RESUMO
Sepsis has emerged as a global health burden associated with multiple organ dysfunction and 20% mortality rate in patients. Numerous clinical studies over the past two decades have correlated the disease severity and mortality in septic patients with impaired heart rate variability (HRV), as a consequence of impaired chronotropic response of sinoatrial node (SAN) pacemaker activity to vagal/parasympathetic stimulation. However, the molecular mechanism(s) downstream to parasympathetic inputs have not been investigated yet in sepsis, particularly in the SAN. Based on electrocardiography, fluorescence Ca2+ imaging, electrophysiology, and protein assays from organ to subcellular level, we report that impaired muscarinic receptor subtype 2-G protein-activated inwardly-rectifying potassium channel (M2R-GIRK) signaling in a lipopolysaccharide-induced proxy septic mouse model plays a critical role in SAN pacemaking and HRV. The parasympathetic responses to a muscarinic agonist, namely IKACh activation in SAN cells, reduction in Ca2+ mobilization of SAN tissues, lowering of heart rate and increase in HRV, were profoundly attenuated upon lipopolysaccharide-induced sepsis. These functional alterations manifested as a direct consequence of reduced expression of key ion-channel components (GIRK1, GIRK4, and M2R) in the mouse SAN tissues and cells, which was further evident in the human right atrial appendages of septic patients and likely not mediated by the common proinflammatory cytokines elevated in sepsis.
Assuntos
Lipopolissacarídeos , Sepse , Humanos , Animais , Camundongos , Lipopolissacarídeos/toxicidade , Lipopolissacarídeos/metabolismo , Nó Sinoatrial/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Transdução de Sinais/fisiologia , Sepse/induzido quimicamente , Sepse/metabolismoRESUMO
Many cardiac insults causing atrial remodeling are linked to either stretch or tachycardia, but a comparative characterization of their effects on early remodeling events in human myocardium is lacking. Here, we applied isometric stretch or sustained tachycardia at 2.5 Hz in human atrial trabeculae for 6 h followed by microarray gene expression profiling. Among largely independent expression patterns, we found a small common fraction with the microRNA miR-1183 as the highest up-regulated transcript (up to 4-fold). Both, acute stretch and tachycardia induced down-regulation of the predicted miR-1183 target genes ADAM20 and PLA2G7. Furthermore, miR-1183 was also significantly up-regulated in chronically remodeled atrial samples from patients with persistent atrial fibrillation (3-fold up-regulation versus sinus rhythm samples), and in ventricular myocardium from dilative cardiomyopathy hearts (2-fold up-regulation) as compared to non-failing controls. In sum, although stretch and tachycardia show distinct transcriptomic signatures in human atrial myocardium, both cardiac insults consistently regulate the expression of miR-1183 and its downstream targets in acute and chronic remodeling. Thus, elevated expression of miR-1183 might serve as a tissue biomarker for atrial remodeling and might be of potential functional significance in cardiac disease.
Assuntos
Fibrilação Atrial , Remodelamento Atrial , MicroRNAs , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Biomarcadores/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Miocárdio/metabolismo , Taquicardia/genética , Taquicardia/metabolismoRESUMO
BACKGROUND: Cardiac power output (CPO), derived from the product of cardiac output and mean aortic pressure, is an important yet underexploited parameter for hemodynamic monitoring of critically ill patients in the intensive-care unit (ICU). The conductance catheter-derived pressure-volume loop area reflects left ventricular stroke work (LV SW). Dividing LV SW by time, a measure of LV SW min- 1 is obtained sharing the same unit as CPO (W). We aimed to validate CPO as a marker of LV SW min- 1 under various inotropic states. METHODS: We retrospectively analysed data obtained from experimental studies of the hemodynamic impact of mild hypothermia and hyperthermia on acute heart failure. Fifty-nine anaesthetized and mechanically ventilated closed-chest Landrace pigs (68 ± 1 kg) were instrumented with Swan-Ganz and LV pressure-volume catheters. Data were obtained at body temperatures of 33.0 °C, 38.0 °C and 40.5 °C; before and after: resuscitation, myocardial infarction, endotoxemia, sevoflurane-induced myocardial depression and beta-adrenergic stimulation. We plotted LVSW min- 1 against CPO by linear regression analysis, as well as against the following classical indices of LV function and work: LV ejection fraction (LV EF), rate-pressure product (RPP), triple product (TP), LV maximum pressure (LVPmax) and maximal rate of rise of LVP (LV dP/dtmax). RESULTS: CPO showed the best correlation with LV SW min- 1 (r2 = 0.89; p < 0.05) while LV EF did not correlate at all (r2 = 0.01; p = 0.259). Further parameters correlated moderately with LV SW min- 1 (LVPmax r2 = 0.47, RPP r2 = 0.67; and TP r2 = 0.54). LV dP/dtmax correlated worst with LV SW min- 1 (r2 = 0.28). CONCLUSION: CPO reflects external cardiac work over a wide range of inotropic states. These data further support the use of CPO to monitor inotropic interventions in the ICU.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Volume Sistólico , Fibrilação Ventricular/fisiopatologia , Função Ventricular Esquerda , Pressão Ventricular , Agonistas Adrenérgicos beta/farmacologia , Animais , Modelos Animais de Doenças , Dobutamina/farmacologia , Endotoxemia/fisiopatologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Hipertermia Induzida , Hipotermia Induzida , Infarto do Miocárdio/diagnóstico , Ressuscitação , Sevoflurano/farmacologia , Volume Sistólico/efeitos dos fármacos , Sus scrofa , Fatores de Tempo , Fibrilação Ventricular/diagnóstico , Fibrilação Ventricular/terapia , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacosRESUMO
Experimental data indicate that stimulation of the nitric oxide-soluble guanylate cyclase(sGC)-cGMP-PKG pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 would increase LV capacitance via titin phosphorylation in healthy and deoxycorticosteroneacetate (DOCA)-induced hypertensive pigs. Nine healthy Landrace pigs and 7 pigs with DOCA-induced hypertension and LV concentric hypertrophy were acutely instrumented to measure LV end-diastolic pressure-volume relationships (EDPVRs) at baseline and during intravenous infusion of BAY 41-8543 (1 and 3 µg·kg-1·min-1 for 30 min, respectively). Separately, in seven healthy and six DOCA pigs, transmural LV biopsies were harvested from the beating heart to measure titin phosphorylation during BAY 41-8543 infusion. LV EDPVRs before and during BAY 41-8543 infusion were superimposable in both healthy and DOCA-treated pigs, whereas mean aortic pressure decreased by 20-30 mmHg in both groups. Myocardial titin phosphorylation was unchanged in healthy pigs, but total and site-specific (Pro-Glu-Val-Lys and N2-Bus domains) titin phosphorylation was increased in DOCA-treated pigs. Bicoronary nitroglycerin infusion in healthy pigs ( n = 5) induced a rightward shift of the LV EDPVR, demonstrating the responsiveness of the pathway in this model. Acute systemic sGC stimulation with the sGC stimulator BAY 41-8543 did not recruit an LV preload reserve in both healthy and hypertrophied LV porcine myocardium, although it increased titin phosphorylation in the latter group. Thus, increased titin phosphorylation is not indicative of increased in vivo LV capacitance. NEW & NOTEWORTHY We demonstrate that acute pharmacological stimulation of soluble guanylate cyclase does not increase left ventricular compliance in normal and hypertrophied porcine hearts. Effects of long-term soluble guanylate cyclase stimulation with oral compounds in disease conditions associated with lowered myocardial cGMP levels, i.e., heart failure with preserved ejection fraction, remain to be investigated.
Assuntos
Cardiomegalia/metabolismo , Ventrículos do Coração/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Capacitância Vascular , Animais , Pressão Sanguínea , Cardiomegalia/etiologia , Cardiomegalia/fisiopatologia , Conectina/metabolismo , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Acetato de Desoxicorticosterona/toxicidade , Feminino , Ventrículos do Coração/efeitos dos fármacos , Morfolinas/farmacologia , Nitroglicerina/farmacologia , Pirimidinas/farmacologia , Suínos , Vasodilatadores/farmacologia , Função Ventricular EsquerdaRESUMO
OBJECTIVE: Application of therapeutic mild hypothermia in patients after resuscitation, often accompanied by myocardial infarction, cardiogenic shock, and systemic inflammation may impact on cardiac rhythm. We therefore tested susceptibility to atrial arrhythmias during hyperthermia (HT, 40.5°C), normothermia (NT, 38.0°C), and mild hypothermia (MH, 33.0°C). METHODS: Nine healthy, anesthetized closed-chest landrace pigs were instrumented with a quadripolar stimulation catheter in the high right atrium and a decapolar catheter in the coronary sinus. Twelve-lead surface electrograms were recorded and core body temperature was altered to HT, NT, and MH using external warming or intravascular cooling. Repetitive measurements of effective atrial refractory period (AERP), atrial fibrillation (AF) inducibility, and electrocardiogram (ECG) parameters at different heart rates were performed. RESULTS: During MH, AERP was significantly longer while the inducibility of AF was significantly higher compared to NT and HT (median [range]: HT 18 (0, 80)%; NT 25 (0, 80)%; MH 68 (0, 100)%; P < 0.05 MH vs NT+HT). Mean AF duration did not differ between groups. Arterial potassium levels decreased with falling temperatures (HT: 4.2 ± 0.1 mmol/L; NT: 4.0 ± 0.2 mmol/L; MH: 3.5 ± 0.1 mmol/L; P < 0.001). Surface ECGs during MH showed reduced spontaneous heart rate (HT: 99 ± 13 beats/min; NT: 87 ± 15 beats/min; MH: 66 ± 10 beats/min; P < 0.05), increased PQ, stim-Q, and QT intervals (P < 0.01) but no change in QRS duration or time from peak to end of the T wave interval. CONCLUSION: Our data imply that MH represents an arrhythmic substrate rendering the atria more susceptible to AF although conduction times as well as refractory periods are increased. Further investigations on potential electrophysiological limits of therapeutic cooling in patients are required.
Assuntos
Fibrilação Atrial/etiologia , Modelos Animais de Doenças , Hipotermia Induzida , Suínos , Animais , Hipotermia Induzida/métodosRESUMO
OBJECTIVES: The results from the recent Targeted Temperature Management trial raised the question whether cooling or merely the avoidance of fever mediates better neurologic outcome in resuscitated patients. As temperature per se is a major determinant of cardiac function, we characterized the effects of hyperthermia (40.5°C), normothermia (38.0°C), and mild hypothermia (33.0°C) on left ventricular contractile function in healthy pigs and compared them with dobutamine infusion. DESIGN: Animal study. SETTING: Large animal facility, Medical University of Graz, Graz, Austria. SUBJECTS: Nine anesthetized and mechanically ventilated closed-chest Landrace pigs (67 ± 2 kg). INTERVENTIONS: Core body temperature was controlled using an intravascular device. At each temperature step, IV dobutamine was titrated to double maximum left ventricular dP/dt (1.8 ± 0.1 µg/kg/min at normothermia). Left ventricular pressure-volume relationships were assessed during short aortic occlusions. Left ventricular contractility was assessed by the calculated left ventricular end-systolic volume at an end-systolic left ventricular pressure of 100 mm Hg. MEASUREMENTS AND MAIN RESULTS: Heart rate (98 ± 4 vs 89 ± 4 vs 65 ± 2 beats/min; all p < 0.05) and cardiac output (6.7 ± 0.3 vs 6.1 ± 0.3 vs 4.4 ± 0.2 L/min) decreased with cooling from hyperthermia to normothermia and mild hypothermia, whereas left ventricular contractility increased (left ventricular end-systolic volume at a pressure of 100 mm Hg: 74 ± 5 mL at hyperthermia, 52 ± 4 mL at normothermia, and 41 ± 3 mL at mild hypothermia; all p < 0.05). The effect of cooling on left ventricular end-systolic volume at a pressure of 100 mm Hg (hyperthermia to normothermia: -28% ± 3% and normothermia to mild hypothermia: -20% ± 5%) was of comparable effect size as dobutamine at a given temperature (hyperthermia: -28% ± 4%, normothermia: -27% ± 6%, and mild hypothermia: -27% ± 9%). CONCLUSIONS: Cooling from hyperthermia to normothermia and from normothermia to mild hypothermia increased left ventricular contractility to a similar degree as a significant dose of dobutamine in the normal porcine heart. These data indicate that cooling can reduce the need for positive inotropes and that lower rather than higher temperatures are appropriate for the resuscitated failing heart.
Assuntos
Dobutamina/farmacologia , Hipertermia Induzida , Hipotermia Induzida , Contração Miocárdica/fisiologia , Função Ventricular Esquerda/fisiologia , Animais , Gasometria , Débito Cardíaco , Frequência Cardíaca/efeitos dos fármacos , Hipertermia Induzida/métodos , Hipotermia Induzida/métodos , Contração Miocárdica/efeitos dos fármacos , Volume Sistólico , Sus scrofa , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Heart failure with preserved ejection fraction (HFPEF) evolves with the accumulation of risk factors. Relevant animal models to identify potential therapeutic targets and to test novel therapies for HFPEF are missing. We induced hypertension and hyperlipidemia in landrace pigs (n = 8) by deoxycorticosteroneacetate (DOCA, 100 mg/kg, 90-day-release subcutaneous depot) and a Western diet (WD) containing high amounts of salt, fat, cholesterol, and sugar for 12 wk. Compared with weight-matched controls (n = 8), DOCA/WD-treated pigs showed left ventricular (LV) concentric hypertrophy and left atrial dilatation in the absence of significant changes in LV ejection fraction or symptoms of heart failure at rest. The LV end-diastolic pressure-volume relationship was markedly shifted leftward. During simultaneous right atrial pacing and dobutamine infusion, cardiac output reserve and LV peak inflow velocities were lower in DOCA/WD-treated pigs at higher LV end-diastolic pressures. In LV biopsies, we observed myocyte hypertrophy, a shift toward the stiffer titin isoform N2B, and reduced total titin phosphorylation. LV superoxide production was increased, in part attributable to nitric oxide synthase (NOS) uncoupling, whereas AKT and NOS isoform expression and phosphorylation were unchanged. In conclusion, we developed a large-animal model in which loss of LV capacitance was associated with a titin isoform shift and dysfunctional NOS, in the presence of preserved LV ejection fraction. Our findings identify potential targets for the treatment of HFPEF in a relevant large-animal model.
Assuntos
Cardiomiopatias/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/fisiopatologia , Miócitos Cardíacos/patologia , Volume Sistólico , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Conectina/metabolismo , Acetato de Desoxicorticosterona/toxicidade , Dieta Ocidental , Dilatação Patológica/etiologia , Dilatação Patológica/fisiopatologia , Modelos Animais de Doenças , Feminino , Átrios do Coração/fisiopatologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/complicações , Hipertensão/induzido quimicamente , Hipertrofia/etiologia , Hipertrofia/patologia , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Mineralocorticoides/toxicidade , Miócitos Cardíacos/metabolismo , Óxido Nítrico Sintase/metabolismo , Fosforilação , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Superóxidos/metabolismo , SuínosRESUMO
TRPC-mediated Ca(2+) entry has been implicated in the control of smooth muscle proliferation and might represent a pivotal mechanism underlying in-stent restenosis. As we have observed significant expression of TRPC3 in human smooth muscle from the coronary artery as well as the aorta, we tested the efficiency of a recently discovered TRPC3 selective Ca(2+) entry blocker Pyr3 to prevent vascular smooth muscle proliferation and stent implantation-induced hyperplasia of human aorta. The effect of Pyr3 on proliferation was measured by detection of BrdU incorporation and PCNA expression in human coronary smooth muscle and microvascular endothelium, which displays significantly smaller expression levels of TRPC3 as compared with smooth muscle. Pyr3 inhibited smooth muscle proliferation but lacked detectable effects on endothelial proliferation. Measurements of ATP-induced Ca(2+) signals revealed that Pyr3 suppressed agonist-induced Ca(2+) entry more effectively in vascular smooth muscle than in endothelial cells. Inhibitory effects of Pyr3 on stent implantation-induced arterial injury was tested using a novel in vitro model of in-stent hyperplasia in human arteries based on organ typical culture of human aortic constructs. Pyr3 effectively prevented increases in tissue levels of PCNA and Ki-67 at 2 weeks after stent implantation into human aortae. Similarly, proliferation markers were significantly suppressed when implanting a Pyr3-releasing stent prototype as compared with a bare metal stent (BMS) control. Our results suggest TRPC3 as a potential target for pharmacological control of smooth muscle proliferation. Selectively inhibition of TRPC Ca(2+) entry channels in vascular smooth muscle is suggested as a promising strategy for in-stent restenosis prevention.
Assuntos
Artérias/efeitos dos fármacos , Oclusão de Enxerto Vascular/prevenção & controle , Pirazóis/farmacologia , Stents/efeitos adversos , Canais de Cátion TRPC/antagonistas & inibidores , Antimetabólitos , Western Blotting , Bromodesoxiuridina , Sinalização do Cálcio/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Vasos Coronários/citologia , Vasos Coronários/efeitos dos fármacos , Humanos , Hiperplasia/fisiopatologia , Imuno-Histoquímica , Isoenzimas/química , Miócitos de Músculo Liso/efeitos dos fármacos , Neointima/patologia , Técnicas de Cultura de Órgãos , RNA/biossíntese , RNA/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , Fixação de TecidosRESUMO
OBJECTIVE: We tested whether mild hypothermia impacts on circulatory and respiratory dysfunction during experimental endotoxemia. DESIGN: Randomized controlled prospective experimental study. SETTING: Large animal facility, Medical University of Graz, Austria. SUBJECTS: Thirteen anesthetized and mechanically ventilated pigs. INTERVENTIONS: Lipopolysaccharide was administered for 4 hours. With the beginning of lipopolysaccharide infusion, animals were assigned to either normothermia (38°C, n = 7) or mild hypothermia (33°C, n = 6, intravascular cooling) and followed for 8 hours in total. MEASUREMENTS AND MAIN RESULTS: At the end of the protocol, cardiac output was lower in mild hypothermia than in normothermia (4.5 ± 0.4 L/min vs 6.6 ± 0.4 L/min, p < 0.05), but systemic vascular resistance (885 ± 77 dyn·s/cm vs 531 ± 29 dyn·s/cm, p < 0.05) and (Equation is included in full-text article.)(77% ± 6% vs 54% ± 3%, p < 0.05) were higher. Indices of left ventricular contractility in vivo were not different between groups. The high-frequency band in spectral analysis of heart rate variability indicated a better preserved vagal autonomic modulation of sinuatrial node activity in mild hypothermia versus normothermia (87 ± 5 vs 47 ± 5, normalized units, p < 0.05). Plasma norepinephrine levels were elevated compared with baseline in normothermia (2.13 ± 0.27 log pg/mL vs 0.27 ± 0.17 log pg/mL, p < 0.05) but not in mild hypothermia (1.02 ± 0.31 vs 0.55 ± 0.26, p = not significant). At 38°C in vitro, left ventricular muscle strips isolated from the mild hypothermia group had a higher force response to isoproterenol. SaO2 (100% ± 0% vs 92% ± 3%, p < 0.05) and the oxygenation index (PO2/FIO2, 386 ± 52 mm Hg vs 132 ± 32 mm Hg, p < 0.05) were substantially higher in mild hypothermia versus normothermia. Plasma cytokine levels were not consistently different between groups (interleukin 10) or higher (tumor necrosis factor-α and interleukin 6 and 8) during mild hypothermia versus normothermia. CONCLUSION: The induction of mild hypothermia attenuates cardiac and respiratory dysfunction and counteracts sympathetic activation during experimental endotoxemia. This was not associated with lower plasma cytokine levels, indicating a reduction of cytokine responsiveness by mild hypothermia.
Assuntos
Endotoxemia/fisiopatologia , Endotoxemia/terapia , Hipotermia Induzida , Animais , Débito Cardíaco , Cardiotônicos/farmacologia , Citocinas/sangue , Endotoxemia/sangue , Endotoxemia/induzido quimicamente , Frequência Cardíaca , Ventrículos do Coração/fisiopatologia , Isoproterenol/farmacologia , Lipopolissacarídeos , Contração Miocárdica/efeitos dos fármacos , Norepinefrina/sangue , Oxigênio/sangue , Distribuição Aleatória , Suínos , Resistência VascularRESUMO
OBJECTIVES: To examine the acute effects of sunitinib on inotropic function, intracellular Ca(2+) transients, myofilament Ca(2+) sensitivity and generation of reactive oxygen species (ROS) in human multicellular myocardium and isolated mouse cardiomyocytes. To search for microRNAs as suitable biomarkers for indicating toxic cardiac effects. PATIENTS AND METHODS: After exposure to sunitinib (0.1-10 µg/mL) developed force, diastolic tension and kinetic variables were assessed in isolated human myocardium. Changes in myocyte sarcomere length, whole-cell calcium transients, myofilament force-Ca(2+) relationship, and ROS generation were examined in isolated ventricular mouse cardiomyocytes. Microarray and realtime-PCR were used to screen for differentially expressed microRNAs in cultured cardiomyocytes that were exposed for 24 h to sunitinib. RESULTS: We found that higher concentrations of sunitinib (1 and 10 µg/mL) decreased developed force at 30 minutes 76.9 + 2.8 and 54.5 + 6.3%, compared to 96.1 + 2.6% in controls (P < 0.01). Sunitinib exposure significantly decreased sarcomere shortening and Ca2+ transients. Myofilament Ca(2+) sensitivity was not altered, while ROS levels were significantly increased after exposure to the drug. MicroRNA expression patterns were not altered by sunitinib. CONCLUSIONS: Sunitinib elicits a dose-dependent negative inotropic effect in myocardium, accompanied by a decline in intracellular Ca(2+) and increased ROS generation. In clinical practice, these cardiotoxic effects should be considered in cases where cardiac concentrations of sunitinib could be increased.
Assuntos
Antineoplásicos/efeitos adversos , Indóis/efeitos adversos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Pirróis/efeitos adversos , Idoso , Animais , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Espectroscopia de Ressonância de Spin Eletrônica , Feminino , Coração/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sarcômeros/efeitos dos fármacos , SunitinibeRESUMO
Lower body negative pressure (LBNP) has been implemented as a tool to simulate systemic effects of hypovolemia, understand orthostatic challenges and study G load stress in humans. However, the exact hemodynamic mechanisms of graded LBNP followed by its abrupt release have not been characterized in detail, limiting its potential applications in humans. Here, we set out to investigate the immediate hemodynamic alterations occurring during LBNP in healthy Landrace pigs. Invasive cardiac monitoring via extensive pressure volume loop analysis was carried out during application of incremental LBNP up to life threatening levels from -15 to -45 mmHg as well as during its abrupt release. Three different sealing positions were evaluated. Incremental LBNP consistently induced a preload dependent depression of systemic hemodynamics according to the Frank-Starling mechanism. Overall, the pressure-volume loop progressively shifted leftwards and downwards with increasing LBNP intensity. The abrupt release of LBNP reverted the above-described hemodynamic changes to baseline values within only three respiratory cycles. These data provide quantitative translational insights into hemodynamic mechanisms of incremental and very high levels of LBNP, levels of seal and effect of abrupt release for future human applications, such as countermeasure development for long spaceflight.
RESUMO
We recently established a large animal model that recapitulates key clinical features of heart failure with preserved ejection fraction (HFpEF) and tested the effects of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). SAHA reversed and prevented the development of cardiopulmonary impairment. This study evaluated the effects of SAHA at the level of cardiomyocyte and contractile protein function to understand how it modulates cardiac function. Both isolated adult feline ventricular cardiomyocytes (AFVM) and left ventricle (LV) trabeculae isolated from non-failing donors were treated with SAHA or vehicle before recording functional data. Skinned myocytes were isolated from AFVM and human trabeculae to assess myofilament function. SAHA-treated AFVM had increased contractility and improved relaxation kinetics but no difference in peak calcium transients, with increased calcium sensitivity and decreased passive stiffness of myofilaments. Mass spectrometry analysis revealed increased acetylation of the myosin regulatory light chain with SAHA treatment. SAHA-treated human trabeculae had decreased diastolic tension and increased developed force. Myofilaments isolated from human trabeculae had increased calcium sensitivity and decreased passive stiffness. These findings suggest that SAHA has an important role in the direct control of cardiac function at the level of the cardiomyocyte and myofilament by increasing myofilament calcium sensitivity and reducing diastolic tension.
RESUMO
Development and progression of atrial fibrillation (AF) is driven by comorbidities such as arterial hypertension and diabetes mellitus. In animal models of chronic hyperglycaemia, progression of AF has been proposed to be triggered by oxidative stress, apoptosis and fibrosis. Acute glycosylation of CaMKII has been associated with increased susceptibility to arrhythmias in acute hyperglycaemia. However, the proarrhythmogenic effect of acute hyperglycaemia has not been investigated. Nine healthy, anesthetized pigs (54 ± 6 kg) were instrumented with electrophysiologic catheters and a multielectrode array on the epicardium of the left atrial anterior wall. Left and right atrial effective refractory periods (AERP), inducibility of AF and left atrial epicardial conduction velocities (CV) were measured at baseline (BL), increasing steps of blood glucose (200-500 mg/dL in steps of 100 mg/dL by glucose infusion) and repeated after normalisation of blood glucose levels (recovery). Serum electrolytes were kept constant during measurements by means of sodium and potassium infusion. There were no significant differences in AERP, CV or AF inducibility between BL and recovery. Heart rate remained constant regardless of blood glucose levels (BL: 103 ± 18 bpm, 500 mg/dL: 103 ± 18 bpm, r = 0.02, p = 0.346). Mean left as well as right AERP increased with higher glucose levels. CV increased with glucose levels (1.25 (1.04, 1.67) m/s at BL vs. 1.53 (1.22, 2.15) m/s at 500 mg/dL, r = 0.85, p = 0.034). Rate of AF inducibility in the left atrium remained constant throughout the whole protocol (AF episodes > 10 s: mean inducibility of 80% at BL vs. 69% at 500 mg/dL, p = 0.32, episodes > 30 s: 0% at BL vs. 0% at 500 mg/dL, p = 0.17). Our data imply that acute hyperglycaemia is associated with lower arrhythmogenic substrate and does not promote AF inducibility.
Assuntos
Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Hiperglicemia/complicações , Doença Aguda , Animais , Biomarcadores , Eletrocardiografia , Sistema de Condução Cardíaco/fisiopatologia , Hiperglicemia/sangue , Hiperglicemia/etiologia , Pericárdio/fisiopatologia , Período Refratário Eletrofisiológico , SuínosRESUMO
Saxagliptin treatment has been associated with increased rate of hospitalization for heart failure in type 2 diabetic patients, though the underlying mechanism(s) remain elusive. To address this, we assessed the effects of saxagliptin on human atrial trabeculae, guinea pig hearts and cardiomyocytes. We found that the primary target of saxagliptin, dipeptidyl peptidase-4, is absent in cardiomyocytes, yet saxagliptin internalized into cardiomyocytes and impaired cardiac contractility via inhibition of the Ca2+/calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca2+-ATPase 2a axis and Na+-Ca2+ exchanger function in Ca2+ extrusion. This resulted in reduced sarcoplasmic reticulum Ca2+ content, diastolic Ca2+ overload, systolic dysfunction and impaired contractile force. Furthermore, saxagliptin reduced protein kinase C-mediated delayed rectifier K+ current that prolonged action potential duration and consequently QTc interval. Importantly, saxagliptin aggravated pre-existing cardiac dysfunction induced by ischemia/reperfusion injury. In conclusion, our novel results provide mechanisms for the off-target deleterious effects of saxagliptin on cardiac function and support the outcome of SAVOR-TIMI 53 trial that linked saxagliptin with the risk of heart failure.
Assuntos
Adamantano/análogos & derivados , Dipeptídeos/toxicidade , Dipeptidil Peptidase 4/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Átrios do Coração/citologia , Miócitos Cardíacos/efeitos dos fármacos , Adamantano/toxicidade , Idoso , Animais , Linhagem Celular , Dipeptidil Peptidase 4/genética , Inibidores da Dipeptidil Peptidase IV/farmacologia , Feminino , Regulação Enzimológica da Expressão Gênica/fisiologia , Cardiopatias/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/enzimologiaRESUMO
BACKGROUND: Mild hypothermia (MH) decreases infarct size and mortality in experimental reperfused myocardial infarction, but may potentiate ischaemia-induced left ventricular (LV) diastolic dysfunction. METHODS: In anaesthetized pigs (70 ± 2 kg), polystyrol microspheres (45 µm) were infused repeatedly into the left circumflex artery until cardiac power output decreased >40%. Then, pigs were assigned to normothermia (NT, 38.0°C, n=8) or MH (33.0°C, n=8, intravascular cooling) and followed for 6h (CME 6h). p<0.05 vs baseline, p<0.05 vs NT. RESULTS: In NT, cardiac output (CO) decreased from 6.2 ± 0.3 to 3.4 ± 0.2 l/min, and heart rate increased from 89 ± 4 to 101 ± 6 bpm. LV end-diastolic volume fell from 139 ± 8 to 64 ± 4 ml, while LV ejection fraction remained constant (49 ± 1 vs 53 ± 4%). The corresponding end-diastolic pressure-volume relationship was progressively shifted leftwards, reflecting severe LV diastolic dysfunction. In MH, CO fell to a similar degree. Spontaneous bradycardia compensated for slowed LV relaxation, and the leftward shift of the end-diastolic pressure-volume relationship was less pronounced during MH. MH increased systemic vascular resistance, such that mean aortic pressure remained higher in MH vs NT (69 ± 2 vs 54 ± 4 mm Hg). Mixed venous oxygen saturation at CME 6h was higher in MH than in NT (59 ± 4 vs 42 ± 2%) due to lowered systemic oxygen demand during cooling. CONCLUSION: We conclude that (i) an acute loss of end-diastolic LV compliance is a major component of acute cardiac pump failure during experimental myocardial infarction, and that (ii) MH does not potentiate this diastolic LV failure, but stabilizes haemodynamics and improves systemic oxygen supply/demand imbalance by reducing demand.
Assuntos
Hipotermia Induzida , Infarto do Miocárdio/complicações , Infarto do Miocárdio/terapia , Disfunção Ventricular Esquerda/etiologia , Animais , Diástole , SuínosRESUMO
Recent years have seen the introduction of a number of additive diagnostic and therapeutic procedures in invasive cardiology. Cardiac catheterization procedures using fluoroscopy reduce patient morbidity and mortality compared to conventional surgical interventions. The associated radiation exposure for the patient is, however, often underestimated, while implantation of cardiac resynchronization therapy (CRT) and/or implantable cardioverter defibrillator (ICD) pacemaker systems sometimes entails even higher radiation exposures due to prolonged fluoroscopic studies. Radiation induced skin injuries including ulceration are mainly dose dependent effects of ionizing radiation and can be acute, subacute or chronic. The time between radiation exposure and manifestation of skin injuries varies greatly, from a few days up to months or even years. We report a 54-year-old male patient who presented to the Department of Dermatology in the year 2006, with erythema in the interscapular area associated with occasional pruritus. His medical report included several diagnostic cardiac catheterization procedures. Several attempts to implant CRT and ICD had failed owing to an undetected congenital anomaly of the upper vena cava system; these attempts had entailed prolonged fluoroscopy. The patient's history, clinical presentation and histopathological findings finally led to the diagnosis of radiation induced cutaneous ulcer.
Assuntos
Cateterismo Cardíaco/efeitos adversos , Terapia de Ressincronização Cardíaca/efeitos adversos , Desfibriladores Implantáveis/efeitos adversos , Radiodermite/etiologia , Úlcera Cutânea/etiologia , Veia Cava Superior/anormalidades , Doença Crônica , Eritema/diagnóstico , Eritema/etiologia , Fluoroscopia/efeitos adversos , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Radiodermite/fisiopatologia , Radiodermite/cirurgia , Medição de Risco , Índice de Gravidade de Doença , Úlcera Cutânea/patologia , Úlcera Cutânea/cirurgia , Resultado do Tratamento , Malformações Vasculares/diagnóstico por imagem , Veia Cava Superior/diagnóstico por imagemRESUMO
An experimental model was established to study circulation in retrograde arterialized venous flaps (RAVF). Venous flaps measuring 7 x 4 cm with a matching venous system were harvested from both forearms of 10 fresh human cadavers. In each trial, both flaps were simultaneously perfused with heparinized human blood driven by a pulsatile circulation model. In each trial there was one flap with retrograde perfusion, and one flap with antegrade perfusion. Clinical assessment, measurement of outflow, and angiographic examination with digitally assisted assessment after 3 h of perfusion showed better results for retrograde perfusion in 8 of the 10 trials. This study indicates that blood circulation in the periphery of arterialized venous flaps can be enhanced by retrograde arterialization.