Cancer-free survival following alemtuzumab induction in heart transplantation.

BACKGROUND: The malignancy rate after alemtuzumab (C-1H) induction in cardiac transplantation is unknown. METHODS: A retrospective analysis from a single center for all patients that underwent cardiac transplantation from January 2000 to January 2011 and that had no history of malignancy before transplantation was performed. Patients induced with alemtuzumab were compared with a group of patients receiving thymoglobulin or no induction and assessed for 4-year cancer-free post-heart transplantation survival. RESULTS: Of 402 patients included, 185 (46.0%) received alemtuzumab, 56 (13.9%) thymoglobulin, and 161 (40.0%) no induction. Baseline characteristics did not differ between groups: mean age 54.0 years, male 77.1%, white 88.6%, ischemic cardiomyopathy 49.0%. The calcineurin inhibitor was tacrolimus in 98.9% of alemtuzumab patients, 98.2% of thymoglobulin patients, and 87.0% of the noninduced (P < .001). The secondary agent was mycophenolate mofetil in all but 16 noninduced patients (9.9%), who received azathioprine. The 4-year cancer-free survival did not differ between groups: 88.1% alemtuzumab, 87.5% thymoglobulin, 88.2% noninduction; P = .088. The 4-year nonskin cancer-free survival was 96.8% for the alemtuzumab group, 96.4% for the thymoglobulin group, and 95.7% for the noninduced; P = .899. CONCLUSIONS: Neither the 4-year cancer-free survival nor the 4-year nonskin cancer-free survival differed between the alemtuzumab, thymoglobulin, and noninduced groups.

Alemtuzumab induction prior to cardiac transplantation with lower intensity maintenance immunosuppression: one-year outcomes.

Induction therapy with alemtuzumab (C-1H) prior to cardiac transplantation (CTX) may allow for lower intensity maintenance immunosuppression. This is a retrospective study of patients who underwent CTX at a single institution from January 2001 until April 2009 and received no induction versus induction with C-1H on a background of tacrolimus and mycophenolate. Those with C-1H received dose-reduced calcineurin inhibitor and no steroids. A total of 220 patients were included, 110 received C-1H and 110 received no induction. Recipient baseline characteristics, donor age and gender were not different between the two groups. Mean tacrolimus levels (ng/mL) for C-1H versus no induction: months 1-3 (8.5 vs. 12.9), month 4-6 (10.2 vs. 13.0), month 7-9 (10.2 vs. 11.9) and month 10-12 (9.9 vs. 11.3) were all significantly lower for the C-1H group, p < 0.001. There were no differences between the C-1H and no induction groups at 12 months for overall survival 85.1% versus 93.6% p = 0.09, but freedom from significant rejection was significantly higher for the C-1H group, 84.5% versus 51.6%, p < 0.0001. In conclusion, induction therapy after CTX with C-1H results in a similar 12 month survival, but a greater freedom from rejection despite lower calcineurin levels and without the use of steroids.

A novel VOCODER for cochlear implants.

A new VOCODER-based speech processing strategy for cochlear implants is presented. The proposed method improves upon existing VOCODER techniques in time-frequency resolution and can offer higher noise immunity. The presented method is based on the effective tracking of nonstationary sinusoid components using a non-linear sinusoid tracking algorithm (STA). The structure of the proposed technique, as well as the underlying STA are presented. It is expected that the improvement in time-frequency resolution will offer superior performance in cochlear implants, as well as improvements in speech coding applications. An eight-band version of the proposed technique is presented and superior performance to existing techniques is shown.

A novel approach for Doppler blood flow measurement.

A new approach to frequency estimation for the velocity estimation in Doppler ultrasound blood flow analysis is presented. The basis of the approach is an adaptive sinusoid-tracking algorithm which is effective in extracting nonstationary signals from within noise and estimating their time-varying parameters, such as the frequency, over time. The preliminary studies conducted using simulated signals show the potential of this approach in estimating Doppler frequency shifts under noisy conditions. A qualitative comparison with the short-time Fourier transform (STFT) is presented to show the advantages of the proposed technique over the STFT. The proposed approach offers advantages over conventional time-frequency analysis techniques in terms of high time-frequency resolution and high noise immunity.

High-resolution analysis of transient evoked otoacoustic emissions.

A new decomposition and time-frequency method applied to the estimation of transient evoked otoacoustic emissions (TEOAEs) is presented. TEOAEs are low-level signals in response to auditory stimuli that are used to monitor the functionality of the cochlea. TEOAE parameter estimation is challenging due to the short duration of the signal (about 20ms) and its highly nonstationary nature. Existing time-frequency methods are incapable of providing accurate estimates of the components within the TEOAE signal. The proposed decomposition and time-frequency method is based on the effective tracking of nonstationary sinusoidal components using a nonlinear iterative sinusoid tracking algorithm. The presented technique improves upon existing techniques by offering a high time-frequency resolution and is capable of providing accurate estimates of components within a TEOAE signal. The structure of the proposed decomposition technique as well as the underlying algorithm are presented. Simulation results are presented to show the performance of the proposed technique. Its performance is also demonstrated on a clinically recorded signal.

Polymorphisms in adenosine receptor genes are associated with infarct size in patients with ischemic cardiomyopathy.

The goal of this experiment was to identify the presence of genetic variants in the adenosine receptor genes and assess their relationship to infarct size in a population of patients with ischemic cardiomyopathy. Adenosine receptors play an important role in protecting the heart during ischemia and in mediating the effects of ischemic preconditioning. We sequenced DNA samples from 273 individuals with ischemic cardiomyopathy and from 203 normal controls to identify the presence of genetic variants in the adenosine receptor genes. Subsequently, we analyzed the relationship between the identified genetic variants and infarct size, left ventricular size, and left ventricular function. Three variants in the 3'-untranslated region of the A(1)-adenosine gene (nt 1689 C/A, nt 2206 Tdel, nt 2683del36) and an informative polymorphism in the coding region of the A3-adenosine gene (nt 1509 A/C I248L) were associated with changes in infarct size. These results suggest that genetic variants in the adenosine receptor genes may predict the heart's response to ischemia or injury and might also influence an individual's response to adenosine therapy.

A labview-based GUI for the measurement of otoacoustic emissions.

This paper presents the outcome of a software development project aimed at creating a stand-alone user-friendly signal processing algorithm for the estimation of distortion product otoacoustic emission (OAE) signals. OAE testing is one of the most commonly used methods of first screening of newborns' hearing. Most of the currently available commercial devices rely upon averaging long strings of data and subsequent discrete Fourier analysis to estimate low level OAE signals from within the background noise in the presence of the strong stimuli. The main shortcoming of the presently employed technology is the need for long measurement time and its low noise immunity. The result of the software development project presented here is a graphical user interface (GUI) module that implements a recently introduced adaptive technique of OAE signal estimation. This software module is easy to use and is freely disseminated on the Internet for the use of the hearing research community. This GUI module allows loading of the a priori recorded OAE signals into the workspace, and provides the user with interactive instructions for the OAE signal estimation. Moreover, the user can generate simulated OAE signals to objectively evaluate the performance capability of the implemented signal processing technique.

Association between beta-adrenergic receptor polymorphisms and their G-protein-coupled receptors with body mass index and obesity in women: a report from the NHLBI-sponsored WISE study.

OBJECTIVES: The beta-adrenergic receptor (betaAR) genes are candidate genes for obesity because of their roles in energy homeostasis and promotion of lipolysis in human adipose tissue. Objective is to determine the association between obesity and polymorphisms in genes of the beta(1)AR (ADRB1), beta(2)AR (ADRB2), beta(3)AR (ADRB3), Gs protein alpha (GNAS1), to which all three beta-receptors couple and the G protein beta3 subunit (GNB3), to which beta(3)ARs couple. DESIGN: A case-control genetic association study. SUBJECTS: A total of 643 black or white women enrolled in Women's Ischemia Syndrome Evaluation (WISE) study. MEASUREMENTS: Genotypes were determined by PCR with single primer extension. Associations between genotype and body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, and obesity were made. RESULTS: Polymorphisms in the three betaAR genes, GNAS1, and GNB3 were not associated with BMI, WHR, waist circumference, or obesity. Linear and logistic regression analyses found no contribution of either genotype or haplotype with anthropometric measurements or obesity. CONCLUSIONS: Our study suggests that among American women with suspected coronary heart disease, polymorphisms in the betaARs and their G-protein-coupled receptors do not contribute to increased BMI, WHR, waist circumference, or obesity. Given that 50% of all women die from coronary heart disease, and a higher percentage have heart disease during their lifetime, our results are likely generalizable to many American women.

A new adaptive technique of estimation of steady state auditory evoked potentials.

A novel technique of fast estimation of steady state auditory evoked potentials (SSAEPs) for rapid assessment of the functionality of the human auditory nervous system is presented. The proposed SSAEP signal estimation is based on a new nonlinear adaptive signal processing method that has shown a great promise in the fast extraction of weak signals buried under large amounts of noise. Currently, the main technical impediment in the widespread clinical use of the SSAEP testing for hearing assessment is the excessively long measurement time needed for the estimation process due to the presence of large amounts of background noise. The studies in this paper show significant reduction in the measurement time achieved by the proposed technique.

New molecular insights into heart failure and cardiomyopathy: potential strategies and therapies.

BACKGROUND: In the most severely affected patients the mortality for congestive heart failure exceeds that of many cancers. While therapies are largely aimed at attenuating neurohumoral responses recent molecular insights reveal other potential targets for therapy. AIMS: To summarise some of the recent developments in the management of heart failure and provide the clinician who treats heart failure with new insights into emerging approaches. METHODS: A literature review was conducted of the recent literature together with personal research data. RESULTS: Large randomised trials will provide a more comprehensive understanding of the interaction of beta-blockers and other heart failure therapies with gene polymorphisms. Cytokines are important in the progression of heart failure, yet therapy aimed at blocking cytokine effects has not been successful. More selective use of anti-cytokine therapy may have beneficial effects. Gene therapy to improve heart failure has not yet reached clinical trials. The molecular genetics of hypertrophic and dilated cardiomyopathy is rapidly improving our understanding so that genetic diagnostics and counselling may soon be performed for patients and families. CONCLUSIONS: The emergence of a molecular based understanding of heart failure will hopefully improve therapy of this common condition.

Lack of tacrolimus-induced cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) has been reported in pediatric transplant patients receiving tacrolimus. It is unclear whether tacrolimus is associated with HCM in adult transplant recipients. OBJECTIVE: To determine the prevalence of HCM in noncardlac adult transplant patients receiving tacrolimus. METHODS: A retrospective analysis of nonheart transplant recipients who received tacrolimus at our institution from January 1982 to April 1996 was conducted. Patients with left-ventricular hypertrophy (LVH) defined as a posterior or septal wall thickness > or = 1.3 cm by echocardiography (ECHO) were independently evaluated. RESULTS: There were 3609 patients who met entry criteria including 2257 liver, 1333 kidney, and 19 other organ transplants. Of the 502 patients who had undergone ECHOs after transplantation, 171 had LVH. The etiology of LVH was categorized as valvular disease (36%), hypertensive disease (29%), ischemic heart disease (17%), or multifactonal (15%). There were six patients in whom, after detailed chart review, no underlying cause of LVH was evident. Five of these patients had HCM, representing an overall prevalence of 0.1% in the entire group of tacrolimus-treated patients, and 1% in patients referred for ECHO. CONCLUSIONS: The prevalence of HCM in our tacrolimus-treated adult transplant population is similar to that reported in general population studies. These data suggest that tacrolimus is not a risk factor for HCM in adult transplant recipients.

Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy.

BACKGROUND: This prospective placebo-controlled trial was designed to determine whether intravenous immune globulin (IVIG) improves left ventricular ejection fraction (LVEF) in adults with recent onset of idiopathic dilated cardiomyopathy or myocarditis. METHODS AND RESULTS: Sixty-two patients (37 men, 25 women; mean age +/-SD 43.0+/-12.3 years) with recent onset (/=0.10 from study entry, and 20 (36%) of 56 normalized their ejection fraction (>/=0.50). The transplant-free survival rate was 92% at 1 year and 88% at 2 years. CONCLUSIONS: These results suggest that for patients with recent-onset dilated cardiomyopathy, IVIG does not augment the improvement in LVEF. However, in this overall cohort, LVEF improved significantly during follow-up, and the short-term prognosis remains favorable.

Pharmacogenetic interactions between beta-blocker therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure.

BACKGROUND: Activation of the renin-angiotensin and sympathetic nervous systems adversely affect heart failure progression. The ACE deletion allele (ACE D) is associated with increased renin-angiotensin activation; however, its influence on patient outcomes remains uncertain, and the pharmacogenetic interactions with beta-blocker therapy have not been previously evaluated. METHODS AND RESULTS: We prospectively followed 328 patients (age, 56.1+/-11.9 years) with systolic dysfunction (left ventricular ejection fraction, 0.24+/-0.08) to assess the impact of the ACE D allele on transplant-free survival (median follow-up, 21 months). Transplant-free survival was compared by genotype for the whole cohort and separately in patients with (n=120) and those without beta-blocker therapy (n=208) at the time of entry. Transplant-free survival was significantly poorer for patients with the D: allele (1-year percent survival II/ID/DD=94/77/75; 2-year=78/65/60; ordered log-rank test, P:=0.044). In patients not treated with beta-blockers, the adverse impact of ACE D allele was dramatically increased (1-year percent survival II/ID/DD=95/75/67; 2-year=81/61/48; P:=0.005). In contrast, in patients receiving beta-blocker therapy, no influence of ACE genotype on transplant-free survival was evident (1-year percent survival II/ID/DD=91/80/86; 2-year=70/71/77; P:=0.73). CONCLUSIONS: In a cohort of patients with systolic dysfunction, the ACE D allele was associated with a significantly poorer transplant-free survival. This effect was primarily evident in patients not treated with beta-blockers and was not seen in patients receiving therapy. These findings suggest a potential pharmacogenetic interaction between the ACE D/I polymorphism and therapy with beta-blockers in the determination of heart failure survival.

Expression of proinflammatory cytokines in the failing human heart: comparison of recent-onset and end-stage congestive heart failure.

BACKGROUND: Plasma levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, are elevated in patients with congestive heart failure (CHF). Recent studies suggest that the failing human heart is a source of proinflammatory cytokines in the end-stage failing heart. However, the relevance of plasma levels to those of the myocardium remains undefined. We sought to compare cytokine expression in early and end-stage CHF, and to evaluate the correlation of tissue expression to plasma levels. METHODS: Two patient populations were studied: patients with recent-onset CHF, all with symptoms less than 6 months (n = 17, duration of symptoms 2.1 +/- 1.6 months, range of New York Heart Association (NYHA) 1 to 3), and end-stage heart-failure patients (n = 7) who underwent left-ventricular assist-device (LVAD) implantation (Duration of symptoms 47.1 +/- 28.0 months, all NYHA class 4). Plasma levels of TNF-alpha and IL-6 proteins were evaluated by an Enzyme-Linked Immuno-Sorbent Assay (ELISA), while myocardial levels of cytokine transcripts were assessed by ribonuclease (Rnase) protection assay. RESULTS: In patients with end-stage heart failure, TNF-alpha and IL-6 were increased in the plasma as well as in the myocardium (plasma: TNF-alpha = 7.7 +/- 2.3 pg/ml, IL-6 = 45.0 +/- 47.1 pg/ml; myocardium: TNF-alpha = 0.31 +/- 0.15% of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression, IL-6 = 1.56 +/- 1.54% ). In contrast, despite elevated plasma levels of TNF-alpha and IL-6, the myocardium of patients with the recent onset of symptoms demonstrated minimal expression of TNF-alpha and IL-6 messenger ribonucleic acid (mRNA) (plasma: TNF-alpha = 4.3 +/- 1.7 pg/ml, IL-6 = 3.3 +/- 1.8 pg/ml; myocardium: TNF-alpha = 0.13 +/- 0. 04%, IL-6 = 0.02 +/- 0.04%). Plasma levels of TNF-alpha were significantly correlated with those in the myocardium when both populations were combined. (r = 0.69, p < 0.001). CONCLUSIONS: Cytokines are expressed in the myocardium in end-stage heart failure to a much greater degree than in patients with the recent-onset of symptoms. This suggests that induction of cytokines in the myocardium is a relatively late event in the pathogenesis of CHF. Furthermore, plasma levels of TNF-alpha correlates with mRNA expression in the myocardium and thus may serve as an appropriate marker of myocardial cytokine activation. Whether the production of cytokines in the failing human heart precedes the elevation of cytokines in the plasma remains undefined. Therefore, we studied expression of TNF-alpha and IL-6 in the myocardium as well as in the plasma in patients with early and end-stage CHF. The results have demonstrated that cytokines are expressed in the myocardium in end-stage heart failure to a much greater degree than in patients with the recent onset of symptoms. This suggests that induction of cytokines in the myocardium is a relatively late event in the pathogenesis of CHF.

Intravenous immune globulin in the therapy of peripartum cardiomyopathy.

OBJECTIVES: We sought to evaluate the effect of therapy with intravenous immune globulin on recovery of left ventricular function in women presenting with peripartum cardiomyopathy. BACKGROUND: Peripartum cardiomyopathy is a rare complication of pregnancy that results in significant morbidity and mortality in women of childbearing age. Intravenous immune globulin has been reported to improve left ventricular systolic function in patients with acute dilated cardiomyopathy and myocarditis, but its effectiveness in peripartum cardiomyopathy is unknown. METHODS: In this retrospective study, we compared the clinical outcomes of six women with peripartum cardiomyopathy treated with intravenous immune globulin (2 g/kg) with those of 11 recent historical control subjects. All women in the study were referred between 1991 and 1998 with class II to IV heart failure and a left ventricular ejection fraction of <0.40. Left ventricular ejection was reassessed during early follow-up (6.1+/-2.9 months). RESULTS: The two groups did not differ in terms of baseline left ventricular ejection fraction, left ventricular end-diastolic diameter, months to presentation, age or multiparity. The improvement in left ventricular ejection fraction in patients treated with immune globulin was significantly greater than in the conventionally treated group (increase of 26+/-8 ejection fraction units vs. 13+/-13, p = 0.042). CONCLUSIONS: In this small retrospective study of women with peripartum cardiomyopathy, patients treated with immune globulin had a greater improvement in ejection fraction during early follow-up than patients treated conventionally. Given the poor prognosis of women with peripartum cardiomyopathy who do not improve, this therapy merits further study.

Predicting short-term outcome in severely ill heart failure patients: implications regarding listing for urgent cardiac transplantation and patient selection for temporary ventricular assist device support.

BACKGROUND: The purpose of this study was to determine which patients on a cardiac transplantation list required a ventricular assist device. METHODS AND RESULTS: In a preliminary study, 26 patients with decompensated severe New York Heart Association class IV chronic heart failure were studied. Blood levels for sodium, hemoglobin, cytokines, neurohormones, and hemodynamics were obtained. During short-term follow-up of 40 days, 12 patients had undergone emergent implantation of a ventricular assist device (range 1-27 days, mean 5 days), 4 died (range 14-38 days, mean 26 days), and 5 were alive and receiving only medical therapy while waiting for a transplantation. In addition, five patients had undergone transplantation (range 5-29 days, mean 18 days, excluded from further analysis). Survival curves were constructed by comparing the incidence of death and the implantation of an emergent ventricular assist device in patients with values of a variable above or below the mean value (or median for nonnormally distributed data). There was a significantly greater incidence of death or need for a ventricular assist device in patients with higher levels of tumor necrosis factor-alpha (P = .008), lower levels of serum sodium and hemoglobin (P = .02 and P = .03, respectively), higher heart rates (P = .03), and higher plasma norepinephrine levels (P = .01). The Cox proportional hazards model demonstrated that only serum sodium (P = .03) independently predicted those patients who died or who required emergent left ventricular assist device. CONCLUSION: Numerous variables, particularly serum sodium, need to be considered when evaluating which patients on the transplant list require early assist device implantation or urgent transplantation. These preliminary observations merit confirmation in a larger patient population.

Effects of tumor necrosis factor gene polymorphisms on patients with congestive heart failure. VEST Investigators for TNF Genotype Analysis. Vesnarinone Survival Trial.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is known to be elevated in patients with congestive heart failure (CHF). Two biallelic polymorphisms have been identified in the TNF gene locus: one in the promoter region of TNF-alpha (TNFA1/2), and the other in the first intron of TNF-beta (TNFB1/2). Both TNFA2 and TNFB2 alleles are associated with high TNF-alpha production in vitro and susceptibility to inflammatory diseases. Given the importance of TNF-alpha in the pathogenesis of CHF, we studied the prevalence of TNF gene polymorphisms in CHF patients and the correlation of genotypes to in vivo TNF-alpha levels. METHODS AND RESULTS: TNFA and TNFB genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism technique. There were no differences in the TNF allele frequencies between CHF (n=229; TNFA1/2=0.84/0.16, TNFB1/2=0.33/0.67) and control subjects (n=139; TNFA1/2=0.84/0.16, TNFB1/2=0.32/0.68). In 211 patients with CHF, circulating levels of TNF-alpha and the soluble receptors type I and type II were measured by ELISA: 6.18+/-3.59 pg/mL, 1768+/-761 pg/mL, and 4484+/-1750 pg/mL, respectively. There were no correlations between TNFA or TNFB genotypes and circulating levels of TNF-alpha or its soluble receptors in the CHF patients. CONCLUSIONS: Despite their association with other inflammatory diseases, neither TNFA nor TNFB polymorphisms are related to the presence of CHF or the elevation of circulating TNF-alpha. Thus, other factors may be more important in determining the circulating levels of TNF-alpha in CHF.