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1.
JAMA Cardiol ; 4(7): 680-684, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141104

RESUMO

Importance: Physician behavior in response to knowledge of a patient's CYP2C19 clopidogrel metabolizer status is unknown. Objective: To investigate the association of mandatory reporting of CYP2C19 pharmacogenomic testing, provided to investigators with no direct recommendations on how to use these results, with changes in P2Y12 inhibitor use, particularly clopidogrel, in the Randomized Trial to Compare the Safety of Rivaroxaban vs Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome (GEMINI-ACS-1) clinical trial. Design, Setting, and Participants: The GEMINI-ACS-1 trial compared rivaroxaban, 2.5 mg twice daily, with aspirin, 100 mg daily, plus open-label clopidogrel or ticagrelor (provided), in patients with recent acute coronary syndromes (ACS). The trial included 371 clinical centers in 21 countries and 3037 patients with ACS. Data were analyzed between May 2017 and February 2019. Interventions: Investigators were required to prestipulate their planned response to CYP2C19 metabolizer status. In response to a regulatory mandate, results for all patients were reported to investigators approximately 1 week after randomization. Main Outcomes and Measures: Reasons for switching P2Y12 inhibitors and occurrence of bleeding and ischemic events were collected. Results: Of 3037 patients enrolled (mean [SD] age, 62.8 [9.0] years; 2275 men [74.9%], and 2824 white race/ethnicity [93.0%]), investigators initially treated 1704 (56.1%) with ticagrelor and 1333 (43.9%) with clopidogrel. Investigators prestipulated that they would use CYP2C19 metabolizer status to change P2Y12 inhibitor in 48.5% of genotyped clopidogrel-treated patients (n = 642 of 1324) and 5.5% of genotyped ticagrelor-treated patients (n = 93 of 1692). P2Y12 inhibitor switching for any reason occurred in 197 patients and was more common in patients treated with ticagrelor (146 of 1704 [8.6%]) compared with clopidogrel (51 of 1333 [3.8%]). Of patients initially treated with ticagrelor, only 1 (0.1% overall; 0.7% of all who switched) was switched based on CYP2C19 status. Of patients initially treated with clopidogrel, 23 (1.7% overall,;45.1% of all who switched) were switched owing to metabolizer status. Of 48 patients (3.6%) with reduced metabolizer status treated initially with clopidogrel, 15 (31.3%) were switched based on metabolizer status, including 48.1% (13 of 27) in which switching was prestipulated. Conclusions and Relevance: Physicians were evenly split on how to respond to knowledge of CYP2C19 metabolizer status in clopidogrel-treated patients. Mandatory provision of this information rarely prompted P2Y12 inhibitor switching overall, including a minority of patients with reduced metabolizer status. These findings highlight the clinical equipoise among physicians regarding use of this information and the reluctance to use information from routine genotyping in the absence of definitive clinical trial data demonstrating the efficacy of this approach. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT02293395.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Clopidogrel/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Aspirina/administração & dosagem , Citocromo P-450 CYP2C19/metabolismo , Esquema de Medicação , Substituição de Medicamentos , Quimioterapia Combinada , Hemorragia/induzido quimicamente , Humanos , Isquemia/induzido quimicamente , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Rivaroxabana/administração & dosagem , Ticagrelor/administração & dosagem
2.
Am J Cardiol ; 122(11): 1896-1901, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30340765

RESUMO

Patients with both acute coronary syndromes (ACS) and congestive heart failure are at an increased risk of recurrent cardiovascular (CV) events attributed in part to both excess thrombin generation and impaired fibrinolysis. We hypothesized that patients with the overlap of ACS and CHF would thus derive particular benefit from antithrombotic therapy with rivaroxaban. ATLAS-ACS-2 Thrombolysis in Myocardial Infarction-51 was a double-blind, multicenter, phase 3 clinical trial that randomized patients within 7 days of an ACS event to standard of care plus either rivaroxaban 2.5 mg BID, 5 mg BID, or placebo (n = 15,526). In this post hoc subgroup analysis, subjects with a history of CHF at randomization (n = 1,694) were evaluated. Among subjects with a history of CHF, both rivaroxaban doses reduced the primary composite end point of CV death, myocardial infarction, or stroke (2.5 mg BID vs placebo: hazard ratio [HR] 0.59, 95% confidence interval [CI] (0.42, 0.81), p = 0.001; 5 mg BID vs placebo: HR 0.61, 95% CI (0.44, 0.84), p = 0.002; p interaction = 0.006). Both doses of rivaroxaban reduced CV mortality (rivaroxaban 2.5 mg BID vs placebo: 4.1% vs 9.0%, HR 0.45, 95% CI [0.27, 0.74], p = 0.002; rivaroxaban 5 mg BID vs placebo: 5.8% vs 9.0%, HR 0.62, 95% CI [0.40, 0.96], p = 0.031) as well as all-cause mortality. There was no significant increase in noncoronary artery bypass graft-related Thrombolysis in Myocardial Infarction major bleeding with either dose of rivaroxaban as compared with placebo (rivaroxaban 2.5 mg BID = 0.4% vs rivaroxaban 5 mg BID = 1.1% vs placebo = 0.5%). Rivaroxaban also did not increase either intracranial hemorrhage or fatal bleeding. In conclusion, in ACS subjects with a history of CHF, secondary prevention with rivaroxaban reduced the composite of CV death, myocardial infarction, or stroke without an increase in noncoronary artery bypass graft-related major bleeding. These findings require further prospective evaluation in an adequately powered phase 3 study.


Assuntos
Síndrome Coronariana Aguda/prevenção & controle , Insuficiência Cardíaca/complicações , Rivaroxabana/administração & dosagem , Prevenção Secundária/métodos , Terapia Trombolítica/métodos , Síndrome Coronariana Aguda/epidemiologia , Síndrome Coronariana Aguda/etiologia , Causas de Morte/tendências , Relação Dose-Resposta a Droga , Método Duplo-Cego , Inibidores do Fator Xa/administração & dosagem , Feminino , Seguimentos , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Estados Unidos/epidemiologia
4.
Eur Heart J Acute Cardiovasc Care ; 4(5): 468-74, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25318481

RESUMO

AIMS: Rivaroxaban reduces cardiovascular death, myocardial infarction (MI), or stroke in patients following acute coronary syndrome (ACS). We aimed to characterize the specific effects of rivaroxaban on the size and type of MI. METHODS: The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) study randomized 15,526 patients with a recent ACS to rivaroxaban 2.5 mg BID, rivaroxaban 5 mg BID, or placebo. An independent clinical events committee adjudicated each MI that occurred during the study and further classified them based on type. Data are presented as two-year Kaplan-Meier event rates and hazard ratios (HRs) and 95% confidence intervals (CI). RESULTS: In total, 665 patients experienced a post-randomization MI. The majority (n=535, 80.5%) were spontaneous (Type 1) events. Rivaroxaban reduced spontaneous MI when compared with placebo (4.4% vs 5.7%, HR 0.80, 95% 0.67-0.95, p=0.01), and there were directionally consistent reductions with both the 2.5 mg BID (4.7% vs 5.7%, HR 0.84, 95% 0.68-1.02, p=0.08) and 5 mg BID doses (4.1% vs 5.7%, HR 0.77, 95% 0.62-0.94, p=0.01) as compared with placebo. Rivaroxaban reduced MI with large elevations in troponin or creatine kinase-MB (CK-MB) fraction (1.8% vs 2.4%, HR 0.73, 95% CI 0.56-0.96, p=0.03) and STEMI events (1.7% vs 2.5%, HR 0.74, 95% CI 0.56-0.99, p=0.04). CONCLUSIONS: In patients stabilized and followed after ACS, the majority of MIs that occur are spontaneous and rivaroxaban significantly reduced the incidence of these events. Notably, rivaroxaban reduced MIs with extensive biomarker release and ST-segment elevation.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Infarto do Miocárdio/prevenção & controle , Rivaroxabana/administração & dosagem , Síndrome Coronariana Aguda/metabolismo , Síndrome Coronariana Aguda/patologia , Biomarcadores/metabolismo , Creatina Quinase Forma MB/metabolismo , Esquema de Medicação , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Prevenção Secundária , Terapia Trombolítica/métodos , Resultado do Tratamento , Troponina/metabolismo
5.
J Am Coll Cardiol ; 61(18): 1853-9, 2013 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-23500262

RESUMO

OBJECTIVES: The present analysis reports on the pre-specified subgroup of ST-elevation myocardial infarction (STEMI) patients, in whom anticoagulant therapy has been of particular interest. BACKGROUND: In ATLAS ACS-2-TIMI-51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51), rivaroxaban reduced cardiovascular events across the spectrum of acute coronary syndrome (ACS). METHODS: Seven thousand eight hundred seventeen patients in ATLAS ACS-2-TIMI 51 presented with a STEMI. After being stabilized (1 to 7 days), they underwent randomization to twice daily rivaroxaban 2.5 mg, rivaroxaban 5 mg, or placebo. Data are presented as 2-year Kaplan-Meier rates, and for intention-to-treat (ITT) and modified ITT (mITT) analyses. RESULTS: Among STEMI patients, rivaroxaban reduced the primary efficacy endpoint of cardiovascular death, myocardial infarction, or stroke, compared with placebo (ITT: 8.4% vs. 10.6%, hazards ratio [HR]: 0.81, 95% confidence interval [CI]: 0.67 to 0.97, p = 0.019; mITT: 8.3% vs. 9.7%, HR: 0.85, 95% CI: 0.70 to 1.03, p = 0.09). This reduction emerged by 30 days (ITT and mITT: 1.7% vs. 2.3%, p = 0.042) and was evident in analyses that included events while patients received background dual antiplatelet therapies (ITT: 7.9% vs. 11.9%, p = 0.010; mITT: 7.7% vs. 10.1%, p = 0.061). In terms of the individual doses, rivaroxaban 2.5 mg reduced cardiovascular death (ITT: 2.5% vs. 4.2%, p = 0.006; mITT: 2.2% vs. 3.9%, p = 0.006), which was not seen with 5 mg of rivaroxaban. Rivaroxaban versus placebo increased non-coronary artery bypass grafting Thrombolysis In Myocardial Infarction major bleeding (2.2% vs. 0.6%, p < 0.001) and intracranial hemorrhage (0.6% vs. 0.1%, p = 0.015) without a significant increase in fatal bleeding (0.2% vs. 0.1%, p = 0.51). CONCLUSIONS: In patients with a recent STEMI, rivaroxaban reduced cardiovascular events. This benefit emerged early and persisted during continued treatment with background antiplatelet therapies. Rivaroxaban compared with placebo increased the rate of major bleeding, but there was no significant increase in fatal bleeding. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965).


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Eletrocardiografia , Morfolinas/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Tiofenos/administração & dosagem , Terapia Trombolítica/métodos , Síndrome Coronariana Aguda/diagnóstico , Idoso , Anticoagulantes/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Inibidores do Fator Xa , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Estudos Prospectivos , Rivaroxabana , Resultado do Tratamento
6.
N Engl J Med ; 366(1): 9-19, 2012 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-22077192

RESUMO

BACKGROUND: Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. RESULTS: Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04). CONCLUSIONS: In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965.).


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Anticoagulantes/uso terapêutico , Inibidores do Fator Xa , Morfolinas/uso terapêutico , Tiofenos/uso terapêutico , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Método Duplo-Cego , Esquema de Medicação , Feminino , Hemorragia/induzido quimicamente , Hemorragia/mortalidade , Humanos , Incidência , Hemorragias Intracranianas/induzido quimicamente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Rivaroxabana , Prevenção Secundária , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos
7.
J Heart Lung Transplant ; 30(2): 218-26, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20947383

RESUMO

BACKGROUND: Heart failure (HF) is associated with a hypercoagulable state that predisposes to thromboembolism and anti-coagulation may improve clinical outcomes. The oral, direct Factor Xa inhibitor, rivaroxaban, has not been studied in patients with HF. We hypothesized that rivaroxaban would also reduce biomarkers of hypercoagulability in patients with HF. METHODS: This study consisted of two cohorts: Cohort 1, open-label, actively controlled with enoxaparin 40 mg once daily, included 8 patients with acute decompensated HF; Cohort 2, double-blind and placebo-controlled, included 18 patients with stable, severe New York Heart Association Class III/IV HF. RESULTS: The pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban were similar across both cohorts. Biomarker assessments were performed in Cohort 2; prothrombin fragment 1.2 (F1.2) mean concentration decreased by 2.7 ng/ml over 7 days with rivaroxaban, and increased by 11.6 ng/ml with placebo, an absolute difference of 14.3 ng/ml (p = 0.0009). A non-significant reduction in rate of increase of D-dimer (DD) and thrombin-anti-thrombin complex (TAT) levels with rivaroxaban was observed over 7 days (p = 0.31 and p = 0.77, respectively). CONCLUSION: Rivaroxaban has similar PK/PD in patients with either acute or chronic HF. In vivo, hypercoagulability biomarkers appear to increase over time. Rivaroxaban reversed this trend for F1.2, and may reduce the rate of increase of DD and TAT in patients with stable, severe HF.


Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Insuficiência Cardíaca/sangue , Morfolinas/farmacologia , Morfolinas/farmacocinética , Fragmentos de Peptídeos/sangue , Peptídeo Hidrolases/sangue , Tiofenos/farmacologia , Tiofenos/farmacocinética , Trombofilia/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Antitrombina III , Biomarcadores/sangue , Doença Crônica , Método Duplo-Cego , Enoxaparina/efeitos adversos , Enoxaparina/farmacocinética , Enoxaparina/farmacologia , Inibidores do Fator Xa , Feminino , Fibrinolíticos/efeitos adversos , Fibrinolíticos/farmacocinética , Fibrinolíticos/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Protrombina , Rivaroxabana , Tiofenos/efeitos adversos
8.
Pharmacoepidemiol Drug Saf ; 19(9): 911-20, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20602345

RESUMO

PURPOSE: Heart failure is a significant public health problem. The present study is intended to explore in a research database whether antithrombotic therapies (ATTs) affect cardiovascular outcomes in patients with incident heart failure (IHF). METHODS: Using the United Kingdom Health Improvement Network research database, several multivariable models (including logistic and Cox's regression models, as well as propensity score methods) were used to examine all-cause mortality and clinical outcomes among five treatment groups. RESULTS: The cohort included 24,554 patients with IHF (50.2% men), with a mean age (standard deviation [SD]) of 76.4 (11.0) years. Nearly three-fourths of patients received at least one form of ATT. Patients receiving ATTs tended to be younger and more likely to be men, and had more cardiovascular comorbidities. During the 18-month follow-up period, the mortality rates were 11.1%, 14.6%, 17.8%, 19.5%, and 32.6% for warfarin combination therapy, warfarin alone, clopidogrel therapy, aspirin (ASA) alone, and no therapy, respectively, yielding odds ratios (95%confidence intervals [CI]) relative to no therapy of 0.28 (0.24, 0.33), 0.38 (0.34, 0.43), 0.46 (0.40, 0.52), and 0.49 (0.45, 0.53) for each therapy group, accordingly. The use of ATTs also appeared to be associated with a reduced risk for ischemic or thrombotic events. CONCLUSIONS: These data contribute to the formulation of the hypothesis that use of ATTs in clinical practice decreases the risk of morbidity and mortality in patients with IHF, although findings require further confirmative studies.


Assuntos
Anticoagulantes/uso terapêutico , Fibrinolíticos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aspirina/uso terapêutico , Clopidogrel , Estudos de Coortes , Bases de Dados Factuais , Feminino , Seguimentos , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores Sexuais , Ticlopidina/análogos & derivados , Ticlopidina/uso terapêutico , Reino Unido/epidemiologia , Varfarina/uso terapêutico , Adulto Jovem
9.
Heart Rhythm ; 5(2): 282-8, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18242555

RESUMO

BACKGROUND: A potential concern about biological pacemakers is their possible malfunction, which might create ventricular tachycardias (VTs). OBJECTIVE: The purpose of this study was to test our hypothesis that should VTs complicate implantation of HCN-channel-based biological pacemakers, they would be suppressed by inhibitors of the pacemaker current, I(f). METHODS: We created a chimeric channel (HCN212) containing the N- and C-termini of mouse HCN2 and the transmembrane region of mouse HCN1 and implanted it in HEK293 cells. Forty-eight hours later, in whole-cell patch clamp recordings, mean steady state block induced by 3 microM ivabradine (IVB) showed HCN1 = HCN212 > HCN2 currents. The HCN212 adenoviral construct was then implanted into the canine left bundle branch in 11 dogs. Complete AV block was created via radiofrequency ablation, and a ventricular demand electronic pacemaker was implanted (VVI 45 bpm). Electrocardiogram, 24-hour Holter monitoring, and pacemaker log record check were performed for 11 days. RESULTS: All dogs developed rapid VT (>120 bpm, maximum rate = 285 +/- 37 bpm) at 0.9 +/- 0.3 days after implantation that persisted through 5 +/- 1 days. IVB, 1 mg/kg over 5 minutes, was administered during rapid VT, and three dogs received a second dose 24 hours later. While VT terminated with IBV in all instances within 3.4 +/- 0.6 minutes, no effect of IVB on sinus rate was noted. CONCLUSION: We conclude that (1) I(f)-associated tachyarrhythmias-if they occur with HCN-based biological pacemakers-can be controlled with I(f)-inhibiting drugs such as IVB; (2) in vitro, IVB appears to have a greater steady state inhibiting effect on HCN1 and HCN212 isoforms than on HCN4; and (3) VT originating from the HCN212 injection site is suppressed more readily than sinus rhythm. This suggests a selectivity of IVB at the concentration attained for ectopic over HCN4-based pacemaker function. This might confer a therapeutic benefit.


Assuntos
Benzazepinas/farmacologia , Canais de Cálcio , Estimulação Cardíaca Artificial , Fármacos Cardiovasculares/farmacologia , Desfibriladores Implantáveis , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/terapia , Animais , Ablação por Cateter , Cães , Eletrofisiologia , Ivabradina , Masculino , Células Musculares , Ratos , Fatores de Risco , Taquicardia Ventricular/tratamento farmacológico
10.
Circulation ; 116(7): 706-13, 2007 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-17646577

RESUMO

BACKGROUND: Biological pacemaking has been performed with viral vectors, human embryonic stem cells, and adult human mesenchymal stem cells (hMSCs) as delivery systems. Only with human embryonic stem cells are data available regarding stability for >2 to 3 weeks, and here, immunosuppression has been used to facilitate survival of xenografts. The purpose of the present study was to determine whether hMSCs provide stable impulse initiation over 6 weeks without the use of immunosuppression, the "dose" of hMSCs that ensures function over this period, and the catecholamine responsiveness of hMSC-packaged pacemakers. METHODS AND RESULTS: A full-length mHCN2 cDNA subcloned in a pIRES2-EGFP vector was electroporated into hMSCs. Transfection efficiency was estimated by GFP expression. I(HCN2) was measured with patch clamp, and cells were administered into the left ventricular anterior wall of adult dogs in complete heart block and with backup electronic pacemakers. Studies encompassed 6 weeks. I(HCN2) for all cells was 32.1+/-1.3 pA/pF (mean+/-SE) at -150 mV. Pacemaker function in intact dogs required 10 to 12 days to fully stabilize and persisted consistently through day 42 in dogs receiving > or =700,000 hMSCs (approximately 40% of which carried current). Rhythms were catecholamine responsive. Tissues from animals killed at 42 days manifested neither apoptosis nor humoral or cellular rejection. CONCLUSIONS: hMSCs provide a means for administering catecholamine-responsive biological pacemakers that function stably for 6 weeks and manifest no cellular or humoral rejection at that time. Cell doses >700,000 are sufficient for pacemaking when administered to left ventricular myocardium.


Assuntos
Coração/fisiologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/fisiologia , Adulto , Animais , Células Cultivadas , Cães , Condutividade Elétrica , Eletrocardiografia , Epinefrina/farmacologia , Bloqueio Cardíaco/fisiopatologia , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Canais Iônicos/genética , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Técnicas de Patch-Clamp , Canais de Potássio , Transfecção , Transplante Heterólogo
11.
Cardiovasc Res ; 74(3): 416-25, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17391659

RESUMO

OBJECTIVE: The contribution of regional electrophysiologic heterogeneity to the T-wave changes of long-term cardiac memory (CM) is not known. We mapped activation and repolarization in dogs after induction of CM and in sham animals. METHODS AND RESULTS: CM was induced by three weeks of AV-sequential pacing at the anterior free wall of the left ventricle (LV), midway between apex and base in 5 dogs. In 4 sham controls a pacemaker was implanted but ventricular pacing was not performed. At 3 weeks, unipolar electrograms were recorded (98 epicardial, 120 intramural and endocardial electrodes) during atrial stimulation (cycle length 450 ms). Activation times (AT) and repolarization times (RT) were measured and activation recovery intervals (ARIs) calculated. CM was associated with 1) deeper T waves on ECG, with no change in QT interval; 2) longer activation time at the site of stimulation in CM (29.7+/-1.0, X+/-SEM) than sham (23.9+/-1.3 ms p<0.01); 3) an LV transmural gradient in repolarization time such that repolarization at the epicardium terminated 12.4+/-2.4 ms later than at the endocardium p<0.01), in contrast to no gradient in shams (2.7+/-4.2 ms); in memory dogs, the repolarization time gradient was greatest at sites around the pacing electrode varying from 13.1+/-2.3 ms to 25.5+/-3.8 ms; 4) more negative left ventricular potentials at the peak of the body surface T wave (-4.9+/-0.8 vs -2.2+/-0.4 mV; p<0.05) but no altered right ventricular epicardial T-wave potentials. ARIs did not differ between groups. Right ventricular activation was delayed but was not associated with altered repolarization because of compensatory shortening of the right ventricular ARIs. CONCLUSION: CM-induced T-wave changes are caused by evolution of transmural repolarization gradients manifested during atrial stimulation that are maximal near the site of ventricular pacing.


Assuntos
Estimulação Cardíaca Artificial , Eletrocardiografia , Sistema de Condução Cardíaco/fisiologia , Potenciais de Ação , Animais , Cães , Endocárdio/fisiologia , Masculino , Pericárdio/fisiologia , Fatores de Tempo , Função Ventricular
12.
Heart Rhythm ; 4(3): 341-8, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17341400

RESUMO

BACKGROUND: The concept that the interval between the peak (T(peak)) and the end (T(end)) of the T wave (T(p-e)) is a measure of transmural dispersion of repolarization time is widely accepted but has not been tested rigorously by transmural mapping of the intact heart. OBJECTIVES: The purpose of this study was to test the relationship of T(p-e) to transmural dispersion of repolarization by correlating local repolarization times at endocardial, midmural, and epicardial sites in the left and right ventricles with the T wave of the ECG. METHODS: Local activation times, activation-recovery intervals, and repolarization times were measured at 98 epicardial sites and up to 120 midmural and endocardial sites in eight open-chest dogs. In four of the dogs, long-term cardiac memory was induced by 3 weeks of ventricular pacing at 130 bpm because previous data suggest that, in this setting, delayed epicardial repolarization increases transmural dispersion. The other four dogs were sham operated. RESULTS: In sham dogs, T(p-e) was 41 +/- 2.2 ms (X +/- SEM), whereas the transmural dispersion of repolarization time was 2.7 +/- 4.2 ms (not significant between endocardium and epicardium). Cardiac memory was associated with evolution of a transmural gradient of 14.5 +/- 1.9 ms (P <.02), with epicardium repolarizing later than endocardium. The corresponding T(p-e) was 43 +/- 2.3 ms (not different from sham). In combined sham and memory dogs, T(p-e) intervals did not correlate with transmural dispersion of repolarization times. In contrast, dispersion of repolarization of the whole heart (measured as the difference between the earliest and the latest moment of repolarization from all left and right ventricular, endocardial, intramural, and epicardial recording sites) did correlate with T(p-e) (P <.0005, r = 0.98), although the latter underestimated total repolarization time by approximately 35%. The explanation for this finding is that parts of the heart fully repolarize before the moment of T(peak). CONCLUSION: T(p-e) does not correlate with transmural dispersion of repolarization but is an index of total dispersion of repolarization.


Assuntos
Eletrocardiografia , Sistema de Condução Cardíaco/fisiologia , Potenciais de Ação , Análise de Variância , Animais , Estimulação Cardíaca Artificial , Cães , Eletrodos Implantados , Técnicas Eletrofisiológicas Cardíacas , Endocárdio/fisiologia , Feminino , Processamento de Imagem Assistida por Computador , Modelos Lineares , Masculino , Modelos Animais , Modelos Cardiovasculares , Pericárdio/fisiologia , Projetos de Pesquisa , Função Ventricular
13.
Circulation ; 114(10): 992-9, 2006 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-16923750

RESUMO

BACKGROUND: Biological pacemakers (BPM) implanted in canine left bundle branch function competitively with electronic pacemakers (EPM). We hypothesized that BPM engineered with the use of mE324A mutant murine HCN2 (mHCN2) genes would improve function over mHCN2 and that BPM/EPM tandems confer advantage over either approach alone. METHODS AND RESULTS: In cultured neonatal rat myocytes, activation midpoint was -46.9 mV in mE324A versus -66.1 mV in mHCN2 (P < 0.05). mE324A manifested a positive shift of voltage dependence of gating kinetics of activation and deactivation compared with mHCN2 (P < 0.05) in myocytes as well as Xenopus oocytes. In intact dogs in complete atrioventricular block, saline (control), mHCN2, or mE324A virus was injected into left bundle branch, and EPM were implanted (VVI 45 bpm). Twenty-four-hour ECGs were monitored for 14 days. With EPM discontinued, there was no difference in duration of overdrive suppression among groups. However, basal heart rates in controls were less than those in mHCN2, which did not differ from those in E324A (45 versus 57 versus 53 bpm; P < 0.05). When spontaneous rate fell below 45 bpm, EPM intervened at that rate, triggering 83% of beats in control, contrasting (P < 0.05) with 26% (mHCN2) and 36% (mE324A). On day 14, epinephrine (1 microg/kg per minute IV) induced a 50% heart rate increase in all mE324A, one third of mHCN2, and one fifth of control (P < 0.05 mE324A versus control or mHCN2). CONCLUSIONS: mE324A induces faster, more positive pacemaker current activation than mHCN2 and stable, catecholamine-sensitive rhythms in situ that compete with EPM comparably but more catecholamine responsively than mHCN2. BPM/EPM tandems function reliably, reduce the number of EPM beats, and confer sympathetic responsiveness to the tandem.


Assuntos
Canais Iônicos/fisiologia , Marca-Passo Artificial , Função Ventricular , Animais , Animais Recém-Nascidos , Linhagem Celular , Modelos Animais de Doenças , Cães , Bloqueio Cardíaco/fisiopatologia , Bloqueio Cardíaco/terapia , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Canais Iônicos/genética , Camundongos , Técnicas de Patch-Clamp , Canais de Potássio , Ratos , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/terapia
14.
Cardiovasc Res ; 71(1): 88-96, 2006 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-16626671

RESUMO

OBJECTIVE: Cardiac memory (CM) is characterized by an altered T-wave morphology, which reflects altered repolarization gradients. We hypothesized that the delayed rectifier currents, I(Kr) and I(Ks), might contribute to these repolarization changes. METHODS: We studied conscious, chronically instrumented dogs paced from the postero-lateral left ventricular (LV) wall at rates 5-10% faster than sinus rate for 3 weeks. ECGs during sinus rhythm were recorded on days 0, 7, 14 and 21 of pacing. Within 3 weeks, CM achieved steady state, hearts were excised, and epicardial and endocardial tissues and myocytes were studied. RESULTS: In unpaced controls, action potential duration to 50% and 90% repolarization (APD) in epicardium was shorter than in endocardium (P < 0.05); in CM epicardial APD increased at CL > or = 500 ms, while endocardial APD was either unchanged or decreased such that the transmural gradient seen in controls diminished (P < 0.05). A transmural I(Kr) gradient occurred in controls (epicardium>endocardium, P < 0.05) and was reversed in CM. No I(Ks) transmural gradient was found in controls, while in CM endocardial I(Ks) was greater than epicardial at greater than +50 mV. Canine ERG (cERG) mRNA and protein in epicardium > endocardium in controls (P < 0.05), and this difference was lost in CM. Expression levels of KCNQ1 and KCNE1 protein were similar in all groups. CONCLUSIONS: A transcriptionally induced change in epicardial I(Kr) contributes to the altered ventricular repolarization that characterizes CM.


Assuntos
Potenciais de Ação/fisiologia , Miócitos Cardíacos/metabolismo , Pericárdio/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Animais , Western Blotting/métodos , Estimulação Cardíaca Artificial , Cães , Eletrocardiografia , Endocárdio/metabolismo , Endocárdio/fisiologia , Canais de Potássio Éter-A-Go-Go/análise , Canais de Potássio Éter-A-Go-Go/genética , Ventrículos do Coração , Canal de Potássio KCNQ1/análise , Canal de Potássio KCNQ1/genética , Potenciais da Membrana/fisiologia , Técnicas de Patch-Clamp , Pericárdio/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/análise , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Remodelação Ventricular
15.
Heart Rhythm ; 2(12): 1376-82, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16360096

RESUMO

Cardiac memory (CM) is identified as an altered T wave on electrocardiogram and vectorcardiogram that is seen when sinus rhythm resumes after a period of abnormal myocardial activation. Specifically, the sinus rhythm T wave tracks the QRS vector of the abnormal impulse. CM frequently is induced by ventricular pacing or arrhythmias and historically has been considered of minor relevance to medical practice. Although it has long been known that CM can mimic the T-wave inversions of myocardial ischemia, we learned more recently that CM can alter the actions of antiarrhythmic drugs. Furthermore, it provides a template for investigating the mechanisms whereby ventricular pacing affects myocardial physiology. In this article we review the mechanisms believed responsible for induction of CM and some of its more recently recognized clinical manifestations. We also discuss the controversies regarding atrial memory and its potential clinical implications.


Assuntos
Eletrocardiografia , Sistema de Condução Cardíaco/fisiopatologia , Ventrículos do Coração/fisiopatologia , Remodelação Ventricular/fisiologia , Animais , Antiarrítmicos/farmacologia , Estimulação Cardíaca Artificial , Humanos
16.
Circulation ; 112(12): 1711-8, 2005 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-16157774

RESUMO

BACKGROUND: Questions remain about the contributions of transmural versus apicobasal repolarization gradients to the configuration of the T wave in control settings and after the induction of short-term cardiac memory. METHODS AND RESULTS: Short-term cardiac memory is seen as T-wave changes induced by altered ventricular activation that persists after restoration of sinus rhythm. We studied cardiac memory in anesthetized, open-chest dogs paced from the ventricle for 2 hours. Unipolar electrograms were recorded from as many as 98 epicardial and 144 intramural sites, and activation times and activation-recovery intervals (ARIs) were measured. In separate experiments, epicardial monophasic action potentials were recorded. We found no appreciable left ventricular intramural gradients in repolarization times (activation time+ARI) in either control conditions or after the induction of memory. In controls, there was a left ventricular apicobasal gradient, with the shortest repolarization times in anterobasal regions and longest repolarization times posteroapically. After induction of memory, repolarization times shortened uniformly throughout the ventricular wall. Monophasic action potential duration at 90% repolarization decreased by approximately 10 ms after induction of memory. CONCLUSIONS: In the intact canine left ventricle at physiological rates, there is no transmural gradient in repolarization. Apicobasal gradients in repolarization time, with shortest repolarization times in anterobasal areas and longest repolarization times in posteroapical regions, are important in the genesis of the T wave. Repolarization times and monophasic action potentials at the 90% repolarization level shorten after the induction of memory. The deeper T wave in the ECG after induction of memory may be explained by the more rapid phase 3 of the action potential.


Assuntos
Potenciais de Ação/fisiologia , Sistema de Condução Cardíaco/fisiologia , Função Ventricular Esquerda/fisiologia , Animais , Pressão Sanguínea , Cães , Eletrocardiografia , Eletrochoque , Masculino , Potenciais da Membrana/fisiologia , Modelos Animais
17.
Cardiovasc Res ; 68(2): 259-67, 2005 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-16054122

RESUMO

OBJECTIVE: Long-term cardiac memory (LTCM), expressed as a specific pattern of T-wave change on ECG, is associated with 1) reduced transient outward potassium current (I(to)), 2) reduced mRNA for the pore-forming protein of I(to), Kv4.3, 3) reduced cAMP response element binding protein (CREB), and 4) diminished binding to its docking site on the DNA, the cAMP response element (CRE). We hypothesized a causal link between the decrease of the transcription factor CREB and down-regulation of I(to) and one of its channel subunits, KChIP2, in LTCM. METHODS: After three weeks of left ventricular pacing to induce LTCM (8 paced, 7 sham control dogs), epicardial KChIP2 mRNA and protein levels were assessed by real-time PCR and Western blotting. Mimicking the CREB down-regulation in LTCM, CREB was knocked down in situ in other dogs using adenoviral anti-sense. Effects on the action potential notch, reflecting I(to), were investigated in situ using monophasic action potential (MAP) recordings and at the cellular level by the whole-cell patch clamp technique. CREB binding in the KChIP2 promoter region was ascertained by electrophoretic mobility-shift assays. RESULTS: In LTCM, epicardial KChIP2 mRNA and protein were reduced by 62% and 76%, respectively, compared to shams (p < 0.05). CREB binding by the canine KChIP2 promoter region was demonstrated. CREB knockdown led to disappearance of the phase1 notch in MAP and ablation of I(to). CONCLUSIONS: These results strengthen the hypothesis that down-regulation of CREB-mediated transcription underlies the attenuation of epicardial I(to) in LTCM. They also emphasize that ventricular pacing exerts effects at a subcellular level contributing to memory and conceivably to other forms of cardiac remodeling.


Assuntos
Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Miocárdio/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Potenciais de Ação , Animais , Western Blotting/métodos , Proteínas de Ligação ao Cálcio/metabolismo , Estimulação Cardíaca Artificial , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/imunologia , Cães , Regulação para Baixo , Eletrocardiografia , Ensaio de Desvio de Mobilidade Eletroforética , Modelos Animais , Oligonucleotídeos Antissenso/farmacologia , Técnicas de Patch-Clamp , Canais de Potássio de Abertura Dependente da Tensão da Membrana/análise , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Remodelação Ventricular
18.
Heart Rhythm ; 2(4): 404-10, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15851344

RESUMO

OBJECTIVES: We tested the utility and comparability of the atrial gradient and atrial ERP as early markers of electrical remodeling and a propensity to atrial fibrillation (AF). BACKGROUND: Pacing at physiologic rates from the left atrium alters the atrial gradient and is associated with atrial tachyarrhythmias. At these physiologic rates, there is no change in the atrial effective refractory period (ERP). METHODS: Sixty-one chronically instrumented mongrel dogs in complete heart block were paced from the left or right atrium at 400 to 900 bpm for 46 +/- 3 days. Dogs were monitored weekly and electrophysiologic studies conducted to determine changes in the atrial gradient, ERP, and rhythm. RESULTS: Rapid atrial pacing was associated with concordant decreases in atrial gradient, ERP, and occurrence of AF. Incidence of AF increased with increasing pacing rate. Although there ultimately was an equal incidence of AF with left atrial and right atrial pacing, the onset of AF occurred earlier with left atrial pacing. As expected, ERP decreased in both atria. Animals with long control ERP did not fibrillate. CONCLUSIONS: Rapid pacing induces changes in atrial gradient, which can be used as a noninvasive marker of electrical remodeling. AF is accompanied by decreases in atrial gradient and ERP, and the incidence is highest in dogs with short control ERP.


Assuntos
Fibrilação Atrial/fisiopatologia , Estimulação Cardíaca Artificial , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Animais , Fibrilação Atrial/diagnóstico , Modelos Animais de Doenças , Cães , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Formaldeído
19.
Circulation ; 110(5): 489-95, 2004 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-15262840

RESUMO

BACKGROUND: Calcium-insensitive transient outward current (I(to)) is important to the development of cardiac memory (CM), which itself reflects the capacity of the heart to remodel electrophysiologically. We used cardiac pacing to test the hypothesis that CM evolution can be explained by developmental maturation of I(to). METHODS AND RESULTS: Acutely anesthetized dogs from 1 day old to adult were paced from the left ventricle (VP, n=29) or left atrial appendage (AP, n=12) to induce CM. T-wave vector displacement (TVD) obtained during VP was greater than with AP (adults, 0.39+/-0.06 mV; neonates, 0.04+/-0.01 mV; P<0.05). TVD began to increase at approximately 40 days of age, reaching adult levels by approximately 200 days. Microelectrode studies performed in 18 dogs (ages 3 to 94 days) after completing the CM protocol and 20 additional dogs (1 day old to adult) revealed that the epicardial action potential notch was absent in neonates, became apparent in the young, and was deepest in adults. The relationship between TVD and epicardial notch was such that as notch magnitude increased, TVD increased (r=-0.65, P<0.05). KChIP2 and Kv4.3 mRNA (measured via reverse transcription-polymerase chain reaction) also increased with age. CONCLUSIONS: The inducibility of CM gradually increases with age in association with evolution of the epicardial action potential notch and mRNA expression for KChIP2 and Kv4.3. This suggests that the capacity of the heart to remodel electrophysiologically and to manifest memory during development depends in part on evolution of the determinants of I(to).


Assuntos
Envelhecimento/fisiologia , Proteínas de Ligação ao Cálcio/biossíntese , Eletrocardiografia , Sistema de Condução Cardíaco/crescimento & desenvolvimento , Canais de Potássio de Abertura Dependente da Tensão da Membrana/biossíntese , Potenciais de Ação , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Estimulação Cardíaca Artificial , Cães , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Sistema de Condução Cardíaco/fisiologia , Transporte de Íons , Proteínas Interatuantes com Canais de Kv , Masculino , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , RNA Mensageiro/biossíntese , Canais de Potássio Shal
20.
Circulation ; 109(4): 506-12, 2004 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-14734518

RESUMO

BACKGROUND: We hypothesized that administration of the HCN2 gene to the left bundle-branch (LBB) system of intact dogs would provide pacemaker function in the physiological range of heart rates. METHODS AND RESULTS: An adenoviral construct incorporating HCN2 and green fluorescent protein (GFP) as a marker was injected via catheter under fluoroscopic control into the posterior division of the LBB. Controls were injected with an adenoviral construct of GFP alone or saline. Animals were monitored electrocardiographically for up to 7 days after surgery, at which time they were anesthetized and subjected to vagal stimulation to permit emergence of escape pacemakers. Hearts were then removed and injection sites visually identified and removed for microelectrode study of action potentials, patch clamp studies of pacemaker current, and/or immunohistochemical studies of HCN2. For 48 hours postoperatively, 7 of 7 animals subjected to 24-hour ECG monitoring showed multiple ventricular premature depolarizations and/or ventricular tachycardia attributable to injection-induced injury. Thereafter, sinus rhythm prevailed. During vagal stimulation, HCN2-injected dogs showed rhythms originating from the left ventricle, the rate of which was significantly more rapid than in the controls. Excised posterior divisions of the LBB from HCN2-injected animals manifested automatic rates significantly greater than the controls. Isolated tissues showed immunohistochemical and biophysical evidence of overexpressed HCN2. CONCLUSIONS: A gene-therapy approach for induction of biological pacemaker activity within the LBB system provides ventricular escape rhythms that have physiologically acceptable rates. Long-term stability and feasibility of the approach remain to be tested.


Assuntos
Arritmias Cardíacas/fisiopatologia , Sistema de Condução Cardíaco , Ventrículos do Coração/fisiopatologia , Canais Iônicos/genética , Proteínas Musculares/genética , Potenciais de Ação , Adenoviridae/genética , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/terapia , Cães , Estimulação Elétrica , Eletrocardiografia , Feminino , Terapia Genética , Vetores Genéticos , Proteínas de Fluorescência Verde , Hematoma/etiologia , Hematoma/patologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Canais Iônicos/análise , Proteínas Luminescentes/genética , Masculino , Proteínas Musculares/análise , Miócitos Cardíacos/fisiologia , Marca-Passo Artificial , Técnicas de Patch-Clamp , Periodicidade , Ramos Subendocárdicos/citologia
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