Improved Multiscale Entropy Technique with Nearest-Neighbor Moving-Average Kernel for Nonlinear and Nonstationary Short-Time Biomedical Signal Analysis.

Analysis of biomedical signals can yield invaluable information for prognosis, diagnosis, therapy evaluation, risk assessment, and disease prevention which is often recorded as short time series data that challenges existing complexity classification algorithms such as Shannon entropy (SE) and other techniques. The purpose of this study was to improve previously developed multiscale entropy (MSE) technique by incorporating nearest-neighbor moving-average kernel, which can be used for analysis of nonlinear and non-stationary short time series physiological data. The approach was tested for robustness with respect to noise analysis using simulated sinusoidal and ECG waveforms. Feasibility of MSE to discriminate between normal sinus rhythm (NSR) and atrial fibrillation (AF) was tested on a single-lead ECG. In addition, the MSE algorithm was applied to identify pivot points of rotors that were induced in ex vivo isolated rabbit hearts. The improved MSE technique robustly estimated the complexity of the signal compared to that of SE with various noises, discriminated NSR and AF on single-lead ECG, and precisely identified the pivot points of ex vivo rotors by providing better contrast between the rotor core and the peripheral region. The improved MSE technique can provide efficient complexity analysis of variety of nonlinear and nonstationary short-time biomedical signals.

Novel approaches for quantitative electrogram analysis for intraprocedural guidance for catheter ablation: A case of a patient with persistent atrial fibrillation.

PURPOSE: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia that causes stroke affecting more than 2.3 million people in the US and is increasing in prevalence due to ageing population causing a new global epidemic. Catheter ablation with pulmonary vein isolation (PVI) to terminate AF is successful for paroxysmal AF but suffers limitations with persistent AF patients as current mapping methods cannot identify AF active substrates outside of PVI region. Recent evidences in the mechanistic understating of AF pathophysiology suggest that ectopic activity, localized re-entrant circuit with fibrillatory propagation and multiple circuit re-entries may all be involved in human AF. The authors developed novel electrogram analysis methods and validated using optical mapping data from isolated rabbit hearts to accurately identify rotor pivot points. The purpose of this study was to assess the feasibility of generating patient-specific 3D maps for intraprocedural guidance for catheter ablation using intracardiac electrograms from a persistent AF patient using novel electrogram analysis methods. METHODS: A persistent AF patient with clinical appointment for AF ablation was recruited for this study with IRB approval. 1055 electrograms throughout the left and right atrium were obtained for offline analysis with the novel approaches such as multiscale entropy, multiscale frequency, recurrence period density entropy, kurtosis and empirical mode decomposition to generate patient specific 3D maps. 3D Shannon Entropy, Renyi Entropy and Dominant frequency maps were also generated for comparison purposes along with local activation time and complex fractionated electrogram analysis maps. RESULTS: Patient specific 3D maps were obtained for each of the different approach. The 3D maps indicate potential active sites outside the PVI region. However, presence of rotors cannot be confirmed and validation of these approaches is required on a larger dataset. CONCLUSIONS: Conventional catheter mapping system can be used for generating patient specific 3D maps with short time series analysis using the novel approaches.

Direct interaction between NHERF1 and Frizzled regulates ß-catenin signaling.

Although Wnt-Frizzled (Fzd) signaling is critical in the pathophysiology of carcinomas, its role in human breast cancer has been difficult to establish. We show here that the adaptor protein Na(+)/H(+) exchange regulatory factor1 (NHERF1), a protein abundantly expressed in normal mammary epithelium, regulates Wnt signaling, maintaining low levels of ß-catenin activation. NHERF1's effects are mediated by direct interactions between one of its PSD-95/drosophila discs large/ZO-1 (PDZ) domains and the C-terminus of a subset of Fzd receptors. Loss of NHERF1 in breast cancer cell lines enhances canonical Wnt signaling and Wnt-dependent cell proliferation. Furthermore, the mammary glands of NHERF1-knockout mice exhibit increased mammary duct density accompanied by increased proliferation and ß-catenin activity. Finally, we demonstrate a negative correlation between NHERF1 expression and nuclear ß-catenin in human breast carcinomas. Taken together, these results provide a novel insight into the regulation of Wnt signaling in normal and neoplastic breast tissues, and identify NHERF1 as an important regulator of the pathogenesis of breast tumors.

Intracardiac echocardiography.

This article describes currently available intracardiac ultrasound (ICE) technology contrasting it with intravascular ultrasound (IVUS) highlighting their differences. Clinical applications in the electrophysiologic and cardiac catheterization laboratory are discussed and current limitations addressed. Intracardiac echocardiography (ICE) is possible because lower frequency transducers (in contrast to higher frequency IVUS devices) have been miniaturized and mounted onto catheters capable of percutaneous insertion into the heart. These lower frequency transducers are capable of enhanced tissue penetration, permitting high-resolution 2D "whole heart" imaging. Also, with the introduction of the newest phased array transducer, Doppler hemodynamic data in addition to high resolution imaging can also be obtained. ICE facilitates electrophysiologic procedures by guiding transseptal catheterization, enabling endocardial anatomy visualization and targeting of arrhythmogenic substrate, ensuring optimal ablation electrode/tissue contact and promptly diagnosing procedural complications. Promising non-electrophysiologic applications include guidance of percutaneous closure of septal defects, percutaneous mitral balloon valvuloplasty and complex cardiac biopsy. Current limitations include monoplanar imaging, narrow field of view, and relatively large size of the catheter. Intra-cardiac imaging is now a clinical tool and has the potential to play an important role in diagnostic and therapeutic interventional procedures. Further refinement and miniaturization of these transducers, through continued technological progress, will make way for primary operator controlled, integrated ultrasound-guided interventional devices.

Parathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets.

The cloning of the so-called 'parathyroid hormone-related protein' (PTHrP) in 1987 was the result of a long quest for the factor which, by mimicking the actions of PTH in bone and kidney, is responsible for the hypercalcemic paraneoplastic syndrome, humoral calcemia of malignancy. PTHrP is distinct from PTH in a number of ways. First, PTHrP is the product of a separate gene. Second, with the exception of a short N-terminal region, the structure of PTHrP is not closely related to that of PTH. Third, in contrast to PTH, PTHrP is a paracrine factor expressed throughout the body. Finally, most of the functions of PTHrP have nothing in common with those of PTH. PTHrP is a poly-hormone which comprises a family of distinct peptide hormones arising from post-translational endoproteolytic cleavage of the initial PTHrP translation products. Mature N-terminal, mid-region and C-terminal secretory forms of PTHrP are thus generated, each of them having their own physiologic functions and probably their own receptors. The type 1 PTHrP receptor, binding both PTH(1-34) and PTHrP(1-36), is the only cloned receptor so far. PTHrP is a PTH-like calciotropic hormone, a myorelaxant, a growth factor and a developmental regulatory molecule. The present review reports recent aspects of PTHrP pharmacology and physiology, including: (a) the identification of new peptides and receptors of the PTH/PTHrP system; (b) the recently discovered nuclear functions of PTHrP and the role of PTHrP as an intracrine regulator of cell growth and cell death; (c) the physiological and developmental actions of PTHrP in the cardiovascular and the renal glomerulo-vascular systems; (d) the role of PTHrP as a regulator of pancreatic beta cell growth and functions, and, (e) the interactions of PTHrP and calcium-sensing receptors for the control of the growth of placental trophoblasts. These new advances have contributed to a better understanding of the pathophysiological role of PTHrP, and will help to identify its therapeutic potential in a number of diseases.

Atrial therapies reduce atrial arrhythmia burden in defibrillator patients.

BACKGROUND: Approximately 25% of patients who receive an implantable cardioverter-defibrillator (ICD) to treat ventricular tachyarrhythmias have documented atrial tachyarrhythmias before implantation. This study assessed the ability of device-based prevention and termination therapies to reduce the burden of spontaneous atrial tachyarrhythmias. METHODS AND RESULTS: Patients with a standard indication for the implantation of an ICD and 2 episodes of atrial tachyarrhythmias in the preceding year received a dual-chamber ICD (Medtronic 7250 Jewel AF) that uses pacing and shock therapies for prevention and/or termination of atrial tachyarrhythmias. In a multicenter trial, patients were randomized to 3-month periods with atrial therapies "on" or "off" and subsequently crossed over. Analysis was performed on the 52 of 269 patients who had episodes of atrial tachyarrhythmia and had >/=30 days of follow-up with atrial therapies on and off. The atrial therapies resulted in a reduction of atrial tachyarrhythmia burden from a mean of 58.5 to 7.8 h/mo. A paired analysis (Wilcoxon signed-rank test) showed that the median difference in burden (1.1 h/mo) was highly significant (P=0.007). When the subgroup of 41 patients treated only with atrial pacing therapies was analyzed, the reduction in burden persisted (P=0.01). CONCLUSIONS: In this study, patients with a standard ICD indication and atrial tachyarrhythmias had a significant reduction in atrial tachyarrhythmia burden with use of atrial pacing and shock therapies.

Intra-atrial conduction block along the mitral valve annulus during accessory pathway ablation: evidence for a left atrial "isthmus".

INTRODUCTION: We observed a change in the atrial activation sequence during radiofrequency (RF) energy application in patients undergoing left accessory pathway (AP) ablation. This occurred without damage to the AP and in the absence of a second AP or alternative arrhythmia mechanism. We hypothesized that block in a left atrial "isthmus" of tissue between the mitral annulus and a left inferior pulmonary vein was responsible for these findings. METHODS AND RESULTS: Electrophysiologic studies of 159 patients who underwent RF ablation of a left free-wall AP from 1995 to 1999 were reviewed. All studies with intra-atrial conduction block resulting from RF energy delivery were identified. Fluoroscopic catheter positions were reviewed. Intra-atrial conduction block was observed following RF delivery in 11 cases (6.9%). This was evidenced by a sudden change in retrograde left atrial activation sequence despite persistent and unaffected pathway conduction. In six patients, reversal of eccentric atrial excitation during orthodromic reciprocating tachycardia falsely suggested the presence of a second (septal) AP. A multipolar coronary sinus catheter in two patients directly demonstrated conduction block along the mitral annulus during tachycardia. CONCLUSION: An isthmus of conductive tissue is present in the low lateral left atrium of some individuals. Awareness of this structure may avoid misinterpretation of the electrogram during left AP ablation and may be useful in future therapies of atypical atrial flutter and fibrillation.

The implantable cardioverter defibrillator.

Implantable cardioverter defibrillators (ICDs) have evolved from the treatment of last resort to the gold standard therapy for patients at high risk for ventricular tachyarrhythmias. High-risk patients include those who have survived life-threatening arrhythmias, and individuals with cardiac diseases who are at risk for such arrhythmias, but are symptomless. Use of an ICD will affect the patient's quality of life. Some drugs can substantially affect defibrillator function and efficacy, and possible drug-device interactions should be considered. Patients with ICDs may encounter cell phones, antitheft detectors, and many other sources of potential electromagnetic Interference. In addition to treating ventricular tachyarrhythmias, new defibrillators provide full featured dual chamber pacing, and could treat atrial arrhythmias, and congestive heart failure by means of biventricular pacing.

Long-term survival after ablation of the atrioventricular node and implantation of a permanent pacemaker in patients with atrial fibrillation.

BACKGROUND: In patients with atrial fibrillation that is refractory to drug therapy, radio-frequency ablation of the atrioventricular node and implantation of a permanent pacemaker are an alternative therapeutic approach. The effect of this procedure on long-term survival is unknown. METHOD: We studied all patients who underwent ablation of the atrioventricular node and implantation of a permanent pacemaker at the Mayo Clinic between 1990 and 1998. Observed survival was compared with the survival rates in two control populations: age- and sex-matched members of the Minnesota population between 1970 and 1990 and consecutive patients with atrial fibrillation who received drug therapy in 1993. RESULTS: A total of 350 patients (mean [+/-SD] age, 68+/-11 years) were studied. During a mean of 36+/-26 months of follow-up, 78 patients died. The observed survival rate was significantly lower than the expected survival rate based on the general Minnesota population (P<0.001). Previous myocardial infarction (P<0.001), a history of congestive heart failure (P=0.02), and treatment with cardiac drugs after ablation (P=0.03) were independent predictors of death. Observed survival among patients without these three risk factors was similar to expected survival (P=0.43). None of the 26 patients with lone atrial fibrillation died during follow-up (37+/-27 months). The observed survival rate among patients who underwent ablation was similar to that among 229 controls with atrial fibrillation (mean age, 67+/-12 years) who received drug therapy (P=0.44). CONCLUSIONS: In the absence of underlying heart disease, survival among patients with atrial fibrillation after ablation of the atrioventricular node is similar to expected survival in the general population. Long-term survival is similar for patients with atrial fibrillation, whether they receive ablation or drug therapy. Control of the ventricular rate by ablation of the atrioventricular node and permanent pacing does not adversely affect long-term survival.

Is sinus node modification appropriate for inappropriate sinus tachycardia with features of postural orthostatic tachycardia syndrome?

Inappropriate sinus tachycardia and postural orthostatic tachycardia are ill-defined syndromes with overlapping features. Although sinus node modification has been reported to effectively slow the sinus rate, long-term clinical response has not been adequately assessed. Furthermore, whether patients with postural orthostatic tachycardia would benefit from sinus node modification is unknown. The study prospectively assessed the short- and long-term clinical outcomes of seven consecutive female patients with postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia who were treated with sinus node modification. The study was conducted in a tertiary care center. The electrophysiological and clinical responses were prospectively assessed as defined by autonomic function testing, including Valsalva maneuver, deep breathing, tilt table testing, and quantitative sudomotor axonal reflex testing. Among the study population (mean age was 41+/-6 years), 5 (71%) patients had successful sinus node modification. At baseline, heart rates were 101+/-12 beats/min before modification and 77+/-9 beats/min after modification (P = 0.001). With isoproterenol, heart rates were 136+/-9 and 105+/-12 beats/min (P = 0.002) before and after modification, respectively. The mean heart rate during 24-hour Holter monitoring was also significantly reduced: 96+/-9 and 72+/-6 beats/min (P = 0.005) before and after modification, respectively. Despite the significant reduction in heart rate, autonomic symptom score index (based on ten categories of clinical symptoms) was unchanged before (15.6+/-4.1) and after (14.6+/-3.6) sinus node modification (P = 0.38). Sinus rate can be effectively slowed by sinus node modification. Clinical symptoms are not significantly improved after sinus node modification in patients with inappropriate sinus tachycardia and postural orthostatic tachycardia. A primary subtle autonomic disregulation is frequently present in this population. Sinus node modification is not recommended in this patient population.

Role of programmed ventricular stimulation and implantable cardioverter defibrillators in patients with idiopathic dilated cardiomyopathy and syncope.

The aim of this study was to evaluate the role of programmed ventricular stimulation and ICDs in patients with idiopathic dilated cardiomyopathy and syncope. Between 1990 and 1998, 54 (mean age 67+/-11 years, 76% men) patients presented with idiopathic dilated cardiomyopathy and syncope. An electrophysiological study was done in 37 of the 54 patients: 10 had inducible sustained monomorphic ventricular tachycardia, 12 had conduction system disease or neurocardiogenic syncope, and 15 had a normal study. Overall, 17 patients received an ICD, 15 patients received a pacemaker, and 22 patients received no device. Nine of the 15 patients with a negative electrophysiological study eventually received an ICD: 3 because they were considered high risk and 6 because of recurrent syncope or presyncope. In the 17 patients who received an ICD, incidence of appropriate shocks at 1 and 3 years was 47% and 74%, respectively, in the inducible sustained monomorphic ventricular tachycardia group, and 40% and 40%, respectively, in the group without inducible sustained monomorphic ventricular tachycardia (P = 0.29, log-rank test). In conclusion, programmed ventricular stimulation is not useful in risk stratification of patients with idiopathic dilated cardiomyopathy and syncope and may delay necessary ICD implantation.

Intracardiac echocardiography.

This article describes currently available intracardiac ultrasound (ICE) technology contrasting it with intravascular ultrasound (IVUS), highlighting their differences. General and specific clinical applications, limitations and future developments of ICE are addressed. ICE is possible because lower frequency transducers (in contrast to higher frequency IVUS devices) have been miniaturized and mounted onto catheters capable of percutaneous insertion into the heart. Since the recent availability of a steerable, 5.5--10MHz phased-array catheter with full Doppler capability, these lower frequency transducers are not only capable of enhanced penetration, permitting high-resolution two-dimensional (2D) imaging but can also provide haemodynamic data. ICE facilitates electrophysiologic procedures by guiding trans-septal catheterization, enabling endocardial anatomy visualization, ensuring ablation electrode/tissue contact and promptly diagnosing procedural complications. Promising non-electrophysiologic applications include guidance of percutaneous closure of septal defects, percutaneous mitral balloon valvuloplasty and complex cardiac biopsy. Current limitations include monoplanar imaging and narrow field of view. Expanded diagnostic techniques such as tissue Doppler, multiplane, three dimensional (3D) and multimodality imaging represent future refinements. ICE is now a clinical tool. With the introduction of the newest phased-array transducer, with full Doppler capability, ICE has the potential to play an important role in diagnostic and therapeutic interventional procedures. Further refinement and miniaturization hold the key to primary operator controlled, integrated ultrasound-guided interventional devices.

Localization of the origin of arrhythmias for ablation: from Electrocardiography to advanced endocardial mapping systems.

Radiofrequency catheter ablation techniques have had a dramatic impact on the treatment of a variety of cardiac arrhythmias. However, catheter ablation of complex arrhythmias, such as intra-atrial reentry, ventricular tachycardias, and atrial fibrillation, continues to pose a major challenge. This stems from limitations of fluoroscopy and conventional catheter-based mapping techniques that limit the accurate anatomic localization of complex arrhythmogenic substrates. In this article, ECG features of complex arrhythmias are reviewed, which may facilitate the planning of an ablation procedure. The physical principles of the newly available catheter-based endocardial mapping techniques and their clinical applicability for treatment of complex arrhythmias are discussed. The role of intracardiac echocardiography to facilitate mapping and ablation is reviewed.

Electrophysiologic characteristics of diverse accessory pathway locations of antidromic reciprocating tachycardia.

This study assessed antidromic reciprocating tachycardia (ART) in patients with paraseptal accessory pathways (APs). Previous clinical experience suggests that paraseptal APs are unable to serve as the anterograde limb during ART. Based on the reentry wavelength concept, we hypothesized that anatomic location of a paraseptal AP may not preclude occurrence of ART. If wavelength criteria were met due to prolonged conduction time retrogradely in the atrioventricular node or anterogradely in the AP, ART may be sustained. All patients who had ART in the electrophysiologic laboratory at our institution (1991 to 1998) were studied. Based on fluoroscopically guided electrophysiologic mapping and radiofrequency ablation, AP location was classified as paraseptal, posterior, or lateral. Conduction time and refractoriness measurements were made for all components of the ART circuit. Of 24 patients with ART, 5 (21%) had ART utilizing a paraseptal AP. Anterograde conduction time through the AP and retrograde atrioventricular nodal conduction time were significantly longer in patients with paraseptal versus lateral pathways. Isoproterenol was required for ART induction in 38% of patients with a posterior AP, 36% with lateral AP location, but not in patients with a paraseptal AP. There were no significant differences in tachycardia cycle length or refractoriness of anterograde and/or retrograde components of the macroreentry circuit between the 3 pathway locations. Thus, ART can occur in patients with a paraseptal AP. Slower anterograde pathway conduction, or retrograde atrioventricular nodal conduction renders the wavelength critical for completion of the antidromic re-entrant circuit.

Obligate mitogen-activated protein kinase activation in parathyroid hormone stimulation of calcium transport but not calcium signaling.

PTH regulates calcium homeostasis through direct actions on its cognate type I receptor in the kidney and bone. PTH inhibits phosphate transport in renal proximal (PCT) tubules and stimulates calcium absorption by distal convoluted tubules (DCT). We examined PTH activation of the mitogen-activated protein kinase (MAPK) cascade raf-MEK-ERK in PCT and DCT cells and its effects on calcium transport and signaling. In DCT cells, PTH stimulates phosphorylation of ERK2 and activation of ERK2 kinase and is blocked by the MEK inhibitor PD98059. In DCT cells, stimulation of calcium entry with ionomycin did not activate ERK2 or augment PTH-stimulated ERK2 activity, indicating that MAPK activation lies upstream of calcium entry. ERK2 activation by PTH was blocked by the protein kinase C inhibitor calphostin-C but was unaffected by the protein kinase A inhibitor Rp-cAMPs. PD98059 abolished the increase of intracellular calcium induced by PTH demonstrating that ERK2 activation is directly involved in the increase of intracellular calcium activated by PTH in the DCT. Thus, PTH- stimulated ERK2 activation is PKC dependent and calcium independent. PTH also induced ERK2 phosphorylation in PCT cells. However, this effect is not involved in the transient rise of intracellular calcium because PD98059 did not inhibit the PTH-stimulated rise of intracellular calcium but abolished ERK2 activation. In conclusion, PTH activates MAPK in both distal and proximal renal tubule cells. However, the rise of [Ca2+]i depends upon MAPK activation only in distal cells. Thus, a common PTH1R exhibits differential signaling along the nephron that contributes to the ability to regulate distinct physiological actions of PTH.