% for the diagnosis of diabetes mellitus, we considered HbA1C as a binary variable (<6.5% and ≥6.5%) in our primary analysis. Multivariate logistic regression analyses for the preoperative variables only revealed that preoperative HbA1C (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1–2.3; P = 0.02), history of MI (OR, 1.9; 95% CI, 1.3–2.8; P = 0.001), and STS risk score per quartile (OR, 1.7; 95% CI, 1.4–2.1; P < 0.001) were associated with MAEs. When postoperative variables were included in the analyses, postoperative glycemic variability (CV per quartile) in the intensive care unit (OR, 1.3; 95% CI, 1.1–1.5; P = 0.03), mean glucose levels averaged over the first 4 postoperative hours (OR, 1.2; 95% CI, 1.0–1.4; P = 0.03), history of MI (OR, 1.8; 95% CI, 1.2–2.6; P = 0.004), and STS risk score per quartile (OR, 1.6; 95% CI, 1.3–2.0; P < 0.001) were associated with MAEs. Glycemic variability as assessed by CV was increased postoperatively in patients with preoperative HbA1C ≥6.5% (0.20 ± 0.09 vs 0.16 ± 0.07, P < 0.001). CONCLUSIONS:Postoperative glycemic variability is associated with MAEs after cardiac surgery. Glycemic variability is only measured when the patient leaves the intensive care unit, and there is no opportunity to intervene earlier. Preoperative HbA1C identifies risk for postoperative glycemic variability and may provide a more rational guide for targeting measures to reduce variability.

Effects of neuropeptide Y on collateral development in a swine model of chronic myocardial ischemia

We investigated the role of neuropeptide Y (NPY), abundant in the myocardial sympathetic nervous system and endothelial cells, in angiogenesis during chronic myocardial ischemia. Adult male Yorkshire swine underwent ameroid constrictor placement on the proximal left circumflex coronary artery. After 3 weeks, an osmotic pump was placed to deliver either placebo (control, n=8) or NPY(3-36) (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. 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). Exogenous NPY(3-36) 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.