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BACKGROUND: In patients with hypertrophic cardiomyopathy (HCM), impaired augmentation of stroke volume and diastolic dysfunction contribute to exercise intolerance. Systolic-diastolic (S-D) coupling characterizes how systolic contraction of the left ventricle (LV) primes efficient elastic recoil during early diastole. Impaired S-D coupling may contribute to the impaired cardiac response to exercise in patients with HCM. METHODS: Patients with HCM (n = 25, age = 47 ± 9 years) and healthy adults (n = 115, age = 49 ± 10 years) underwent a cardiopulmonary exercise testing (CPET) and echocardiogram. S-D coupling was defined as the ratio of LV longitudinal excursion of the mitral annulus during early diastole (EDexc) and systole (Sexc) and compared between groups. Peak oxygen uptake (peak VÌO2) (Douglas bags), cardiac index (C2H2 rebreathe), and stroke volume index (SVi) were assessed during CPET. Linear regression was performed between S-D coupling and peak VÌO2, peak cardiac index, and peak SVi. RESULTS: S-D coupling was lower in HCM (Controls: 0.63 ± 0.08, HCM: 0.56 ± 0.10, p < 0.001). Peak VÌO2 and stroke volume reserve were lower in patients with HCM (Peak VO2 Controls: 28.5 ± 5.5, HCM: 23.7 ± 7.2 mL/kg/min, p < 0.001, SV reserve: Controls 39 ± 16, HCM 30 ± 18 mL, p = 0.008). In patients with HCM, S-D coupling was associated with peak VÌO2 (r = 0.47, p = 0.018), peak cardiac index (r = 0.60, p = 0.002), and peak SVi (r = 0.63, p < 0.001). CONCLUSION: Systolic-diastolic coupling was impaired in patients with HCM and was associated with fitness and the cardiac response to exercise. Inefficient S-D coupling may link insufficient stroke volume generation, diastolic dysfunction, and exercise intolerance in HCM.
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Cardiomiopatía Hipertrófica , Diástole , Prueba de Esfuerzo , Volumen Sistólico , Sístole , Humanos , Cardiomiopatía Hipertrófica/fisiopatología , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Masculino , Femenino , Persona de Mediana Edad , Prueba de Esfuerzo/métodos , Volumen Sistólico/fisiología , Ecocardiografía/métodos , Tolerancia al Ejercicio/fisiología , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/diagnóstico por imagen , Adulto , Ejercicio Físico/fisiología , Consumo de Oxígeno/fisiologíaRESUMEN
Background Moderate intensity exercise training (MIT) is safe and effective for patients with hypertrophic cardiomyopathy, yet the efficacy of high intensity training (HIT) remains unknown. This study aimed to compare the efficacy of HIT compared with MIT in patients with hypertrophic cardiomyopathy. Methods and Results Patients with hypertrophic cardiomyopathy were randomized to either 5 months of MIT, or 1 month of MIT followed by 4 months of progressive HIT. Peak oxygen uptake (VËO2; Douglas bags), cardiac output (acetylene rebreathing), and arteriovenous oxygen difference (Fick equation) were measured before and after training. Left ventricular outflow gradient and volumes were measured by echocardiography. Fifteen patients completed training (MIT, n=8, age 52±7 years; HIT, n=7, age 42±8 years). Both HIT and MIT improved peak VËO2 by 1.3 mL/kg per min (P=0.009). HIT (+1.5 mL/kg per min) had a slightly greater effect than MIT (+1.1 mL/kg per min) but with no statistical difference (group×exercise P=0.628). A greater augmentation of arteriovenous oxygen difference occurred with exercise (Δ1.6 mL/100 mL P=0.005). HIT increased left ventricular end-diastolic volume (+17 mL, group×exercise P=0.015) compared with MIT. No serious arrhythmias or adverse cardiac events occurred. Conclusions This randomized trial of exercise training in patients with hypertrophic cardiomyopathy demonstrated that both HIT and MIT improved fitness without clear superiority of either. Although the study was underpowered for safety outcomes, no serious adverse events occurred. Exercise training resulted in salutary peripheral and cardiac adaptations. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03335332.
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Cardiomiopatía Hipertrófica , Sistema Cardiovascular , Humanos , Persona de Mediana Edad , Adulto , Ejercicio Físico , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/terapia , Corazón , OxígenoRESUMEN
BACKGROUND: Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients. OBJECTIVES: This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM. METHODS: Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout. RESULTS: From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: -40 ± 27 mm Hg, and -43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (-36 ± 27 mm Hg and -53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (-6% ± 7.5% and -12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro-B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms. CONCLUSIONS: Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.
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Cardiomiopatía Hipertrófica , Insuficiencia Cardíaca , Obstrucción del Flujo Ventricular Externo , Humanos , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/tratamiento farmacológico , Cardiomiopatía Hipertrófica/diagnósticoRESUMEN
Patients with hypertrophic cardiomyopathy (HCM) often have reduced exercise capacity, and it is unclear whether cardiovascular regulation during exercise is intact in these patients. We aimed to determine the relationship between cardiac output (QÌc) and oxygen uptake (VÌo2), and stroke volume (SV) reserve in HCM compared with healthy participants and participants with left ventricular hypertrophy (LVH) but not HCM. Sixteen patients with HCM (48 ± 7 yr, 44% female), 16 participants with LVH (49 ± 5 yr, 44% female), and 61 healthy controls (CON: 52 ± 5 yr, 52% female) completed submaximal steady-state treadmill exercise followed by a maximal exercise test. VÌo2, QÌc, SV, and arteriovenous oxygen difference were measured during rest and exercise, and QÌc/VÌo2 slopes were constructed, The QÌc/VÌo2 slope was blunted in HCM compared with CON and LVH [HCM 4.9 ± 0.7 vs. CON 5.5 ± 1.0 (P = 0.027) vs. LVH 6.0 ± 1.0 AU (P = 0.002)] and participants with HCM had a lower SV reserve (HCM 53 ± 33%, controls 83 ± 33%, LVH 82 ± 22%; HCM vs. controls P = 0.002; HCM vs. LVH P = 0.015). Despite a blunted QÌc/VÌo2 slope, 75% of patients with HCM achieved ≥80% predicted VÌo2max by augmenting a-vo2 difference at maximal exercise (16.0 ± 0.8 mL/100 mL vs. 13.8 ± 2.7 mL/100 mL, P = 0.021). Patients with HCM do not appropriately match QÌc to metabolic demand, primarily due to inadequate stroke volume augmentation. Despite this central limitation, many patients achieve normal exercise capacities by significantly increasing peripheral oxygen extraction.NEW & NOTEWORTHY Through state-of-the-art hemodynamic and oxygen uptake methodologies, this study found the cardiac output response to increasing metabolic demand is blunted among patients with hypertrophic cardiomyopathy (HCM), primarily due to a reduced stroke volume reserve. Many patients with HCM augment their peripheral oxygen extraction during maximal exercise to achieve normal exercise capacity and overcome ineffective matching of cardiac output. Peripheral adaptations that compensate for cardiac limitations may contribute to the heterogeneity of functional limitations observed within this patient population.
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Cardiomiopatía Hipertrófica , Gasto Cardíaco , Cardiomiopatía Hipertrófica/metabolismo , Prueba de Esfuerzo/métodos , Femenino , Humanos , Hipertrofia Ventricular Izquierda , Masculino , Oxígeno , Volumen Sistólico/fisiologíaRESUMEN
A 78-year-old woman with bioprosthetic mitral valve degeneration at high risk for reoperation was referred for transcatheter mitral valve replacement. We describe the use of a preemptive alcohol septal ablation pre-procedurally to minimize the risk of acute left ventricular outflow tract obstruction given the anticipated need for a bioprosthetic valve fracture. (Level of Difficulty: Advanced.).
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BACKGROUND: Excess adipose tissue has been implicated in the pathogenesis of insulin resistance and atherosclerosis and is a key risk factor for blood pressure (BP) elevation. However, circulating levels of adiponectin, a protein produced by adipose tissue and widely implicated in the pathogenesis of insulin resistance and atherosclerosis, are inversely proportional to adiposity. The relationship between adiponectin and incident hypertension has not been determined in the general US population. METHODS: Normotensive participants (n = 1233) enrolled in the Dallas Heart Study, a multiethnic, probability-based population sample of Dallas County adults were followed for median of 7 years. Retroperitoneal, intraperitoneal, visceral, and subcutaneous adipose tissue were measured at baseline by magnetic resonance imaging. Liver fat content was measured by 1 H-magnetic resonance spectroscopy. Relative risk regression was used to determine the association of adiponectin with incident hypertension after adjustment for age, race, sex, BMI, smoking, diabetes, baseline systolic BP, total cholesterol, and regional fat depot. RESULTS: Of the 1233 study participants (median age 40 years, 40% black, and 56% women), 391 (32%) had developed hypertension over a median follow-up of 7 years. Adiponectin levels were associated with reduced risk of incident hypertension (RR 0.81, 95% CI [0.68-0.96]) in the fully adjusted model, which included liver fat. Similar results were observed after adjustment for subcutaneous or visceral fat depots when tested individually or simultaneously in the model. CONCLUSION: Our study suggested a protective role of adiponectin against incident hypertension independent of body fat distribution.
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Adiponectina/metabolismo , Aterosclerosis/fisiopatología , Distribución de la Grasa Corporal/estadística & datos numéricos , Hipertensión/prevención & control , Obesidad/fisiopatología , Adiposidad , Adolescente , Adulto , Anciano , Presión Sanguínea , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/epidemiología , Hipertensión/metabolismo , Incidencia , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Texas/epidemiología , Adulto JovenAsunto(s)
Adiponectina , Péptido Natriurético Encefálico , Tejido Adiposo , Insuficiencia Cardíaca , HumanosRESUMEN
Adiponectin is a key component in multiple metabolic pathways. Studies evaluating associations of adiponectin with clinical outcomes in older adults have reported conflicting results. We investigated the association of adiponectin with mortality and cardiovascular disease (CVD) morbidity in a young, multiethnic adult population. We analyzed data from participants in the Dallas Heart Study without baseline CVD who underwent assessment of total adiponectin from 2000 to 2002. The primary outcome of all-cause mortality was assessed over median 10.4 years of follow-up using multivariable-adjusted Cox proportional hazards models. Secondary outcomes included CVD mortality, major adverse cardiovascular and cerebrovascular events (MACCE), and heart failure (HF). The study cohort included 3,263 participants, mean age 43.4 years, 44% women, and 50% black. There were 184 deaths (63 CVD), 207 MACCE, and 46 HF events. In multivariable models adjusted for age, gender, race, hypertension, diabetes, smoking, high-density lipoprotein cholesterol-C, hyperlipidemia, high-sensitivity C-reactive protein level, estimated glomerular filtration rate, and body mass index, increasing adiponectin quartiles were positively associated with all-cause mortality Q4 versus Q1 (hazard ratio [HR] = 2.27; 95% confidence interval [CI] 1.47, 3.50); CVD mortality Q4 versus Q1 (HR = 2.43; 95% CI 1.15, 5.15); MACCE Q4 versus Q1 (HR = 1.71; 95% CI 1.13, 2.60); and HF Q4 versus Q1 (HR = 2.95; 95% CI 1.14, 7.67). Findings were similar with adiponectin as a continuous variable and consistent across subgroups defined by age, gender, race, obesity, diabetes, metabolic syndrome, or elevated high-sensitivity C-reactive protein. In conclusion, higher adiponectin was associated with increased mortality and CVD morbidity in a young, multiethnic population. These findings may have implications for strategies aimed at lowering adiponectin to prevent adverse outcomes.
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Adiponectina/sangre , Enfermedades Cardiovasculares/epidemiología , Adulto , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Causas de Muerte/tendencias , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Morbilidad/tendencias , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia/tendencias , Texas/epidemiología , Factores de TiempoRESUMEN
More than 1 in 10 US adolescents have prediabetes or diabetes, and elevated glycosylated haemoglobin (HbA1C) in youth is associated with increased risk of death before the age of 55 years. We conducted a prospective, cross-sectional study of 31,546 consecutive volunteer blood donors, 16-19 years of age, who donated blood during school blood drives between 1 September 2011 and 21 December 2012 in Texas. In the overall cohort, the prevalence of elevated HbA1C was 11.5%, including 11.0% in the prediabetes range (HbA1C 5.7%-6.4%) and 0.5% in the diabetes range (HbA1C ⩾ 6.5%). The prevalence of elevated HbA1C was higher in boys compared with girls (15.7% vs. 7.9%, p < 0.001) and was especially high in racial/ethnic minorities (Blacks 32.7%, Asians 19.7%, Hispanics 13.1%) compared with Whites (8.0%, p < 0.001). There was a significant increase in total cholesterol and blood pressure across categories of increasing HbA1C in the overall cohort and stratified by sex and race/ethnicity. Blood donation programmes can serve as unique portals for health screening with potential for intervention in adolescents.
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Donantes de Sangre , Diabetes Mellitus/epidemiología , Hemoglobina Glucada/metabolismo , Estado Prediabético/epidemiología , Adolescente , Negro o Afroamericano/estadística & datos numéricos , Asiático/estadística & datos numéricos , Presión Sanguínea , Colesterol/metabolismo , Estudios de Cohortes , Estudios Transversales , Diabetes Mellitus/etnología , Diabetes Mellitus/metabolismo , Femenino , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Hipercolesterolemia/epidemiología , Hipercolesterolemia/etnología , Hipercolesterolemia/metabolismo , Hipertensión/epidemiología , Masculino , Tamizaje Masivo , Estado Prediabético/etnología , Estado Prediabético/metabolismo , Estudios Prospectivos , Población Rural , Distribución por Sexo , Estados Unidos/epidemiología , Población Urbana , Población Blanca/estadística & datos numéricos , Adulto JovenAsunto(s)
Distribución de la Grasa Corporal , Enfermedades Cardiovasculares , Obesidad/complicaciones , Adulto , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/metabolismo , Humanos , Obesidad/epidemiología , Estados Unidos/epidemiologíaRESUMEN
Therapies targeting high-density lipoprotein cholesterol content (HDL-C) have not improved coronary heart disease (CHD) outcomes. High-density lipoprotein particle concentration (HDL-P) may better predict CHD. However, the impact of race/ethnicity on the relations between HDL-P and subclinical atherosclerosis and incident CHD events has not been described. Participants from the Dallas Heart Study (DHS), a multiethnic, probability-based, population cohort of Dallas County adults, underwent the following baseline measurements: HDL-C, HDL-P by nuclear magnetic resonance imaging, and coronary artery calcium by electron-beam computed tomography. Participants were followed for a median of 9.3 years for incident CHD events (composite of first myocardial infarction, stroke, coronary revascularization, or cardiovascular death). The study comprised 1,977 participants free of CHD (51% women, 46% black). In adjusted models, HDL-C was not associated with prevalent coronary artery calcium (p = 0.13) or incident CHD overall (hazard ratio [HR] per 1 SD 0.89, 95% confidence interval [CI] 0.76 to 1.05). However, HDL-C was inversely associated with incident CHD among nonblack (adjusted HR per 1 SD 0.67, 95% CI 0.46 to 0.97) but not black participants (HR 0.94, 95% CI 0.78 to 1.13, pinteraction = 0.05). Conversely, HDL-P, adjusted for risk factors and HDL-C, was inversely associated with prevalent coronary artery calcium (p = 0.009) and with incident CHD overall (adjusted HR per 1 SD 0.73, 95% CI 0.62 to 0.86), with no interaction by black race/ethnicity (pinteraction = 0.57). In conclusion, in contrast to HDL-C, the inverse relation between HDL-P and incident CHD events is consistent across ethnicities. These findings suggest that HDL-P is superior to HDL-C in predicting prevalent atherosclerosis as well as incident CHD events across a diverse population and should be considered as a therapeutic target.
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Aterosclerosis/etnología , Negro o Afroamericano , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/etnología , Vigilancia de la Población , Medición de Riesgo/métodos , Adulto , Anciano , Aterosclerosis/sangre , Enfermedad de la Arteria Coronaria/sangre , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Factores de Riesgo , Texas/epidemiologíaRESUMEN
BACKGROUND: Obesity has been linked to the development of hypertension, but whether total adiposity or site-specific fat accumulation underpins this relationship is unclear. OBJECTIVES: This study sought to determine the relationship between adipose tissue distribution and incident hypertension. METHODS: Normotensive participants enrolled in the Dallas Heart Study were followed for a median of 7 years for the development of hypertension (systolic blood pressure [SBP] ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of blood pressure medications). Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) was quantified by magnetic resonance imaging and proton-spectroscopic imaging, and lower body fat (LBF) was imaged by dual-energy x-ray absorptiometry. Multivariable relative risk regression was performed to test the association between individual fat depots and incident hypertension, adjusting for age, sex, race/ethnicity, diabetes, smoking, SBP, and body mass index (BMI). RESULTS: Among 903 participants (median age, 40 years; 57% women; 60% nonwhite; median BMI 27.5 kg/m(2)), 230 (25%) developed incident hypertension. In multivariable analyses, higher BMI was significantly associated with incident hypertension (relative risk: 1.24; 95% confidence interval: 1.12 to 1.36, per 1-SD increase). However, when VAT, SAT, and LBF were added to the model, only VAT remained independently associated with incident hypertension (relative risk: 1.22; 95% confidence interval: 1.06 to 1.39, per 1-SD increase). CONCLUSIONS: Increased visceral adiposity, but not total or subcutaneous adiposity, was robustly associated with incident hypertension. Additional studies will be needed to elucidate the mechanisms behind this association.
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Distribución de la Grasa Corporal/estadística & datos numéricos , Índice de Masa Corporal , Hipertensión/epidemiología , Obesidad/epidemiología , Adulto , Distribución por Edad , Estudios de Cohortes , Comorbilidad , Intervalos de Confianza , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/diagnóstico , Incidencia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Obesidad/diagnóstico , Análisis de Regresión , Medición de Riesgo , Distribución por Sexo , Estadísticas no Paramétricas , TexasRESUMEN
OBJECTIVE: To determine whether increases in cardiac work lead to alterations in the plasma metabolome and whether such changes arise from the heart or peripheral organs. BACKGROUND: There is growing evidence that the heart influences systemic metabolism through endocrine effects and affecting pathways involved in energy homeostasis. METHODS: Nineteen patients referred for cardiac catheterization were enrolled. Peripheral and selective coronary sinus (CS) blood sampling was performed at serial timepoints following the initiation of pacing, and metabolite profiling was performed by liquid chromatography-mass spectrometry (LC-MS). RESULTS: Pacing-stress resulted in a 225% increase in the median rate·pressure product from baseline. Increased myocardial work induced significant changes in the peripheral concentration of 43 of 125 metabolites assayed, including large changes in purine [adenosine (+99%, pâ=â0.006), ADP (+42%, pâ=â0.01), AMP (+79%, pâ=â0.004), GDP (+69%, pâ=â0.003), GMP (+58%, pâ=â0.01), IMP (+50%, pâ=â0.03), xanthine (+61%, pâ=â0.0006)], and several bile acid metabolites. The CS changes in metabolites qualitatively mirrored those in the peripheral blood in both timing and magnitude, suggesting the heart was not the major source of the metabolite release. CONCLUSIONS: Isolated increases in myocardial work can induce changes in the plasma metabolome, but these changes do not appear to be directly cardiac in origin. A number of these dynamic metabolites have known signaling functions. Our study provides additional evidence to a growing body of literature on metabolic 'cross-talk' between the heart and other organs.
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Angina de Pecho/sangre , Ácidos y Sales Biliares/sangre , Estimulación Cardíaca Artificial , Metaboloma , Contracción Miocárdica/fisiología , Aminoácidos/metabolismo , Angina de Pecho/fisiopatología , Carbohidratos/sangre , Cateterismo Cardíaco , Estimulación Cardíaca Artificial/efectos adversos , Comorbilidad , Seno Coronario , Femenino , Corazón/fisiología , Compuestos Heterocíclicos/sangre , Humanos , Lipólisis , Masculino , Espectrometría de Masas , Síndrome Metabólico/sangre , Persona de Mediana Edad , Isquemia Miocárdica/sangre , Isquemia Miocárdica/fisiopatología , Fumar/sangre , Hormonas Tiroideas/sangre , Triptófano Hidroxilasa/metabolismoRESUMEN
OBJECTIVES: This study sought to examine the frequency and hemodynamic correlates of shortness of breath when bending forward, a symptom we have termed "bendopnea." BACKGROUND: Many heart failure patients describe bendopnea such as when putting on their shoes. This symptom has not previously been characterized. METHODS: We conducted a prospective study of 102 subjects with systolic heart failure referred for right-heart catheterization. Time to onset of bendopnea was measured prior to catheterization. Forty-six subjects also underwent hemodynamic assessment when sitting and bending. Hemodynamic profiles were assigned on the basis of whether pulmonary capillary wedge pressure (PCWP) was ≥ 22 mm Hg and cardiac index (CI) was ≤ 2.2 l/min/m(2). RESULTS: Bendopnea was present in 29 of 102 (28%) subjects with median (25th, 75th percentiles) time to onset of 8 (7, 11) seconds. Subjects with bendopnea had higher supine right atrial pressure (RAP) (p = 0.001) and PCWP (p = 0.0004) than those without bendopnea but similar CI (p = 0.2). RAP and PCWP increased comparably in subjects with and without bendopnea when bending, but CI did not change. In those with, versus without, bendopnea, there was more than a 3-fold higher frequency of a supine hemodynamic profile consisting of elevated PCWP with low CI (55% vs. 16%, respectively, p < 0.001) but no association with a profile of elevated PCWP with normal CI (p = 0.95). CONCLUSIONS: Bendopnea is mediated via a further increase in filling pressures during bending when filling pressures are already high, particularly if CI is reduced. Awareness of bendopnea should improve noninvasive assessment of hemodynamics in subjects with heart failure.
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Disnea/etiología , Insuficiencia Cardíaca/complicaciones , Postura/fisiología , Anciano , Disnea/fisiopatología , Femenino , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/fisiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Posición Supina/fisiologíaRESUMEN
BACKGROUND: Reperfusion accounts for a substantial fraction of the myocardial injury occurring with ischemic heart disease. Yet, no standard therapies are available targeting reperfusion injury. Here, we tested the hypothesis that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor approved for cancer treatment by the US Food and Drug Administration, will blunt reperfusion injury. METHODS AND RESULTS: Twenty-one rabbits were randomly assigned to 3 groups: (1) vehicle control, (2) SAHA pretreatment (1 day before and at surgery), and (3) SAHA treatment at the time of reperfusion only. Each arm was subjected to ischemia/reperfusion surgery (30 minutes coronary ligation, 24 hours reperfusion). In addition, cultured neonatal and adult rat ventricular cardiomyocytes were subjected to simulated ischemia/reperfusion to probe mechanism. SAHA reduced infarct size and partially rescued systolic function when administered either before surgery (pretreatment) or solely at the time of reperfusion. SAHA plasma concentrations were similar to those achieved in patients with cancer. In the infarct border zone, SAHA increased autophagic flux, assayed in both rabbit myocardium and in mice harboring an RFP-GFP-LC3 transgene. In cultured myocytes subjected to simulated ischemia/reperfusion, SAHA pretreatment reduced cell death by 40%. This reduction in cell death correlated with increased autophagic activity in SAHA-treated cells. RNAi-mediated knockdown of ATG7 and ATG5, essential autophagy proteins, abolished SAHA's cardioprotective effects. CONCLUSIONS: The US Food and Drug Administration-approved anticancer histone deacetylase inhibitor, SAHA, reduces myocardial infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during ischemia/reperfusion occur, at least in part, through the induction of autophagic flux.
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Autofagia/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/efectos de los fármacos , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Animales , Animales Modificados Genéticamente , Apoptosis/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/patología , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/patología , Miocitos Cardíacos/patología , Conejos , Ratas , Ratas Sprague-Dawley , VorinostatRESUMEN
BACKGROUND: The Fick principle (cardiac output = oxygen uptake ( O2)/systemic arterio-venous oxygen difference) is used to determine cardiac output in numerous clinical situations. However, estimated rather than measured O2 is commonly used because of complexities of the measurement, though the accuracy of estimation remains uncertain in contemporary clinical practice. METHODS AND RESULTS: From 1996 to 2005, resting O2 was measured via the Douglas bag technique in adult patients undergoing right heart catheterization. Resting O2 was estimated by each of 3 published formulae. Agreement between measured and estimated O2 was assessed overall, and across strata of body mass index, sex, and age. The study included 535 patients, with mean age 55 yrs, mean body mass index 28.4 kg/m2; 53% women; 64% non-white. Mean (±standard deviation) measured O2 was 241 ± 57 ml/min. Measured O2 differed significantly from values derived from all 3 formulae, with median (interquartile range) absolute differences of 28.4 (13.1, 50.2) ml/min, 37.7 (19.4, 63.3) ml/min, and 31.7 (14.4, 54.5) ml/min, for the formulae of Dehmer, LaFarge, and Bergstra, respectively (P<0.0001 for each). The measured and estimated values differed by >25% in 17% to 25% of patients depending on the formula used. Median absolute differences were greater in severely obese patients (body mass index > 40 kg/m2), but were not affected by sex or age. CONCLUSIONS: Estimates of resting O2 derived from conventional formulae are inaccurate, especially in severely obese individuals. When accurate hemodynamic assessment is important for clinical decision-making, O2 should be directly measured.
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Cateterismo Cardíaco , Gasto Cardíaco/fisiología , Consumo de Oxígeno/fisiología , Descanso/fisiología , Adulto , Anciano , Toma de Decisiones , Femenino , Hemodinámica/fisiología , Humanos , Masculino , Persona de Mediana Edad , Modelos Cardiovasculares , Monitoreo Fisiológico/métodos , Curva ROC , Estudios RetrospectivosRESUMEN
BACKGROUND: Prediabetes defined by fasting plasma glucose (FPG) and glycosylated haemoglobin (HbA1c) predicts incident diabetes, but their individual and joint associations with micro- and macro-vascular risk remain poorly defined. METHODS: FPG, HbA1c, coronary artery calcium (CAC), carotid wall thickness, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) were measured in adults free from prior diabetes or cardiovascular disease (CVD) in the Dallas Heart Study 2 (DHS-2), a population-based cohort study. Prediabetes was defined by FPG 100-125 mg/dL and/or HbA1c 5.7%-6.4%. Multivariable logistic regression was used to analyse associations of HbA1c and/or FPG in the prediabetes range with subclinical atherosclerosis and renal measures. RESULTS: The study comprised 2340 participants, median age = 49 years; 60% women and 50% black. Those with prediabetes were older (52 vs 48 years), more often men (63% vs 53%), black (53% vs 47%) and obese (58% vs 40%; p < 0.001 for each). Prediabetes was captured by FPG alone (43%), HbA1c alone (30%) or both (27%). Those with prediabetes by HbA1c or FPG versus normal HbA1c/FPG had more CAC [odds ratio (OR) = 1.8; 95% confidence interval (CI) = 1.5-2.2], higher carotid wall thickness (1.32 vs 1.29 mm, p < 0.001), eGFR < 60 mL/min [OR = 1.6 (95% CI = 1.1-2.4)], UACR > 30 mg/dL [OR = 1.8 (95% CI = 1.2-2.7)] and a higher odds for the composite eGFR + UACR [chronic kidney disease (CKD) ≥ 2] [OR = 1.9 (95% CI = 1.5-2.6)]. After multivariable adjustment, none of these associations remained significant. CONCLUSION: Prediabetes defined by HbA1c and/or FPG criteria is crudely associated with markers of diabetic macro- and micro-vascular disease, but not after statistical adjustment, suggesting the relationships are attributable to other characteristics of the prediabetes population.
Asunto(s)
Aterosclerosis/epidemiología , Glucemia/análisis , Angiopatías Diabéticas/epidemiología , Nefropatías Diabéticas/epidemiología , Hemoglobina Glucada/análisis , Estado Prediabético/diagnóstico , Insuficiencia Renal/epidemiología , Centros Médicos Académicos , Adulto , Aterosclerosis/complicaciones , Aterosclerosis/diagnóstico , Aterosclerosis/fisiopatología , Estudios de Cohortes , Estudios Transversales , Angiopatías Diabéticas/complicaciones , Angiopatías Diabéticas/diagnóstico , Angiopatías Diabéticas/fisiopatología , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/fisiopatología , Diagnóstico Precoz , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estado Prediabético/sangre , Estado Prediabético/complicaciones , Prevalencia , Insuficiencia Renal/complicaciones , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/fisiopatología , Factores de Riesgo , Índice de Severidad de la Enfermedad , Texas/epidemiología , Salud UrbanaRESUMEN
BACKGROUND: Aggregation of metabolic risk factors-i.e., elevated plasma triglyceride (TG), reduced high-density lipoprotein cholesterol (HDL-C), elevated blood pressure, and raised plasma glucose-convey increased risk for atherosclerotic cardiovascular disease and type 2 diabetes. METHODS: This study was carried out to determine the association of waist girth, ethnicity, and gender with susceptibility for metabolic risk. Included were 1671 adult women (50.7% black) and 1339 men (46.5% black) enrolled in the Dallas Heart Study. Subjects were stratified into three categories by waist girth-low, intermediate, and high, corresponding to BMI ranges of <25 kg/m(2), 25-29.9 kg/m(2), and ≥30 kg/m(2). RESULTS: Risk factor prevalence rose progressively through each waist-girth category. However, even among those with high waist-girth, prevalence of three or more risk factors was less than 50%. Several differences among the ethnic groups were noted; for example, Hispanic men had a higher prevalence of elevated TG compared to whites; black men, on the other hand, had a lower frequency of high TG. There were also fewer black men with low HDL-C than in the other groups. Black and Hispanic men had a higher prevalence of elevated glucose and updated homeostasis model assessment of insulin resistance (HOMA2-IR) than whites. More black men had elevated blood pressure than other groups. These differences were less pronounced among ethnic groups of women. CONCLUSION: Although ethnic and gender differences in risk factor prevalence may exist, it is notable that the majority of subjects, even when obese, did not have elevated risk factors. This finding points to the need to focus largely on subjects with metabolic risk factors when implementing therapeutic interventions.