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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.
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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'.
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Hipertensão Arterial Pulmonar , Nó Sinoatrial , Ratos , Animais , Nó Sinoatrial/metabolismo , Hipertensão Arterial Pulmonar/metabolismo , Síndrome do Nó Sinusal/metabolismo , Canais Iônicos/genética , Canais Iônicos/metabolismo , FibroseRESUMO
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.
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Relógios Circadianos/genética , Ritmo Circadiano/genética , Coração/fisiologia , Transcriptoma/genética , Sistema Nervoso Autônomo/metabolismo , Estudo de Associação Genômica Ampla , Frequência Cardíaca/genética , Humanos , Canais Iônicos/genética , RNA-Seq , Transdução de Sinais/genética , Nó Sinoatrial/metabolismo , Sequenciamento do ExomaRESUMO
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.
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Fibrilação Atrial , Nó Atrioventricular , Potenciais de Ação , Frequência Cardíaca , Humanos , Nó SinoatrialRESUMO
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.
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Potenciais de Ação/fisiologia , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Remodelação Ventricular/fisiologia , Animais , Estimulação Cardíaca Artificial/efeitos adversos , Eletrocardiografia/métodos , Frequência Cardíaca/fisiologia , Masculino , Modelos Animais , Coelhos , Microtomografia por Raio-X/efeitos adversosRESUMO
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.
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Bradicardia/genética , Relógios Circadianos/fisiologia , Eletrocardiografia/métodos , Regulação da Expressão Gênica , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , RNA/genética , Nó Sinoatrial/fisiopatologia , Animais , Bradicardia/metabolismo , Bradicardia/fisiopatologia , Modelos Animais de Doenças , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/biossíntese , CamundongosRESUMO
OBJECTIVES: In this study we investigate whether differences exist in human skeletal muscle (MM) and subcutaneous (SC) tissue gas tensions between chronic cigarette smokers and non-smokers measured under room air and hyperbaric conditions. METHODS: Gas tensions in resting MM and SC tissues were recorded using a mass spectrometer at four-minute intervals during two and one-half to three-hour period in smokers and non-smokers during normobaric, normoxic (room air) and hyperbaric conditions. Two hyperbaric oxygen (HBO2) protocols were utilized: Protocol A employed the continuous breathing of oxygen (O2) at 2 ATA, a typical monoplace hyperbaric chamber treatment, while Protocol B utilized intermittent air breaks between O2 breathing periods at 2 ATA representative of a multiplace hyperbaric chamber treatment. RESULTS: All tissue gas tensions changed significantly (repeated measures of variance, p=0.00001) with time as pressures and gas mixtures breathed were altered. Significant Individual Step Analysis (ISA) differences occurred with unloading of nitrogen (N2) from the muscle compartment in both protocols (T-test and Wilcoxon Rank Sum). The interaction of grouping variable and time revealed significant differences between smokers and non-smokers in unloading MM N2 in both protocols: Protocol A (p=0.02) and in Protocol B (p=0.022). Carbon dioxide (CO2) levels in both protocols decreased significantly with time when exposed to HBO2 while increasing when breathing air at 2 ATA. CONCLUSIONS: This study demonstrates: 1) Smokers release MM N2 more slowly than nonsmokers during hyperbaric oxygen exposures regardless of the treatment protocol used; 2) There were no significant differences in O2 loading of MM and SC tissues during HBO2 exposures between smokers and nonsmokers; 3) The CO2 levels in both protocols decrease with time when exposed to HBO2 while increasing with breathing air at 2 ATA; 4) The known vasoconstriction effect in subcutaneous tissue from nicotine lasts less than one hour with the topical adiabatic heating increasing the O2 loading specifically in the SC tissues of smokers; 5) Wounds heal more slowly due to the chronically injured endothelium from carbon monoxide, hydrogen cyanide, and other toxic products in smoke rather than from the transient elevations of nicotine.
Assuntos
Oxigenoterapia Hiperbárica/métodos , Músculo Esquelético/metabolismo , Nitrogênio/metabolismo , Oxigênio/metabolismo , Fumar/metabolismo , Gordura Subcutânea/metabolismo , Adulto , Dióxido de Carbono/metabolismo , Monóxido de Carbono/metabolismo , Protocolos Clínicos , Mergulho/fisiologia , Feminino , Humanos , Masculino , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Pressão Parcial , Fumar/efeitos adversos , Estatísticas não Paramétricas , Fatores de TempoRESUMO
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.
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Inativação Gênica , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , MicroRNAs/metabolismo , Nó Sinoatrial/fisiopatologia , Animais , Sítios de Ligação , Peso Corporal , Cardiomegalia , Biologia Computacional , Regulação para Baixo , Fibrose , Insuficiência Cardíaca/metabolismo , Frequência Cardíaca , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , RatosRESUMO
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.
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Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Sinvastatina/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Animais , Canais de Cálcio/fisiologia , Modelos Animais de Doenças , Endotélio Vascular/fisiologia , Masculino , Relaxamento Muscular/fisiologia , Músculo Liso Vascular/fisiologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Fenilefrina/farmacologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/fisiologia , Ratos , Ratos WistarRESUMO
Women are at increased risk of having drug-induced arrhythmias such as torsade de pointes but less susceptible to arrhythmias associated with myocardial ischaemia. We have shown previously that 17beta-estradiol had greater antiarrhythmic activity in female rats than in male rats subject to myocardial ischaemia. The aim of this work was to investigate the effects of acute administration of 17beta-estradiol in both sexes in an established in vivo model of drug-induced arrhythmias. In alpha(1)-adrenoceptor-stimulated, pentobarbital-anaesthetized rabbits, 17beta-estradiol (100, 300 or 1000 ng/kg bolus followed by 10, 30 or 100 ng/kg/min infusion) tended to increase the incidence of torsade de pointes, induced by clofilium, in both sexes: from 50% in controls to 80%, 70% and 80% in females; from 40% in controls to 60%, 70% and 80% in males with increasing doses of 17beta-estradiol (n=10 per group). The total duration of all episodes of torsade de pointes was increased significantly by the highest dose of 17beta-estradiol compared to vehicle in both female and male rabbits: from 9+/-4 s to 93+/-26 s in females; from 26+/-14 s to 96+/-20 s in males. There were no baseline differences between the sexes in heart rate, QTc interval or epicardial monophasic action potential duration. The proarrhythmic effect of acute administration of 17beta-estradiol in the alpha(1)-adrenoceptor-stimulated anaesthetized rabbit model was independent of gender. This indicates that the underlying mechanism differs from that involved in the gender-selective reduction of ischaemia-induced arrhythmias by 17beta-estradiol.
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Potenciais de Ação/efeitos dos fármacos , Anestésicos/administração & dosagem , Antiarrítmicos/farmacologia , Estradiol/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Isquemia Miocárdica/induzido quimicamente , Caracteres Sexuais , Potenciais de Ação/fisiologia , Animais , Relação Dose-Resposta a Droga , Eletrocardiografia , Feminino , Frequência Cardíaca/fisiologia , Masculino , Isquemia Miocárdica/patologia , Coelhos , Fatores de Tempo , Torsades de Pointes/diagnósticoRESUMO
1. Pharmacological inhibitors of protein kinase A (PKA) and protein phosphatases 1/2A were used to determine whether basal L-type Ca(2+) current (I(Ca)) observed in the absence of exogenous beta-adrenergic receptor stimulation is sustained by PKA-mediated phosphorylation. Amphotericin B was used to record whole-cell I(Ca) in the perforated patch-clamp configuration. 2. Calyculin A and isoprenaline (both 1 micromol l(-1)) increased basal I(Ca) (P<0.05), whereas H-89 inhibited I(Ca) in a concentration-dependent manner with an IC(50) approximately 5 micromol l(-1). H-89 also inhibited the response to 1.0 micromol l(-1) isoprenaline, although relatively high concentrations (30 micromol l(-1)) were required to achieve complete suppression of the response. 3. Double-pulse protocols were used to study the effects of 10 micromol l(-1) H-89 on time-dependent recovery of I(Ca) from voltage-dependent inactivation as well as the steady-state gating of I(Ca). T(0.5) (time for I(Ca) to recover to 50% of the preinactivation amplitude) increased in the presence of H-89 (P<0.05) but was unaffected by calyculin A or isoprenaline. 4. Steady-state activation/inactivation properties of I(Ca) were unaffected by 10 micromol l(-1) H-89 or 1 micromol l(-1) calyculin A, whereas isoprenaline caused a leftward shift in both curves so that V(0.5) for activation and inactivation became more negative. 5. Data show that basal I(Ca) is regulated by cAMP-PKA-mediated phosphorylation in the absence of externally applied beta-receptor agonists and that relatively high concentrations of H-89 are required to fully suppress the response to beta-adrenergic receptor stimulation, thereby limiting the value of H-89 as a useful tool in dissecting signalling pathways in intact myocytes.
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Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ventrículos do Coração/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Ventrículos do Coração/citologia , Ventrículos do Coração/enzimologia , Isoquinolinas/farmacologia , Masculino , Potenciais da Membrana , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Wistar , Sulfonamidas/farmacologiaRESUMO
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.
Assuntos
Arritmias Cardíacas/genética , Canais de Cálcio/genética , Ventrículos do Coração/metabolismo , Obesidade/genética , Animais , Arritmias Cardíacas/etiologia , Canais de Cálcio/metabolismo , Gorduras na Dieta/administração & dosagem , Regulação da Expressão Gênica , Masculino , Obesidade/complicações , Reação em Cadeia da Polimerase , Ratos , Ratos WistarRESUMO
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.
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Nó Atrioventricular/metabolismo , Bloqueio Cardíaco/metabolismo , Hipertensão Pulmonar/metabolismo , Canais Iônicos/metabolismo , Transcriptoma , Animais , Nó Atrioventricular/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo , Ecocardiografia , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Bloqueio Cardíaco/etiologia , Bloqueio Cardíaco/fisiopatologia , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Canais Iônicos/genética , Masculino , Monocrotalina , Reação em Cadeia da Polimerase , Ratos , Ratos WistarRESUMO
OBJECTIVE: Catecholamines that accompany acute physiological stress are also involved in mediating the development of hypertrophy and failure. However, the cellular mechanisms involved in catecholamine-induced cardiac hypertrophy, particularly Ca2+ handling, are largely unknown. We therefore investigated the effects of cardiac hypertrophy, produced by isoprenaline, on I(Na/Ca) and sarcoplasmic reticulum (SR) function in isolated myocytes. METHODS: I(Na/Ca) was studied in myocytes from Wistar rats, using descending (+80 to -110 mV) voltage ramps under steady state conditions. Myocytes were also loaded with fura-2 and either field stimulated or voltage clamped to assess [Ca2+]i and SR Ca2+ content. RESULTS: Ca2+-dependent, steady state I(Na/Ca) density was increased in hypertrophied myocytes (P<0.05). Ca2+ release from the SR was also increased, whereas resting [Ca2+]i and the rate of decline of [Ca2+]i to control levels were unchanged. SR Ca2+ content, estimated by using 10.0 mmol/l caffeine, was also significantly increased in hypertrophied myocytes, but only when myocytes were held and stimulated from their normal resting potential (-80 mV) but not from -40 mV. However, the rate of decline of caffeine-induced Ca2+ transients or I(Na/Ca) was not significantly different between control and hypertrophied myocytes. Ca2+-dependence of I(Na/Ca), examined by comparing the slope of the descending phase of the hysteresis plots of I(Na/Ca) vs. [Ca2+]i, was also similar in the two groups of cells. CONCLUSION: Data show that SR Ca2+ release and SR Ca2+ content were increased in hypertrophied myocytes, despite an increase in the steady state I(Na/Ca) density. The observation that increased SR function occurred only when myocytes were stimulated from -80 mV suggests that Na+ influx may play a role in altering Ca2+ homeostasis in hypertrophied cardiac muscle, possibly through increased reverse Na+/Ca2+ exchange, particularly at low stimulation frequencies.
Assuntos
Sinalização do Cálcio , Cardiomegalia/metabolismo , Miócitos Cardíacos/metabolismo , Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Potenciais de Ação , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Cardiomegalia/fisiopatologia , Catecolaminas , Masculino , Técnicas de Patch-Clamp , Ratos , Ratos WistarRESUMO
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.
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Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Ramos Subendocárdicos , Função Ventricular/fisiologia , Animais , Simulação por Computador , Modelos Cardiovasculares , Ramos Subendocárdicos/fisiologia , Ramos Subendocárdicos/fisiopatologia , CoelhosRESUMO
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.
Assuntos
Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Canais Iônicos/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Animais , Remodelamento Atrial , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Conexina 43/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Eletrocardiografia , Insuficiência Cardíaca/diagnóstico , Masculino , RNA Mensageiro/genética , Coelhos , Remodelação Ventricular , Microtomografia por Raio-XRESUMO
Controversy exists as to what transcutaneous oxygen (P(tc)O2) levels are required for wound healing and what role hyperbaric oxygen has for this. Current information suggests that 30 to 40 mmHg juxta-wound oxygen tensions in room air are required. We recorded P(tc)O2 measurements in room air and with hyperbaric oxygen in 190 patients with foot wounds; then looked retrospectively and prospectively whether there was any effect on healing. Transcutaneous oxygen measurements under hyperbaric oxygen conditions defined a responder group (P(tc)O2 > 200 mmHg) with a sensitivity of 0.80 and a positive predictive value of 0.88 for healing, regardless of room air measurements when hyperbaric oxygen was used as an adjunct to wound management. This information helps to objectify the indications for hyperbaric oxygen and predict healing especially in those patients with problem wounds of the foot and ankle.
Assuntos
Monitorização Transcutânea dos Gases Sanguíneos/métodos , Oxigenoterapia Hiperbárica , Cicatrização , Amputação Cirúrgica , Traumatismos do Tornozelo/sangue , Traumatismos do Tornozelo/fisiopatologia , Traumatismos do Tornozelo/terapia , Traumatismos do Pé/sangue , Traumatismos do Pé/fisiopatologia , Traumatismos do Pé/terapia , Humanos , Valor Preditivo dos Testes , Estudos Prospectivos , Estudos RetrospectivosRESUMO
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.
RESUMO
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.