The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma.

BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy are typically poor. The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival versus CHOP for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL. PATIENTS AND METHODS: ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase III study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group. RESULTS: A total of 452 patients were randomized (1 : 1) to six or eight cycles of A+CHP (N = 226) or CHOP (N = 226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% [95% confidence interval (CI): 42.8% to 59.4%] with A+CHP versus 43.0% (95% CI: 35.8% to 50.0%) with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3% to 75.9%) with A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP. CONCLUSIONS: In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.

The evolution of leukaemia from pre-leukaemic and leukaemic stem cells.

Haematopoietic stem and progenitor cells (HSPCs) are defined as unspecialized cells that give rise to more differentiated cells. In a similar way, leukaemic stem and progenitor cells (LSPCs) are defined as unspecialized leukaemic cells, which can give rise to more differentiated cells. Leukaemic cells carry leukaemic mutations/variants and have clear differentiation abnormalities. Pre-leukaemic HSPCs (PreL-HSPCs) carry pre-leukaemic mutations/variants (pLMs) and are capable of producing mature functional cells, which will carry the same variants. Under the roof of LSPCs, one can find a broad range of cell types genetic and disease phenotypes. Present-day knowledge suggests that this phenotypic heterogeneity is the result of interactions between the cell of origin, the genetic background and the microenvironment background. The combination of these attributes will define the LSPC phenotype, frequency, differentiation capacity and evolutionary trajectory. Importantly, as LSPCs are leukaemia-initiating cells that sustain clinical remission and are the source of relapse, an improved understanding of LSPCs phenotype would offer better clinical opportunities for the treatment and hopefully prevention of human leukaemia. The current review will focus on LSPCs attributes in the context of human haematologic malignancies.

Ommochromes from the Compound Eyes of Insects: Physicochemical Properties and Antioxidant Activity.

The objective of this study was screening of ommochromes from the compound eyes of insects and comparison of their antioxidant properties. Ommochromes were isolated in preparative quantities from insects of five different families: Stratiomyidae, Sphingidae, Blaberidae, Acrididae, and Tenebrionidae. The yield of ommochromes (dry pigment weight) was 0.9-5.4% of tissue wet weight depending on the insect species. Isolated pigments were analyzed by high-performance liquid chromatography and represented a mixture of several ommochromes of the ommatin series. The isolated ommochromes displayed a pronounced fluorescence with the emission maxima at 435-450 nm and 520-535 nm; furthermore, the emission intensity increased significantly upon ommochrome oxidation with hydrogen peroxide. The ommochromes produced a stable EPR signal consisting of a singlet line with g = 2.0045-2.0048, width of 1.20-1.27 mT, and high concentration of paramagnetic centers (> 1017 spin/g dry weight). All the investigated ommochromes demonstrated high antiradical activity measured from the degree of chemiluminescence quenching in a model system containing luminol, hemoglobin, and hydrogen peroxide. The ommochromes strongly inhibited peroxidation of the photoreceptor cell outer segments induced by visible light in the presence of lipofuscin granules from the human retinal pigment epithelium, as well as suppressed iron/ascorbate-mediated lipid peroxidation. The obtained results are important for understanding the biological functions of ommochromes in invertebrates and identifying invertebrate species that could be used as efficient sources of ommochromes for pharmacological preparations to prevent and treat pathologies associated with the oxidative stress development.

Femtosecond and Picosecond Dynamics of Recombinant Bacteriorhodopsin Primary Reactions Compared to the Native Protein in Trimeric and Monomeric Forms.

Photochemical reaction dynamics of the primary events in recombinant bacteriorhodopsin (bRrec) was studied by femtosecond laser absorption spectroscopy with 25-fs time resolution. bRrec was produced in an Escherichia coli expression system. Since bRrec was prepared in a DMPC-CHAPS micelle system in the monomeric form, its comparison with trimeric and monomeric forms of the native bacteriorhodopsin (bRtrim and bRmon, respectively) was carried out. We found that bRrec intermediate I (excited state of bR) was formed in the range of 100 fs, as in the case of bRtrim and bRmon. Further processes, namely the decay of the excited state I and the formation of intermediates J and K of bRrec, occurred more slowly compared to bRtrim, but similarly to bRmon. The lifetime of intermediate I, judging from the signal of ΔAESA(470-480 nm), was 0.68 ps (78%) and 4.4 ps (22%) for bRrec, 0.52 ps (73%) and 1.7 ps (27%) for bRmon, and 0.45 ps (90%) and 1.75 ps (10%) for bRtrim. The formation time of intermediate K, judging from the signal of ΔAGSA(625-635 nm), was 13.5 ps for bRrec, 9.8 ps for bRmon, and 4.3 ps for bRtrim. In addition, there was a decrease in the photoreaction efficiency of bRrec and bRmon as seen by a decrease in absorbance in the differential spectrum of the intermediate K by ~14%. Since photochemical properties of bRrec are similar to those of the monomeric form of the native protein, bRrec and its mutants can be considered as a basis for further studies of the mechanism of bacteriorhodopsin functioning.

Estimation of fluorescence lifetime of lipofuscin fluorophores contained in lipofuscin granules of retinal pigment epithelium of human cadaver eyes without signs of pathology.

The fluorescence lifetimes of lipofuscin fluorophores contained in chloroform extracts from retinal pigment epithelium (RPE) of human cadaver eyes without signs of pathology were evaluated by single photon counting. The comparison of fluorescence lifetimes of N-retinylidene-N-retinylethanolamine (A2E) and its photooxidation and photodegradation products has been carried out. It was shown that the contribution of A2E to the total fluorescence of chloroform extract from lipofuscin granules is not major. The results are important for the improvement of noninvasive diagnostic method of degenerative diseases of the retina and RPE-fundus autofluorescence (FAF).

The fluorescence lifetime of lipofuscin granule fluorophores contained in the retinal pigment epithelium cells from human cadaver eyes in normal state and in the case of visualized pathology.

A comparative analysis of fluorescence lifetime of lipofuscin granule fluorophores contained in the retinal pigment epithelium cells from human cadaver eyes in normal state and in the case of visualized pathology was carried out. Measurements of fluorescence lifetimes of bis-retinoids and their photooxidation and photodegradation products were carried out using the method of counting time-correlated photons. Comparative analysis showed that, in the case of visualized pathology, the contribution of photooxidation and photodegradation products of bis-retinoids to the total fluorescence of the retinal pigment epithelium cell suspension increases in comparison with the norm.

Quantum-classical model of retinal photoisomerization reaction in visual pigment rhodopsin.

A quantum-classical model of photoisomerization of the visual pigment rhodopsin chromophore is proposed. At certain (and more realistic) parameter value combinations, the model is shown to accurately reproduce a number of independent experimental data on the photoreaction dynamics: the quantum yield, the time to reach the point of conical intersection of potential energy surfaces, the termination time of the evolution of quantum subsystem, as well as the characteristic low frequencies of retinal molecular lattice fluctuations during photoisomerization. In addition, the model behavior is in good accordance with experimental data about coherence and local character of quantum transition.

Comparative characteristics of two anion-channel rhodopsins and prospects of their use in optogenetics.

Anion-selective opsins slow ChloC and ACR2 were expressed in rat brain cortical neurons by electroporation in utero. It is shown that the light-activated channel ACR2 has pronounced advantages in terms of both the inactivation kinetics and the neuron inhibition intensity, which is associated with a more negative value of the light-activated current reversal potential compared to the slow ChloC channel. The identified properties of opsin ACR2 indicate that it can be used for strictly controlled suppression of neuronal activity in optogenetic experiments, including the expression in the retinal ganglionic cells for reconstituting the OFF-component of their receptive field, which is essential for optogenetic prosthetics of degenerative retina.

Study of visual pigment rhodopsin supramolecular organization in photoreceptor membrane by small-angle neutron scattering method with contrast variation.

Supramolecular organization of rhodopsin in the photoreceptor membrane was investigated by small-angle neutron scattering method. The experiments, which were performed with mixtures of heavy/light water as solvent (contrast variation method), were aimed at obtaining information about the lipid and protein components of the photoreceptor disc membrane separately. It was shown that the packaging density of the rhodopsin molecules in the photoreceptor membrane was unusually high: the distance between the centers of the molecules was approximately 56 Å. The probability of the monomeric state of rhodopsin molecules in the photoreceptor membrane, according to the data obtained, is rather high.

Anion-selective channelrhodopsin expressed in neuronal cell culture and in vivo in murine brain: Light-induced inhibition of generation of action potentials.

Anionic channelrhodopsin slow ChloC was expressed in the culture of nerve cells and in vivo in mouse brain. We demonstrated ability of slow ChloC to suppress effectively the activity of the neuron in response to the illumination with the visible light. It has been shown for a first time that slow ChloC works equally efficiently in both neuronal culture and in the whole brain being expressed in vivo. Thus, slow ChloC could be considered as an effective optogenetic tool capable in response to light stimulation to inhibit the generation of action potentials in the neuron.

Final results of phase II trial of doxorubicin HCl liposome injection followed by bexarotene in advanced cutaneous T-cell lymphoma.

BACKGROUND: High response rates for doxorubicin HCl liposome injection (DLI) in cutaneous T-cell lymphoma (CTCL) have been reported with vague criteria until recently. Approximately 50% of CTCL patients respond to bexarotene (Bex). PATIENTS AND METHODS: A phase II trial was carried out to clarify the true overall response rate (ORR) for DLI and to assess the role of sequential Bex. Patients were treated with DLI 20 mg/m(2) i.v. every 2 weeks for 16 weeks (8 doses) followed by 16 weeks with Bex 300 mg/m(2) orally. Response assessments were carried out after 16 (DLI) and 32 weeks (Bex). Skin responses were measured by the modified Severity-Weighted Assessment Tool (mSWAT) and the Composite Assessment of Index Lesion Severity (CA). RESULTS: Thirty-seven patients were treated: stage IV (22, 8 with Sézary syndrome), IIB (10), earlier stage refractory to skin-directed therapies or radiation therapy (5). For 34 assessable patients: ORR 14/34 [41%: partial response (PR) 12, clinical complete response (CCR) 2]. Maximum responses were all seen after 16 weeks DLI. Median progression-free survival (PFS) was 5 months. There were 22 deaths: 21 of disease and 1 of heart failure. Twenty-seven grade 3 and 5 grade 4 toxic events were observed. CONCLUSION(S): With strict criteria, DLI ORR is among the highest reported for single agents in CTCL. Sequential Bex did not increase the response rate or duration.

Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy.

BACKGROUND: Optimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear. PATIENTS AND METHODS: We examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses. RESULTS: PTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I-II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34-0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22-0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14-0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17-0.40, P < 0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission. CONCLUSIONS: This analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.

Sexual problems in MS: Sex differences and their impact on quality of life.

BACKGROUND: Low sexual function and satisfaction are common problems among people with multiple sclerosis (PwMS), but the literature on which patient variables are associated with these issues is inconsistent. OBJECTIVE: To investigate the associations between sexual function and satisfaction in PwMS with clinical, demographic, and patient-reported quality of life (QOL) measures and determine if sex differences exist. METHODS: This analysis includes PwMS enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB), who completed patient-reported outcome measures: Multiple Sclerosis Quality of Life-54 (MSQOL-54), Modified Fatigue Impact Scale (MFIS), and Center for Epidemiologic Studies Depression Scale (CES-D). Regression models were used to analyze associations between patient variables and function and satisfaction. Results were stratified by sex. Cross-sectional and longitudinal data were used. RESULTS: 702 PwMS (526 females,176 males, mean age 42.2 +/-11.1, median EDSS 1.5) were included in the cross-sectional analysis. Data from 341 PwMS were used in the three-year longitudinal analysis. Increasing age, disease duration, and disability were associated with reduced sexual function and satisfaction to the same degree in males and females. However, sex differences existed in the strength of associations with QOL variables. There was no significant longitudinal change in females or males. CONCLUSIONS: Age and disease duration were associated with reduced sexual function and satisfaction in males and females. In females, function was significantly associated with disability and satisfaction with fatigue. Males had stronger associations with sexual function in domains related to emotional well-being, health perceptions, and overall QOL. Males had stronger associations with satisfaction in emotional and social functioning and physical health domains. These findings can help better understand the multidimensional problems of sexual function and satisfaction in PwMS and better guide patient care.

Photobiology of lipofuscin granules in the retinal pigment epithelium cells of the eye: norm, pathology, age.

Lipofuscin granules (LGs) are accumulated in the retinal pigment epithelium (RPE) cells. The progressive LG accumulation can somehow lead to pathology and accelerate the aging process. The review examines composition, spectral properties and photoactivity of LGs isolated from the human cadaver eyes. By use of atomic force microscopy and near-field microscopy, we have revealed the fluorescent heterogeneity of LGs. We have discovered the generation of reactive oxygen species by LGs, and found that LGs and melanolipofuscin granules are capable of photoinduced oxidation of lipids. It was shown that A2E, as the main fluorophore (bisretinoid) of LGs, is much less active as an oxidation photosensitizer than other fluorophores (bisretinoids) of LGs. Photooxidized products of bisretinoids pose a much greater danger to the cell than non-oxidized one. Our studies of the fluorescent properties of LGs and their fluorophores (bisretinoids) showed for the first time that their spectral characteristics change (shift to the short-wavelength region) in pathology and after exposure to ionizing radiation. By recording the fluorescence spectra and fluorescence decay kinetics of oxidized products of LG fluorophores, it is possible to improve the methods of early diagnosis of degenerative diseases. Lipofuscin ("aging pigment") is not an inert "slag". The photoactivity of LGs can pose a significant danger to the RPE cells. Fluorescence characteristics of LGs are a tool to detect early stages of degeneration in the retina and RPE.

Femtosecond formation dynamics of primary photoproducts of visual pigment rhodopsin.

The coherent 11-cis-retinal photoisomerization dynamics in bovine rhodopsin was studied by femtosecond time-resolved laser absorption spectroscopy at 30-fs resolution. Femtosecond pulses of 500, 535, and 560 nm wavelength were used for rhodopsin excitation to produce different initial Franck-Condon states and relevant distinct values of the vibrational energy of the molecule in its electron excited state. Time evolution of the photoinduced rhodopsin absorption spectra was monitored after femtosecond excitation in the spectral range of 400-720 nm. Oscillations of the time-resolved absorption signals of rhodopsin photoproducts represented by photorhodopsin(570) with vibrationally-excited all-trans-retinal and rhodopsin(498) in its initial state with vibrationally-excited 11-cis-retinal were studied. These oscillations reflect the dynamics of coherent vibrational wave-packets in the ground state of photoproducts. Fourier analysis of these oscillatory components has revealed frequencies, amplitudes, and initial phases of different vibrational modes, along which the motion of wave-packets of both photoproducts occurs. The main vibrational modes established are 62, 160 cm(-1) and 44, 142 cm(-1) for photorhodopsin(570) and for rhodopsin(498), respectively. These vibrational modes are directly involved in the coherent reaction under the study, and their amplitudes in the power spectrum obtained through the Fourier transform of the kinetic curves depend on the excitation wavelength of rhodopsin.

Fractional flow reserve compared with intravascular ultrasound guidance for optimizing stent deployment.

BACKGROUND: Determination of fractional flow reserve (FFR) has been proposed as a means to assess stent deployment. In this prospective, multicenter trial, we evaluate the use of FFR to optimize stenting by comparing it with standard intravascular ultrasound (IVUS) criteria. METHODS AND RESULTS: Eighty-four stable patients with isolated coronary lesions underwent coronary stent deployment starting at 10 atm and increased serially by 2 atm until the FFR was >/=0.94 or 16 atm was achieved. IVUS was then performed. FFR was measured with a coronary pressure wire with intracoronary adenosine to induce hyperemia. The diagnostic characteristics of an FFR <0.94 to predict suboptimal stent expansion by IVUS, defined in both absolute and relative terms, were calculated. Over a range of IVUS criteria, the highest sensitivity, specificity, and predictive accuracy of FFR were 80%, 30%, and 42%, respectively. Receiver operator characteristic analysis defined an optimal FFR cut point at >/=0.96; at this threshold, the sensitivity, specificity, and predictive accuracy of FFR were 75%, 58%, and 62%, respectively (P=0.03 for comparison of predictive accuracy, P=0.01 for concordance between FFR and IVUS). The negative predictive value was 88%. Significantly better diagnostic performance was achieved in a subgroup that received higher doses (>30 microgram) of intracoronary adenosine during pressure measurements, suggesting that FFR might be overestimated in the other group. CONCLUSIONS: A fractional flow reserve <0.96, measured after stent deployment, predicts a suboptimal result based on validated intravascular ultrasound criteria; however, an FFR >/=0.96 does not reliably predict an optimal stent result. Higher doses of intracoronary adenosine than previously used to measure FFR improve these results.

Inoue balloon mitral valvotomy in patients with severe valvular and subvalvular deformity.

OBJECTIVES: This study evaluated the immediate and long-term results of percutaneous Inoue balloon mitral valvotomy in patients with severe valvular and subvalvular deformity. METHODS: We reviewed the prevalvotomy transthoracic echocardiograms of patients from the North American multicenter Inoue registry with total Massachusetts General Hospital (MGH) echocardiographic scores > or = 10. The echocardiograms were rescored by two investigators to assess valvular and subvalvular morphology to eliminate interinstitutional variability. Ninety patients were originally assigned scores > or = 10. After rescoring, 18 patients (20%) were eliminated, leaving 72 study patients. RESULTS: Balloon mitral valvotomy was technically successful in 69 (96%) of the 72 patients. Mean (+/- SD) mitral valve area increased from 0.9 +/- 0.3 to 1.5 +/- 0.5 cm2. An immediate optimal result, defined as > or = 50% increase in mitral valve area or a final area > or = 1.5 cm2 with no major complications, was achieved in 46 patients (64%). End points for clinical follow-up (events) included mitral valve replacement, repeat valvotomy or death. At a mean follow-up of 22.9 +/- 11.0 months, 22 patients (31%) required mitral valve replacement or a second valvotomy, 9 patients (13%) died, and 32 patients (45%) were in New York Heart Association functional class I or II. Univariate predictors of an immediate optimal result included sinus rhythm, male gender and a lower University of Southern California commissural calcium score. Only sinus rhythm predicted an optimal result by multivariate analysis. Actuarial 3-year event-free survival was 42%. Univariate predictors of event-free survival were a lower grade of mitral regurgitation, lower MGH total echocardiographic score, lower MGH leaflet thickness subscore and lower prevalvotomy left ventricular systolic pressure. Only grade of mitral regurgitation after valvotomy predicted event-free survival by multivariate analysis. CONCLUSIONS: Inoue mitral valvotomy in patients with severe valvular and subvalvular deformity has a high technical success rate and good immediate hemodynamic result but a high cardiovascular event rate in follow-up. Mitral valve replacement should be considered in surgical candidates with an MGH total echocardiographic score > or = 10 because it may be able to provide better long-term event-free survival. Balloon valvotomy remains a reasonable palliative therapeutic option for some patients with severe valvular deformity and high surgical risk.

Comparison of early and recent results with rotational atherectomy.

OBJECTIVES: We compared an early registry of rotational atherectomy with a recent registry to examine the evolution of patient profiles, lesion characteristics and procedural outcomes for patients treated with rotational atherectomy. BACKGROUND: With increased experience, the selection of patients and lesions treated with a device matures. This study documents the changes in the application of rotational atherectomy. METHODS: The patient characteristics and procedural outcomes from two multicenter patient registries-Registry I: 2,953 procedures, 3,717 lesions from 1988 to 1993; and Registry II: 200 procedures, 268 lesions from 1994-were analyzed and compared. RESULTS: There was an increase in the average age of the patients (63 vs. 65 years, p < 0.02) and the proportion of patients with unstable angina (42.9% vs. 56.5%, p < 0.01) or previous coronary artery bypass graft surgery (18.8% vs. 24.5%, p < 0.05) in Registry II. Registry II included fewer left anterior descending coronary lesions (46.5% vs. 32.8%, p < 0.01), more type B and C lesions (83.1% vs. 91.8%, p < 0.01), more eccentric lesions (69.0% vs. 79.5%, p < 0.01) and more calcified lesions (50.3% vs. 69.4%, p < 0.01). Complications, including urgent bypass surgery, Q and non-Q wave myocardial infarction, dissection, acute occlusion and perforation, were similar in the two groups. However, mortality increased from 1.0% to 3.0% (p < 0.05) in Registry II. CONCLUSIONS: Comparison of recent and early patients treated with rotational atherectomy revealed an increase in the complexity of patients and lesions. Although the rate of death was increased, the overall rate of major complications was not significantly changed (4.7% vs. 6.0%, p = NS).

Contrast echocardiography for evaluation of myocardial perfusion: effects of coronary angioplasty.

Assessment of viable myocardium before and after interventional therapy has become a critical issue in modern cardiology. This report describes a new contrast echocardiographic technique using conventional two-dimensional imaging during direct intracoronary injections of small volumes (1.5 to 2.0 cc) of sonicated Renografin-76. Contrast echocardiography was performed before and after coronary angioplasty in seven patients with single vessel coronary artery disease. Before angioplasty a contrast (that is, perfusion) defect was noted in all seven patients. This defect correlated with the anatomic distribution of the epicardial coronary stenosis. After angioplasty the mean gradient across the stenotic lesion decreased from 52 +/- 11 to 13 +/- 14 mm Hg (p less than 0.01) in association with a fall in the mean diameter of the lesion from 84 +/- 8 to 29 +/- 13% (p less than 0.001). Increased myocardial perfusion to the area of "contrast defect" was demonstrated in only five of the seven patients, despite hemodynamically and angiographically successful angioplasty. Thus, contrast echocardiographic techniques performed during interventional therapy and used in conjunction with standard coronary angiographic procedures may provide additional physiologic information regarding regional myocardial perfusion after attempts at revascularization.

Myocardial mechanics in hyperthyroidism: importance of left ventricular loading conditions, heart rate and contractile state.

Hyperthyroidism has been reported to affect all of the major determinants of left ventricular performance in a manner that would augment ventricular shortening characteristics. The hypothesis tested in this study is that reduced afterload in conjunction with increased preload and heart rate, rather than augmented contractility, accounts for much of the increase in left ventricular performance noted previously in these patients. To investigate this hypothesis, 11 hyperthyroid patients were evaluated serially over 4 +/- 2 months. With therapy, serum total thyroxin (T4) decreased significantly (p less than 0.001). Ventricular hemodynamics were assessed by two-dimensional targeted M-mode echocardiograms and calibrated carotid pulse tracings. Ventricular preload was estimated by end-diastolic dimension, whereas afterload was measured as end-systolic wall stress. Overall left ventricular performance was quantitated by the extent and velocity of shortening, whereas myocardial work was assessed by ventricular systolic stress-length relations. With therapy, overall left ventricular performance declined (p less than 0.01). This change was associated with no change in end-diastolic dimension or end-systolic wall stress, and a 24% fall in heart rate (p less than 0.01). This latter finding has been shown previously to have no significant effect on left ventricular contractile state over the range of heart rates encountered in this study. In all cases, the end-systolic stress/rate-corrected shortening velocity relation fell with attainment of normal thyroid status, characteristic of a decline in contractility. There was a strong positive correlation between left ventricular contractility and serum thyroid hormone level (r = 0.83). In addition, ventricular minute work declined with therapy (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)