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Rationale: Cardiac involvement and hypotension dominate the prognosis of light-chain amyloidosis (AL). Evidence suggests that there is also peripheral vascular involvement in AL but its prognostic significance is unknown. Objective: To evaluate vascular dysfunction in patients with AL as a potential future area of intervention, we assessed the prognostic utility of flow-mediated dilatation (FMD), a marker of vascular reactivity, which is augmented under conditions of hypotension and autonomic dysfunction. Methods and Results: We prospectively evaluated 115 newly diagnosed untreated AL patients in whom FMD was measured. FMD in AL patients was significantly higher than age-, sex- and risk factors-matched controls (4.0% versus 2.32%; P=0.006) and comparable with control groups at lower cardiovascular risk (P>0.1). Amyloidosis patients presented increased plasma and exhaled markers of the NO pathway while their FMD significantly correlated with augmented sustained vasodilatation after sympathetic stimulation. Increased FMD (≥4.5%) was associated with early mortality (hazard ratio, 4.36; 95% CI, 1.41-13.5; P=0.010) and worse survival (hazard ratio, 2.11; 95% CI, 1.17-3.82; P=0.013), even after adjustment for Mayo stage, nerve involvement and low systolic blood pressure. This finding was confirmed in a temporal validation AL cohort (n=55; hazard ratio, 4.2; 95% CI, 1.45-12.3; P=0.008). FMD provided significant reclassification value over the best prognostic model (continuous Net Reclassification Index, 0.61; P=0.001). Finally, better hematologic response was associated with lower posttreatment FMD. Conclusions: FMD is relatively increased in AL and independently associated with inferior survival with substantial reclassification value. Reactive vasodilation merits further investigation as a novel risk biomarker in AL.Visual Overview: An online visual overview is available for this article.
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Amiloidose de Cadeia Leve de Imunoglobulina/fisiopatologia , Vasodilatação , Idoso , Pressão Sanguínea , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico por imagem , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Fluxometria por Laser-Doppler , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional , Taxa de SobrevidaRESUMO
Clinical trials with carfilzomib have indicated a low but reproducible incidence of cardiovascular and renal toxicities. Among 60 consecutive myeloma patients treated with carfilzomib-based regimens who were thoroughly evaluated for cardiovascular risk factors, 12% (95% confidence interval, 3.8%-20%) experienced a reversible reduction of left ventricular ejection fraction (LVEF) by ≥20%, an objective measure of cardiac dysfunction. The incidence of LVEF reduction was 5% at 3 months, 8% at 6 months, 10% at 12 months, and 12% at 15 months, whereas the respective carfilzomib discontinuation rate unrelated to toxicity was 17%, 35%, 41%, and 49%. The presence of any previously known cardiovascular disease was associated with an increased incidence of cardiac events (23.5% vs 7%; P = .07), but there was no association with the dose of carfilzomib or the duration of infusion. Re-treatment with carfilzomib at lower doses was possible. Carfilzomib was commonly associated with a transient reduction of estimated glomerular filtration rate (eGFR) but also improved renal function in 55% of patients with baseline eGFR <60 mL/min/1.73 m2. Further investigation is needed to elucidate the underlying mechanisms of carfilzomib-related cardiorenal toxicity.
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OBJECTIVE: Ambulatory blood pressure monitoring provides a unique tool in the evaluation of night-time blood pressure (BP), having a critical role in the detection of a blunted nocturnal fall and of elevated night-time BP. Both nondipping status and nocturnal hypertension are associated with increased cardiovascular risk and target organ damage. The aim of our study was to investigate the impact of both nondipping status and nocturnal hypertension on left ventricular mass (LVM), assessed by means of echocardiography in a consecutive cohort of untreated participants. METHODS: A total of 937 individuals were assessed by means of ambulatory blood pressure monitoring and echocardiography. Participants were divided into dippers and nondippers with or without systolic nocturnal hypertension (SNH). SNH was defined as night-time systolic blood pressure of 120 mmHg or more, and nondipping status was defined as an average reduction in systolic blood pressure at night less than 10% compared with the daytime BP. RESULTS: Dippers and nondippers with SNH presented significantly higher values of left ventricular mass index compared with dippers and nondippers without SNH, respectively. Multiple regression analysis revealed that age (ß=0.182, P<0.001), male gender (ß=0.168, P<0.001), body mass index (ß=0.080, P=0.011), and nocturnal SBP (ß=0.174, P=0.037) were significant and independent determinants of LVM. Nondipping status was not found as an independent factor associated with LVM (P=0.136). CONCLUSION: Nocturnal hypertension rather than nondipping status seems to be an independent factor associated with left ventricular mass index. The concomitant presence of both nondipping status and nocturnal hypertension is associated with higher LVM, indicating an enhanced cardiovascular risk.
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Ecocardiografia , Ventrículos do Coração/diagnóstico por imagem , Hipertensão/diagnóstico por imagem , Adulto , Idoso , Monitorização Ambulatorial da Pressão Arterial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do ÓrgãoRESUMO
BACKGROUND: Left ventricular (LV) remodeling after acute myocardial infarction (AMI) is related to increased morbidity and mortality. The aim of the present study was to examine whether LV deformational and torsional parameters can predict LV remodeling in patients with AMI. METHODS: Forty-two patients (age 57 ± 14 years) presenting with an anterior ST-elevation AMI and treated with primary percutaneous transluminal coronary angioplasty (PTCA) were included in the study. Four days post MI, LV ejection fraction (EF), LV torsion, longitudinal (4-, 3- & 2-chamber) and circumferential strain of the LV apex were evaluated by conventional and speckle-tracking echocardiography. The echocardiographic study was repeated at 3 months post-AMI and patients with LV remodeling, i.e. an increase >15% in LV end-systolic volume (LVESV), were identified. RESULTS: The 13 patients with LV remodeling had significantly more impaired apical circumferential strain (-7.3 ± 2.2% vs. -18.9 ± 5.2%, p=0.001), EF (42 ± 7% vs. 48.9 ± 6%, p=0.005), LV apical rotation (6.8 ± 4.8° vs. 11.1 ± 4.0°, p=0.027), and LV global longitudinal strain (-9.7 ± 1.9% vs. -12.9 ± 2.9%, p=0.03) on the 4th day post-AMI, in comparison to those without LV remodeling. Apical circumferential strain on the 4th day post-AMI showed the strongest correlation with the LVESV 3 months post-AMI (r=0.76, p=0.001), compared to EF (r=-0.60, p=0.001), global longitudinal strain (r=0.56, p=0.001), and LV apical rotation (r=-0.53, p=0.001). Furthermore, apical circumferential strain demonstrated the highest diagnostic accuracy: area under the receiver operating characteristic (ROC) curve 0.98, with sensitivity 100% and specificity 96% for prediction of LV remodeling, using a cutoff value <-11.0%. CONCLUSION: In patients with anterior AMI, LV apical circumferential strain in the early post-MI period constitutes a significant prognostic factor for LV remodeling at 3 months. Assessment of this parameter may identify patients at high risk for heart failure development.
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Ventrículos do Coração/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular , Ecocardiografia , Feminino , Seguimentos , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/cirurgia , Intervenção Coronária Percutânea , Período Pós-Operatório , Prognóstico , Curva ROC , Fatores de TempoRESUMO
AIMS: During pregnancy, important hemodynamic changes occur, consistent with an increase in preload and decrease in afterload and systemic vascular resistance. The aim of the present study was to investigate the changes in left ventricular (LV) strain and rotational properties during the 3 trimesters of normal pregnancy and to examine the factors that drive these changes. METHODS AND RESULTS: Twenty-seven pregnant women (29.7 ± 6.9 years) and 11 age-matched nonpregnant controls (29.9 ± 5.4 years) were evaluated. Conventional echocardiography and two-dimensional speckle tracking imaging were performed at 8-12 (1st trimester), 21-28 (2nd trimester), and 33-36 (3rd trimester) weeks of pregnancy. LV rotation, twist, untwisting rate, and circumferential strain were measured using the parasternal short-axis views at basal and apical levels. Global longitudinal strain was calculated from the LV apical views. Peak LV twist and peak untwisting rate increased significantly in the 3rd trimester of normal pregnancy (13.48 ± 2.90°, 13.12 ± 3.30°, 16.83 ± 3.61°, P < 0.001; and -111.52 ± 23.54°/sec, -107.40 ± 26.58°/sec, -144.30 ± 45.14°/sec, P < 0.001; in the 1st, 2nd, and 3rd trimester, respectively). Global longitudinal and circumferential strain of the apex decreased significantly from the 2nd trimester. An independent association was found between the change in LV twist and the change in LV end-systolic volume between the 1st and 3rd trimester. Peak untwisting rate at the 3rd trimester correlated significantly with peak twist and LV end-diastolic volume. CONCLUSIONS: During normal pregnancy, LV twist and peak untwisting rate increase in the 3rd trimester and correlate with end-systolic and end-diastolic volume, respectively. Circumferential strain of the apex and global longitudinal strain decrease from the 2nd trimester.
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Ecocardiografia/métodos , Técnicas de Imagem por Elasticidade/métodos , Ventrículos do Coração/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Gravidez/fisiologia , Função Ventricular Esquerda/fisiologia , Adulto , Módulo de Elasticidade , Feminino , Humanos , Reprodutibilidade dos Testes , Rotação , Sensibilidade e Especificidade , TorqueRESUMO
In this phase 1/2 study, we explored the feasibility and activity of an oral regimen of lenalidomide with low-dose dexamethasone and low-dose oral cyclophosphamide (RdC) in patients with primary systemic light chain amyloidosis. RdC was given for up to 12 cycles in prespecified cohorts at escalated doses: 13 patients were treated in phase 1 and 24 in phase 2; 65% were previously untreated, and most had renal and/or cardiac involvement and elevated cardiac biomarkers. Lenalidomide 15 mg/d and cyclophosphamide 100 mg/d were further evaluated in phase 2. On intention to treat, 20 (55%) patients achieved a hematologic response, including 3 (8%) complete remissions. Hematologic responses were seen at all dose levels and in 4 of 5 patients who had received bortezomib previously. An organ response was recorded in 22% of patients on intention-to-treat and in 40% of patients who survived at least 6 months. The median time to progression was 10 months and the 2-year survival was 41%. Fatigue, nonneutropenic infections, and rash were the most common toxicities. The results of the present study show that RdC is an oral regimen with activity in primary systemic light chain amyloidosis and may be an additional treatment option, especially for patients with preserved organ function or for patients who cannot receive or who relapse after bortezomib. This study is registered at www.clinicaltrials.gov as NCT00981708.
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Amiloidose/tratamento farmacológico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Dexametasona/uso terapêutico , Talidomida/análogos & derivados , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Estudos de Coortes , Ciclofosfamida/administração & dosagem , Ciclofosfamida/toxicidade , Dexametasona/administração & dosagem , Dexametasona/toxicidade , Esquema de Medicação , Feminino , Testes Hematológicos , Humanos , Testes de Função Renal , Lenalidomida , Masculino , Pessoa de Meia-Idade , Talidomida/administração & dosagem , Talidomida/uso terapêutico , Talidomida/toxicidadeRESUMO
BACKGROUND AND OBJECTIVES: High-dose melphalan and autologous stem cell transplantation is currently the treatment of choice for selected patients with AL amyloidosis; however, new treatments are needed for patients who are ineligible for or relapse after this procedure. Bortezomib is a proteasome inhibitor with proven activity in multiple myeloma, and the addition of dexamethasone results in superior outcome. We evaluated the activity and feasibility of the combination of bortezomib and dexamethasone (BD) in patients with AL amyloidosis. DESIGN AND METHODS: Consecutive patients with histologically proven, symptomatic AL amyloidosis were treated with BD. RESULTS: Eighteen patients, including seven who had relapsed or progressed after previous therapies were treated with BD. Eleven (61%) patients had two or more organs involved; kidneys and heart were affected in 14 and 15 patients, respectively. The majority of patients had impaired performance status and high brain natriuretic peptide values; serum creatinine was elevated in six patients. Among evaluable patients, 94% had a hematologic response and 44% a hematologic complete response, including all five patients who had not responded to prior high dose dexamethasone-based treatment and one patient under dialysis. Five patients (28%) had a response in at least one affected organ. Hematologic responses were rapid (median 0.9 months) and median time to organ response was 4 months. Neurotoxicity, fatigue, peripheral edema, constipation and exacerbation of postural hypotension were manageable although necessitated dose adjustment or treatment discontinuation in 11 patients. INTERPRETATION AND CONCLUSIONS: The combination of BD is feasible in patients with AL amyloidosis. Patients achieve a rapid hematologic response and toxicity can be managed with close follow-up and appropriate dose adjustment. This treatment may be a valid option for patients with severe heart or kidney impairment.