Heart-lung interactions during neurally adjusted ventilatory assist

Introduction Assist in unison to the patient’s inspiratory neural effort and feedback-controlled limitation of lung distension with neurally adjusted ventilatory assist (NAVA) may reduce the negative effects of mechanical ventilation on right ventricular function. Methods Heart–lung interaction was evaluated in 10 intubated patients with impaired cardiac function using esophageal balloons, pulmonary artery catheters and echocardiography. Adequate NAVA level identified by a titration procedure to breathing pattern (NAVAal), 50% NAVAal, and 200% NAVAal and adequate pressure support (PSVal, defined clinically), 50% PSVal, and 150% PSVal were implemented at constant positive end-expiratory pressure for 20 minutes each. Results NAVAal was 3.1 ± 1.1cmH2O/μV and PSVal was 17 ± 2 cmH20. For all NAVA levels negative esophageal pressure deflections were observed during inspiration whereas this pattern was reversed during PSVal and PSVhigh. As compared to expiration, inspiratory right ventricular outflow tract velocity time integral (surrogating stroke volume) was 103 ± 4%, 109 ± 5%, and 100 ± 4% for NAVAlow, NAVAal, and NAVAhigh and 101 ± 3%, 89 ± 6%, and 83 ± 9% for PSVlow, PSVal, and PSVhigh, respectively (p < 0.001 level-mode interaction, ANOVA). Right ventricular systolic isovolumetric pressure increased from 11.0 ± 4.6 mmHg at PSVlow to 14.0 ± 4.6 mmHg at PSVhigh but remained unchanged (11.5 ± 4.7 mmHg (NAVAlow) and 10.8 ± 4.2 mmHg (NAVAhigh), level-mode interaction p = 0.005). Both indicate progressive right ventricular outflow impedance with increasing pressure support ventilation (PSV), but no change with increasing NAVA level. Conclusions Right ventricular performance is less impaired during NAVA compared to PSV as used in this study. Proposed mechanisms are preservation of cyclic intrathoracic pressure changes characteristic of spontaneous breathing and limitation of right-ventricular outflow impedance during inspiration, regardless of the NAVA level.

Clinical role of atrial arrhythmias in patients with arrhythmogenic right ventricular dysplasia

BACKGROUND: The clinical role of atrial fibrillation/atrial flutter (AF-AFl) and variables predicting these arrhythmias are not well defined in patients with arrhythmogenic right ventricular dysplasia (ARVD). We hypothesized that transthoracic echocardiography (TTE) and 12-lead electrocardiography (ECG) would be helpful in predicting AF-AFl in these patients. METHODS AND RESULTS: ECGs and TTEs of 90 patients diagnosed with definite or borderline ARVD (2010 Task Force Criteria) were analyzed. Data were compared in (1) patients with AF-AFl and (2) all other patients. A total of 18 (20%) patients experienced AF-AFl during a median follow-up of 5.8 years (interquartile range 2.0-10.4). Kaplan-Meier analysis revealed reduced times to AF-AFl among patients with echocardiographic RV fractional area change <27% (P<0.001), left atrial diameter ≥24.4 mm/m(2)(parasternal long-axis, P=0.001), and right atrial short-axis diameter ≥22.1 mm/m(2)(apical 4-chamber view, P=0.05). From all ECG variables, P mitrale conferred the highest hazard ratio (3.37, 95% confidence interval 0.92-12.36, P=0.067). Five patients with AF-AFl experienced inappropriate implantable cardioverter-defibrillator (ICD) shocks compared with 4 without AF-AFl (36% vs. 9%, P=0.03). AF-AFl was more prevalent in heart-transplant patients and those who died of cardiac causes (56% vs. 16%, P=0.014). CONCLUSIONS: AF-AFl is associated with inappropriate ICD shocks, heart transplantation, and cardiac death in patients with ARVD. Evidence of reduced RV function and atrial dilation helps to identify the ARVD patients at increased risk for AF-AFl.

Usefulness of electrocardiographic parameters for risk prediction in arrhythmogenic right ventricular dysplasia

The value of electrocardiographic findings predicting adverse outcome in patients with arrhythmogenic right ventricular dysplasia (ARVD) is not well known. We hypothesized that ventricular depolarization and repolarization abnormalities on the 12-lead surface electrocardiogram (ECG) predict adverse outcome in patients with ARVD. ECGs of 111 patients screened for the 2010 ARVD Task Force Criteria from 3 Swiss tertiary care centers were digitized and analyzed with a digital caliper by 2 independent observers blinded to the outcome. ECGs were compared in 2 patient groups: (1) patients with major adverse cardiovascular events (MACE: a composite of cardiac death, heart transplantation, survived sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia, or arrhythmic syncope) and (2) all remaining patients. A total of 51 patients (46%) experienced MACE during a follow-up period with median of 4.6 years (interquartile range 1.8 to 10.0). Kaplan-Meier analysis revealed reduced times to MACE for patients with repolarization abnormalities according to Task Force Criteria (p = 0.009), a precordial QRS amplitude ratio (∑QRS mV V1 to V3/∑QRS mV V1 to V6) of ≤ 0.48 (p = 0.019), and QRS fragmentation (p = 0.045). In multivariable Cox regression, a precordial QRS amplitude ratio of ≤ 0.48 (hazard ratio [HR] 2.92, 95% confidence interval [CI] 1.39 to 6.15, p = 0.005), inferior leads T-wave inversions (HR 2.44, 95% CI 1.15 to 5.18, p = 0.020), and QRS fragmentation (HR 2.65, 95% CI 1.1 to 6.34, p = 0.029) remained as independent predictors of MACE. In conclusion, in this multicenter, observational, long-term study, electrocardiographic findings were useful for risk stratification in patients with ARVD, with repolarization criteria, inferior leads TWI, a precordial QRS amplitude ratio of ≤ 0.48, and QRS fragmentation constituting valuable variables to predict adverse outcome.

Transdiaphragmatic Resuscitative Open Cardiac Massage: Description of the Technique and a First Case-Series of an Alternative Approach to the Heart

Abstract BACKGROUND: The purpose of this paper is to describe the transdiaphragmatic approach to the heart for open CPR in patients that arrest at laparotomy and to present a first case series of patients that have undergone this procedure. METHODS: All patients who had undergone intraperitoneal transdiaphragmatic open CPR between January 1, 2002 and December 31, 2012 were retrieved from the operation registry at Bern University Hospital, Switzerland. Transdiaphragmatic access to the heart is initiated with a 10-cm-long anterocaudal incision in the central tendon of the diaphragm--approximately at 2 o'clock. Internal cardiac compression through the diaphragmatic incision can be performed from both sides of the patient. From the right side of the patient, cardiac massage is performed with the right hand and vice versa. RESULTS: A total of six patients were identified that suffered cardiac arrest during laparotomy with open CPR performed through the transdiaphragmatic approach. Four patients suffered cardiac arrest during orthotopic liver transplantation and two trauma patients suffered cardiac arrest during damage control laparotomy. In three patients, cardiac activity was never reestablished. However, three patients regained a perfusion heart rhythm and two of these survived to the ICU. One patient ultimately survived to discharge. CONCLUSIONS: In patients suffering cardiac arrest during laparotomy, the transdiaphragmatic approach allows for a rapid, technically easy, and almost atraumatic access to the heart, with excellent CPR performance. After this potentially life-saving procedure, pulmonary or surgical site complications are expected to occur much less compared with the conventionally performed emergency department left-sided thoracotomy.

Investigation of hemodynamics in an in vitro system simulating left ventricular support through the right subclavian artery using 4-dimensional flow magnetic resonance imaging.

OBJECTIVES Left ventricular assist devices are an important treatment option for patients with heart failure alter the hemodynamics in the heart and great vessels. Because in vivo magnetic resonance studies of patients with ventricular assist devices are not possible, in vitro models represent an important tool to investigate flow alterations caused by these systems. By using an in vitro magnetic resonance-compatible model that mimics physiologic conditions as close as possible, this work investigated the flow characteristics using 4-dimensional flow-sensitive magnetic resonance imaging of a left ventricular assist device with outflow via the right subclavian artery as commonly used in cardiothoracic surgery in the recent past. METHODS An in vitro model was developed consisting of an aorta with its supra-aortic branches connected to a left ventricular assist device simulating the pulsatile flow of the native failing heart. A second left ventricular assist device supplied the aorta with continuous flow via the right subclavian artery. Four-dimensional flow-sensitive magnetic resonance imaging was performed for different flow rates of the left ventricular assist device simulating the native heart and the left ventricular assist device providing the continuous flow. Flow characteristics were qualitatively and quantitatively evaluated in the entire vessel system. RESULTS Flow characteristics inside the aorta and its upper branching vessels revealed that the right subclavian artery and the right carotid artery were solely supported by the continuous-flow left ventricular assist device for all flow rates. The flow rates in the brain-supplying arteries are only marginally affected by different operating conditions. The qualitative analysis revealed only minor effects on the flow characteristics, such as weakly pronounced vortex flow caused by the retrograde flow via the brachiocephalic artery. CONCLUSIONS The results indicate that, despite the massive alterations in natural hemodynamics due to the retrograde flow via the right subclavian and brachiocephalic arteries, there are no drastic consequences on the flow in the brain-feeding arteries and the flow characteristics in the ascending and descending aortas. It may be beneficial to adjust the operating condition of the left ventricular assist device to the residual function of the failing heart.

Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls.

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is mainly an autosomal dominant disease characterized by fibrofatty infiltration of the right ventricle, leading to ventricular arrhythmias. Mutations in desmosomal proteins can be identified in about half of the patients. The pathogenic mechanisms leading to disease expression remain unclear. OBJECTIVE The purpose of this study was to investigate myocardial expression profiles of candidate molecules involved in the pathogenesis of ARVC/D. METHODS Myocardial messenger RNA (mRNA) expression of 62 junctional molecules, 5 cardiac ion channel molecules, 8 structural molecules, 4 apoptotic molecules, and 6 adipogenic molecules was studied. The averaged expression of candidate mRNAs was compared between ARVC/D samples (n = 10), nonfamilial dilated cardiomyopathy (DCM) samples (n = 10), and healthy control samples (n = 8). Immunohistochemistry and quantitative protein expression analysis were performed. Genetic analysis using next generation sequencing was performed in all patients with ARVC/D. RESULTS Following mRNA levels were significantly increased in patients with ARVC/D compared to those with DCM and healthy controls: phospholamban (P ≤ .001 vs DCM; P ≤ .001 vs controls), healthy tumor protein 53 apoptosis effector (P = .001 vs DCM; P ≤ .001 vs controls), and carnitine palmitoyltransferase 1β (P ≤ .001 vs DCM; P = 0.008 vs controls). Plakophillin-2 (PKP-2) mRNA was downregulated in patients with ARVC/D with PKP-2 mutations compared with patients with ARVC/D without PKP-2 mutations (P = .04). Immunohistochemistry revealed significantly increased protein expression of phospholamban, tumor protein 53 apoptosis effector, and carnitine palmitoyltransferase 1β in patients with ARVC/D and decreased PKP-2 expression in patients with ARVC/D carrying a PKP-2 mutation. CONCLUSION Changes in the expression profiles of sarcolemmal calcium channel regulation, apoptosis, and adipogenesis suggest that these molecular pathways may play a critical role in the pathogenesis of ARVC/D, independent of the underlying genetic mutations.

Postmortem magnetic resonance imaging: Reproducing typical autopsy heart measurements

PURPOSE The aim of this study was to evaluate the utility of cardiac postmortem magnetic resonance (PMMR) to perform routine measurements of the ventricular wall thicknesses and the heart valves and to assess if imaging measurements are consistent with traditional autopsy measurements. METHODS In this retrospective study, 25 cases with cardiac PMMR and subsequent autopsy were included. The thicknesses of the myocardial walls as well as the circumferences of all heart valves were measured on cardiac PMMR and compared to autopsy measurements. Paired samples T-test and the Wilcoxon-Signed rank test, were used to compare autopsy and cardiac PMMR measurements. For exploring correlations, the Pearson's Correlation coefficient and the Spearman's Rho test were used. RESULTS Cardiac PMMR measurements of the aortic and pulmonary valve circumferences showed no significant differences from autopsy measurements. The mitral and tricuspid valves circumferences differed significantly from autopsy measurements. Left myocardial and right myocardial wall thickness also differed significantly from autopsy measurements. Left and right myocardial wall thickness, and tricuspid valve circumference measurements on cardiac PMMR and autopsy, correlated strongly and significantly. CONCLUSION Several PMMR measurements of cardiac parameters differ significantly from corresponding autopsy measurements. However, there is a strong correlation between cardiac PMMR measurements and autopsy measurements in the majority of these parameters. It is important to note that myocardial walls are thicker when measured in situ on cardiac PMMR than when measured at autopsy. Investigators using post-mortem MR should be aware of these differences in order to avoid false diagnoses of cardiac pathology based on cardiac PMMR.

Thrombolytic therapy for acute myocardial infarction: A cohort study to evaluate a selective approach to invasive diagnosis and therapy. The Corpus Christi Heart Project

Coronary perfusion with thrombolytic therapy and selective reperfusion by percutaneous transluminal coronary angioplasty (PTCA) were examined in the Corpus Christi Heart Project, a population-based surveillance program for hospitalized acute myocardial infarction (MI) patients in a biethnic community of Mexican-Americans (MAs) and non-Hispanic whites (NHWs). Results were based on 250 (12.4%) patients who received thromobolytic therapy in a cohort of 2011 acute MI cases. Out of these 107 (42.8%) underwent PTCA with a mean follow-up of 25 months. There were 186 (74.4%) men and 64 (25.6%) women; 148 (59.2%) were NHWs, 86 (34.4%) were MAs. Thrombolysis and PTCA were performed less frequently in women than in men, and less frequently in MAs than in NHWs.^ According to the coronary reperfusion interventions used, patients were divided in two groups, those that received no-PTCA (57.2%) and the other that underwent PTCA (42.8%) after thrombolysis. The case-fatality rate was higher in no-PTCA patients than in the PTCA (7.7% versus 5.6%), as was mortality at one year (16.2% versus 10.5%). Reperfusion was successful in 48.0% in the entire cohort and (51.4% versus 45.6%) in the PTCA and no-PTCA groups. Mortality in the successful reperfusion patients was 5.0% compared to 22.3% in the unsuccessful reperfusion group (p = 0.00016, 95% CI: 1.98-11.6).^ Cardiac catheterization was performed in 86.4% thrombolytic patients. Severe stenosis ($>$75%) obstruction was present most commonly in the left descending artery (52.8%) and in the right coronary artery (52.8%). The occurrence of adverse in-hospital clinical events was higher in the no-PTCA as compared to the PTCA and catheterized patients with the exception of reperfusion arrythmias (p = 0.140; Fisher's exact test p = 0.129).^ Cox regression analysis was used to study the relationship between selected variables and mortality. Apart from successful reperfusion, age group (p = 0.028, 95% CI: 2.1-12.42), site of acute MI index (p = 0.050) and ejection-fraction (p = 0.052) were predictors of long-term survival. The ejection-fraction in the PTCA group was higher than (median 78% versus 53%) in the no-PTCA group. Assessed by logistic regression analysis history of high cholesterol ($>$200mg/dl) and diabetes mellites did have significant prognostic value (p = 0.0233; p = 0.0318) in long-term survival irrespective of treatment status.^ In conclusion, the results of this study support the idea that the use of PTCA as a selective intervention following thrombolysis improves survival of patients with acute MI. The use of PTCA in this setting appears to be safe. However, we can not exclude the possibility that some of these results may have occurred due to the exclusion from PTCA of high risk patients (selection bias). ^

Genetic analysis of Pitx2 in left -right asymmetry and cardiovascular development

Pitx2, a paired-related homeobox gene that is mutated in human Rieger Syndrome, plays a key role in transferring the early asymmetric signals to individual organs. Pitx2 encodes three isoforms, Pitx2a, Pitx2b and Pitx2c. I found that Pitx2c was the Pitx2 isoform for regulating left-right asymmetry in heart, lung and the predominant isoform in guts. Previous studies suggested that the generation of left-right asymmetry within individual organs is an all or none, random event. Phenotypic analysis of various Pitx2 allelic combinations, that encode graded levels of Pitx2c, reveals an organ-intrinsic mechanism for regulating left-right asymmetric morphogenesis based on differential response to Pitx2c levels. The heart needs low Pitx2c levels, while the lungs and duodenum require higher doses of Pitx2c. In addition, the duodenal rotation is under strict control of Pitx2c activity. Left-right asymmetry development for aortic arch arteries involves complex vascular remodeling. Left-sided expression of Pitx2c in these developing vessels implied its potential function in this process. In order to determine if Pitx2c also can regulate the left-right asymmetry of the aortic arch arteries, a Pitx2c-specific loss of function mutation is generated. Although in wild type mice, the direction of the aortic arch is always oriented toward the left side, the directions of the aortic arches in the mutants were randomized, showing that Pitx2c also determined the left-right asymmetry of these vessels. I have further showed that the cardiac neural crest wasn't involved in this vascular remodeling process. In addition, all mutant embryos had Double Outlet Right Ventricle (DORV), a common congenital heart disease. This study provided insight into the mechanism of Pitx2c-mediated late stages of left-right asymmetry development and identified the roles of Pitx2c in regulation of aortic arch remodeling and heart development. ^

Rat heart: A site of oxytocin production and action

We report here that the rat heart is a site of oxytocin (OT) synthesis and release. Oxytocin was detected in all four chambers of the heart. The highest OT concentration was in the right atrium (2128 ± 114 pg/mg protein), which was 19-fold higher than in rat uterus but 3.3-fold lower than in the hypothalamus. OT concentrations were significantly greater in the right and left atria than in the corresponding ventricles. Furthermore, OT was released into the effluent of isolated, perfused rat heart (34.5 ± 4.7 pg/min) and into the medium of cultured atrial myocytes. Reverse-phase HPLC purification of the heart extracts and heart perfusates revealed a main peak identical with the retention time of synthetic OT. Southern blots of reverse transcription–PCR products from rat heart revealed gene expression of specific OT mRNA. OT immunostaining likewise was found in atrial myocytes and fibroblasts, and the intensity of positive stains from OT receptors paralleled the atrial natriuretic peptide stores. Our findings suggest that heart OT is structurally identical, and therefore derived from, the same gene as the OT that is primarily found in the hypothalamus. Thus, the heart synthesizes and processes a biologically active form of OT. The presence of OT and OT receptor in all of the heart’s chambers suggests an autocrine and/or paracrine role for the peptide. Our finding of abundant OT receptor in atrial myocytes supports our hypothesis that OT, directly and/or via atrial natriuretic peptide release, can regulate the force of cardiac contraction.

Nonmuscle myosin II-B is required for normal development of the mouse heart

We used targeted gene disruption in mice to ablate nonmuscle myosin heavy chain B (NMHC-B), one of the two isoforms of nonmuscle myosin II present in all vertebrate cells. Approximately 65% of the NMHC-B−/− embryos died prior to birth, and those that were born suffered from congestive heart failure and died during the first day. No abnormalities were detected in NMHC-B+/− mice. The absence of NMHC-B resulted in a significant increase in the transverse diameters of the cardiac myocytes from 7.8 ± 1.8 μm (right ventricle) and 7.8 ± 1.3 μm (left ventricle) in NMHC-B+/+ and B+/− mice to 14.7 ± 1.1 μm and 13.8 ± 2.3 μm, respectively, in NMHC-B−/− mice (in both cases, P < 0.001). The increase in size of the cardiac myocytes was seen as early as embryonic day 12.5 (4.5 ± 0.2 μm for NMHC-B+/+ and B+/− vs. 7.2 ± 0.6 μm for NMHC-B−/− mice (P < 0.01)). Six of seven NMHC-B−/− newborn mice analyzed by serial sectioning also showed structural cardiac defects, including a ventricular septal defect, an aortic root that either straddled the defect or originated from the right ventricle, and muscular obstruction to right ventricular outflow. Some of the hearts of NMHC-B−/− mice showed evidence for up-regulation of NMHC-A protein. These studies suggest that nonmuscle myosin II-B is required for normal cardiac myocyte development and that its absence results in structural defects resembling, in part, two common human congenital heart diseases, tetralogy of Fallot and double outlet right ventricle.

The First Century of Right to Arms Litigation

This Article examines state court cases involving the right to arms, during the first century following ratification of the Amendment in 1791. This is not the first article to survey some of those cases. This Article includes additional cases, and details the procedural postures and facts, not only the holdings. The Article closely examines how the Supreme Court integrated the nineteenth century arms cases into Heller and McDonald to shape modern Second Amendment law. Part I briefly explains two English cases which greatly influenced American legal understandings. Semayne’s Case is the foundation of “castle doctrine” — the right to home security which includes the right of armed self-defense in the home. Sir John Knight’s Case fortified the tradition of the right to bear arms, providing that the person must bear arms in a non-terrifying manner. Part II examines American antebellum cases; these are the cases to which Heller looked for guidance on the meaning of the Second Amendment. Part III looks at cases from Reconstruction and the early years of Jim Crow, through 1891. As with the antebellum cases, the large majority of post-war cases are from the Southeast, which during the nineteenth century was the region most ardent for gun control. The heart of gun control country was Tennessee and Arkansas; courts there resisted some infringements of the right to arms, but eventually gave up. Heller and McDonald did not look to the Jim Crow cases as constructive precedents on the Second Amendment.

Investigation of signaling pathways that mediate the inotropic effect of urotensin-II in human heart

Objective: This study investigated signaling pathways that may contribute to the potent positive inotropic effect of human urotensin-II (hU-II) in human isolated right atrial trabeculae obtained from patients with coronary artery disease. Methods: Trabeculae were set up in tissue baths and stimulated to contract at 1 Hz. Tissues were incubated with 20 nM hU-II with or without phorbol 12-myristate 13-acetate (PMA, 10 muM) to desensitize PKC, the PKC inhibitor chelerythrine (10 muM), 10 muM 4alpha-phorbol that does not desensitize PKC, the myosin light chain kinase inhibitor wortmannin (50 nM, 10 muM), or the Rho kinase inhibitor Y-27632 (0.1 - 10 muM). Activated RhoA was determined by affinity immunoprecipitation, and phosphorylation of signaling proteins was determined by SDS-PAGE. Results: hU-II caused a potent positive inotropic response in atrial trabeculae, and this was concomitant with increased phosphorylation of regulatory myosin light chain (MLC-2, 1.8 +/- 0.4-fold, P < 0.05, n = 6) and PKCalpha/betaII (1.4 +/- 0.2-fold compared to non-stimulated controls, P < 0.05, n = 7). Pretreatment of tissues with PMA caused a marked reduction in the inotropic effect of hU-II, but did not affect hU-II-mediated phosphorylation of MLC-2. The inotropic response was inhibited by chelerythrine, but not 4alpha-phorbol or wortmannin. Although Y-27632 also reduced the positive inotropic response to hU-II, this was associated with a marked reduction in basal force of contraction. RhoA. GTP was immunoprecipitated in tissues pretreated with or without hU-II, with findings showing no detectable activation of RhoA in the agonist stimulated tissues. Conclusions: The findings indicated that hU-II increased force of contraction in human heart via a PKC-dependent mechanism and increased phosphorylation of MLC-2, although this was independent of PKC. The positive inotropic effect was independent of myosin light chain kinase and RhoA-Rho kinase signaling pathways. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Functional serotonin 5-HT4 receptors in porcine and human ventricular myocardium with increased 5-HT4 mRNA in heart failure

Serotonin (5-hydroxytryptamine, 5-HT) increases contractile force and elicits arrhythmias through 5-HT4 receptors in porcine and human atrium, but its ventricular effects are unknown. We now report functional 5-HT4 receptors in porcine and human ventricle. 5-HT4 mRNA levels were determined in porcine and human ventricles and contractility studied in ventricular trabeculae. Cyclic AMP-dependent protein kinase (PKA) activity was measured in porcine ventricle. Porcine and human ventricles expressed 5-HT4 receptor mRNA. Ventricular 5-HT4(b) mRNA was increased by four times in 20 failing human hearts compared with five donor hearts. 5-HT increased contractile force maximally by 16% (EC50=890 nM) and PKA activity by 20% of the effects of (-)-isoproterenol (200 muM) in ventricular trabeculae from new-born piglets in the presence of the phosphodiesterase-inhibitor 3-isobutyl-1-methylxanthine. In ventricular trabeculae from adult pigs (3-isobutyl-1-methylxanthine present) 5-HT increased force by 32% (EC50=60 nM) and PKA activity by 39% of (-)-iso-proterenol. In right and left ventricular trabeculae from failing hearts, exposed to modified Krebs solution, 5-HT produced variable increases in contractile force in right ventricular trabeculae from 4 out of 6 hearts and in left ventricular trabeculae from 3 out of 3 hearts- range 1-39% of (-)-isoproterenol, average 8%. In 11 left ventricular trabeculae from the failing hearts of four beta-blocker-treated patients, pre-exposed to a relaxant solution with 0.5 mM Ca2+ and 1.2 mM Mg2+ followed by a switch to 2.5 mM Ca2+ and 1 mM Mg2+, 5-HT (1-100 muM, 3-isobutyl-1-melhylxanthine present) consistently increased contractile force and hastened relaxation by 46% and 25% of (-)-isoproterenol respectively. 5-HT caused arrhythmias in three trabeculae from 3 out of I I patients. In the absence of phosphodiesterase inhibitor, 5-HT increased force in two trabeculae, but not in another six trabeculae from 4 patients. All 5-HT responses were blocked by 5-HT4 receptor antagonists. We conclude that phosphodiesterase inhibition uncovers functional ventricular 5-HT4 receptors, coupled to a PKA pathway, through which 5-HT enhances contractility, hastens relaxation and can potentially cause arrhythmias.

Fetal echocardiography: are we getting it right?

Objective To determine the diagnostic accuracy of prenatal fetal echocardiography. Methods The study was a retrospective chart review of 190 consecutive patients over a 3-year period from November 1998 to February 2002 of all women referred to the Maternal Fetal Medicine unit, Mater Mothers Hospital, for fetal echocardiography. The prenatal diagnosis was compared with the postnatal diagnosis made by postnatal echocardiography, surgical findings or post-mortem. The accuracy of prenatal diagnosis was described on a predetermined 4-point scale. Results Of the 89 patients, for whom complete diagnostic follow-up was available, there was complete agreement between the prenatal and postnatal diagnosis in 63 cases, minor discrepancies in 25 cases and major disagreement in 1 case. Conclusions In experienced hands, fetal echocardiography is accurate and allows medical staff and patients information in order manage a pregnancy appropriately. Copyright (C) 2004 John Wiley Sons, Ltd.