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M R Bristow,
H Krause-Steinrauf,
R Nuzzo,
Cheng-Seng Liang,
J Lindenfeld,
B D Lowes,
B Hattler, W T Abraham,
L Olson,
S Krueger,
S Thaneemit-Chen,
J M Hare,
H S Loeb,
M J Domanski,
E J Eichhorn,
R Zelis,
P Lavori
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ABSTRACT: Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent.
Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the beta-Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the beta-blocker/sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant (P<0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization. In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months.
In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation beta-blocker.
Circulation 10/2004; 110(11):1437-42. · 14.74 Impact Factor
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W T Abraham,
E M Gilbert,
B D Lowes,
W A Minobe,
P Larrabee,
R L Roden,
D Dutcher,
J Sederberg,
J A Lindenfeld,
E E Wolfel,
S F Shakar,
D Ferguson,
K Volkman,
J V Linseman,
R A Quaife,
A D Robertson,
M R Bristow
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ABSTRACT: The most common cause of chronic heart failure in the US is secondary or primary dilated cardiomyopathy (DCM). The DCM phenotype exhibits changes in the expression of genes that regulate contractile function and pathologic hypertrophy. However, it is unclear if any of these alterations in gene expression are disease producing or modifying.
One approach to providing evidence for cause-effect of a disease-influencing gene is to quantitatively compare changes in phenotype to changes in gene expression by employing serial measurements in a longitudinal experimental design. We investigated the quantitative relationships between changes in gene expression and phenotype n 47 patients with idiopathic DCM. In endomyocardial biopsies at baseline and 6 months later, we measured mRNA expression of genes regulating contractile function (beta-adrenergic receptors, sarcoplasmic reticulum Ca(2) + ATPase, and alpha- and beta-myosin heavy chain isoforms) or associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide), plus beta-adrenergic receptor protein expression. Left ventricular phenotype was assessed by radionuclide ejection fraction.
Improvement in DCM phenotype was directly related to a coordinate increase in alpha- and a decrease in beta-myosin heavy chain mRNA expression. In contrast, modification of phenotype was unrelated to changes in the expression of beta(1)- or beta(2)-adrenergic receptor mRNA or protein, or to the mRNA expression of sarcoplasmic reticulum Ca(2) + ATPase and atrial natriuretic peptide.
We conclude that in human DCM, phenotypic modification is selectively associated with myosin heavy chain isoform changes. These data support the hypothesis that myosin heavy chain isoform changes contribute to disease progression in human DCM.
Molecular Medicine 12/2002; 8(11):750-60. · 3.76 Impact Factor
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ABSTRACT: Clinical trials of beta blockers in heart failure have generally required that patients be receiving optimal drug therapy before randomization to the study medication. Therefore, because beta blockers are used in addition to conventional drug therapy, review of the standard drug therapy of mild-to-moderate heart failure before the advent of beta blockade is essential to understanding the role of beta blockers in the treatment of heart failure. The conventional medical management of systolic heart failure includes angiotensin-converting enzyme (ACE) inhibitors, which should be used as first-line therapy; diuretics, for the management of body fluid-volume excess; digoxin; and some other vasodilators. These therapies have been evaluated in large-scale, randomized, controlled trials. ACE inhibitors have been shown to significantly attenuate disease progression and improve outcome (ie, morbidity and mortality) in patients with mild-to-moderate systolic heart failure. Controversial or unproven therapies include nonglycoside inotropic agents, angiotensin II receptor antagonists, antiarrhythmic agents, anticoagulants, and calcium channel blockers. The pharmacologic management of diastolic heart failure is largely empirical and is directed at reducing symptoms. Symptoms caused by increased ventricular filling pressures may be treated with diuretics and long-acting nitrates. Some calcium channel blockers and most beta blockers prolong diastolic filling time by slowing heart rate, thereby potentially improving the symptoms of diastolic heart failure. Calcium antagonists, beta blockers, diuretics, and ACE inhibitors may also promote regression of left ventricular hypertrophy and thus improve ventricular compliance, possibly preventing the development of diastolic dysfunction. Because randomized controlled trials of diastolic heart failure are lacking, this review focuses on the conventional management of mild-to-moderate systolic heart failure before the advent of beta blockade.
The American Journal of Medicine 06/2001; 110 Suppl 7A:47S-62S. · 5.43 Impact Factor
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ABSTRACT: Carvedilol has been shown to decrease the progression of heart failure and improve left ventricular function and survival in patients with a left ventricular ejection fraction (LVEF) less than 35%. However, not all patients respond uniformly to this therapy. We proposed to identify variables that could, potentially, be used to predict response to carvedilol therapy as measured by the change in LVEF after treatment (Delta LVEF), and to identify pretreatment variables associated with hospitalization for heart failure after carvedilol therapy.
A retrospective analysis of 98 patients treated with open-label carvedilol for a mean period of 16 months was performed by using bivariate and step-wise multivariate analyses. Bivariate analysis showed a positive correlation of Delta LVEF with heart rate at baseline (P =.001). There was a negative correlation of Delta LVEF with baseline LVEF (P <.01), diabetes mellitus (P =.04), and ischemic cardiomyopathy (P =.0002). Multivariate analysis showed a positive correlation of Delta LVEF with heart rate at baseline (P =.01) and a negative correlation with initial LVEF (P =.02) and ischemic cardiomyopathy (P =.006). Variables associated with hospitalization after initiation of carvedilol therapy were New York Heart Association (NYHA) classification (P =.001), lower extremity edema (P =.001), presence of an S3 (P =.02), hyponatremia (P =.02), elevated blood urea nitrogen (BUN) (P =.002), atrial fibrillation (P =.001), diabetes mellitus (P =.02), and obstructive sleep apnea (P =.009).
Heart failure patients with the lowest LVEF or the highest heart rate at baseline had the greatest gain in LVEF after treatment with carvedilol. Patients with ischemic cardiomyopathy derived less benefit. Patients with clinical evidence of decompensated heart failure were at greater risk for hospitalization after initiation of carvedilol therapy.
Journal of Cardiac Failure 04/2001; 7(1):4-12. · 3.66 Impact Factor
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R Dash,
V Kadambi,
A G Schmidt,
N M Tepe,
D Biniakiewicz,
M J Gerst,
A M Canning, W T Abraham,
B D Hoit,
S B Liggett,
J N Lorenz,
G W Dorn,
E G Kranias
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ABSTRACT: Relieving the inhibition of sarcoplasmic reticular function by phospholamban is a major target of beta-adrenergic stimulation. Chronic beta-adrenergic receptor activity has been suggested to be detrimental, on the basis of transgenic overexpression of the receptor or its signaling effectors. However, it is not known whether physiological levels of sympathetic tone, in the absence of preexisting heart failure, are similarly detrimental.
Transgenic mice overexpressing phospholamban at 4-fold normal levels were generated, and at 3 months, they exhibited mildly depressed ventricular contractility without heart failure. As expected, transgenic cardiomyocyte mechanics and calcium kinetics were depressed, but isoproterenol reversed the inhibitory effects of phospholamban on these parameters. In vivo cardiac function was substantially depressed by propranolol administration, suggesting enhanced sympathetic tone. Indeed, plasma norepinephrine levels and the phosphorylation status of phospholamban were elevated, reflecting increased adrenergic drive in transgenic hearts. On aging, the chronic enhancement of adrenergic tone was associated with a desensitization of adenylyl cyclase (which intensified the inhibitory effects of phospholamban), the development of overt heart failure, and a premature mortality.
The unique interaction between phospholamban and increased adrenergic drive, elucidated herein, provides the first evidence that compensatory increases in catecholamine stimulation can, even in the absence of preexisting heart failure, be a primary causative factor in the development of cardiomyopathy and early mortality.
Circulation 03/2001; 103(6):889-96. · 14.74 Impact Factor
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ABSTRACT: This article reviews the current understanding of the pathophysiology and clinical spectrum of heart failure. A cascade of hemodynamic and neurohormonal derangements result from a decrease in ventricular performance or cardiac output. Because neurohormonal activation has become a target for intervention in heart failure, the role of selected systems (sympathetic nervous, renin-angiotensin-aldosterone) and of natriuretic peptides is detailed. The spectrum (from compensated to acute decompensated) within which congestive heart failure patients present is reviewed, with special attention paid to the intermediate, transitional group of patients, who pose unique diagnostic and therapeutic challenges. Given these variable presentations, there is an obligation to tailor therapy accordingly.
Reviews in cardiovascular medicine 02/2001; 2 Suppl 2:S2-6. · 0.58 Impact Factor
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W T Abraham
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ABSTRACT: Up to 50% of patients with chronic systolic heart failure have interventricular conduction delays, such as left bundle branch block, that result in abnormal electrical depolarization of the heart. Prolonged QRS duration results in abnormal interventricular septal wall motion, decreased contractility, reduced diastolic filling time, and prolonged duration of mitral regurgitation, which places the failing heart at a significant mechanical disadvantage. Prolonged QRS duration has been associated with poor outcome in heart failure patients. Atrial-synchronized, biventricular pacing or cardiac resynchronization therapy optimizes atrial-ventricular delay, narrows QRS duration, and seems promising in the management of advanced heart failure patients. Initial studies show improved quality of life and functional capacity compared with baseline or with no pacing. These studies, however, were either uncontrolled or poorly controlled, unblinded or only single-blinded, and enrolled small numbers of patients. The Multicenter InSync Randomized Clinical Evaluation (MIRACLE) is a large, prospective, randomized, double-blind, controlled trial designed to more definitively evaluate the clinical efficacy and safety of cardiac resynchronization for heart failure. The study is being completed in 3 phases (an initial pilot phase, a pivotal phase, and an expansion phase), enrolling 500 patients with New York Heart Association (NYHA) class III and IV systolic heart failure and QRS durations of 130 ms or more. Prospectively defined primary end points for the pivotal phase include evaluation of safety (implant success rate, freedom from stimulator- and ventricular-lead-related complications) and effects on functional status (quality of life, NYHA class, 6-minute hall walk distance) at 6 months. A variety of secondary end points will further define the efficacy and mechanism(s) of action of cardiac resynchronization in heart failure. The pivotal phase of MIRACLE will conclude in January 2001.
Journal of Cardiac Failure 01/2001; 6(4):369-80. · 3.66 Impact Factor
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ABSTRACT: Despite conventional therapy, there is still much room for improvement in the prognosis of patients with chronic systolic heart failure. Evidence supports a role for endothelin-1 (ET-1), a potent vasoconstrictor, in the pathophysiology of heart failure. Given its potentially deleterious effects, the optimal treatment of heart failure may need to include efforts directed toward antagonizing this hormone. In support of this notion, the use of ET receptor antagonists produces a number of beneficial effects in heart failure, including both improvements in hemodynamics and reductions in the levels of other vasoconstricting neurohormones. There are at least 2 receptors for ET-1 (the ET-A and ET-B receptor), and the effects of ET-1 binding differ depending on the receptor involved. It is still unclear whether blockade of the ET-A receptor alone or the combined blockade of both the ET-A and ET-B receptors will be most efficacious as a therapeutic strategy. Long-term benefits have been achieved with the use of a mixed ET-A/B receptor antagonist, when added to standard triple-drug therapy, in patients with severe heart failure. We await the results of ongoing trials to determine if these agents will fulfill the promise of adding substantial incremental benefit to the treatment of the disease.
Journal of Cardiac Failure 01/2001; 6(4):359-68. · 3.66 Impact Factor
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ABSTRACT: The success of beta-blocking agents in clinical trials of heart failure (HF) has led to a widespread call for their increased use, which assumes these agents will perform as well in the usual care setting. Given the traditional contraindication of the use of beta-blocking agents in HF, and their perception as difficult to use in HF, observing how they perform in the usual care setting could be critical in accelerating their widespread application. Carvedilol is the only beta-blocking agent currently approved in the United States for use in HF.
The Coreg (brand of carvedilol; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) Heart Failure Registry (COHERE) is intended to collect data on outcomes and other clinical variables in a typical HF population and to observe experience with carvedilol in the hands of community practitioners. COHERE does not include any specific patient selection or exclusion criteria. The decision to use carvedilol is entirely at the discretion of the participant physician, based on evidence of HF as judged by assessments the practitioner usually uses. All patients will be followed for 1 year, with information on outcomes and other clinical variables collected and analyzed at baseline, the end of titration, and at 6 and 12 months after reaching the maximum tolerated dose. About 600 participant physicians selected to be as representative as possible of the community practice setting will enroll approximately 6,000 patients.
COHERE will be the first and largest prospective observational experience with a new treatment, ie, carvedilol, in patients with HF managed in the usual care setting and should provide valuable information about this new treatment in this environment compared with the more rigid clinical trials setting.
Journal of Cardiac Failure 10/2000; 6(3):264-71. · 3.66 Impact Factor
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W S Colucci,
U Elkayam,
D P Horton, W T Abraham,
R C Bourge,
A D Johnson,
L E Wagoner,
M M Givertz,
C S Liang,
M Neibaur,
W H Haught,
T H LeJemtel
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ABSTRACT: Intravenous infusion of nesiritide, a brain (B-type) natriuretic peptide, has beneficial hemodynamic effects in patients with decompensated congestive heart failure. We investigated the clinical use of nesiritide in such patients.
Patients hospitalized because of symptomatic congestive heart failure were enrolled in either an efficacy trial or a comparative trial. In the efficacy trial, which required the placement of a Swan-Ganz catheter, 127 patients with a pulmonary-capillary wedge pressure of 18 mm Hg or higher and a cardiac index of 2.7 liters per minute per square meter of body-surface area or less were randomly assigned to double-blind treatment with placebo or nesiritide (infused at a rate of 0.015 or 0.030 microg per kilogram of body weight per minute) for six hours. In the comparative trial, which did not require hemodynamic monitoring, 305 patients were randomly assigned to open-label therapy with standard agents or nesiritide for up to seven days.
In the efficacy trial, at six hours, nesiritide infusion at rates of 0.015 and 0.030 microg per kilogram per minute decreased pulmonary-capillary wedge pressure by 6.0 and 9.6 mm Hg, respectively (as compared with an increase of 2.0 mm Hg with placebo, P<0.001), resulted in improvements in global clinical status in 60 percent and 67 percent of the patients (as compared with 14 percent of those receiving placebo, P<0.001), reduced dyspnea in 57 percent and 53 percent of the patients (as compared with 12 percent of those receiving placebo, P<0.001), and reduced fatigue in 32 percent and 38 percent of the patients (as compared with 5 percent of those receiving placebo, P<0.001). In the comparative trial, the improvements in global clinical status, dyspnea, and fatigue were sustained with nesiritide therapy for up to seven days and were similar to those observed with standard intravenous therapy for heart failure. The most common side effect was dose-related hypotension, which was usually asymptomatic.
In patients hospitalized with decompensated congestive heart failure, nesiritide improves hemodynamic function and clinical status. Nesiritide is useful for the treatment of decompensated congestive heart failure.
New England Journal of Medicine 08/2000; 343(4):246-53. · 53.30 Impact Factor
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W T Abraham
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ABSTRACT: Many physicians are reluctant to prescribe beta-blockers to patients with mild heart failure, especially when standard therapy (diuretics and an angiotensin-converting enzyme inhibitor, with or without digitalis glycosides) seems to be effective at relieving symptoms. However, current first-line medications for heart failure either ignore or incompletely inhibit adrenergic activation, one of the primary contributors to progressive left ventricular systolic dysfunction. Thus, even effective standard "triple" therapy does not safeguard the patient against further catastrophic deterioration of cardiac performance. Clinical trials have shown that the use of beta-blockers in addition to standard therapy improves left ventricular function, reduces hospitalizations, and-in the cases of bisoprolol, long-acting metoprolol, and carvedilol-improves survival in patients with chronic heart failure. In addition, carvedilol has been found to significantly slow disease progression even in mildly symptomatic patients. Though achieving beta-blockade in patients with heart failure requires extra effort by the clinician (appropriate patient selection, optimization of background therapy, initiating drug treatment at low doses, and titrating slowly with careful vigilance for early signs of clinical instability), the cost is small compared with the consequence of postponing adrenergic intervention. The educational objective of this article is to provide the primary care physician with a review of the current understanding of the pathophysiological characteristics underlying chronic systolic heart failure, the clinical benefits of administering beta-blockers during the early stages of heart failure, and the practical considerations of initiating therapy.
Archives of Internal Medicine 06/2000; 160(9):1237-47. · 11.46 Impact Factor
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ABSTRACT: The beta(2)-adrenergic receptor (beta(2)AR) exists in multiple polymorphic forms with different characteristics. Their relevance to heart failure (HF) physiology is unknown. Cardiopulmonary exercise testing was performed on 232 compensated HF patients with a defined beta(2)AR genotype. Patients with the uncommon Ile164 polymorphism had a lower peak VO(2) (15.0+/-0.9 mL. kg(-1). min(-1)) than did patients with Thr164 (17.9+/-0.9 mL. kg(-1). min(-1), P<0.0001). The percentage achieved of predicted peak VO(2) was also lower in patients with Ile164 (62. 3+/-4.5% versus 71.5+/-5.1%, P=0.045). The relative risk of a patient having a VO(2) </=14 mL. kg(-1). min(-1) who had Ile164 was 8.0 (P=0.009). Catheterization-based invasive exercise testing revealed depressed changes in the exercise-induced cardiac index, systemic vascular resistance, stroke volume, and VO(2) in patients with Ile164. The polymorphisms at position 16 also impacted exercise capacity: peak VO(2) for Arg16 versus Gly16 was 17.0+/-0.8 versus 15. 6+/-0.5 mL. kg(-1). min(-1), respectively (P=0.03). Because the polymorphisms at loci 16 and 27 can occur together, 4 homozygous combinations exist. Patients with Arg16/Glu27 had the highest percentage achieved of predicted peak VO(2) (75. 7+/-6.4%), whereas those with Gly16/Gln27 had the lowest (55.3+/-2. 8%, P=0.0032). The above findings were not confounded by baseline clinical characteristics, including beta-blocker usage. We conclude that the beta(2)AR polymorphisms Ile164, Gly16, and the combination of Gly16 and Gln27 are associated with depressed exercise performance in HF and represent a genetically determined factor in the pathophysiology of HF.
Circulation Research 05/2000; 86(8):834-40. · 9.49 Impact Factor
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ABSTRACT: The incidence and prevalence of heart failure is on the rise. It has become the single most expensive health care item in the United States and the number one discharge diagnosis in the elderly. The goals of therapy include both prevention and treatment of heart failure. In recent years research studies and randomized clinical trials have revolutionized the understanding of the pathophysiology and treatment of this disease. This article focuses on the medical management of chronic systolic heart failure based on the pathophysiology of the disease. Systolic heart failure is characterized by a decrease in left ventricular function and cardiac output, which results in activation of several neurohormonal compensatory systems. The long term effects of this neurohormonal activation leads to further deterioration of cardiac function. The use of hydralazine and nitrates to reduce the systemic vascular resistance was the first to show an improvement in mortality and morbidity. Then angiotensin converting enzyme inhibitors, by inhibiting the renin angiotensin system, demonstrated a greater improvement in mortality and morbidity. More recently the inhibition of the sympathetic stimulation with beta-blockers has been shown to have an additive effect on morbidity and mortality in combination with angiotensin-converting enzyme inhibitors. Digoxin and diuretics remain important for improving symptoms and decreasing hospitalizations but have not been shown to decrease mortality. The most recent advance in the treatment of cardiac failure is the demonstration that the aldosterone antagonists, spironolactone decreases morbidity and mortality.
Kidney International 05/2000; 57(4):1418-25. · 6.61 Impact Factor
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ABSTRACT: Our understanding of the pathophysiology of chronic heart failure is rapidly expanding. recent investigations suggest a role for various proinflammatory and vasoconstrictive cytokines in the development and progression of the disease. In particular, tumor necrosis factor-alpha, interlukin-6, and endothelin have all been implicated in heart failure desease progression. These cytokines appear to be activated in response to a remodeling, induction of programmed cell death, neurohormonal activation, and hemodynamics, these agents cause a variety of deleterious effects in the setting of ventricular dysfunction. Investigational inhibitors and antagonists of these substances show promise for the future treatment of heart failure.
Current Cardiology Reports 04/2000; 2(2):120-8.
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ABSTRACT: In the failing heart, several changes occur in cardiac adrenergic receptor-signal transduction pathways. The most striking of these changes occur in beta-ARs, and of the changes in beta-adrenergic receptors, beta1-receptor down-regulation is the most prominent. Other changes include uncoupling of beta2-adrenergic receptors and increased activity of the inhibitory G-protein, Gi. Most of these changes appear to be related to increased activity of the adrenergic nervous system, i.e. increased exposure to norepinephrine. Antagonists of the adrenergic nervous system improve left ventricular function and outcome in patients with heart failure. This fact supports the notion that activation of these neurohormonal systems exerts a net long-term detrimental effect on the natural history of chronic heart failure and that myocardial adrenergic desensitization phenomena are at least partially adaptive in the setting of left ventricular dysfunction.
Heart Failure Reviews 04/2000; 5(1):7-16. · 3.20 Impact Factor
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ABSTRACT: Left ventricular assist device support mechanically unloads the failing ventricle with resultant improvement in cardiac geometry and function in patients with end-stage heart failure. Activation of the G alpha q signaling pathway, including protein kinase C, appears to be involved in the progression of heart failure. Similarly down-regulation of Ca2+ cycling proteins may contribute to contractile depression in this clinical syndrome. Thus we examined whether protein kinase C activation and decreased Ca2+ cycling protein levels could be reversed by left ventricular assist device support.
Left ventricular myocardial specimens were obtained from seven patients during placement of left ventricular assist device and heart transplantation. We examined changes in protein levels of G alpha q, phospholipase C beta 1, regulators of G protein signaling (RGS), sarcoplasmic reticulum Ca2+ ATPase, phospholamban and translocation of protein kinase C isoforms (alpha, beta 1, and beta 2).
The paired pre- and post-left ventricular assist device samples revealed that RGS2, a selective inhibitor of G alpha q, was decreased (P < 0.01), while the status of G alpha q, phospholipase C beta 1, RGS3 and RGS4 were unchanged after left ventricular assist device implantation. Translocation of protein kinase C isoforms remained unchanged. Left ventricular assist device support increased sarcoplasmic reticulum Ca2+ ATPase protein level (P < 0.01), while phospholamban abundance was unchanged.
We conclude that altered protein expression and stoichiometry of the major cardiomyocyte Ca2+ cycling proteins rather than reduced phospholipase C beta 1 activation may contribute to improved mechanical function produced by left ventricular assist device support in human heart failure.
Cardiovascular Research 04/2000; 45(4):883-8. · 6.06 Impact Factor
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ABSTRACT: Aquaporin-2 (AQP-2), a water channel located on the apical membrane of collecting duct cells, regulates water reabsorption under the control of vasopressin (AVP). Using an antibody directed to human AQP-2, a quantitative Western blot analysis was performed to determine the collecting duct responsiveness to an oral, nonpeptide, V2 receptor antagonist (VPA-985) in patients with chronic NYHA II and III heart failure. Standards were derived by conjugating the immunizing peptide to maleimide-activated bovine serum albumin and a standard curve was generated for each blot. Quantification of baseline steady-state AQP-2 excretion was done by collecting urine on the day before study drug administration. The next day patients received either placebo or VPA-985 at one of four different doses and urine was collected every 2 h. Thereafter, urinary AQP-2 excretion was calculated as a ratio of the urine flow and was expressed in pmol/h. During baseline, steady-state excretion did not change significantly (T0-T2, 458 +/- 44; T2-T4, 443 +/- 35; T4-T6, 422 +/- 35; T6-T8, 401 +/- 30). Compared to placebo, urinary AQP-2 excretion decreased significantly and in all groups in a dose-dependent manner during VPA-985 administration. The most impressive decrease was observed in the 250-mg group (T0-T2, 89 +/- 5; T2-T4, 50 +/- 18; T4-T6, 43 +/- 22; T6-T8, 42 +/- 23; P < 0.001 during each period compared with baseline and placebo results). VPA-985 significantly increased solute-free water clearance and urine output and significantly decreased urinary osmolality. Urinary AQP-2 excretion correlated best with solute-free water clearance during T0-T2 and T2-T4 collection, but a correlation with urinary osmolality and urinary output was also found during these periods. In conclusion, AQP-2 urinary excretion, as measured by quantitative Western analysis, is a sensitive biologic marker to assess the short-term responsiveness of the collecting duct to a V2 receptor AVP antagonist in chronic heart failure.
Journal of the American Society of Nephrology 11/1999; 10(10):2165-70. · 9.66 Impact Factor
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W T Abraham
Journal of Cardiac Failure 10/1999; 5(3):265-8. · 3.66 Impact Factor
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New England Journal of Medicine 09/1999; 341(8):577-85. · 53.30 Impact Factor
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ABSTRACT: Published clinical practice guidelines from the U.S. Agency for Health Care Policy and Research, the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the Task Force of the Working Group on Heart Failure of the European Society of Cardiology--supported by the results of numerous large-scale randomized controlled trials--define the standard universal pharmacologic approach to all patients with left ventricular systolic dysfunction. According to these guidelines, all heart failure patients regardless of etiology (with rare exceptions such as obstructive valvular heart disease) should be treated with an angiotensin-converting enzyme (ACE) inhibitor as first-line treatment of the heart failure. In fact, the non-edematous patient with only mild exertional dyspnea may be treated with an ACE inhibitor as sole therapy of the left ventricular dysfunction. As patients become edematous or complain of more moderate congestive symptoms, it is then appropriate to add a diuretic along with the ACE inhibitor. Digoxin is reserved for those patients who remain symptomatic on an ACE inhibitor and diuretic. Carvedilol, the only beta-adrenergic receptor blocker approved by the U.S. Food and Drug Administration for the treatment of heart failure, has been shown to reduce morbidity and mortality in patients with New York Heart Association Class II or III symptoms. In the U.S. Carvedilol Heart Failure Trials Program, carvedilol's benefit was seen in patients with either ischemic or nonischemic etiologies of heart failure. Similar findings of benefit in both ischemic and nonischemic heart failure have been observed in the recently reported Second Cardiac Insufficiency Bisoprolol Study (CIBIS II) trial as well as in ACE inhibitor heart failure trials. Studies suggesting differences in outcome based on etiology during pharmacologic treatment of heart failure have been too small (inadequately powered) or have assessed this difference only in post-hoc analyses. Thus, the universal pharmacologic management of heart failure with an ACE inhibitor, diuretic, beta-blocker (e.g. carvedilol), and digoxin may be applied to all patients with ischemic or nonischemic heart failure. This makes sense since the pathophysiology of heart failure following myocardial injury is similar for both forms of the disease.
Journal of Cardiovascular Pharmacology 07/1999; 33 Suppl 3:S1-7. · 2.29 Impact Factor
