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.

Activation of common signaling pathways during remodeling of the heart and the bladder

The heart and the urinary bladder are hollow muscular organs, which can be afflicted by pressure overload injury due to pathological conditions such as hypertension and bladder outlet obstruction. This increased outflow resistance induces hypertrophy, marked by dramatic changes in the organs' phenotype and function. The end result in both the heart and the bladder can be acute organ failure due to advanced fibrosis and the subsequent loss of contractility. There is emerging evidence that microRNAs (miRNAs) play an important role in the pathogenesis of heart failure and bladder dysfunction. MiRNAs are endogenous non-coding single-stranded RNAs, which regulate gene expression and control adaptive and maladaptive organ remodeling processes. This Review summarizes the current knowledge of molecular alterations in the heart and the bladder and highlights common signaling pathways and regulatory events. The miRNA expression analysis and experimental target validation done in the heart provide a valuable source of information for investigators working on the bladder and other organs undergoing the process of fibrotic remodeling. Aberrantly expressed miRNA are amendable to pharmacological manipulation, offering an opportunity for development of new therapies for cardiac and bladder hypertrophy and failure.

Right ventricular dysfunction in children and adolescents conceived by assisted reproductive technologies.

Assisted reproductive technologies (ART) predispose the offspring to vascular dysfunction, arterial hypertension, and hypoxic pulmonary hypertension. Recently, cardiac remodeling and dysfunction during fetal and early postnatal life have been reported in offspring of ART, but it is not known whether these cardiac alterations persist later in life and whether confounding factors contribute to this problem. We, therefore, assessed cardiac function and pulmonary artery pressure by echocardiography in 54 healthy children conceived by ART (mean age 11.5 ± 2.4 yr) and 54 age-matched (12.2 ± 2.3 yr) and sex-matched control children. Because ART is often associated with low birth weight and prematurity, two potential confounders associated with cardiac dysfunction, only singletons born with normal birth weight at term were studied. Moreover, because cardiac remodeling in infants conceived by ART was observed in utero, a situation associated with increased right heart load, we also assessed cardiac function during high-altitude exposure, a condition associated with hypoxic pulmonary hypertension-induced right ventricular overload. We found that, while at low altitude cardiac morphometry and function was not different between children conceived by ART and control children, under the stressful conditions of high-altitude-induced pressure overload and hypoxia, larger right ventricular end-diastolic area and diastolic dysfunction (evidenced by lower E-wave tissue Doppler velocity and A-wave tissue Doppler velocity of the lateral tricuspid annulus) were detectable in children and adolescents conceived by ART. In conclusion, right ventricular dysfunction persists in children and adolescents conceived by ART. These cardiac alterations appear to be related to ART per se rather than to low birth weight or prematurity.

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.

Motion-insensitive determination of B1+ amplitudes based on the bloch-siegert shift in single voxels of moving organs including the human heart.

PURPOSE To reliably determine the amplitude of the transmit radiofrequency ( B1+) field in moving organs like the liver and heart, where most current techniques are usually not feasible. METHODS B1+ field measurement based on the Bloch-Siegert shift induced by a pair of Fermi pulses in a double-triggered modified Point RESolved Spectroscopy (PRESS) sequence with motion-compensated crusher gradients has been developed. Performance of the sequence was tested in moving phantoms and in muscle, liver, and heart of six healthy volunteers each, using different arrangements of transmit/receive coils. RESULTS B1+ determination in a moving phantom was almost independent of type and amplitude of the motion and agreed well with theory. In vivo, repeated measurements led to very small coefficients of variance (CV) if the amplitude of the Fermi pulse was chosen above an appropriate level (CV in muscle 0.6%, liver 1.6%, heart 2.3% with moderate amplitude of the Fermi pulses and 1.2% with stronger Fermi pulses). CONCLUSION The proposed sequence shows a very robust determination of B1+ in a single voxel even under challenging conditions (transmission with a surface coil or measurements in the heart without breath-hold). Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

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). ^

In vitro evolution of horse heart myoglobin to increase peroxidase activity

Random mutagenesis and screening for enzymatic activity has been used to engineer horse heart myoglobin to enhance its intrinsic peroxidase activity. A chemically synthesized gene encoding horse heart myoglobin was subjected to successive cycles of PCR random mutagenesis. The mutated myoglobin gene was expressed in Escherichia coli LE392, and the variants were screened for peroxidase activity with a plate assay. Four cycles of mutagenesis and screening produced a series of single, double, triple, and quadruple variants with enhanced peroxidase activity. Steady-state kinetics analysis demonstrated that the quadruple variant T39I/K45D/F46L/I107F exhibits peroxidase activity significantly greater than that of the wild-type protein with k1 (for H2O2 oxidation of metmyoglobin) of 1.34 × 104 M−1 s−1 (≈25-fold that of wild-type myoglobin) and k3 [for reducing the substrate (2, 2′-azino-di-(3-ethyl)benzthiazoline-6-sulfonic acid] of 1.4 × 106 M−1 s−1 (1.6-fold that of wild-type myoglobin). Thermal stability of these variants as measured with circular dichroism spectroscopy demonstrated that the Tm of the quadruple variant is decreased only slightly compared with wild-type (74.1°C vs. 76.5°C). The rate constants for binding of dioxygen exhibited by the quadruple variant are identical to the those observed for wild-type myoglobin (kon, 22.2 × 10−6 M−1 s−1 vs. 22.3 × 10−6 M−1 s−1; koff, 24.3 s−1 vs. 24.2 s−1; KO2, 0.91 × 10−6 M−1 vs. 0.92 × 10−6 M−1). The affinity of the quadruple variant for CO is increased slightly (kon, 0.90 × 10−6 M−1s−1 vs. 0.51 × 10−6 M−1s−1; koff, 5.08 s−1 vs. 3.51 s−1; KCO, 1.77 × 10−7 M−1 vs. 1.45 × 10−7 M−1). All four substitutions are in the heme pocket and within 5 Å of the heme group.

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.

Corticotropin-releasing hormone causes antidiuresis and antinatriuresis by stimulating vasopressin and inhibiting atrial natriuretic peptide release in male rats

In both normally hydrated and volume-expanded rats, there was a biphasic effect of corticotropin-releasing hormone (CRH) (1–10 μg, i.v.) on renal function. Within the first hour, CRH caused antidiuresis, antinatriuresis, and antikaliuresis together with reduction in urinary cGMP output that, in the fourth hour, were replaced by diuresis, natriuresis, and kaliuresis accompanied by increased cGMP output. Plasma arginine vasopressin (AVP) concentrations increased significantly within 5 min, reached a peak at 15 min, and declined by 30 min to still-elevated values maintained for 180 min. Changes in plasma atrial natriuretic peptide (ANP) were the mirror image of those of AVP. Plasma ANP levels were correlated with decreased ANP in the left ventricle at 30 min and increased ANP mRNA in the right atrium at 180 min. All urinary changes were reversed by a potent AVP type 2 receptor (V2R) antagonist. Control 0.9% NaCl injections evoked an immediate increase in blood pressure and heart rate measured by telemetry within 3–5 min. This elevation of blood pressure was markedly inhibited by CRH (5 μg). We hypothesize that the effects are mediated by rapid, direct vasodilation induced by CRH that decreases baroreceptor input to the brain stem, leading to a rapid release of AVP that induces the antidiuresis by direct action on the V2Rs in the kidney. Simultaneously, acting on V2Rs in the heart, AVP inhibits ANP release and synthesis, resulting in a decrease in renal cGMP output that is responsible for the antinatriuretic and antikaliuretic effects.

Cystic fibrosis gene encodes a cAMP-dependent chloride channel in heart.

cAMP-dependent chloride channels in heart contribute to autonomic regulation of action potential duration and membrane potential and have been inferred to be due to cardiac expression of the epithelial cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. In this report, a cDNA from rabbit ventricle was isolated and sequenced, which encodes an exon 5 splice variant (exon 5-) of CFTR, with >90% identity to human CFTR cDNA present in epithelial cells. Expression of this cDNA in Xenopus oocytes gave rise to robust cAMP-activated chloride currents that were absent in control water-injected oocytes. Antisense oligodeoxynucleotides directed against CFTR significantly reduced the density of cAMP-dependent chloride currents in acutely cultured myocytes, thereby establishing a direct functional link between cardiac expression of CFTR protein and an endogenous chloride channel in native cardiac myocytes.

Characterization of a voltage-gated K+ channel beta subunit expressed in human heart.

Voltage-gated K+ channels are important modulators of the cardiac action potential. However, the correlation of endogenous myocyte currents with K+ channels cloned from human heart is complicated by the possibility that heterotetrameric alpha-subunit combinations and function-altering beta subunits exist in native tissue. Therefore, a variety of subunit interactions may generate cardiac K+ channel diversity. We report here the cloning of a voltage-gated K+ channel beta subunit, hKv beta 3, from adult human left ventricle that shows 84% and 74% amino acid sequence identity with the previously cloned rat Kv beta 1 and Kv beta 2 subunits, respectively. Together these three Kv beta subunits share > 82% identity in the carboxyl-terminal 329 aa and show low identity in the amino-terminal 79 aa. RNA analysis indicated that hKv beta 3 message is 2-fold more abundant in human ventricle than in atrium and is expressed in both healthy and diseased human hearts. Coinjection of hKv beta 3 with a human cardiac delayed rectifier, hKv1.5, in Xenopus oocytes increased inactivation, induced an 18-mV hyperpolarizing shift in the activation curve, and slowed deactivation (tau = 8.0 msec vs. 35.4 msec at -50 mV). hKv beta 3 was localized to human chromosome 3 by using a human/rodent cell hybrid mapping panel. These data confirm the presence of functionally important K+ channel beta subunits in human heart and indicate that beta-subunit composition must be accounted for when comparing cloned channels with endogenous cardiac currents.

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.

Double Reasonableness and the Fourth Amendment

Recently the Supreme Court has placed new limits on both the substance of the Fourth Amendment and the exclusionary that serves as the principal remedy for Fourth Amendment violations. In this Article we briefly summarize these limitations and then argue that the curtailment of the exclusionary rule has the potential to ameliorate substantive Fourth Amendment doctrine. The limited reach of the modern exclusionary rule provides the Court with license to develop an expansive new substantive framework free of the specter of a correspondingly expansive remedial framework. One point on which nearly all jurists and commentators agree is that current Fourth Amendment doctrine is a mess. We argue that the Court’s exclusionary rule cases, while frustrating and ill-conceived if viewed in isolation, provide the Court with an opportunity to revisit problematic Fourth Amendment doctrine that was born under a very different remedial regime. Such an approach would allow the Court to adhere to its current view of the exclusionary rule as a remedy of last resort while creating a Fourth Amendment with teeth. The goal is a Fourth Amendment right that is more substantial and clearly defined, but a remedy that remains limited to egregious violations of clear substantive rules. The time is now to lift the Fourth Amendment fog.