Approach to Management of Premature Ventricular Contractions.

PURPOSE OF REVIEW: Premature ventricular contractions (PVCs) are arrhythmias with presentation ranging from asymptomatic and benign to symptomatic, frequent and capable of inducing cardiomyopathy. Work in the late 1970s-1980s showed that they could be representative of underlying coronary artery disease, hypertension, or left ventricular hypertrophy. Furthermore, their presence is independently linked to an increased risk of stroke and sudden cardiac death. Since characterization of PVC-induced cardiomyopathy 21 years ago, there has been progressive interest in treating PVCs. This review aims to present an approach that practitioners can use for the treatment of PVCs. RECENT FINDINGS: Recent efforts have focused on optimizing techniques for mapping and ablation of PVCs in patients with symptoms or reduced LVEF. However, an understanding of the medical treatment options is necessary because medical management is still the first line of therapy. The practitioner will need to weigh the risks and benefits of these strategies in order to help the patient determine the best course of action. PVCs are recognized as a clinically significant arrhythmia, and evolving treatment strategies can improve cardiovascular outcomes. This review provides a concise summary of the current state of PVC treatment.

Epicardial injection of nanoformulated calcium into cardiac ganglionic plexi suppresses autonomic nerve activity and postoperative atrial fibrillation.

BACKGROUND: Imbalanced activation of the cardiac autonomic nervous system triggers postoperative atrial fibrillation (POAF). Neuronal calcium overload induces apoptosis. We hypothesize that epicardial injection of timed-release nanoformulated CaCl2 (nCaCl2) into left atrial ganglionic plexi (GP) modulates autonomic function and suppresses POAF. OBJECTIVE: The purpose of this study was to determine whether nCaCl2 GP therapy suppresses POAF. METHODS: We used a novel canine model of POAF with implanted radiotelemetry to record nerve activity (NA) from the left stellate ganglion (SNA), left cardiac vagus nerve, and GP. At week 3, nCaCl2 (n = 7) or vehicle control (sham; n = 3) was injected into left pulmonary vein GP (LGP), followed by right pulmonary vein GP at week 4. Atrial effective refractory period (AERP) and atrial fibrillation vulnerability (AFV) were assessed in vivo. Resting and exercise NA and heart rate (HR) were assessed before and after LGP treatment. RESULTS: AERP decreased (P < .0001) and AFV increased (P = .008) at week 3 vs baseline. However, nCaCl2-LGP treatment reversed these changes and restored them to baseline after 1 week (P = .04). Subsequent nCaCl2-right pulmonary vein GP treatment further reduced AFV (P = .03). In contrast, AFV increased (P = .001) and AERP remained decreased (P = .01) 1 week after sham-LGP treatment vs baseline. nCaCl2-LGP treatment reduced NA from GP (P < .02) and NA from the left cardiac vagus nerve (P < .05) and increased SNA (P < .02). Despite increased SNA, HR was decreased (P < .01) with loss of HR-SNA correlation (R = 0.62). After sham-LGP treatment, NA was unchanged and HR-SNA remained correlated (R = 0.95). Histology confirmed nCaCl2-GP colocalization, apoptosis, and loss of immunoreactivity in nCaCl2-treated somas. CONCLUSION: Epicardial injection of nCaCl2 into left atrial GP induced neuroapoptosis and modulated autonomic function. This reversed a postoperative reduction in AERP and suppressed POAF.

Cardiac arrest due to ventricular fibrillation in a 23-year-old woman with broken heart syndrome.

Broken heart syndrome, also known as takotsubo cardiomyopathy, is a syndrome characterized by a transient regional systolic dysfunction of the left ventricle associated to a psychological stress. We herein describe a case of a 23-year-old female habitual marijuana user who was resuscitated after cardiac arrest and then diagnosed with midventricular stress cardiomyopathy complicated by subendocardial hemorrhage. We discuss this unique pathological finding, the incidence of arrhythmias in this syndrome, and the possible relation with chronic cannabis and tobacco use. Unfortunately, the patient did not survive, but had she survived, the management of the patient for secondary prevention would have been challenging considering the risk of recurrence with this disease.

Cryoinjury models of the adult and neonatal mouse heart for studies of scarring and regeneration.

A major limitation in studies of the injured heart is animal-to-animal variability in wound size resulting from commonly used techniques such as left anterior descending coronary artery ligation. This variability can make standard errors sufficiently large that mean separation between treatment and control groups can be difficult without replicating numbers (n) of animals in groups by excessive amounts. Here, we describe the materials and protocol necessary for delivering a standardized non-transmural cryoinjury to the left ventricle of an adult mouse heart that may in part obviate the issue of injury variance between animals. As reported previously, this cryoinjury model generates a necrotic wound to the ventricle of consistent size and shape that resolves into a scar of uniform size, shape, and organization. The cryo-model also provides an extended injury border zone that exhibits classic markers of remodeling found in surviving cardiac tissue at the edge of a myocardial infarction, including connexin43 (Cx43) lateralization. In a further extension of the method, we describe how we have adapted the model to deliver a cryoinjury to the apex of the heart of neonatal mice-a modification that may be useful for studies of myocardial regeneration in mammals.

A Connexin43 Mimetic Peptide Promotes Regenerative Healing and Improves Mechanical Properties in Skin and Heart.

SIGNIFICANCE: Evidence is building that the gap junction protein connexin43 (Cx43) is an important molecule in regenerative healing of skin and heart. Excess scarring from skin wound healing is a continuing clinical problem. Humans generally lack the ability to regenerate tissue following injury, and some degree of fibrotic repair occurs. In the skin, this results in unsightly scars with inferior mechanical properties. In the heart, scarring causes disruption in the contractility of cardiac muscle and increases the risk of deadly arrhythmia. Therapies that tip the balance of wound healing away from scar tissue and toward regeneration would thus represent a significant medical advance. RECENT ADVANCES: A cell-permeant peptide, αCT1 (alpha connexin carboxyl-terminal peptide), based on the carboxyl-terminus of connexin43, has been shown to elicit changes in gap junction organization and intracellular communication. In the skin, αCT1 applied at acute time points results in decreased inflammatory response, reduced area of scar progenitor tissue, and restoration of more normal dermal structure and mechanical strength. αCT1 application to infarcted hearts improved cardiac contractility, reduced the propensity for arrhythmia, and increased conduction velocity through the injured heart. CRITICAL ISSUES: Application of therapies like αCT1 could reduce cutaneous scarring and improve mechanical properties of healed skin and the contractile function and electrical stability of the heart following injury or surgery. FUTURE DIRECTIONS: αCT1 is a potential therapy for cutaneous wounds that could lead to reduced scarring and improvements in the mechanical properties of healed skin. For injured myocardial tissues, this Cx43 mimetic peptide may also provide a therapeutic approach for targeting pathological fibrosis and reducing the likelihood of sudden death from cardiac arrhythmias.

GATA6 reporter gene reveals myocardial phenotypic heterogeneity that is related to variations in gap junction coupling.

This study examined transgenic mice whose expression of a ß-galactosidase (lacZ) reporter is driven by a GATA6 gene enhancer. Previous investigations established that transcription of the transgene was associated with precardiac mesoderm and primary heart tube myocardium, which decreased progressively, so that its expression was no longer observed within ventricular myocardium by midgestation. Expression of this reporter in the adult was investigated for insights into myocyte homeostasis and cardiovascular biology. Morphometric analysis determined that <1% of myocytes, often found in small clusters, express this GATA6-associated reporter in the adult heart. LacZ expression was also found in the ascending aorta. Myocardial expression of the transgene was not associated with a proliferative phenotype or new myocyte formation, as lacZ-positive myocytes neither labeled with cell division markers nor following 5-bromodeoxyuridine pulse-chase experimentation. Despite exhibiting normal adherens junctions, these myocytes appeared to exhibit decreased connexin 43 gap junctions. Treatment with the gap junctional blocker heptanol both in vivo and in culture elevated myocardial ß-galactosidase activity, suggesting that deficient gap junctional communication underlies expression of the transgenic reporter. LacZ expression within the myocardium was also enhanced in response to cryoinjury and isoproterenol-induced hypertrophy. These results reveal a previously uncharacterized phenotypic heterogeneity in the myocardium and suggest that decreased gap junctional coupling leads to induction of a signaling pathway that utilizes a unique GATA6 enhancer. Upregulation of lacZ reporter gene expression following cardiac injury indicates this transgenic mouse may serve as a model for examining the transition of the heart from healthy to pathological states.

Patterns of hospitalisation before and following initiation of haemodialysis: a 5 year single centre study.

BACKGROUND The utilisation of healthcare resources by prevalent haemodialysis patients has been robustly evaluated with regard to the provision of outpatient haemodialysis; however, the impact of hospitalisation among such patients is poorly defined. Minimal information is available in the UK to estimate the health and economic burden associated with the inpatient management of prevalent haemodialysis patients. The aim of this study was to assess the pattern of hospitalisation among a cohort of haemodialysis patients, before and following their initiation of haemodialysis. In addition the study sought to assess the impact of their admissions on bed occupancy in a large tertiary referral hospital in a single region in the UK. METHODS All admission episodes were reviewed and those receiving dialysis with the Belfast City Hospital Programme were identified over a 5 year period from January 2001 to December 2005. This tertiary referral centre provides dialysis services for a population of approximately 700 000 and additional specialist renal services for the remainder of Northern Ireland. The frequency and duration of hospitalisation, and contribution to bed day occupancy of haemodialysis patients, was determined and compared to other common conditions which are known to be associated with high bed occupancy. In addition, the pattern and timing of admissions in dialysis patients in relation to their dialysis initiation date was assessed. RESULTS Over the 5 year study period, 798 haemodialysis patients were admitted a total of 2882 times. These accounted for 2.5% of all admissions episodes; the median number of admissions for these patients was 3 (2-5) which compared with 1 (1-2) for non-dialysis patients. The majority of first hospitalisations (54%) were within 100 days before or after commencement of maintenance dialysis therapy. In all clinical specialties the median length of stay for haemodialysis patients was significantly longer than for patients not on haemodialysis (p=0.004). In multivariate analysis with adjustment for age, gender, and other clinically relevant diagnostic codes, maintenance haemodialysis patients stayed on average 3.75 times longer than other patient groups (ratio of geometric means 3.75, IQR 3.46-4.06). CONCLUSIONS Maintenance haemodialysis therapy is an important risk factor for prolonged hospitalisation regardless of the primary reason for admission. Such patients require admission more frequently than the general hospital population, particularly within 100 days before and after initiation of their first dialysis treatment.

A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury.

RATIONALE: Remodeling of connexin (Cx)43 gap junctions (GJs) is linked to ventricular arrhythmia. OBJECTIVES: A peptide mimetic of the carboxyl terminal (CT) of Cx43, incorporating a postsynaptic density-95/disks-large/ZO-1 (PDZ)-binding domain, reduces Cx43/ZO-1 interaction and GJ size remodeling in vitro. Here, we determined: (1) whether the Cx43-CT mimetic αCT1 altered GJ remodeling following left ventricular (LV) injury in vivo; (2) whether αCT1 affected arrhythmic propensity; and (3) the mechanism of αCT1 effects on arrhythmogenicity and GJ remodeling. METHODS AND RESULTS: A cryoinjury model generating a reproducible wound and injury border zone (IBZ) in the LV was used. Adherent methylcellulose patches formulated to locally release αCT1 (< 48 hours) were placed on cryoinjuries. Relative to controls, Cx43/ZO-1 colocalization in the IBZ was reduced by αCT1 by 24 hours after injury. Programmed electric stimulation ex vivo and optical mapping of voltage transients indicated that peptide-treated hearts showed reduced inducible arrhythmias and increased ventricular depolarization rates 7 to 9 days after injury. At 24 hours and 1 week after injury, αCT1-treated hearts maintained Cx43 in intercalated disks (IDs) in the IBZ, whereas by 1 week after injury, controls demonstrated Cx43 remodeling from IDs to lateralized distributions. Over a postinjury time course of 1 week, αCT1-treated IBZs showed increased Cx43 phosphorylation at serine368 (Cx43-pS368) relative to control tissues. In biochemical assays, αCT1 promoted phosphorylation of serine368 by protein kinase (PK)C-ε in a dose-dependent manner that was modulated by, but did not require ZO-1 PDZ2. CONCLUSIONS: αCT1 increases Cx43-pS368 in vitro in a PKC-ε-dependent manner and in the IBZ in vivo acutely following ventricular injury. αCT1-mediated increase in Cx43-pS368 phosphorylation may contribute to reductions in inducible-arrhythmia following injury.

The finding of reduced estimated glomerular filtration rate is associated with increased mortality in a large UK population.

BACKGROUND: CKD as defined by KDIGO/KDOQI has been shown to affect ~ 8.5% of the UK population. The prevalence of CKD in the UK is similar to that in the USA, yet incident dialysis rates are dramatically different. This retrospective cohort study investigates the association between reduced kidney function and mortality in a large UK population. METHODS: All serum creatinine results covering Northern Ireland's 1.7 million population were collected between 1 January 2001 and 31 December 2002. Estimated glomerular filtration rates (eGFR) were calculated for all serum creatinine measurements using four-variable MDRD equation (IDMS aligned). Patients were followed up for both all-cause and cardiovascular mortality data until the end of December 2006. Patients on renal replacement therapy were excluded. Subgroup analysis in the 75,345 subjects enrolled within a parallel primary care study permitted additional survival analysis with adjustment for traditional cardiovascular risk factors. RESULTS: A total of 1,967,827 serum creatinine results from 533,798 patients were collected. During the period of follow-up, 59,980 deaths occurred. In multivariate survival analysis, using eGFR as a time-varying covariate, a graded association between CKD (defined by eGFR) and all-cause mortality was identified. Compared with participants with an eGFR of > 60 mL/min/1.73 m(2), the adjusted hazard ratios (and 95% confidence intervals) for participants with an eGFR of 45-59 mL/min/1.73 m(2) was 1.02 (0.99-1.04), an eGFR of 30-44 mL/min/1.73 m(2) was 1.44 (1.40-1.47), an eGFR of 15-29 mL/min/1.73 m(2) was 2.12 (2.05-2.20) and an eGFR of < 15 mL/min/1.73 m(2) was 3.46 (3.24-3.70). Significantly, increased all-cause mortality was associated with an eGFR < 45 mL/min/1.73 m(2) following adjustment for age and gender. The association between cardiovascular mortality and reduced renal function continued to be significant for participants with an eGFR of 45-65 mL/min/1.73 m(2). Subgroup analysis in 75,345 individuals with more detailed clinical information available confirmed this association following adjustment for traditional cardiovascular risk factors in addition to age and gender. CONCLUSIONS: This study demonstrates a graded association between reduced renal function as represented by eGFR and mortality in a UK population. The all-cause and cardiovascular mortality risk increases sharply when estimated GFR falls < 45 mL/min/1.73 m(2). The association between an eGFR measured between 45 and 65 mL/min/1.73 m(2) and cardiovascular mortality persists in this cohort and highlights the ongoing uncertainty in accurately categorizing renal dysfunction.

ZO-1 determines adherens and gap junction localization at intercalated disks.

The disruption of the spatial order of electromechanical junctions at myocyte-intercalated disks (ICDs) is a poorly understood characteristic of many cardiac disease states. Here, in vitro and in vivo evidence is provided that zonula occludens-1 (ZO-1) regulates the organization of gap junctions (GJs) and adherens junctions (AJs) at ICDs. We investigated the contribution of ZO-1 to cell-cell junction localization by expressing a dominant-negative ZO-1 construct (DN-ZO-1) in rat ventricular myocytes (VMs). The expression of DN-ZO-1 in cultured neonatal VMs for 72 h reduced the interaction of ZO-1 and N-cadherin, as assayed by colocalization and coimmunoprecipitation, prompting cytoplasmic internalization of AJ and GJ proteins. DN-ZO-1 expression in adult VMs in vivo also reduced N-cadherin colocalization with ZO-1, a phenomenon not observed when the connexin-43 (Cx43)-ZO-1 interaction was disrupted using a mimetic of the ZO-1-binding ligand from Cx43. DN-ZO-1-infected VMs demonstrated large GJs at the ICD periphery and showed a loss of focal ZO-1 concentrations along plaque edges facing the disk interior. Additionally, there was breakdown of the characteristic ICD pattern of small interior and large peripheral GJs. Continuous DN-ZO-1 expression in VMs over postnatal development reduced ICD-associated Cx43 GJs and increased lateralized and cytoplasmic Cx43. We conclude that ZO-1 regulation of GJ localization is via an association with the N-cadherin multiprotein complex and that this is a key determinant of stable localization of both AJs and GJs at the ICD.

The impact of admissions for the management of end-stage renal disease on hospital bed occupancy.

BACKGROUND: End-stage renal disease (ESRD) is increasingly prevalent but the inpatient costs associated with this condition are poorly defined due to limitations with data extraction and failure to differentiate between hospitalisation for renal and non-renal disease reasons. The impact of admissions primarily for the management of ESRD on hospital bed utilisation was assessed over a 5-year period in a large teaching hospital. METHODS: All admission episodes were reviewed and the ESRD group was identified by a primary International Classification of Diseases code for ESRD or a non-specific primary renal failure code with a secondary code for ESRD. The frequency and duration of hospitalisation and contribution to bed day occupancy of this group with ESRD was determined. RESULTS: There were 70,808 patients responsible for a total of 116,915 admissions and 919,212 bed days over the study period. Of these, 988 (1.4%) patients were admitted for the management of ESRD, accounting for 2,387 (2.0%) of admissions and utilisation of 23,011 (2.5%) bed days. After adjustment for age and gender, those admitted for ESRD management were significantly more likely to have a prolonged admission exceeding 30 days (odds ratio 1.46, 95% confidence interval 1.23-1.72, p < 0.001). When the admission was an emergency rather than an elective event, the patient was 4.6 times more likely to be hospitalised for over 30 days. CONCLUSIONS: Persons admitted for ESRD management are hospitalised more frequently and for longer than the overall inpatient population, occupying a substantial number of bed days.

Titanium(IV) halide mediated coupling of alkoxides and alkynes: an efficient and stereoselective route to trisubstituted (E)-alkenyl halides.

Alkoxide C-O bond cleavage occurs readily at room temperature in the presence of titanium(IV) halide. Capture of the resultant carbocation by alkynes provides an efficient route to trisubstituted (E)-alkenyl halides with high stereoselectivity.

Connexin43 carboxyl-terminal peptides reduce scar progenitor and promote regenerative healing following skin wounding.

AIM: Gap-junctional connexin43 (Cx43) has roles in multiple aspects of skin wound healing - including scarring. The aim here was to study the effects of a cell-permeant peptide from the Cx43 carboxyl-terminus (CT) on scarring and regeneration following cutaneous injury. MATERIALS & METHODS: The effects of Cx43 CT peptide were studied in mouse and pig models of cutaneous injury. The parameters assessed included neutrophil density, wound closure, granulation, regeneration and skin tensile properties. RESULTS: Cx43 CT-peptide prompted decreases in area of scar progenitor tissue and promoted restoration of dermal histoarchitecture and mechanical strength following wounding of skin. These changes in healing were preceded by peptide-induced reduction in inflammatory neutrophil infiltration and alterations in the organization of epidermal Cx43, including increased connexon aggregation. CONCLUSION: Cx43 CT peptide promotes regenerative healing of cutaneous wounds and may have applications in tissues other than skin, including heart, cornea and spinal cord.

The practical implications of using standardized estimation equations in calculating the prevalence of chronic kidney disease.

BACKGROUND: Kidney Disease Outcomes Quality Initiative (KDOQI) chronic kidney disease (CKD) guidelines have focused on the utility of using the modified four-variable MDRD equation (now traceable by isotope dilution mass spectrometry IDMS) in calculating estimated glomerular filtration rates (eGFRs). This study assesses the practical implications of eGFR correction equations on the range of creatinine assays currently used in the UK and further investigates the effect of these equations on the calculated prevalence of CKD in one UK region METHODS: Using simulation, a range of creatinine data (30-300 micromol/l) was generated for male and female patients aged 20-100 years. The maximum differences between the IDMS and MDRD equations for all 14 UK laboratory techniques for serum creatinine measurement were explored with an average of individual eGFRs calculated according to MDRD and IDMS < 60 ml/min/1.73 m(2) and 30 ml/min/1.73 m(2). Similar procedures were applied to 712,540 samples from patients > or = 18 years (reflecting the five methods for serum creatinine measurement utilized in Northern Ireland) to explore, graphically, maximum differences in assays. CKD prevalence using both estimation equations was compared using an existing cohort of observed data. RESULTS: Simulated data indicates that the majority of laboratories in the UK have small differences between the IDMS and MDRD methods of eGFR measurement for stages 4 and 5 CKD (where the averaged maximum difference for all laboratory methods was 1.27 ml/min/1.73 m(2) for females and 1.59 ml/min/1.73 m(2) for males). MDRD deviated furthest from the IDMS results for the Endpoint Jaffe method: the maximum difference of 9.93 ml/min/1.73 m(2) for females and 5.42 ml/min/1.73 m(2) for males occurred at extreme ages and in those with eGFR > 30 ml/min/1.73 m(2). Observed data for 93,870 patients yielded a first MDRD eGFR < 60 ml/min/1.73 m(2) in 2001. 66,429 (71%) had a second test > 3 months later of which 47,093 (71%) continued to have an eGFR < 60 ml/min/1.73 m(2). Estimated crude prevalence was 3.97% for laboratory detected CKD in adults using the MDRD equation which fell to 3.69% when applying the IDMS equation. Over 95% of this difference in prevalence was explained by older females with stage 3 CKD (eGFR 30-59 ml/min/1.73 m(2)) close to the stage 2 CKD (eGFR 60-90 ml/min/1.73 m(2)) interface. CONCLUSIONS: Improved accuracy of eGFR is obtainable by using IDMS correction especially in the earlier stages of CKD 1-3. Our data indicates that this improved accuracy could lead to reduced prevalence estimates and potentially a decreased likelihood of onward referral to nephrology services particularly in older females.

Prospective evaluation of platelet B2 bradykinin and thrombopoietin receptor levels from preeclamptic compared to non-preeclamptic pregnancy patients.

Our recent study determined a difference between preeclamptic and non-preeclamptic patients in platelet potentiation by thrombopoietin (TPO) of reactivity to collagen. The main conclusion was that non-preeclamptic, but not preeclamptic, pregnancy patients' platelets showed significant TPO potentiation at first and third trimesters. Since TPO or B2 Bradykinin platelet receptor levels might influence TPO potentiation, we obtained platelet samples from 187 first trimester pregnant patients prospectively followed through pregnancy. Patients were additionally sampled at third trimester, delivery, and 4 to 6 weeks postpartum. A total of 43 patients, including 11 diagnosed as preeclamptic at third trimester, were sampled at least three different times. We used Western blotting normalized with glyceraldehyde 3 phosphate dehydrogenase as a loading and staining control. There were no significant differences in relative receptor levels between groups or sampling times using repeated measures ANOVA with the mixed model allowing for missing samples. While the mechanism for differences in thrombopoietin potentiation of platelet activation by collagen remains unknown, it may be a first trimester indicator of developing preeclampsia.