RESUMEN
BACKGROUND: Baseline plasma androgen-receptor copy number (AR-CN) is a promising biomarker for metastatic castration-resistant prostate cancer (mCRPC) outcome and treatment response; however, the role of its longitudinal testing is unproven. We aimed to evaluate the prognostic role of AR-CN assessed before subsequent treatment lines in mCRPC patients. METHODS: A subgroup analysis of a prospective multicenter biomarker trial (IRSTB030) was carried out. Plasma AR-CN status (classified as normal or gain, cut-off value = 2) was assessed with digital PCR before each treatment line. RESULTS: Forty mCRPC patients receiving sequentially docetaxel, cabazitaxel and an AR signaling inhibitor (abiraterone or enzalutamide) were analyzed. At multivariate analysis, at each assessment overall survival (OS) was independently correlated with AR-CN status [first line: hazard ratio (HR) 4.1 [95% confidence interval (CI) 1.6-10.5]; second line: HR 2.4 (95% CI 1.1-5.3); third line: HR 2.1 (95% CI 1.0-4.3)] and median prostate-specific antigen [first line: HR 4.4 (95% CI 1.8-10.9); second line: HR 3.4 (95% CI 1.6-7.2); third line: HR 2.5 (95% CI 1.2-5.6)]. In the three subsequent assessments, AR-CN status changed from normal to gain in 15 (38%) patients. These patients had longer OS (47 months) compared with patients presenting AR-CN gain from first assessment (36 months), but shorter than those maintaining normal AR-CN (69 months) (P = 0.003). CONCLUSIONS: Plasma AR-CN correlates with survival not only at baseline (before first treatment), but also in the assessments before the following lines. Interestingly, AR-CN status may change from normal to gain across subsequent treatments in a significant number of cases, identifying a group of patients with intermediate outcomes. Longitudinal assessment of AR-CN status could represent a promising method to capture mCRPC intrinsic heterogeneity and to improve clinical management.
Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos , Masculino , Humanos , Receptores Androgénicos/genética , Receptores Androgénicos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Variaciones en el Número de Copia de ADN , Estudios Prospectivos , Antígeno Prostático Específico/uso terapéuticoRESUMEN
In localized prostate cancer (PCa), Grade Group (GG) and Gleason Score (GS) have a well-established prognostic role. In metastatic castration resistant prostate cancer (mCRPC), the prognostic role of GS and GG is less defined. In first-line treatment of mCRPC, androgen receptor (AR)-directed drugs (abiraterone acetate, enzalutamide) and docetaxel represent the referring options. There is no evidence that the GS/GG systems can add information to guide the choice between AR-directed drugs and docetaxel in the first-line setting of mCRPC. Nowadays there are no validated biomarkers, which define patients who may benefit or not from hormonal treatments or chemotherapy. Androgen receptor (AR) copy number variations (CNV) are predictive factors of poor response to abiraterone and enzalutamide. There are no available data about the association between AR CNV and GG. In this retrospective study, we analysed the association of the highest GG score with AR CNV and their impact on the clinical outcome of AR-directed drugs and docetaxel as first-line therapy for mCRPC patients. Patients benefit from docetaxel, abiraterone or enzalutamide regardless the GG. However, the presence of GG5 and AR CNV gain identifies a subgroup of patients with poor prognosis, which could benefit from front-line docetaxel instead of AR-directed drugs.
Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Variaciones en el Número de Copia de ADN , Docetaxel/uso terapéutico , Humanos , Masculino , Nitrilos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/genética , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Androgen receptor (AR) signaling inhibitors represent the standard treatment in metastatic castration resistance prostate cancer (mCRPC) patients. However, some patients display a primary resistance, and several studies investigated the role of the AR as a predictive biomarker of response to treatment. This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients. METHODS: Six milliliters of plasma samples were collected before first-line treatment with abiraterone or enzalutamide. Circulating free DNA (cfDNA) and exosome-RNA were isolated for analysis of AR gain and AR splice variant 7 (AR-V7), respectively, by digital droplet PCR. RESULTS: Eighty-four mCRPC patients received abiraterone (n = 40) or enzalutamide (n = 44) as first-line therapy. Twelve patients (14.3%) presented AR gain and 30 (35.7%) AR-V7+ at baseline. Median progression-free survival (PFS) and overall survival (OS) were significantly longer in AR-V7- vs AR-V7+ patients (24.3 vs 5.4 months, p < 0.0001; not reached vs 16.2 months, p = 0.0001, respectively). Patients carrying the AR gain had a median PFS of 4.8 vs 24.3 months for AR normal patients (p < 0.0001). Median OS was significantly longer in AR normal vs patients with AR gain (not reached vs 8.17 months, p < 0.0001). A significant correlation between AR-V7 and AR gain was observed (r = 0.28; p = 0.01). The AR gain/AR-V7 combined analysis confirmed a strong predictive effect for biomarkers combination vs patients without any AR aberration (PFS 3.8 vs 28 month, respectively; OS 6.1 vs not reached, respectively; p < 0.0001). CONCLUSIONS: The present study demonstrates that cfDNA and exosome-RNA are both a reliable source of AR variants and their combined detection in liquid biopsy predicts resistance to AR signaling inhibitors.
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Empalme Alternativo , Androstenos/uso terapéutico , Benzamidas/uso terapéutico , Ácidos Nucleicos Libres de Células/genética , Exosomas/genética , Nitrilos/uso terapéutico , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/genética , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/sangre , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The association between choline uptake and androgen receptor (AR) expression is suggested by the upregulation of choline kinase-alpha in prostate cancer. Recently, detection of AR aberration in cell-free DNA as well as early 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) were associated with outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone and enzalutamide. We aimed to make a direct comparison between circulating AR copy number (CN) and choline uptake at FCH-PET/CT. We analysed 80 mCRPC patients progressing after docetaxel treated with abiraterone (n = 47) or enzalutamide (n = 33). We analysed AR CN from plasma samples using digital PCR and Taqman CN assays and total lesion activity (TLA) and metabolic tumor volume (MTV) on FCH-PET/CT at baseline. A meaningful correlation was showed among AR gain and TLA/MTV compared to AR non-gained cases (P = 0.001 and P = 0.004, respectively), independently from type of treatment. Multivariate analysis revealed that AR CN and only TLA were associated with both shorter PFS (P < 0.0009 and P = 0.026, respectively) and OS (P < 0.031 and P = 0.039, respectively). AR gain appeared significantly correlated with choline uptake represented mainly by TLA. Further prospective studies are warranted to better address this pathway of AR-signalling and to identify multiplex biomarker strategies including plasma AR and FCH-PET/CT in mCRPC patients.
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Adenocarcinoma/tratamiento farmacológico , Cloro/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/sangre , Receptores Androgénicos/genética , Adenocarcinoma/sangre , Adulto , Anciano , Anciano de 80 o más Años , Androstenos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas , Biomarcadores de Tumor/metabolismo , Colina/análogos & derivados , Colina/metabolismo , Docetaxel/uso terapéutico , Dosificación de Gen , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/uso terapéutico , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata Resistentes a la Castración/sangre , Transducción de SeñalRESUMEN
BACKGROUND: There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC. METHODS: We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial). RESULTS: In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74-9.10; P < 0.001 and HR 3.81; 95% CI 2.28-6.37; P < 0.001, respectively], PFS (HR 2.18; 95% CI 1.08-4.39; P = 0.03, and HR 1.95; 95% CI 1.23-3.11; P = 0.01, respectively) and rate of PSA decline ≥50% [odds ratio (OR), 4.7; 95% CI 1.17-19.17; P = 0.035 and OR, 5.0; 95% CI 1.70-14.91; P = 0.003, respectively]. AR mutations [2105T>A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; P < 0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26-19.93; P < 0.001) and OS (HR 11.08; 95% CI 2.16-56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts. CONCLUSION: Plasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required. CLINICAL TRIAL NUMBER: NCT02288936 (PREMIERE trial).
Asunto(s)
Androstenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/sangre , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/sangre , Adulto , Anciano , Anciano de 80 o más Años , Androstenos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Benzamidas , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Análisis Mutacional de ADN , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Europa (Continente) , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex , Análisis Multivariante , Mutación , Nitrilos , Oportunidad Relativa , Selección de Paciente , Feniltiohidantoína/efectos adversos , Feniltiohidantoína/uso terapéutico , Medicina de Precisión , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Receptores Androgénicos/genética , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Esofagitis/inducido químicamente , Esofagoscopía , Neoplasias Hepáticas/tratamiento farmacológico , Piperazinas/efectos adversos , Pirimidinas/efectos adversos , Benzamidas , Biopsia con Aguja , Quimioterapia Adyuvante , Esofagitis/patología , Estudios de Seguimiento , Gastrectomía/métodos , Tumores del Estroma Gastrointestinal/secundario , Tumores del Estroma Gastrointestinal/terapia , Humanos , Mesilato de Imatinib , Inmunohistoquímica , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Medición de Riesgo , Índice de Severidad de la Enfermedad , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Tomografía Computarizada por Rayos XRESUMEN
We conducted an echocardiographic study to determine the incidence and spectrum of morphologic and functional cardiac abnormalities in systemic lupus erythematosus (SLE) and to relate these findings to the disease activity and duration, and the presence of antiphospholipid (APL) antibodies. Thirty consecutive patients with LES (5 male and 25 female, mean age 37 +/- 11 years) were studied with a clinical cardiovascular examination and M-mode, 2-D Doppler echocardiogram. All patients fulfilled the American Rheumatism Association criteria for diagnosis of SLE. Disease activity was scored using the "Lupus Activity Criteria Count". The duration of the disease was less than 1 year in 5 patients (16.7%), between 1 and 5 years in 7 (23.3%), and superior to 5 years in 18 (60%). No patient had a history of rheumatic fever or infective endocarditis. All patients had received steroid therapy. In 26.7% of patients the disease was active, and in 33.3% APL antibodies were present. Patients were matched by number, age and sex with the control group. In 73.3% of the patients the echocardiogram resulted abnormal; valvular disease occurred in 30% and the echocardiographic features were of diffuse thickening, with 4 mitral and 2 aortic regurgitations. No valvular dysfunctions were significant, nor was Libman-Sacks endocarditis present. Pericardial disease, effusion or thickening was detected in 33.3% of the echocardiograms. Furthermore, there was one patient with left ventricular mild hypertrophy; 2 with a mild enlargement of the left ventricle with no segmental abnormalities of wall motion and no systolic disfunction; 8 patients (26.7%) were normal. Compared with the control group, patients with SLE had an increased prevalence of echocardiographic abnormalities, especially pericardial (p < 0.001) and valvular (p < 0.01). No association was found between activity, duration of the disease and prevalence of cardiac abnormalities. On the contrary, an association between the presence of APL antibodies and cardiac abnormalities at the echocardiographic examination was evident (p < 0.05).
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Anticuerpos Antifosfolípidos/sangre , Cardiopatías/epidemiología , Lupus Eritematoso Sistémico/complicaciones , Adulto , Distribución de Chi-Cuadrado , Enfermedad Crónica , Ecocardiografía , Ecocardiografía Doppler , Femenino , Cardiopatías/diagnóstico por imagen , Cardiopatías/etiología , Cardiopatías/inmunología , Humanos , Lupus Eritematoso Sistémico/diagnóstico por imagen , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , PrevalenciaRESUMEN
The authors evaluated the efficacy of medium term prophylaxis of atrial fibrillation (AF) with propafenon (P) in 33 symptomatic patients. Consecutive patients were treated with P replacing previous therapy with amiodarone (A) withdrawn on account of adverse side effects occurring on average after 1.8 years' treatment. Quantification of AF episodes was based on symptoms reported by patients, ECG, and dynamic Holter-ECG performed every 3-6 months. During A treatment (average daily dosage 216 mg) 32% of patients had reported more than two episodes of AF, 52% one or two episodes, and 16 none during the last 6 months. During 6 months of P treatment (average daily dosage 586 mg) 28% had more than two episodes, 64% had one or two, and 8% had none. The difference of incidence of AF episodes between the two treatments was not statistically significant. Side effects requiring withdrawal of the drug were not observed with P. The results obtained confirm P as a valid therapeutic resource for treatment of recurrent paroxysmall AF. In addition, the drug was also well tolerated during medium term application.
Asunto(s)
Amiodarona/efectos adversos , Fibrilación Atrial/prevención & control , Propafenona/uso terapéutico , Adulto , Anciano , Evaluación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Many side-effects of alpha interferon (alpha-I) therapy have occurred as a result of its widespread clinical applications. The hypothesis of alpha-I related cardiomyopathy is particularly interesting. Our study involved echocardiographic evaluation of left ventricular function and cardiovascular complications in 35 patients with chronic hepatitis treated with alpha-I at 20 MU/week for an average of 10.8 months. The results were compared with those of a control group. Of the values studied, only Max E V and the E/A ratio were statistically significant. No cardiovascular side-effects were found.
Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Ecocardiografía Doppler , Ecocardiografía , Interferón-alfa/efectos adversos , Función Ventricular Izquierda/efectos de los fármacos , Adulto , Sistema Cardiovascular/diagnóstico por imagen , Sistema Cardiovascular/fisiopatología , Enfermedad Crónica , Evaluación de Medicamentos , Femenino , Hepatitis/diagnóstico por imagen , Hepatitis/fisiopatología , Hepatitis/terapia , Humanos , Masculino , Persona de Mediana EdadRESUMEN
In order to assess whether the metabolic clearance of insulin changes overnight, 11 patients with Type 1 (insulin-dependent) diabetes and low insulin antibody titre, and 6 nondiabetic subjects were studied. In these studies insulin was always infused by a Harvard pump. Initially, the nocturnal insulin requirements were assessed in the diabetic patients by an overnight feedback insulin infusion to maintain euglycaemia. The insulin requirements decreased continuously after midnight to a nadir of 0.115 +/- 0.014 mU X kg-1 X min-1 at 04.30 hours, but after 05.00 hours the insulin requirements increased nearly 40 percent to a maximum of 0.16 +/- 0.012 mU X kg-1 X min-1 at 07.00 hours. To assess whether plasma insulin clearance changes overnight, the diabetic patients were studied on two different occasions, from 22.00-02.30 hours and from 04.00-08.30 hours. During each of these two studies insulin was infused in sequential steps of 90 min each at the rate of 0.13, 0.40 and 0.20 mU X kg-1 X min-1. Despite changes in plasma free insulin concentration, the metabolic clearance of insulin in the interval 22.00-02.30 hours (12.6 +/- 0.17 ml X kg-1 X min-1) was no different from that of the interval 04.00-08.30 hours (12.5 +/- 0.19 ml X kg-1 X min-1). The nondiabetic subjects were studied on two different occasions to assess whether the metabolic clearance of insulin changes overnight. Somatostatin (0.25 mg/h) and insulin (0.3 mU X kg-1 X min-1) were infused from 22.00-02.30 hours on one occasion, and from 04.00-08.30 hours on the other.(ABSTRACT TRUNCATED AT 250 WORDS)
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Ritmo Circadiano , Diabetes Mellitus Tipo 1/metabolismo , Insulina/metabolismo , Adulto , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inmunología , Femenino , Humanos , Insulina/administración & dosificación , Anticuerpos Insulínicos/análisis , Resistencia a la Insulina , Masculino , Tasa de Depuración MetabólicaRESUMEN
The short-term hemodynamic effects of molsidomine (4 mg sublingually) were evaluated in 13 patients with congestive heart failure following acute myocardial infarction. Right heart catheterization was performed by means of a Swan-Ganz thermodilution catheter. Hemodynamic measurements were made 30, 60, 120, and 180 minutes after the administration of the drug. Molsidomine significantly reduced systolic blood pressure from 121.5 +/- 3.3 (mean +/- SEM) to 111.1 +/- 2.9 mm Hg (p less than 0.001) after 60 minutes, mean right atrial pressure from 6.1 +/- 1 to 2.6 +/- 0.6 mm Hg (p less than 0.0001), mean pulmonary arterial pressure from 29.8 +/- 1.9 to 20.1 +/- 1.3 mm Hg (p less than 0.0001), and left ventricular filling pressure from 20.3 +/- 0.6 to 12.2 +/- 0.7 mm Hg (p less than 0.0001). No significant change occurred in heart rate, diastolic and mean blood pressure, cardiac index, stroke volume index, left ventricular stroke work index, systemic vascular resistance, and pulmonary vascular resistance. No side effects were seen after the administration of molsidomine.
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Insuficiencia Cardíaca/tratamiento farmacológico , Hemodinámica/efectos de los fármacos , Infarto del Miocardio/tratamiento farmacológico , Oxadiazoles/uso terapéutico , Sidnonas/uso terapéutico , Vasodilatadores/uso terapéutico , Anciano , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Molsidomina , Infarto del Miocardio/complicaciones , Infarto del Miocardio/fisiopatología , Sidnonas/farmacología , Factores de Tiempo , Vasodilatadores/farmacologíaRESUMEN
We studied the pattern of inheritance of hypertrophic cardiomyopathy among 111 first-degree relatives of 30 patients with the disease. Results of segregation analysis suggest a genetic heterogeneity for hypertrophic cardiomyopathy in that both autosomal dominant and autosomal recessive mode of inheritance can occur.
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Cardiomiopatía Hipertrófica/genética , Genes Dominantes , Genes Recesivos , Cardiomiopatía Hipertrófica/diagnóstico , Ecocardiografía , Femenino , Humanos , Masculino , Modelos Genéticos , Linaje , FenotipoRESUMEN
To ascertain whether the dawn phenomenon occurs in nondiabetic individuals and, if so, whether it is due to an increase in glucose production or a decrease in glucose utilization, we determined plasma concentrations of glucose, insulin, C-peptide, and counterregulatory hormones, as well as rates of glucose production, glucose utilization, and insulin secretion at one-half-hourly intervals between 1:00 and 9:00 a.m. in eight normal volunteers. After 5:30 a.m., plasma glucose, insulin, and C-peptide concentrations all increased significantly; rates of glucose production, glucose utilization, and insulin secretion also increased (all P less than 0.05). Plasma cortisol, epinephrine, and norepinephrine increased significantly from nocturnal nadirs between 4:00 and 6:30 a.m. Plasma growth hormone, which had increased episodically between 1:00 and 4:30 a.m., decreased thereafter nearly 50% (P less than 0.05). Plasma glucagon did not change significantly throughout the period of observation. These results indicate that a dawn-like phenomenon, initiated by an increase in glucose production, occurs in nondiabetic individuals. Thus, early morning increases in plasma glucose concentrations and insulin requirements observed in IDDM and NIDDM may be an exaggeration of a physiologic circadian variation in hepatic insulin sensitivity induced by antecedent changes in catecholamine and/or growth hormone secretion.
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Glucemia/fisiología , Ritmo Circadiano , Homeostasis , Adulto , Péptido C/análisis , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Epinefrina/sangre , Hormona del Crecimiento/sangre , Humanos , Hidrocortisona/sangre , Insulina/sangre , Masculino , Norepinefrina/sangreRESUMEN
The detection of myocardial depression is an important goal in the management of patients with chronic severe aortic regurgitation but may be quite difficult at an early stage by the conventional basal measures of contractility. The response to afterload stress determined by angiotensin challenge and the end-systolic pressure-volume relationship was evaluated echocardiographically in 16 asymptomatic or mildly symptomatic patients with chronic severe aortic regurgitation, ages 15 to 56 years (mean 32 +/- 12). Nine normal subjects, ages 25 to 41 years (mean 31 +/- 5), served as a control group. In the group with aortic regurgitation, end-systolic dimensions were greater than 55 mm in five of 16 patients and fractional shortening was 25% or less in two of 16. In the control group angiotensin caused a decrease of stroke volume index in six out of nine patients (15% at the most) and a mild increase in three. In the group with aortic regurgitation stroke volume index decreased by 15% or more of the basal value in nine of 16 patients and increased or decreased by less than 15% in seven of 16. Ejection fraction decreased in both groups, from 61 +/- 6% to 52 +/- 7% in the control group and from 56 +/- 6% to 45 +/- 5% in the group with aortic regurgitation. Ventricular function curves were derived by relating end-diastolic volume index to stroke work index; seven of 16 patients had abnormal responses reflecting an afterload mismatch.(ABSTRACT TRUNCATED AT 250 WORDS)