A Transplant-Inclusive Value-Based Kidney Care Payment Model.

In the United States, kidney care payment models are migrating toward value-based care (VBC) models incentivizing quality of care at lower cost. Current kidney VBC models will continue through 2026. We propose a future transplant-inclusive VBC (TIVBC) model designed to supplement current models focusing on patients with advanced chronic kidney disease (CKD) and end-stage kidney disease (ESKD). The proposed TIVBC is structured as an episode-of-care model with risk-based reimbursement for "referral/evaluation/waitlisting" (REW, referencing kidney transplantation), "primary hospitalization to 180 days posttransplant," and "long-term graft survival." Challenges around organ acquisition costs, adjustments to quality metrics, and potential criticisms of the proposed model are discussed. We propose next steps in risk-adjustment and cost-prediction to develop as an end-to-end, TIVBC model.

Remodelling and dysfunction of the sinus node in pulmonary arterial hypertension.

Patients with pulmonary arterial hypertension (PAH) have a high burden of arrhythmias, including arrhythmias arising from sinus node dysfunction, and the aim of this study was to investigate the effects of PAH on the sinus node. In the rat, PAH was induced by an injection of monocrotaline. Three weeks after injection, there was a decrease of the intrinsic heart rate (heart rate in the absence of autonomic tone) as well as the normal heart rate, evidence of sinus node dysfunction. In the sinus node of PAH rats, there was a significant downregulation of many ion channels and Ca2+-handling genes that could explain the dysfunction: HCN1 and HCN4 (responsible for pacemaker current, If), Cav1.2, Cav1.3 and Cav3.1 (responsible for L- and T-type Ca2+ currents, ICa,L and ICa,T), NCX1 (responsible for Na+-Ca2+ exchanger) and SERCA2 and RYR2 (Ca2+-handling molecules). In the sinus node of PAH rats, there was also a significant upregulation of many fibrosis genes that could also help explain the dysfunction: vimentin, collagen type 1, elastin, fibronectin and transforming growth factor ß1. In summary, in PAH, there is a remodelling of ion channel, Ca2+-handling and fibrosis genes in the sinus node that is likely to be responsible for the sinus node dysfunction. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Regulation of sinus node pacemaking and atrioventricular node conduction by HCN channels in health and disease.

The funny current, If, was first recorded in the heart 40 or more years ago by Dario DiFrancesco and others. Since then, we have learnt that If plays an important role in pacemaking in the sinus node, the innate pacemaker of the heart, and more recently evidence has accumulated to show that If may play an important role in action potential conduction through the atrioventricular (AV) node. Evidence has also accumulated to show that regulation of the transcription and translation of the underlying Hcn genes plays an important role in the regulation of sinus node pacemaking and AV node conduction under normal physiological conditions - in athletes, during the circadian rhythm, in pregnancy, and during postnatal development - as well as pathological states - ageing, heart failure, pulmonary hypertension, diabetes and atrial fibrillation. There may be yet more pathological conditions involving changes in the expression of the Hcn genes. Here, we review the role of If and the underlying HCN channels in physiological and pathological changes of the sinus and AV nodes and we begin to explore the signalling pathways (microRNAs, transcription factors, GIRK4, the autonomic nervous system and inflammation) involved in this regulation. This review is dedicated to Dario DiFrancesco on his retirement.

Remodeling of the Purkinje Network in Congestive Heart Failure in the Rabbit.

BACKGROUND: Purkinje fibers (PFs) control timing of ventricular conduction and play a key role in arrhythmogenesis in heart failure (HF) patients. We investigated the effects of HF on PFs. METHODS: Echocardiography, electrocardiography, micro-computed tomography, quantitative polymerase chain reaction, immunohistochemistry, volume electron microscopy, and sharp microelectrode electrophysiology were used. RESULTS: Congestive HF was induced in rabbits by left ventricular volume- and pressure-overload producing left ventricular hypertrophy, diminished fractional shortening and ejection fraction, and increased left ventricular dimensions. HF baseline QRS and corrected QT interval were prolonged by 17% and 21% (mean±SEMs: 303±6 ms HF, 249±11 ms control; n=8/7; P=0.0002), suggesting PF dysfunction and impaired ventricular repolarization. Micro-computed tomography imaging showed increased free-running left PF network volume and length in HF. mRNA levels for 40 ion channels, Ca2+-handling proteins, connexins, and proinflammatory and fibrosis markers were assessed: 50% and 35% were dysregulated in left and right PFs respectively, whereas only 12.5% and 7.5% changed in left and right ventricular muscle. Funny channels, Ca2+-channels, and K+-channels were significantly reduced in left PFs. Microelectrode recordings from left PFs revealed more negative resting membrane potential, reduced action potential upstroke velocity, prolonged duration (action potential duration at 90% repolarization: 378±24 ms HF, 249±5 ms control; n=23/38; P<0.0001), and arrhythmic events in HF. Similar electrical remodeling was seen at the left PF-ventricular junction. In the failing left ventricle, upstroke velocity and amplitude were increased, but action potential duration at 90% repolarization was unaffected. CONCLUSIONS: Severe volume- followed by pressure-overload causes rapidly progressing HF with extensive remodeling of PFs. The PF network is central to both arrhythmogenesis and contractile dysfunction and the pathological remodeling may increase the risk of fatal arrhythmias in HF patients.

RNAseq shows an all-pervasive day-night rhythm in the transcriptome of the pacemaker of the heart.

Physiological systems vary in a day-night manner anticipating increased demand at a particular time. Heart is no exception. Cardiac output is primarily determined by heart rate and unsurprisingly this varies in a day-night manner and is higher during the day in the human (anticipating increased day-time demand). Although this is attributed to a day-night rhythm in post-translational ion channel regulation in the heart's pacemaker, the sinus node, by the autonomic nervous system, we investigated whether there is a day-night rhythm in transcription. RNAseq revealed that ~ 44% of the sinus node transcriptome (7134 of 16,387 transcripts) has a significant day-night rhythm. The data revealed the oscillating components of an intrinsic circadian clock. Presumably this clock (or perhaps the master circadian clock in the suprachiasmatic nucleus) is responsible for the rhythm observed in the transcriptional machinery, which in turn is responsible for the rhythm observed in the transcriptome. For example, there is a rhythm in transcripts responsible for the two principal pacemaker mechanisms (membrane and Ca2+ clocks), transcripts responsible for receptors and signalling pathways known to control pacemaking, transcripts from genes identified by GWAS as determinants of resting heart rate, and transcripts from genes responsible for familial and acquired sick sinus syndrome.

A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate.

BACKGROUND: Heart rate follows a diurnal variation, and slow heart rhythms occur primarily at night. OBJECTIVE: The lower heart rate during sleep is assumed to be neural in origin, but here we tested whether a day-night difference in intrinsic pacemaking is involved. METHODS: In vivo and in vitro electrocardiographic recordings, vagotomy, transgenics, quantitative polymerase chain reaction, Western blotting, immunohistochemistry, patch clamp, reporter bioluminescence recordings, and chromatin immunoprecipitation were used. RESULTS: The day-night difference in the average heart rate of mice was independent of fluctuations in average locomotor activity and persisted under pharmacological, surgical, and transgenic interruption of autonomic input to the heart. Spontaneous beating rate of isolated (ie, denervated) sinus node (SN) preparations exhibited a day-night rhythm concomitant with rhythmic messenger RNA expression of ion channels including hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4). In vitro studies demonstrated 24-hour rhythms in the human HCN4 promoter and the corresponding funny current. The day-night heart rate difference in mice was abolished by HCN block, both in vivo and in the isolated SN. Rhythmic expression of canonical circadian clock transcription factors, for example, Brain and muscle ARNT-Like 1 (BMAL1) and Cryptochrome (CRY) was identified in the SN and disruption of the local clock (by cardiomyocyte-specific knockout of Bmal1) abolished the day-night difference in Hcn4 and intrinsic heart rate. Chromatin immunoprecipitation revealed specific BMAL1 binding sites on Hcn4, linking the local clock with intrinsic rate control. CONCLUSION: The circadian variation in heart rate involves SN local clock-dependent Hcn4 rhythmicity. Data reveal a novel regulator of heart rate and mechanistic insight into bradycardia during sleep.

Silencing miR-370-3p rescues funny current and sinus node function in heart failure.

Bradyarrhythmias are an important cause of mortality in heart failure and previous studies indicate a mechanistic role for electrical remodelling of the key pacemaking ion channel HCN4 in this process. Here we show that, in a mouse model of heart failure in which there is sinus bradycardia, there is upregulation of a microRNA (miR-370-3p), downregulation of the pacemaker ion channel, HCN4, and downregulation of the corresponding ionic current, If, in the sinus node. In vitro, exogenous miR-370-3p inhibits HCN4 mRNA and causes downregulation of HCN4 protein, downregulation of If, and bradycardia in the isolated sinus node. In vivo, intraperitoneal injection of an antimiR to miR-370-3p into heart failure mice silences miR-370-3p and restores HCN4 mRNA and protein and If in the sinus node and blunts the sinus bradycardia. In addition, it partially restores ventricular function and reduces mortality. This represents a novel approach to heart failure treatment.

Simvastatin causes pulmonary artery relaxation by blocking smooth muscle ROCK and calcium channels: Evidence for an endothelium-independent mechanism.

Simvastatin reduces pulmonary arterial pressure and right ventricular hypertrophy in animal models of pulmonary arterial hypertension (PAH) and is thought to restore endothelial dysfunction. In vivo effects of drugs are complicated by several factors and little is known of the direct effects of statins on pulmonary arteries. This study investigated the direct effects of simvastatin on pulmonary arteries isolated from rats with or without monocrotaline-induced PAH. Simvastatin suppressed contractions evoked by the thromboxane A2 receptor agonist U46619 (30 nM), the α1-adrenergic agonist phenylephrine (5 µM) and KCl (50 mM) by ~50% in healthy and diseased arteries, but did not reduce contraction evoked by sarco/endoplasmic reticulum ATPase blockers. It relaxed hypertensive arteries in the absence of stimulation. Removing the endothelium or inhibiting eNOS did not prevent the inhibition by simvastatin. Inhibiting RhoA/rho kinase (ROCK) with Y27632 (10 µM) suppressed contractions to U46619 and phenylephrine by ~80% and prevented their inhibition by simvastatin. Y27632 reduced KCl-induced contraction by ~30%, but did not prevent simvastatin inhibition. Simvastatin suppressed Ca2+ entry into smooth muscle cells, as detected by Mn2+ quench of fura-2 fluorescence. The calcium antagonist, nifedipine (1 µM), almost abolished K+-induced contraction with less effect against U46619 and phenylephrine. We conclude that simvastatin relaxes pulmonary arteries by acting on smooth muscle to interfere with signalling through G-protein coupled receptors and voltage-dependent Ca2+ entry. Its actions likely include inhibition of ROCK-dependent Ca2+ sensitisation and voltage-gated Ca2+ channels. These are likely to contribute to the beneficial effects of simvastatin in animal models of PAH.

Atrioventricular Node Dysfunction and Ion Channel Transcriptome in Pulmonary Hypertension.

BACKGROUND: Heart block is associated with pulmonary hypertension, and the aim of the study was to test the hypothesis that the heart block is the result of a change in the ion channel transcriptome of the atrioventricular (AV) node. METHODS AND RESULTS: The most commonly used animal model of pulmonary hypertension, the monocrotaline-injected rat, was used. The functional consequences of monocrotaline injection were determined by echocardiography, ECG recording, and electrophysiological experiments on the Langendorff-perfused heart and isolated AV node. The ion channel transcriptome was measured by quantitative PCR, and biophysically detailed computer modeling was used to explore the changes observed. After monocrotaline injection, echocardiography revealed the pattern of pulmonary artery blood flow characteristic of pulmonary hypertension and right-sided hypertrophy and failure; the Langendorff-perfused heart and isolated AV node revealed dysfunction of the AV node (eg, 50% incidence of heart block in isolated AV node); and quantitative PCR revealed a widespread downregulation of ion channel and related genes in the AV node (eg, >50% downregulation of Cav1.2/3 and HCN1/2/4 channels). Computer modeling predicted that the changes in the transcriptome if translated into protein and function would result in heart block. CONCLUSIONS: Pulmonary hypertension results in a derangement of the ion channel transcriptome in the AV node, and this is the likely cause of AV node dysfunction in this disease.

Altered Left Ventricular Ion Channel Transcriptome in a High-Fat-Fed Rat Model of Obesity: Insight into Obesity-Induced Arrhythmogenesis.

Introduction. Obesity is increasingly common and is associated with an increased prevalence of cardiac arrhythmias. The aim of this study was to see whether in obesity there is proarrhythmic gene expression of ventricular ion channels and related molecules. Methods and Results. Rats were fed on a high-fat diet and compared to control rats on a normal diet (n = 8). After 8 weeks, rats on the high-fat diet showed significantly greater weight gain and higher adiposity. Left ventricle samples were removed at 8 weeks and mRNA expression of ion channels and other molecules was measured using qPCR. Obese rats had significant upregulation of Cav1.2, HCN4, Kir2.1, RYR2, NCX1, SERCA2a, and RYR2 mRNA and downregulation of ERG mRNA. In the case of HCN4, it was confirmed that there was a significant increase in protein expression. The potential effects of the mRNA changes on the ventricular action potential and intracellular Ca2+ transient were predicted using computer modelling. Modelling predicted prolongation of the ventricular action potential and an increase in the intracellular Ca2+ transient, both of which would be expected to be arrhythmogenic. Conclusion. High-fat diet causing obesity results in arrhythmogenic cardiac gene expression of ion channels and related molecules.

Congestive Heart Failure Leads to Prolongation of the PR Interval and Atrioventricular Junction Enlargement and Ion Channel Remodelling in the Rabbit.

Heart failure is a major killer worldwide. Atrioventricular conduction block is common in heart failure; it is associated with worse outcomes and can lead to syncope and bradycardic death. We examine the effect of heart failure on anatomical and ion channel remodelling in the rabbit atrioventricular junction (AVJ). Heart failure was induced in New Zealand rabbits by disruption of the aortic valve and banding of the abdominal aorta resulting in volume and pressure overload. Laser micro-dissection and real-time polymerase chain reaction (RT-PCR) were employed to investigate the effects of heart failure on ion channel remodelling in four regions of the rabbit AVJ and in septal tissues. Investigation of the AVJ anatomy was performed using micro-computed tomography (micro-CT). Heart failure animals developed first degree heart block. Heart failure caused ventricular myocardial volume increase with a 35% elongation of the AVJ. There was downregulation of HCN1 and Cx43 mRNA transcripts across all regions and downregulation of Cav1.3 in the transitional tissue. Cx40 mRNA was significantly downregulated in the atrial septum and AVJ tissues but not in the ventricular septum. mRNA abundance for ANP, CLCN2 and Navß1 was increased with heart failure; Nav1.1 was increased in the inferior nodal extension/compact node area. Heart failure in the rabbit leads to prolongation of the PR interval and this is accompanied by downregulation of HCN1, Cav1.3, Cx40 and Cx43 mRNAs and anatomical enlargement of the entire heart and AVJ.

From the Purkinje fibres to the ventricle: One dimensional computer simulation for the healthy and failing heart.

This study used one-dimensional computer simulation to investigate the influence of heart failure on action potential conduction through the left Purkinje fibres to the left ventricle. The study was based on a rabbit model of left ventricular heart failure caused by volume and pressure overload. To simulate the effect of heart failure, we began with models of the healthy rabbit Purkinje fibre action potential and healthy left ventricular (endocardial) action potential. In the absence of ionic current measurements from failing rabbit Purkinje fibres, we assumed that changes in ionic currents mirrored changes in ion channel expression (measured at the messenger RNA level): ionic conductances were adjusted based on changes in expression of the relevant ion channels. Ionic currents in the left ventricle were adjusted in the same way, but in addition, changes in ionic currents measured in the failing rabbit left ventricle by Ruijter et al. and Powizd et al. were used in simulations. The simulations predict a gradient in action potential duration from the Purkinje fibres to the ventricle and this gradient is exacerbated in heart failure. The predicted changes in the Purkinje fibre and left ventricular action potential were compared to actual changes measured using sharp microelectrodes.

Exercise training reduces resting heart rate via downregulation of the funny channel HCN4.

Endurance athletes exhibit sinus bradycardia, that is a slow resting heart rate, associated with a higher incidence of sinus node (pacemaker) disease and electronic pacemaker implantation. Here we show that training-induced bradycardia is not a consequence of changes in the activity of the autonomic nervous system but is caused by intrinsic electrophysiological changes in the sinus node. We demonstrate that training-induced bradycardia persists after blockade of the autonomous nervous system in vivo in mice and in vitro in the denervated sinus node. We also show that a widespread remodelling of pacemaker ion channels, notably a downregulation of HCN4 and the corresponding ionic current, If. Block of If abolishes the difference in heart rate between trained and sedentary animals in vivo and in vitro. We further observe training-induced downregulation of Tbx3 and upregulation of NRSF and miR-1 (transcriptional regulators) that explains the downregulation of HCN4. Our findings provide a molecular explanation for the potentially pathological heart rate adaptation to exercise training.

Warfarin Management Pathway: A clear and safe algorithm, from admission to discharge.

Warfarin is the most commonly prescribed anticoagulant in the UK and the one most frequently associated with both fatal medication errors and litigation claims [1]. Its life-threatening interactions and side effects are a concern for all doctors. Identifying and implementing solutions to achieve safer prescribing and monitoring is imperative to improve patient safety. The National Patient Safety Agency (NPSA) has outlined the major risks associated with anticoagulant therapy and sought to establish safer practice [1]. The monitoring of safety indicators has been highlighted as a solution. This quality improvement project (QIP) introduces a management algorithm for oral anticoagulant therapy in hospital patients, validated through a completed audit cycle. It was completed at one district general hospital (DGH) in England and involved all inpatient wards. Doctors and pharmacists were interviewed to assess their knowledge of the correct pathways for management of patients on warfarin. The number of errors on hospital warfarin charts was audited over three weeks. These results, coupled with senior haematological advice led to the production of an algorithm illustrating the gold-standard pathway for warfarin management from admission to discharge. It was emailed to all doctors in the Trust and a laminated copy attached to hospital Pneumatic Tube System (PTS) machines. The warfarin charts were re-audited over the following three weeks. The results showed a marked decrease in errors and incomplete anticoagulation referrals as well as a reduction in doctors' anxiety around prescribing warfarin.

Defining the magnitude of measurement variability in the virtual histology analysis of acute coronary syndrome plaques.

BACKGROUND: Previous intravascular ultrasound-based virtual histology (IVUS-VH) measurement variability studies have been confined to single-frame or short-segment analysis in stable patients with minimal disease. We sought to determine the magnitude of human measurement variability in acute coronary syndrome (ACS) plaques. METHODS AND RESULTS: Prior to percutaneous coronary intervention, we performed IVUS-VH analysis in troponin-positive ACS culprit lesions. A total of 3840 IVUS-VH frames were analysed by two operators to determine intra- and inter-observer variability. The plaque constituent area and volumes were compared using intra-class correlation coefficient (ICC); within-subjects standard deviation (WSSD, mm(2) or mm(3)) and the repeatability coefficient (RCO) to quantify the magnitude of operator error that 95% of future measurements should not exceed. The majority of intra- and inter-observer measurements had ICC of >0.92 confirming excellent agreement. Only the fibrous area (0.86), fibro-fatty (FF) area (0.72) and FF volume (0.87) had ICC levels suggesting an operator error >10%. However, the mean RCO and the percentage this represents in single-frame analysis (area error) varied across the plaque subtypes: fibrous area = 1.64 mm(2) (59%); FF area = 0.49 mm(2) (140%); necrotic core (NC) area = 0.39 mm(2) (21.3%); dense calcium (DC) area = 0.29 mm(2) (33.7%). For full lesion pullbacks (volume error): fibrous volume = 8.14 mm(3) (9.9%); FF volume = 5.63 mm(3) (53.8%); NC volume = 3.78 mm(3) (6.9%) and DC = 2.4 mm(3) (9.6%) CONCLUSION: As in previous studies, intra- and inter-observer ICC suggests good agreement between observers. However, this can still represent large measurement error values and percentages. These findings could impact on the interpretation of previous studies and influence future studies using IVUS-VH measurements as endpoints.

Congestive heart failure: experimental model.

INTRODUCTION: Surgically induced, combined volume and pressure overload has been used in rabbits to create a simplified and reproducible model of acute left ventricular (LV) failure. MATERIALS AND METHODS: New Zealand white male rabbits (n = 24, mean weight 3.1 ± 0.2 kg) were randomly assigned to either the Control group (n = 10) or to the Heart Failure group (HF, n = 14). Animals in the Control group underwent "sham" procedures. Animals in the HF group underwent procedures to induce LV volume overload by inducing severe aortic valve regurgitation with aortic cusp disruption and pressure overload using an occlusive silver clip positioned around the pre-renal abdominal aorta. RESULTS: Following Procedure-1 (volume overload) echocardiography confirmed severe aortic regurgitation in all animals in the HF group, with increased mean pulse pressure difference from 18 ± 3 to 38 ± 3 mmHg (P < 0.0001). After Procedure-2 (pressure overload) all animals in the HF group showed clinical and echocardiographic signs of constriction of the abdominal aorta and echocardiography confirmed progressively declining LV function. At the end of the protocol there was a significant increase of the heart/body weight ratio in the HF group vs. Control group (4.6 ± 0.2 vs. 2.9 ± 0.1 g/kg, P < 0.05), and echocardiography showed in HF group significant increase of the LV end-diastolic diameter (2.15 ± 0.09 vs. 1.49 ± 0.03 cm, P < 0.001) and reduction of the LV shortening fraction (26.3 ± 3.8 vs. 41.3 ± 1.6%, P < 0.001). CONCLUSION: This experimental model: (a) consistently produces LV hypertrophy/dilatation and subsequent congestive heart failure, (b) provides new data on the time course of LV dilatation, hypertrophy and failure, (c) allows study of the progress and evolution of LV systolic and diastolic dysfunction in the presence of induced LV failure, (d) is suitable to study intervention or pharmacological administration to reduce the negative effects of acute LV failure.

Unilateral isolated extraocular muscle lymphoma.

The authors would like to present an unusual case of ocular adnexal, mucosa-associated lymphoid tissue lymphoma, isolated to a single extraocular muscle. A 59-year-old woman presented with a 3-month history of slowly progressive double vision, worse on elevation, for which her optometrist had given her prisms. A swollen left upper eyelid was present for 10 days. CT scan of the brain and orbits revealed a 3 cm × 1.5 cm mass arising from the region of the left superior rectus with no signs of bone erosion. Histology showed infiltration by small lymphoid cells. Stage 1AE low-grade marginal zone B cell lymphoma was diagnosed. Possible aetiologies included Chlamydia psittaci infection and the recently recognised IgG4-related sclerosing disease. After oral doxycycline 200 mg once a day failed to show improvement, localised radiotherapy 30 Gy resulted in excellent clinical and radiological resolution of this isolated lymphoma.

Contrast enhanced micro-computed tomography resolves the 3-dimensional morphology of the cardiac conduction system in mammalian hearts.

The general anatomy of the cardiac conduction system (CCS) has been known for 100 years, but its complex and irregular three-dimensional (3D) geometry is not so well understood. This is largely because the conducting tissue is not distinct from the surrounding tissue by dissection. The best descriptions of its anatomy come from studies based on serial sectioning of samples taken from the appropriate areas of the heart. Low X-ray attenuation has formerly ruled out micro-computed tomography (micro-CT) as a modality to resolve internal structures of soft tissue, but incorporation of iodine, which has a high molecular weight, into those tissues enhances the differential attenuation of X-rays and allows visualisation of fine detail in embryos and skeletal muscle. Here, with the use of a iodine based contrast agent (I(2)KI), we present contrast enhanced micro-CT images of cardiac tissue from rat and rabbit in which the three major subdivisions of the CCS can be differentiated from the surrounding contractile myocardium and visualised in 3D. Structures identified include the sinoatrial node (SAN) and the atrioventricular conduction axis: the penetrating bundle, His bundle, the bundle branches and the Purkinje network. Although the current findings are consistent with existing anatomical representations, the representations shown here offer superior resolution and are the first 3D representations of the CCS within a single intact mammalian heart.