RESUMO
BACKGROUND: Phosphodiesterase type-1 (PDE1) hydrolyzes cAMP and cGMP and is constitutively expressed in the heart, although cardiac effects from its acute inhibition in vivo are largely unknown. Existing data are limited to rodents expressing mostly the cGMP-favoring PDE1A isoform. Human heart predominantly expresses PDE1C with balanced selectivity for cAMP and cGMP. Here, we determined the acute effects of PDE1 inhibition in PDE1C-expressing mammals, dogs, and rabbits, in normal and failing hearts, and explored its regulatory pathways. METHODS: Conscious dogs chronically instrumented for pressure-volume relations were studied before and after tachypacing-induced heart failure (HF). A selective PDE1 inhibitor (ITI-214) was administered orally or intravenously±dobutamine. Pressure-volume analysis in anesthetized rabbits tested the role of ß-adrenergic and adenosine receptor signaling on ITI-214 effects. Sarcomere and calcium dynamics were studied in rabbit left ventricular myocytes. RESULTS: In normal and HF dogs, ITI-214 increased load-independent contractility, improved relaxation, and reduced systemic arterial resistance, raising cardiac output without altering systolic blood pressure. Heart rate increased, but less so in HF dogs. ITI-214 effects were additive to ß-adrenergic receptor agonism (dobutamine). Dobutamine but not ITI-214 increased plasma cAMP. ITI-214 induced similar cardiovascular effects in rabbits, whereas mice displayed only mild vasodilation and no contractility effects. In rabbits, ß-adrenergic receptor blockade (esmolol) prevented ITI-214-mediated chronotropy, but inotropy and vasodilation remained unchanged. By contrast, adenosine A2B-receptor blockade (MRS-1754) suppressed ITI-214 cardiovascular effects. Adding fixed-rate atrial pacing did not alter the findings. ITI-214 alone did not affect sarcomere or whole-cell calcium dynamics, whereas ß-adrenergic receptor agonism (isoproterenol) or PDE3 inhibition (cilostamide) increased both. Unlike cilostamide, which further enhanced shortening and peak calcium when combined with isoproterenol, ITI-214 had no impact on these responses. Both PDE1 and PDE3 inhibitors increased shortening and accelerated calcium decay when combined with forskolin, yet only cilostamide increased calcium transients. CONCLUSIONS: PDE1 inhibition by ITI-214 in vivo confers acute inotropic, lusitropic, and arterial vasodilatory effects in PDE1C-expressing mammals with and without HF. The effects appear related to cAMP signaling that is different from that provided via ß-adrenergic receptors or PDE3 modulation. ITI-214, which has completed phase I trials, may provide a novel therapy for HF.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Miócitos Cardíacos/fisiologia , Animais , Cálcio/metabolismo , AMP Cíclico/sangue , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Dobutamina/uso terapêutico , Cães , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Coelhos , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The indications for postmastectomy radiotherapy (PMRT) have expanded over the past decade. This study examines PMRT and reconstruction compared with a control group without radiotherapy. There were 919 reconstructed breasts identified (1999-2006) and separated into 3 groups: mastectomy with PMRT before reconstruction (n = 57), immediate reconstruction then PMRT (n = 59), and reconstruction without PMRT (n = 665). A validated questionnaire assessed patient satisfaction (response rate 73.7%). Overall complication rates for patients undergoing PMRT (before and after reconstruction) were higher than that of the controls (39.66% vs. 23.16%, P < 0.001). Immediate reconstruction before PMRT had increased overall and late (>90 days) complication rates, compared with controls (47.46% vs. 23.16%, P < 0.001; 33.90% vs. 15.59%, P < 0.001, respectively); however general and aesthetic satisfaction was similar. In contrast, PMRT before reconstruction has similar complication rates and general satisfaction with controls, but decreased aesthetic satisfaction (50% vs. 66.88%, P < 0.035).
Assuntos
Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Mamoplastia/métodos , Satisfação do Paciente , Complicações Pós-Operatórias/epidemiologia , Adulto , Neoplasias da Mama/psicologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Terapia Combinada , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Retalhos Cirúrgicos , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Background Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined. Methods and Results To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with dilated cardiomyopathy and TTNtv cardiomyopathy and not significantly different from a cohort of patients with LMNA-associated cardiomyopathy. Conclusions Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level.
Assuntos
Arritmias Cardíacas/genética , Cardiomiopatias/genética , Proteínas de Ligação a RNA/genética , Morte Súbita Cardíaca/etiologia , Humanos , Mutação , Sistema de RegistrosRESUMO
The title compound, C(24)H(12)BrCl(2)NO(4), was synthesized from 2-amino-3-bromo-1,4-naphthoquinone and 2-chloro-benzoyl chloride. The crystal structure shows that each of the chloro-phenyl rings is inclined at about 60° to the naphthoquinone ring system. The two chloro-phenyl rings adopt a conformation that ensures that chlorine substituents are anti so as to reduce electronic repulsion. An examination of the packing shows close Oâ¯Br and Clâ¯Cl contacts of 2.947â (2) and 3.346â (1)â Å, respectively. In addition, the molecules are linked by weak intermolecular C-Hâ¯O and C-Hâ¯Cl interactions.
RESUMO
The naphthoquinone ring is almost perpendicular [dihedral angle 71.02â (3)°] to the phenyl group of the title compound, C(17)H(9)Cl(2)NO(3), while the dihedral angle between the amide group and the 4-chloro-phenyl ring is 21.9â (2)°. The conformation of the N-H and C=O bonds are anti to each other. N-Hâ¯Cl hydrogen bonds link the mol-ecules into chains in the a-axis direction. In addition, these chains are linked by weak inter-molecular C-Hâ¯O inter-actions.
RESUMO
PURPOSE: To assess LVAD complications and their overall effect on mortality and determine factors associated with development of early and long-term complications. METHODS: A retrospective cohort study of patients who underwent continuous flow LVAD placement between January 1, 2000 and November 30, 2013 was performed. The incidence of complications (sepsis or bacteremia, driveline infections, gastrointestinal bleeding, pump thrombosis, cerebrovascular accidents and anemia requiring transfusion) was collected and logistic regression and Cox proportional hazards analyses were performed. RESULTS: 108 patients met our inclusion criteria. Median length of follow-up was 2.2 years. In univariable logistic regression analysis, higher blood urea nitrogen (BUN), creatinine clearance <60, no prior inotrope use, higher INTERMACS class and lower platelet count were associated with early complications. On multivariable analysis, factors associated with early complications included higher BUN (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.001-1.06 per mg/dL BUN), no prior inotrope use (OR 4.92, 95% CI 1.64- 14.7) and lower platelet count (OR 4.29, 95% CI 1.45-12.7 <200 10(3) cu mm); 24% of patients developed early complications and 18.5% developed an early and late complication. Early complications were significantly associated with death (p = 0.017). The presence of 2 or more complications was associated with a 2.7-fold increase in the odds of death (p = 0.016) and odds of death increased by 20% with each subsequent complication (p = 0.004). CONCLUSIONS: LVADs are associated with significant long-term complications including stroke and sepsis and minimizing time on LVADs may decrease the risk of complications and subsequent morbidity and mortality.
Assuntos
Insuficiência Cardíaca/terapia , Coração Auxiliar/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Idoso , Feminino , Seguimentos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Retrospectivos , Fatores de Risco , Sepse/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Resultado do TratamentoRESUMO
The 20th century saw cardiovascular disease ascend as the leading cause of death in the world. In response to the new challenge that heart disease imposed, the cardiovascular community responded with ground breaking innovations in the form of evidence based medications that have improved survival, imaging modalities that allow for precise diagnosis and guide treatment; revascularization strategies that have not only reduced morbidity, but also improved survival following an acute myocardial infarction. However the benefits have not been distributed equitably and as a result disparities have arisen in cardiovascular care. There is tremendous data from the United States demonstrating the many phenotypical forms of disparities. This paper takes a global view of disparities and highlights that disparate care is not limited to the United States and it is another challenge that the medical community should rise and face head on.
Assuntos
Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/terapia , Disparidades nos Níveis de Saúde , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Técnicas de Imagem Cardíaca/métodos , Saúde Global , Humanos , Revascularização Miocárdica/métodos , SobrevidaRESUMO
Cardiovascular disease is the leading cause of death in the United States. In 2010, the Centers for Disease Control and Prevention estimated that $444 billion was spent on cardiovascular diseases alone, about $1 of every $6 spent on health care. As life expectancy continues to increase, this annual cost will also increase, making cost-effective primary prevention of cardiovascular disease highly desirable. Because of its role in development of atherosclerosis and clinical events, dyslipidemia management is a high priority in cardiovascular prevention. Multiple major dyslipidemia guidelines have been published around the world recently, four of them by independent organizations in the United States alone. They share the goal of providing clinical guidance on optimal dyslipidemia management, but guidelines differ in their emphasis on pharmacotherapy, stratification of groups, emphasis on lifestyle modification, and use of a fixed target or percentage reduction in low density lipoprotein cholesterol. This review summarizes eight major guidelines for dyslipidemia management and considers the basis for their recommendations. Our primary aim is to enhance understanding of dyslipidemia management guidelines in patient care for primary prevention of future cardiovascular risk.
RESUMO
BACKGROUND: In the general population, the exercise treadmill testing variables of lower resting heart rate, higher peak heart rate, and greater fitness have favorable prognosis for mortality. Patients with obstructive lung disease have increased mortality risk. Furthermore, some pulmonary medications (ie, beta2-agonists) can influence heart rate. We determined whether exercise treadmill test parameters carry the same prognostic value in patients who are using versus not using pulmonary medications. METHODS: We analyzed data on 69,855 patients (mean age, 55 years) who completed a clinically indicated exercise treadmill test. Patients were defined as having "lung disease" if they were taking medications routinely used to treat obstructive lung disease (n = 6145, 9%). International Classification of Diseases, 9th Revision codes regarding the type of lung disease were not available. Multivariate-adjusted Cox models were used to determine the risk of mortality, major adverse cardiac events, and myocardial infarction over a mean of 11 years follow-up. RESULTS: Higher resting heart rate was associated with increased mortality risk, and higher peak heart rate and fitness were associated with decreased risk. No significant interaction for lung disease status was seen for the heart rate variables, but a slightly stronger protective effect was observed for higher fitness among patients with lung disease (P interaction = .032). The results were similar for major adverse cardiac events and myocardial infarction. CONCLUSIONS: Heart rate parameters achieved on exercise treadmill tests are equally prognostic among patients using versus not using pulmonary medications. Higher fitness was associated with improved clinical outcomes for both; however, the relative benefit of fitness on survival was even greater in patients using pulmonary medications compared with those not using them.
Assuntos
Teste de Esforço/estatística & dados numéricos , Pneumopatias Obstrutivas/mortalidade , Adulto , Idoso , Doença da Artéria Coronariana/epidemiologia , Feminino , Frequência Cardíaca , Humanos , Pneumopatias Obstrutivas/tratamento farmacológico , Pneumopatias Obstrutivas/fisiopatologia , Masculino , Michigan/epidemiologia , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
PURPOSE: There are few long-term studies of how the sequencing of postmastectomy radiotherapy (PMRT) and breast reconstruction (BR) affects the time to development of complications or patient satisfaction with BR. We therefore studied this issue. METHODS AND MATERIALS: One hundred thirteen women who underwent BR at Beth Israel Deaconess Medical Center (Boston, MA) from 1999-2006 and also received PMRT were included. Complications requiring surgery were categorized as early (within 90 days of BR) or late. The median length of follow-up after BR was 46.5 months. Patients' general and esthetic satisfaction was assessed with a validated questionnaire. RESULTS: Complications occurred among 32% of 57 women receiving PMRT before BR and 44% of 57 patients having BR before PMRT (p = 0.176). Early complications were more frequent in patients who had PMRT first (18%) than for those with BR first (11%) (p = 0.210); conversely, late complication rates in the two groups were 14% and 33%, respectively (p = 0.009). General satisfaction was comparable between the PMRT-first and BR-first groups (68% and 68%, respectively; p = 0.995); esthetic satisfaction rates were also similar (50% and 62%, respectively; p = 0.238). CONCLUSIONS: The sequencing of PMRT and BR did not have a substantial impact on the total risk of complications or patients' general and esthetic satisfaction. However, early complications tended to develop in patients having PMRT first, whereas patients having BR first had a higher risk of late complications. Additional study of the effects of sequencing of PMRT on particular types of reconstructions may help devise strategies for reducing these risks.
Assuntos
Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Mamoplastia/efeitos adversos , Mastectomia/efeitos adversos , Satisfação do Paciente , Complicações Pós-Operatórias , Adulto , Idoso , Neoplasias da Mama/psicologia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Terapia Combinada/psicologia , Feminino , Seguimentos , Humanos , Mamoplastia/métodos , Mamoplastia/psicologia , Pessoa de Meia-Idade , Complicações Pós-Operatórias/cirurgia , Dosagem Radioterapêutica , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Despite a growing literature on patient satisfaction in breast reconstruction, few studies have compared perforator flaps with the more commonly practiced methods. The authors compared four reconstructive techniques and identified factors influencing patient satisfaction. METHODS: All patients undergoing postmastectomy breast reconstruction between 1999 and 2006 at a single academic institution were included in our study. A total of 583 patients with tissue expander/implant, latissimus, pedicle transverse rectus abdominis muscle (TRAM), and deep inferior epigastric perforator (DIEP) flap reconstructions received a validated questionnaire on satisfaction, health-related quality of life, and sociodemographic data. RESULTS: Patient response was 75 percent, with 439 completed questionnaires including 87 tissue expander/implant, 116 latissimus, and 119 pedicle TRAM and 117 DIEP flap patients. DIEP patients had the highest level of general satisfaction at 80 percent, and pedicle TRAM patients had the highest level of aesthetic satisfaction at 77 percent (p < 0.001 and p < 0.001, respectively). Health-related quality of life and length of time since surgery were identified as significant covariates influencing patient satisfaction. After logistic regression analysis, autologous reconstruction had significantly higher general and aesthetic satisfaction than implant-based reconstruction (p = 0.017 and p < 0.001). Among the autologous reconstructions, abdominal-based flaps had significantly higher general and aesthetic satisfaction than latissimus flaps (p = 0.011 and p = 0.016). When comparing the abdominal-based reconstructions, general and aesthetic satisfaction were no longer statistically significant between pedicle TRAM and DIEP flaps (p = 0.659 and p = 0.198). CONCLUSIONS: Autologous, abdominal-based reconstructions had the highest satisfaction rates across all four groups. After logistic regression analysis, differences in patient satisfaction between pedicle TRAM and DIEP flap reconstruction were no longer observed. Discussing satisfaction outcomes with patients will help them make educated decisions about breast reconstruction.