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Biomedical subjects

Leslie W Miller

Publications and source records attributed to Leslie W Miller.

At least 19 recordsLinked to original sources
PubMed2006

Myocardial expression of the arginine:glycine amidinotransferase gene is elevated in heart failure and normalized after recovery: potential implications for local creatine synthesis.

BACKGROUND: Combination therapy consisting of mechanical unloading using a left ventricular assist device (LVAD) and pharmacological intervention can promote recovery from end-stage heart failure, but the mechanism is unknown. Preliminary microarray analysis revealed a significant and unexpected decrease in myocardial arginine:glycine amidinotransferase (AGAT) gene expression during recovery in these patients. The aim of this study was to evaluate the expression and role of AGAT expression in heart failure and recovery. METHODS AND RESULTS: We used quantitative real time (TaqMan) polymerase chain reaction to examine myocardial AGAT mRNA expression in implant and explant samples from recovering patients after combination therapy (n=12), end-stage heart failure (ESHF) samples from stable patients undergoing transplantation without LVAD support (n=10), and donor hearts with normal hemodynamic function (n=8). AGAT mRNA expression was significantly elevated in all heart failure patients relative to donors (4.3-fold [P<0.001] and 2.7-fold [P<0.005] in LVAD and ESHF relative to donors, respectively) and returned to normal levels after recovery. AGAT enzyme activity was detectable in both human and rat myocardia and was elevated in heart failure. CONCLUSIONS: Our data highlight local and potentially regulated expression of AGAT activity in the myocardium and suggest a specific response to heart failure involving elevated local creatine synthesis. These findings have implications both for the management of recovery patients undergoing combination therapy and for heart failure in general.

Adolescent↗
PubMed2006

Improved mechanical reliability of the HeartMate XVE left ventricular assist system.

BACKGROUND: The HeartMate XVE left ventricular assist device is a valuable treatment option for patients with end-stage heart failure. During the past several years, the XVE has undergone a series of design enhancements to improve reliability. We compared the reliability of the two most recent design iterations of the XVE pump (stitch modification to the inflow valve assembly and new inflow valve housing redesign) to the earlier VE version. METHODS: A retrospective evaluation of device reliability was performed for 268 devices implanted in 245 patients (VE: n = 167 devices, 147 patients, implant dates October 16, 1998, to December 19, 2003; XVE: n = 101 devices, 98 patients, implant dates August 1, 2002, to April 14, 2004). RESULTS: Median duration of device support for the VE and XVE was 159 days (range, 0 to 1,206 days) and 229 days (range, 0 to 693 days), respectively (p = 0.495). Significantly fewer major device malfunctions occurred within the XVE group as compared with the VE group (6 versus 36, respectively; p = 0.0003). The number of major device malfunctions per patient-year of support for inflow valve dysfunction, bearing wear, and other failures for the VE and XVE were 0.2 versus 0.04 (p = 0.006), 0.16 versus 0.01 (p = 0.005), and 0.06 versus 0.04 (p = 1.000), respectively. The freedom from major device malfunction at 1 year was 76% +/- 6% for the VE and 97% +/- 2% for the XVE device (p < 0.001). The freedom from death as a result of major device malfunction at 1 year was 97% +/- 2% for the VE and 98% +/- 2% for the XVE (p = 0.698). CONCLUSIONS: Design enhancements to the HeartMate XVE have significantly reduced the incidence of major device malfunctions compared with the earlier VE model because of a reduction in failure modes from bearing wear and inlet valve dysfunction. Further follow-up is necessary to establish the long-term durability of the most recent XVE pump version.

Adolescent↗
PubMed2006

Hospital costs for left ventricular assist devices for destination therapy: lower costs for implantation in the post-REMATCH era.

BACKGROUND: The use of left ventricular assist devices (LVADs) as an alternative to transplant, or destination therapy (end of life support), is an increasingly important option for patients with end-stage heart failure. Prior studies have examined hospital costs for LVAD implants performed during investigational studies (e.g., REMATCH), but none has been published since that trial was completed. METHODS: We performed a retrospective analysis of 23 consecutive patients who had a HeartMate XVE pump implanted as destination therapy at 2 high-volume ventricular assist device implant centers after US Food and Drug Administration approval in October 2003. We evaluated survival to discharge during the implantation hospitalization, hospital length of stay, and hospital costs, and compared them with outcomes reported from the REMATCH (RM) trial. RESULTS: All patients in this cohort implanted post-REMATCH (PRM) had class IV heart failure and were similar in age, gender, and nearly all other pre-implantation clinical measures to the RM subjects. Mean hospital costs for PRM patients were 40% lower than for RM patients when measured from implantation to discharge (dollar 128,084 vs dollar 210,187, p < 0.01). PRM patients who survived implantation hospitalization had 48% lower costs than those who did not survive (dollar 114,979 vs dollar 215,456, p < 0.01), a finding similar to the RM experience. PRM patients in this cohort were more likely to survive to discharge compared with RM patients (87.0% vs 67.3%, p = 0.09). Mean hospital length of stay was 25% lower in the PRM group (44 vs 33 days) but did not reach statistical significance (p = 0.50). CONCLUSIONS: Outcomes with use of LVADs as destination therapy have improved in the post-REMATCH era, including significantly lower hospital costs as well as strong trends toward better survival to hospital discharge and shorter average length of stay.

Aged↗
PubMed2005

Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial.

CONTEXT: Pulmonary artery catheters (PACs) have been used to guide therapy in multiple settings, but recent studies have raised concerns that PACs may lead to increased mortality in hospitalized patients. OBJECTIVE: To determine whether PAC use is safe and improves clinical outcomes in patients hospitalized with severe symptomatic and recurrent heart failure. DESIGN, SETTING, AND PARTICIPANTS: The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) was a randomized controlled trial of 433 patients at 26 sites conducted from January 18, 2000, to November 17, 2003. Patients were assigned to receive therapy guided by clinical assessment and a PAC or clinical assessment alone. The target in both groups was resolution of clinical congestion, with additional PAC targets of a pulmonary capillary wedge pressure of 15 mm Hg and a right atrial pressure of 8 mm Hg. Medications were not specified, but inotrope use was explicitly discouraged. MAIN OUTCOME MEASURES: The primary end point was days alive out of the hospital during the first 6 months, with secondary end points of exercise, quality of life, biochemical, and echocardiographic changes. RESULTS: Severity of illness was reflected by the following values: average left ventricular ejection fraction, 19%; systolic blood pressure, 106 mm Hg; sodium level, 137 mEq/L; urea nitrogen, 35 mg/dL (12.40 mmol/L); and creatinine, 1.5 mg/dL (132.6 micromol/L). Therapy in both groups led to substantial reduction in symptoms, jugular venous pressure, and edema. Use of the PAC did not significantly affect the primary end point of days alive and out of the hospital during the first 6 months (133 days vs 135 days; hazard ratio [HR], 1.00 [95% confidence interval {CI}, 0.82-1.21]; P = .99), mortality (43 patients [10%] vs 38 patients [9%]; odds ratio [OR], 1.26 [95% CI, 0.78-2.03]; P = .35), or the number of days hospitalized (8.7 vs 8.3; HR, 1.04 [95% CI, 0.86-1.27]; P = .67). In-hospital adverse events were more common among patients in the PAC group (47 [21.9%] vs 25 [11.5%]; P = .04). There were no deaths related to PAC use, and no difference for in-hospital plus 30-day mortality (10 [4.7%] vs 11 [5.0%]; OR, 0.97 [95% CI, 0.38-2.22]; P = .97). Exercise and quality of life end points improved in both groups with a trend toward greater improvement with the PAC, which reached significance for the time trade-off at all time points after randomization. CONCLUSIONS: Therapy to reduce volume overload during hospitalization for heart failure led to marked improvement in signs and symptoms of elevated filling pressures with or without the PAC. Addition of the PAC to careful clinical assessment increased anticipated adverse events, but did not affect overall mortality and hospitalization. Future trials should test noninvasive assessments with specific treatment strategies that could be used to better tailor therapy for both survival time and survival quality as valued by patients.

Catheterization, Swan-Ganz↗
PubMed2005

Myocardial insulin-like growth factor-I gene expression during recovery from heart failure after combined left ventricular assist device and clenbuterol therapy.

BACKGROUND: Patients who undergo mechanical support with a left ventricular assist device (LVAD) exhibit reverse remodeling and in some cases recover from heart failure. We have developed a combination therapy using LVAD support combined with pharmacological therapy to maximize reverse remodeling, followed by the beta2 adrenergic agonist clenbuterol. We recently found that clenbuterol induces insulin-like growth factor I (IGF-I) in cardiac myocytes in vitro. The purpose of this study is to examine IGF-I expression in recovery patients after combination therapy. METHODS AND RESULTS: Myocardial mRNA levels were determined by real-time quantitative polymerase chain reaction in 12 recovery patients (at LVAD implantation, explantation, and 1 year after explantation). IGF-I mRNA was elevated at the time of LVAD explantation relative to donors, with 2 groups distinguishable: Those with low IGF-I mRNA at implantation who showed significant increase during recovery and those with high IGF-I mRNA at implantation who remained high. Levels returned to normal by 1 year after explantation. Microarray analysis of implantation and explantation samples of recovery patients further revealed elevated IGF-II and IGF binding proteins IGFBP4 and IGFBP6. IGF-I levels correlated with stromal cell-derived factor mRNA measured both in LVAD patients and in a wider cohort of heart failure patients. CONCLUSIONS: The data suggest involvement of elevated myocardial IGF-I mRNA in recovery. IGF-I may act to limit atrophy and apoptosis during reverse remodeling and to promote repair and regeneration in concert with stromal cell derived factor.

Adrenergic beta-2 Receptor Agonists↗
PubMed2005

Gene profiling changes in cytoskeletal proteins during clinical recovery after left ventricular-assist device support.

BACKGROUND: After left ventricular-assist device (LVAD) support, a proportion of patients recover sufficient ventricular function to enable explantation of the device. The exact molecular mechanisms involved in myocardial recovery remain unknown. Cytoskeletal proteins are essential for the structure and function of the cardiac myocyte and might play a major role. METHODS AND RESULTS: A total of 15 patients with nonischemic cardiomyopathy who required LVAD implantation were studied; 6 recovered sufficiently to allow explantation of the device compared with 9 who did not recover and required transplantation. LV myocardial samples were collected at implantation and explantation/transplantation. Affymetrix microarray analysis was performed on the paired samples and analyzed with reference to sarcomeric and nonsarcomeric cytoskeletal proteins. In the recovery group, of the nonsarcomeric proteins, lamin A/C increased 1.5-fold (P<0.05) and spectrin 1.6-fold (P<0.05) between the times of implantation and explantation. Integrins beta1, beta6, and alpha7 decreased 1.7-fold (P<0.05), 2.4-fold (P<0.05), and 1.5-fold (P<0.05), respectively, but integrins alpha5 and beta5 increased 2.3-fold (P<0.01) and 1.2-fold (P<0.01) at explantation. The following sarcomeric proteins changed in the recovered group only: beta-actin increased 1.4-fold (P<0.05); alpha-tropomyosin, 1.3-fold (P<0.05); alpha1-actinin, 1.8-fold (P<0.01); and alpha-filamin A, 1.6-fold (P<0.05). Both troponin T3 and alpha2-actinin decreased by 1.6-fold at the time of explantation (P<0.05). Vinculin decreased 1.7-fold (P=0.001) in the recovered group but increased by 1.7-fold (P<0.05) in the nonrecovered group. Vinculin protein levels decreased 4.1-fold in the recovered group. CONCLUSIONS: Myocardial recovery was associated with a specific pattern of changes in sarcomeric, nonsarcomeric, and membrane-associated proteins, which could have important implications in understanding the mechanisms involved.

Adrenergic beta-2 Receptor Agonists↗
PubMed2005

A comparative study of discriminating human heart failure etiology using gene expression profiles.

BACKGROUND: Human heart failure is a complex disease that manifests from multiple genetic and environmental factors. Although ischemic and non-ischemic heart disease present clinically with many similar decreases in ventricular function, emerging work suggests that they are distinct diseases with different responses to therapy. The ability to distinguish between ischemic and non-ischemic heart failure may be essential to guide appropriate therapy and determine prognosis for successful treatment. In this paper we consider discriminating the etiologies of heart failure using gene expression libraries from two separate institutions. RESULTS: We apply five new statistical methods, including partial least squares, penalized partial least squares, LASSO, nearest shrunken centroids and random forest, to two real datasets and compare their performance for multiclass classification. It is found that the five statistical methods perform similarly on each of the two datasets: it is difficult to correctly distinguish the etiologies of heart failure in one dataset whereas it is easy for the other one. In a simulation study, it is confirmed that the five methods tend to have close performance, though the random forest seems to have a slight edge. CONCLUSIONS: For some gene expression data, several recently developed discriminant methods may perform similarly. More importantly, one must remain cautious when assessing the discriminating performance using gene expression profiles based on a small dataset; our analysis suggests the importance of utilizing multiple or larger datasets.

Data Interpretation, Statistical↗
PubMed2005

Borrowing information from relevant microarray studies for sample classification using weighted partial least squares.

With an increasing number of publicly available microarray datasets, it becomes attractive to borrow information from other relevant studies to have more reliable and powerful analysis of a given dataset. We do not assume that subjects in the current study and other relevant studies are drawn from the same population as assumed by meta-analysis. In particular, the set of parameters in the current study may be different from that of the other studies. We consider sample classification based on gene expression profiles in this context. We propose two new methods, a weighted partial least squares (WPLS) method and a weighted penalized partial least squares (WPPLS) method, to build a classifier by a combined use of multiple datasets. The methods can weight the individual datasets depending on their relevance to the current study. A more standard approach is first to build a classifier using each of the individual datasets, then to combine the outputs of the multiple classifiers using a weighted voting. Using two quite different datasets on human heart failure, we show first that WPLS/WPPLS, by borrowing information from the other dataset, can improve the performance of PLS/PPLS built on only a single dataset. Second, WPLS/WPPLS performs better than the standard approach of combining multiple classifiers. Third, WPPLS can improve over WPLS, just as PPLS does over PLS for a single dataset.

Gene Expression Profiling↗
PubMed2005

Will left-ventricular assist device therapy replace heart transplantation in the foreseeable future?

PURPOSE OF REVIEW: Implantation of circulatory assist devices as a permanent alternative to heart transplantation, so-called Destination Therapy, has become a promising new option for treatment of patients with advanced heart failure who are not candidates for heart transplantation. RECENT FINDINGS: The landmark REMATCH trial demonstrated that the implantation of left-ventricular assist devices is superior to any available medical therapy in patients with end-stage heart failure who are not eligible for transplantation. SUMMARY: Although the outcomes of device therapy are still limited by device durability and complications, the potential of Destination Therapy should continue to expand through the development of newer, smaller, and more innovative ventricular assist devices. This review discusses the current state of knowledge and future directions of Destination Therapy for end-stage heart failure.

Contraindications↗
PubMed2005

Preoperative predictors for postoperative problems in heart transplantation: psychiatric and psychosocial considerations.

The psychiatric and psychosocial evaluation of the heart transplant candidate can identify particular predictors for postoperative problems. These factors, as identified during the comprehensive evaluation phase, provide an assessment of the candidate in context of the proposed transplantation protocol. Previous issues with compliance, substance abuse, and psychosis are clear indictors of postoperative problems. The prolonged waiting list time provides an additional period to evaluate and provide support to patients having a terminal disease who need a heart transplant, and are undergoing prolonged hospitalization. Following transplantation, the patient is faced with additional challenges of a new self-image, multiple concerns, anxiety, and depression. Ultimately, the success of the heart transplantation remains dependent upon the recipient's ability to cope psychologically and comply with the medication regimen. The limited resource of donor hearts and the high emotional and financial cost of heart transplantation lead to an exhaustive effort to select those patients who will benefit from the improved physical health the heart transplant confers.

Adaptation, Psychological↗
PubMed2004

Identification of a gene expression profile that differentiates between ischemic and nonischemic cardiomyopathy.

BACKGROUND: Gene expression profiling refines diagnostic and prognostic assessment in oncology but has not yet been applied to myocardial diseases. We hypothesized that gene expression differentiates ischemic and nonischemic cardiomyopathy, demonstrating that gene expression profiling by clinical parameters is feasible in cardiology. METHODS AND RESULTS: Affymetrix U133A microarrays of 48 myocardial samples from Johns Hopkins Hospital (JHH) and the University of Minnesota (UM) obtained (1) at transplantation or left ventricular assist device (LVAD) placement (end-stage; n=25), (2) after LVAD support (post-LVAD; n=16), and (3) from newly diagnosed patients (biopsy; n=7) were analyzed with prediction analysis of microarrays. A training set was used to develop the profile and test sets to validate the accuracy of the profile. An etiology prediction profile developed in end-stage JHH samples was tested in independent samples from both JHH and UM with 100% sensitivity and 100% specificity in end-stage samples and 33% sensitivity and 100% specificity in both post-LVAD and biopsy samples. The overall sensitivity was 89% (95% CI 75% to 100%), and specificity was 89% (95% CI 60% to 100%) over 210 random partitions of end-stage samples into training and test sets. Age, gender, and hemodynamic differences did not affect the profile's accuracy in stratified analyses. Select gene expression was confirmed with quantitative polymerase chain reaction. CONCLUSIONS: Gene expression profiling accurately predicts cardiomyopathy etiology, is generalizable to samples from separate institutions, is specific to disease stage, and is unaffected by differences in clinical characteristics. This strongly supports ongoing efforts to incorporate expression profiling-based biomarkers in determining prognosis and response to therapy in heart failure.

Adult↗
PubMed2004

Left ventricular assist device as destination for patients undergoing intravenous inotropic therapy: a subset analysis from REMATCH (Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure).

BACKGROUND: Left ventricular assist devices (LVADs) have improved survival in patients with end-stage heart failure. Compared with previous trials, the Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure (REMATCH) trial enrolled patients with more advanced heart failure and high prevalence of intravenous inotropic therapy. This study analyzes, on a post hoc basis, outcomes in patients undergoing inotropic infusions at randomization. METHODS AND RESULTS: Of 129 patients randomized, 91 were receiving intravenous inotropic therapy at randomization to LVAD or optimal medical management (OMM). Mean systolic pressure was 100 versus 107 mm Hg in those not receiving inotropes, serum sodium was 134 versus 137 mEq/L, and left ventricular ejection fraction was 17% for both groups. LVADs improved survival throughout follow-up for patients undergoing baseline inotropic infusions (P=0.0014); for the LVAD group versus the OMM group, respectively, 6-month survival was 60% versus 39%, 1-year survival rates were 49% versus 24%, and 2-year survival rates were 28% versus 11%. For 38 patients not undergoing inotropic infusions, 6-month survival was 61% for those with LVADs and 67% for those with OMM, whereas 1-year rates were 57% and 40%, respectively (P=0.55). Quality-of-life scores for survivors improved. Median days out of hospital for patients on inotropic therapy at randomization were 255 with LVAD and 105 with OMM. CONCLUSIONS: Despite severe compromise, patients undergoing inotropic infusions at randomization derived major LVAD survival benefit with improved quality of life. Patients not undergoing inotropic infusions had higher survival rates both with and without LVAD, but differences did not reach significance. Future studies should prespecify analyses of inotropic and other therapies to determine how disease severity and parallel medical treatment influence the benefits offered by mechanical circulatory support.

Adrenergic beta-Antagonists↗
PubMed2004

Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart.

We screened a compendium of gene profiles from 19 paired human heart samples harvested at the time of implant and explant of a left ventricular assist device (LVAD) for novel genes regulating the Ras/MEK/ERK cascade. From this analysis we identified Sprouty1, an evolutionally conserved gene that acts as an intrinsic inhibitor of the Ras/MEK/ERK pathway. Sprouty1 mRNA and protein were significantly upregulated in the heart in response to mechanical unloading with a LVAD. The upregulation of Sprouty1 in the heart following mechanical unloading was accompanied by a significant decrease in phosphorylated ERK1/2. Gain of function experiments demonstrated that upregulation of Sprouty1 in isolated cardiac myocytes led to a significant decrease and altered kinetics of ERK1/2 phosphorylation. Immunohistochemistry of human hearts revealed that Sprouty1 was also expressed in the microvasculature. Upregulation of Sprouty1 in endothelial cells led to a significant decrease in VEGF-induced endothelial cell proliferation. To our knowledge, these findings are the first to define Sprouty expression in the heart and suggest that Sprouty1 may serve as an intrinsic mediator governing ventricular remodeling through a coordinated coupling of both myocyte and vascular alterations in response to mechanical load.

Animals↗
PubMed2004

Genomic profiling of the human heart before and after mechanical support with a ventricular assist device reveals alterations in vascular signaling networks.

Mechanical unloading of the heart with a left ventricular assist device (LVAD) significantly decreases mortality in patients with heart failure. Moreover, it provides a human model to define the critical regulatory genes governing myocardial remodeling in response to significant reductions in wall stress. Statistical analysis of a gene expression library of 19 paired human heart samples harvested at the time of LVAD implant and again at explant revealed a set of 22 genes that were downregulated and 85 genes that were upregulated in response to mechanical unloading with a false discovery rate of less than 1%. The analysis revealed a high percentage of genes involved in the regulation of vascular networks including neuropilin-1 (a VEGF receptor), FGF9, Sprouty1, stromal-derived factor 1, and endomucin. Taken together these findings suggest that mechanical unloading alters the regulation of vascular organization and migration in the heart. In addition to vascular signaling networks, GATA-4 binding protein, a critical mediator of myocyte hypertrophy, was significantly downregulated following mechanical unloading. In summary, these findings may have important implications for defining the role of mechanical stretch and load on autocrine/paracrine signals directing vascular organization in the failing human heart and the role of GATA-4 in orchestrating reverse myocardial remodeling. This unbiased gene discovery approach in paired human heart samples has the potential to provide critical clues to the next generation of therapeutic treatments aimed at heart failure.

Adult↗
PubMed2004

Modeling the relationship between LVAD support time and gene expression changes in the human heart by penalized partial least squares.

MOTIVATION: Heart failure affects more than 20 million people in the world. Heart transplantation is the most effective therapy, but the number of eligible patients far outweighs the number of available donor hearts. The left mechanical ventricular assist device (LVAD) has been developed as a successful substitution therapy that aids the failing ventricle while a patient is waiting for the donor heart. We obtained genomics data from paired human heart samples harvested at the time of LVAD implant and explant. The heart failure patients in our study were supported by the LVAD for various periods of time. The goal of this study is to model the relationship between the time of LVAD support and gene expression changes. RESULTS: To serve the purpose, we propose a novel penalized partial least squares (PPLS) method to build a regression model. Compared with partial least squares and Breiman's random forest method, PPLS gives the best prediction results for the LVAD data.

Adaptation, Physiological↗
PubMed2004

Infection in permanent circulatory support: experience from the REMATCH trial.

BACKGROUND: This analysis of the REMATCH Trial focuses on infection, which was an important source of morbidity and mortality. We use the information to suggest ways to decrease the incidence and effects of device-related infection. METHODS: Patients were randomized prospectively to receive left ventricular assist devices (LVADs) or optimal medical management (OMM) for end-stage heart failure. Infection variables included sepsis adjudicated as the cause of death; sepsis reported as a serious adverse event; percutaneous site or pocket infection; and pump housing, inflow- or outflow-tract infection. We compared the incidence and prevalence of events between groups and generated time-related descriptions. RESULTS: Survival with LVAD (n=68 patients) was superior to OMM survival (n=61 patients) with a 47% decrease in risk of death (p <0.001), but the aggregate adverse event rate was greater for patients with LVADs (risk ratio, 2.29; 95% confidence interval, 1.85-2.84). Freedom from sepsis in patients with LVADs was 58% at 1 year and 48% at 2 years after implantation with superior survival in non-septic patients (60% vs 39% at 1 year and 38% vs 8% at 2 years in non-septic vs septic patients with LVADs, p <0.06). Percutaneous site or pocket infection did not affect survival (p=0.86). The hazard for onset of sepsis peaked within the first 3 weeks after implantation. CONCLUSIONS: Survival is improved with permanent LVAD implantation compared with OMM therapy. However, infection causes substantial morbidity and mortality. Decreasing infections will increase survival and decrease morbidity in permanent LVAD recipients and will improve the risk-benefit ratio for permanent LVAD therapy.

Antibiotic Prophylaxis↗