RESUMO
BACKGROUND: Leakage of Ca2+ from the sarcoplasmic reticulum (SR) is a critical contributing factor to heart failure pathophysiology. Therefore, reducing SR Ca2+ leaks may provide significant additive benefits when used in combination with conventional therapies. Dantrolene, a drug routinely used to treat malignant hyperthermia, also stabilizes the cardiac isoform of the release channel (RyR2), thus decreasing SR Ca2+ leaks. The purpose of this study is to evaluate the effect of chronic administration of dantrolene on heart failure and lethal arrhythmia in patients with chronic heart failure and reduced ejection fraction in a multicenter, randomized, double-blind, controlled study. METHODS: Patients with chronic heart failure who had functional status of New York Heart Association class II and III and a left ventricular ejection fraction <40% were treated according to the Japanese Circulation Society, the European Society of Cardiology, and the American Heart Association/the American College of Cardiology guidelines for diagnosis and treatment of acute and chronic heart failure. Patients were randomized and divided into two groups in a double-blind fashion: dantrolene group and placebo group (target sample size: 300 cases). These drugs were administered for 96 weeks. The primary endpoint is cardiovascular death, first hospitalization for exacerbation of heart failure, or lethal arrhythmia [ventricular tachycardia (VT) storm, sustained VT, ventricular fibrillation] for 2 years after starting administration of dantrolene 1 cap (25mg) three times daily (if not tolerable, two times daily) or matching placebo. RESULTS: This paper presents the rationale and trial design of the study. Recruitment for the study started on 8 December 2017. CONCLUSIONS: The results of this trial will clarify the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction during guideline-directed medical treatment.
Assuntos
Dantroleno/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Taquicardia Ventricular/tratamento farmacológico , Doença Crônica , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Morbidade , Projetos de Pesquisa , Volume Sistólico , Taquicardia Ventricular/epidemiologia , Taquicardia Ventricular/mortalidade , Taquicardia Ventricular/fisiopatologia , Resultado do TratamentoRESUMO
BACKGROUND: In heart failure, protein kinase A-mediated hyperphosphorylation of ryanodine receptors (RyRs) in sarcoplasmic reticulum (SR) causes dissociation of FKBP12.6 from RyRs. This results in an abnormal Ca2+ leak through RyRs, possibly leading to cardiac dysfunction. In the present study, we assess whether beta-blockers can correct this defect in RyR in tachycardia-induced heart failure and thereby improve cardiac function. METHODS AND RESULTS: SRs were isolated from dog left ventricular muscles (normal group, 4 weeks of rapid right ventricular pacing with or without propranolol [P(+) or P(-)]). End-diastolic and end-systolic diameters both increased less in P(+) than P(-), associated with a smaller decrease in fractional shortening in P(+). In SR from P(-), a prominent Ca2+ leak was observed, and FK506 (which dissociates FKBP12.6 from RyR) did not induce an additional Ca2+ leak. However, there was no appreciable Ca2+ leak in SR from P(+), although FK506 induced a Ca2+ leak as in normal SRs. In SR from P(+), an FK506-induced conformational change in RyR, which was virtually absent in SR from P(-), was observed as in normal SRs. Both the stoichiometry of FKBP12.6 versus RyR, assessed by [3H]FK506 and [3H]ryanodine binding assays, and the protein expression of FKBP12.6, assessed by Western blot analysis, were restored by propranolol toward the levels seen in normal SRs. CONCLUSIONS: Low-dose propranolol corrects the defective interaction of FKBP12.6 with RyR (restoration of RyR conformational change and prevention of Ca2+ leak from RyR), apparently resulting in an attenuation of intracellular Ca2+ overload and hence preventing the development of left ventricular remodeling in heart failure.
Assuntos
Insuficiência Cardíaca/prevenção & controle , Insuficiência Cardíaca/fisiopatologia , Miocárdio/metabolismo , Propranolol/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Cálcio/metabolismo , Estimulação Cardíaca Artificial , Diástole/efeitos dos fármacos , Modelos Animais de Doenças , Cães , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Conformação Proteica/efeitos dos fármacos , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo , Sístole/efeitos dos fármacos , Tacrolimo/farmacologia , Remodelação Ventricular/efeitos dos fármacosRESUMO
BACKGROUND: Although angiotensin II receptor blockade is considered to be useful for the treatment of human heart failure, little beneficial hemodynamic effect has been shown in some experimental failing hearts. In this study, we assessed the effect of an angiotensin II receptor blocker, valsartan, on sarcoplasmic reticulum (SR) function, defectiveness of which is a major pathogenic mechanism in heart failure. METHODS AND RESULTS: SR vesicles were isolated from dog left ventricular muscle (normal or exposed to 4-week rapid ventricular pacing with or without valsartan). In the untreated and valsartan-treated paced dogs, cardiac function showed similar deterioration (compared with before pacing). However, both the density of beta-receptors and the contractile response to dobutamine were greater in the valsartan-treated paced dogs than in the untreated paced dogs. In untreated paced hearts, the ryanodine receptor was protein kinase A-hyperphosphorylated, showed an abnormal Ca2+ leak, and had a decreased amount of ryanodine receptor-bound FKBP12.6. No such phenomena were seen in the valsartan-treated paced hearts. Both the SR Ca2+ uptake function and the amount of Ca2+-ATPase were decreased in the untreated failing SR, but both were restored in the valsartan-treated SR. CONCLUSIONS: During the development of pacing-induced heart failure, valsartan preserved the density of beta-receptors and concurrently restored SR function without improving resting cardiac function.
Assuntos
Angiotensina II/antagonistas & inibidores , Insuficiência Cardíaca/tratamento farmacológico , Retículo Sarcoplasmático/efeitos dos fármacos , Tetrazóis/uso terapêutico , Valina/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Animais , Sinalização do Cálcio/efeitos dos fármacos , ATPases Transportadoras de Cálcio/metabolismo , Estimulação Cardíaca Artificial/efeitos adversos , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dobutamina/farmacologia , Cães , Avaliação Pré-Clínica de Medicamentos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Contração Miocárdica/efeitos dos fármacos , Norepinefrina/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Receptores Adrenérgicos beta/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/fisiologia , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/fisiopatologia , Proteínas de Ligação a Tacrolimo/metabolismo , Tetrazóis/farmacologia , Valina/análogos & derivados , Valina/farmacologia , Valsartana , Remodelação Ventricular/efeitos dos fármacosRESUMO
BACKGROUND: The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury. METHODS AND RESULTS: Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts. CONCLUSIONS: During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.
Assuntos
Insuficiência Cardíaca/prevenção & controle , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Tiazepinas/uso terapêutico , Animais , Cálcio/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/farmacologia , Cães , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica , Transporte de Íons , Modelos Cardiovasculares , Miocárdio/metabolismo , Fosforilação , Retículo Sarcoplasmático/metabolismo , Tacrolimo/metabolismo , Proteínas de Ligação a Tacrolimo/análise , Remodelação VentricularRESUMO
To establish the relationship between the cross-sectional geometry of the post-deployment stent and the degree of in-stent neointimal hyperplasia (INH), intravascular ultrasound (IVUS) was used to examine cross-sections of the coronary arteries from 23 patients with coronary stents 6 months after implantation. Stent cross-sectional area (Sa) and stent perimeter (Sp) from 200 stent cross-sections, and the stent radius (Sr) and thickness of INH (Id) of 2,880 radial axes, were measured, and the mean degree of roundness (Rd) of stent cross-section was calculated for each stent as Rd=4piSa/Sp2. The degree of deformity (Df) of the stent cross-section was also calculated by comparing it with a hypothetical circle (the area of this hypothetical circle was equal to the Sa): Df=Sr/R, where R is the radius of the hypothetical circle. The area of INH was significantly larger in the Rd<0.87 group (n=84) than in the Rd> or =0.87 group (n=116) (3.83+/-1.26 vs 3.16+/-1.32 mm2, p<0.0005). There were significant differences in the thickness of INH among the 3 groups classified by the value of Df (Df<0.95: n=425, 0.21+/-0.12mm; 0.95< or =Df<1.05: n=2008, 0.29+/-0.15mm; Df> or =1.05: n=447, 0.34+/-0.15mm, overall p<0.0001). These data suggest that in-stent neointimal proliferation is more likely to occur in stented coronary arteries with a more oval than rounded cross-section, and particularly within the more pronounced and curved portion of the oval.
Assuntos
Vasos Coronários/diagnóstico por imagem , Stents/efeitos adversos , Ultrassonografia de Intervenção , Adulto , Idoso , Reestenose Coronária/etiologia , Falha de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Defective interaction between FKBP12.6 and ryanodine receptors (RyR) is a possible cause of cardiac dysfunction in heart failure (HF). Here, we assess whether the new cardioprotective agent JTV519 can correct it in tachycardia-induced HF. HF was induced in dogs by 4-wk rapid ventricular pacing, and sarcoplasmic reticulum (SR) was isolated from left ventricular muscles. In failing SR, JTV519 increased the rate of Ca(2+) release and [(3)H]ryanodine binding. RyR were then labeled in a site-directed fashion with the fluorescent conformational probe methylcoumarin acetamide. In failing SR, the polylysine induced a rapid change in methylcoumarin acetamide fluorescence, presumably because the channel opening preceding the Ca(2+) release was smaller than in normal SR (consistent with a decreased rate of Ca(2+) release in failing SR), and JTV519 increased it. In conclusion, JTV519, a new 1,4-benzothiazepine derivative, corrected the defective channel gating in RyR (increase in both the rapid conformational change and the subsequent Ca(2+) release rate) in HF.